CN116836293A

CN116836293A - Coronavirus vaccine compositions, methods and uses thereof

Info

Publication number: CN116836293A
Application number: CN202210294222.3A
Authority: CN
Inventors: 梁果; 梁朋; 宿丹梅
Original assignee: Sichuan Clover Biopharmaceuticals Inc
Current assignee: Sichuan Clover Biopharmaceuticals Inc
Priority date: 2022-03-24
Filing date: 2022-03-24
Publication date: 2023-10-03
Also published as: WO2023179514A1

Abstract

The invention relates in some aspects to immunogenic compositions comprising recombinant peptides and proteins comprising coronavirus antigens and immunogens, such as SARS-CoV-2 coronavirus delta (delta, b.1.617.2) variant S protein peptides or fragments, variants or mutants thereof, such as chimeric antigens and immunogens comprising a delta variant receptor binding domain and Hu-1 or other variant S protein peptide sequences. In some aspects, the immunogenic composition comprises a secreted fusion protein comprising a soluble coronavirus antigen linked by in-frame fusion to a C-terminal portion of collagen capable of self-trimerization to form a disulfide-linked trimeric fusion protein. In some aspects, the immunogenic compositions provided herein can be used to generate an immune response, for example, as a vaccine for preventing coronavirus infection.

Description

Coronavirus vaccine compositions, methods and uses thereof

Technical Field

The present disclosure relates in some aspects to immunogenic compositions for treating and/or preventing coronavirus infections comprising recombinant peptides and proteins including coronavirus antigens And immunogens, such as coronavirus S protein peptides, including S protein peptides based on the SARS-CoV-2 delta (B.1.617.2) strain, are trimerized by trimerization ^TM Subunit vaccines formed by disulfide linkage between tag polypeptides.

Background

Coronaviruses infect a wide range of birds and mammals, including humans. Coronaviruses may spread annually in humans and often cause mild respiratory disease, although more severe in infants, elderly and immunocompromised individuals. However, certain coronaviruses, including the middle east respiratory syndrome coronavirus (MERS-CoV), the severe acute respiratory syndrome coronavirus (SARS-CoV-1), and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are highly pathogenic. The high pathogenicity, air-borne nature, high mortality and vague epidemiology of coronaviruses have made an urgent need for effective vaccines and related therapeutic agents. In particular, there is an urgent need for vaccines that can rapidly induce an effective immune response against SARS-CoV-2. The present invention provides methods, uses and articles (article of manufacture) that meet the above and other needs.

Disclosure of Invention

The emergence and spread of multiple variant SARS-CoV-2 strains carrying mutations that may lead to immune escape from the end of 2020 necessitates rapid assessment of second generation vaccines in order to induce optimized immune responses with broad protection.

Despite the tremendous progress and unprecedented speed of the development of the covd-19 vaccine, a new record was created of daily cases of covd-19 at 2021, month 4, 16 months after the first occurrence of the SARS-CoV-2 virus outbreak. The total number of deaths caused by covd-19 exceeds 300 tens of thousands at 2021, 5 months, and 100 tens of thousands of deaths are accumulated only in the first 3 months.

Most worrying is that, along with the proliferation of global covd-19 cases, a number of new SARS-CoV-2 Variants (VOCs) began to appear from the end of 2020. These VOCs appear to be associated with mutations in spike (S) proteins that may increase viral transmission rates and/or immune escape due to primary wave COVID-19 vaccination based on SARS-CoV-2Hu-1 strain. The emergence and spread of variant b.1.1.7 in the UK, variant b.1.351 in south africa and variant p.1 in brazil led to its classification as VOC. These VOCs all include an N501Y mutation in the Receptor Binding Domain (RBD) of the S protein, which has been reported to increase transmission by 40% to 70%. B.1.351 and p.1 variants there are two additional RBD mutations, E484K and K417, which may allow immune escape from Hu-1 vaccine and naturally infection-induced antibodies.

Random control clinical trials of the covd-19 vaccine showed reduced effectiveness of the vaccine against VOCs compared to the SARS-CoV-2Hu-1 strain. The adjuvant protein based covd-19 vaccine NVX-CoV2373 was 89% effective in the uk (b.1.1.7 predominate) but only 49% effective in south africa (b.1.351 predominate). The adenovirus vector covd-19 vaccine chaadox 1 was only 10% effective against variant b.1.351. The efficacy of the gabion vaccinators was 75% for variant B.1.351 and 95% for Hu-1. Coronavac is an inactivated vaccine based on the Hu-1 strain, and subjects vaccinated with this vaccine did not detect neutralizing antibody titers against P.1.

While there is some encouraging evidence that Hu-1 COVID-19 vaccine may prevent serious disease and death from VOCs, vaccine efficacy against any disease with increased spread of COVID-19 may make it particularly difficult to achieve mass immunization and global shortage of COVID-19 vaccine may further exacerbate this problem. If not effectively controlled, rapid spread of SARS-CoV-2VOC worldwide may lead to continued emergence of new target varieties or VOCs that may contain new escape mutations, such as Indian varieties (B.1.617), which are concurrent with the massive proliferation of cases of spring COVID-19 in 2021, have now been declared as new VOCs by the world health organization. The b.1.617.2 variety of this lineage was named Delta. Recently, the first discovered variant b.1.1.529 in south africa was renamed omicon.

In these cases, a re-booster strategy must be evaluated rapidly to enhance the neutralizing antibody response to VOCs and develop a second generation covd-19 vaccine that may provide optimized broad protection and cross-neutralization characteristics.

In some embodiments, disclosed herein are proteins comprising a plurality of recombinant polypeptides, each recombinant polypeptide comprising a coronavirus surface antigen linked to a C-terminal propeptide of collagen, wherein the C-terminal propeptide of the recombinant polypeptide forms an inter-polypeptide disulfide bond. The recombinant polypeptide or protein may be used as an immunogen, such as a vaccine.

In some embodiments, disclosed herein are recombinant subunit vaccines comprising an extracellular domain (e.g., without a transmembrane and cytoplasmic domain) of an S protein or fragment thereof from a coronavirus (e.g., SARS-CoV-2 delta (b.1.617.2)) fused in frame to a C-propeptide of collagen capable of forming a disulfide-linked homotrimer.

In some embodiments, the coronavirus is a Severe Acute Respiratory Syndrome (SARS) coronavirus (SARS-CoV-1), SARS coronavirus 2 (SARS-CoV-2), SARS-like coronavirus, middle East Respiratory Syndrome (MERS) coronavirus (MERS-CoV), MERS-like coronavirus, NL63-CoV, 229E-CoV, OC43-CoV, HKU1-CoV, WIV1-CoV, MHV, HKU9-CoV, PEDV-CoV, or SDCV.

In any of the foregoing embodiments, the surface antigen may comprise a coronavirus spike (S) protein or fragment or epitope thereof, wherein the epitope is optionally a linear epitope or a conformational epitope, and wherein the protein comprises three recombinant polypeptides.

In any of the foregoing embodiments, the surface antigen may comprise a signal peptide, an S1 subunit peptide, an S2 subunit peptide, or any combination thereof.

In any of the foregoing embodiments, the surface antigen may comprise a signal peptide, a Receptor Binding Domain (RBD) peptide, a Receptor Binding Motif (RBM) peptide, a Fusion Peptide (FP), a heptad repeat 1 (HR 1), or a heptad repeat 2 (HR 2), or any combination thereof.

In any of the foregoing embodiments, the surface antigen may comprise a Receptor Binding Domain (RBD) of an S protein.

In any of the foregoing embodiments, the surface antigen may comprise an S1 subunit and an S2 subunit of an S protein.

In any of the foregoing embodiments, the surface antigen may be free of Transmembrane (TM) domain peptides and/or Cytoplasmic (CP) domain peptides.

In any of the foregoing embodiments, the surface antigen may comprise a protease cleavage site, wherein the protease is optionally furin (furin), trypsin, factor Xa, thrombin or cathepsin L.

In any of the foregoing embodiments, the surface antigen may be free of protease cleavage sites, wherein the protease is optionally furin (furin), trypsin, factor Xa, thrombin or cathepsin L, or may comprise mutated protease cleavage sites that are not cleavable by a protease.

In any of the foregoing embodiments, the surface antigen may be soluble or not directly bound to a lipid bilayer, such as a membrane or viral envelope.

In any of the foregoing embodiments, the surface antigens may be the same or different in the recombinant polypeptide of the protein.

In any of the foregoing embodiments, the surface antigen can be directly fused to the C-terminal propeptide, or can be linked to the C-terminal propeptide by a linker (e.g., a linker comprising a glycine-X-Y repeat sequence, wherein X and Y are independently any amino acid and optionally proline or hydroxyproline).

In any of the foregoing embodiments, the protein may be soluble or not directly bound to a lipid bilayer, such as a membrane or viral envelope.

In any of the foregoing embodiments, the protein may bind to a cell surface receptor of the subject, optionally wherein the subject is a mammal, such as a primate, e.g., a human.

In any of the foregoing embodiments, the cell surface receptor may be angiotensin converting enzyme 2 (ACE 2), dipeptidyl peptidase 4 (DPP 4), dendritic cell-specific intercellular adhesion molecule-3-grasping non-integrin (DC-SIGN) or liver/lymph node-SIGN (L-SIGN).

In any of the foregoing embodiments, the C-terminal propeptide may be human collagen.

In any of the foregoing embodiments, the C-terminal propeptide may comprise a C-terminal propeptide of proα1 (I), proα1 (II), proα1 (III), proα1 (V), proα1 (XI), proα2 (I), proα2 (V), proα2 (XI), or proα3 (XI), or a fragment thereof.

In any of the foregoing embodiments, the C-terminal propeptide may be the same or different in the recombinant polypeptide.

In any of the foregoing embodiments, the C-terminal propeptide may comprise any of SEQ ID NOS.67-80, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% sequence homology to any of SEQ ID NOS.67-80, capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise SEQ ID NO 67 or an amino acid sequence that is at least 95% identical to it that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise SEQ ID NO 68 or an amino acid sequence that is at least 95% identical to it that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise SEQ ID NO 69 or an amino acid sequence that is at least 95% identical to it that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise SEQ ID NO 70 or an amino acid sequence that is at least 95% identical to it that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise SEQ ID NO 71 or an amino acid sequence that is at least 95% identical to it, capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise SEQ ID NO 72 or an amino acid sequence that is at least 95% identical to it that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise SEQ ID NO 73 or an amino acid sequence that is at least 95% identical to it that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise SEQ ID NO 74 or an amino acid sequence that is at least 95% identical to it that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise SEQ ID NO 75 or an amino acid sequence that is at least 95% identical to it that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise SEQ ID NO 76 or an amino acid sequence that is at least 95% identical to it that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise SEQ ID NO 77 or an amino acid sequence that is at least 95% identical to it, capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise SEQ ID NO 78 or an amino acid sequence that is at least 95% identical thereto and is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise SEQ ID NO 79 or an amino acid sequence that is at least 95% identical thereto that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise SEQ ID NO 80 or an amino acid sequence that is at least 95% identical to it that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the C-terminal propeptide may comprise a sequence comprising a glycine-X-Y repeat sequence linked to the N-terminus of any of SEQ ID NOS: 67-80, wherein X and Y are independently any amino acid and optionally proline or hydroxyproline, or an amino acid sequence at least 90% identical thereto, capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

In any of the foregoing embodiments, the surface antigen in each recombinant polypeptide may be in a pre-fusion conformation.

In any of the foregoing embodiments, the surface antigen in each recombinant polypeptide may be in a post-fusion conformation.

In any of the foregoing embodiments, the surface antigen in each recombinant polypeptide may comprise any one of SEQ ID NOS 27-66 and 81-84 or an amino acid sequence at least 80% identical thereto.

In any of the foregoing embodiments, the recombinant polypeptide may comprise an amino acid sequence of any one of SEQ ID NOs 1-26 and 85-92 or at least 80% identical thereto.

Also provided herein are immunogens comprising the proteins provided herein. Provided herein are protein nanoparticles comprising a protein provided herein directly or indirectly linked to a nanoparticle. Provided herein are Viroids (VLPs) comprising the proteins provided herein.

Also provided herein are isolated nucleic acids encoding one, two, three or more recombinant polypeptides of the proteins provided herein. In some embodiments, the polypeptide encoding the S protein peptide is fused in frame to a polypeptide encoding a C-terminal propeptide of collagen. In some embodiments, an isolated nucleic acid provided herein is operably linked to a promoter.

In some embodiments, the isolated nucleic acids provided herein are DNA molecules. In some embodiments, the isolated nucleic acid provided herein is an RNA molecule, optionally an mRNA molecule, e.g., a nucleoside modified mRNA, a non-amplified mRNA, a self-amplified mRNA, or a trans-amplified mRNA.

Also provided herein are vectors comprising the isolated nucleic acids provided herein. In some embodiments, the vector is a viral vector.

In some aspects, provided herein are viruses, pseudoviruses, or cells comprising the vectors provided herein, optionally wherein the viruses or cells have a recombinant genome. In some aspects, provided herein are immunogenic compositions comprising a protein, immunogen, protein nanoparticle, VLP, isolated nucleic acid, vector, virus, pseudovirus, or cell provided herein, and a pharmaceutically acceptable carrier.

Also provided herein are vaccines comprising the immunogenic compositions provided herein and optionally an adjuvant, wherein the vaccine is optionally a subunit vaccine. In some embodiments, the vaccine is a prophylactic and/or therapeutic vaccine. Optional adjuvants may be used in the starter and/or booster. Independently, adjuvants of the initial agent and/or of any one or more of the booster agents may include: aluminum-containing adjuvants, such as alum and/or aluminum hydroxide-containing adjuvants; an oligonucleotide-containing adjuvant, such as a CpG oligodeoxynucleotide (CpG-ODN) -containing adjuvant; an adjuvant comprising a TLR9 agonist; adjuvants comprising metabolisable oil, alpha-tocopherol, and/or polyoxyethylene sorbitan monooleate (tween-80), for example adjuvants comprising squalene, alpha-tocopherol, and tween-80 and/or Span 85 in the form of an oil in water emulsion; or any one of the adjuvant combinations.

In some aspects, provided herein are methods of producing a protein comprising: expressing an isolated nucleic acid or vector provided herein in a host cell to produce a protein provided herein; and purifying the protein. Provided herein are proteins produced by the methods provided herein.

Provided herein are methods for generating an immune response to an S protein peptide of a coronavirus or a fragment or epitope thereof in a subject, comprising administering to the subject an effective amount of a protein, immunogen, protein nanoparticle, VLP, isolated nucleic acid, vector, virus, pseudovirus, cell, immunogenic composition, or vaccine as provided herein to generate an immune response. In some embodiments, the methods provided herein are for treating or preventing a coronavirus infection. In some embodiments, generating an immune response inhibits or reduces replication of a coronavirus in a subject. In some embodiments, the immune response comprises a cell-mediated response and/or a humoral response, optionally comprising the production of one or more neutralizing antibodies, such as polyclonal or monoclonal antibodies. In some embodiments, the immune response is directed against an S protein peptide of a coronavirus or a fragment or epitope thereof, but not against a C-terminal propeptide. In some embodiments, administration to a subject does not result in an increased Antibody Dependence (ADE) in the subject due to prior exposure to one or more coronaviruses. In some embodiments, administration does not result in an antibody-dependent enhancement (ADE) in the subject when subsequently exposed to one or more coronaviruses. In some embodiments, the method further comprises a priming step (priming step) and/or a boosting step (boosting step). In some embodiments, the administering step is performed by topical, transdermal, subcutaneous, intradermal, oral, intranasal (e.g., intranasal spray), intratracheal, sublingual, buccal, rectal, vaginal, inhalation, intravenous (e.g., intravenous), intraarterial, intramuscular (e.g., intramuscular injection), intracardiac, intraosseous, intraperitoneal, transmucosal, intravitreal, subretinal, intra-articular, periarticular, topical, or skin-applied (epikutaneous) administration. In some embodiments, the effective amount is administered in a single dose or a series of doses having one interval or more intervals. In some embodiments, an effective amount is administered without the use of an adjuvant. In some embodiments, an effective amount is administered with an adjuvant.

Provided herein are methods comprising administering to a subject an effective amount of a protein provided herein to produce neutralizing antibodies or neutralizing antisera to a coronavirus in the subject. In some embodiments, the subject is a mammal, optionally a human or non-human primate. In some embodiments, the method further comprises isolating neutralizing antibodies or neutralizing antisera from the subject. In some embodiments, the method further comprises administering to the human subject an effective amount of an isolated neutralizing antibody or neutralizing antisera by passive immunization to prevent or treat the coronavirus infection. In some embodiments, the neutralizing antibody or neutralizing antisera to the coronavirus comprises a polyclonal antibody to a coronavirus S protein peptide or fragment or epitope thereof, optionally wherein the neutralizing antibody or neutralizing antisera is free or substantially free of antibodies to a C-terminal pro-peptide of collagen. In some embodiments, the neutralizing antibody comprises a monoclonal antibody directed against a coronavirus S protein peptide or fragment or epitope thereof, optionally wherein the neutralizing antibody is free or substantially free of antibodies directed against a C-terminal propeptide of collagen.

In some aspects, the proteins, immunogens, protein nanoparticles, VLPs, isolated nucleic acids, vectors, viruses, pseudoviruses, cells, immunogenic compositions, or vaccines provided herein are useful for inducing an immune response to a coronavirus in a subject, and/or for treating or preventing a coronavirus infection.

In some aspects, provided herein are uses of the proteins, immunogens, protein nanoparticles, VLPs, isolated nucleic acids, vectors, viruses, pseudoviruses, cells, immunogenic compositions, or vaccines provided herein for inducing an immune response to a coronavirus in a subject, and/or for treating or preventing a coronavirus infection. In some aspects, provided herein is the use of a protein, immunogen, protein nanoparticle, VLP, isolated nucleic acid, vector, virus, pseudovirus, cell, immunogenic composition or vaccine provided herein for the manufacture of a medicament or prophylactic agent for inducing an immune response to coronavirus in a subject, and/or for treating or preventing a coronavirus infection.

Also provided herein are methods for analyzing a sample, comprising: the sample is contacted with a protein provided herein and binding between the protein and an analyte capable of specifically binding to the S protein peptide of coronavirus or a fragment or epitope thereof is detected. In some embodiments, the analyte is an antibody, receptor, or cell that recognizes an S protein peptide or fragment or epitope thereof. In some embodiments, binding indicates the presence of an analyte in the sample, and/or the presence of a coronavirus infection in the subject from which the sample was derived.

Provided herein are kits comprising the proteins provided herein and a matrix, pad or vial containing or immobilizing the proteins, optionally wherein the kit is an ELISA or lateral flow assay kit (lateral flow assay kit).

Drawings

FIGS. 1A-1B illustrate structural features of an exemplary soluble S-trimer subunit vaccine for SARS-CoV-2. FIG. 1A is a schematic representation of an S-trimer domain, and FIG. 1B is a three-dimensional conformation of its trimers and covalent linkages.

FIG. 2 shows that serum-free culture highly expressed exemplary SARS-CoV-2 delta S-trimer. Reduction SDS-PAGE Coomassie blue staining was used to analyze secreted delta S-trimer proteins, and more than 1g/L delta S-trimer protein was obtained by culturing in CHO cells for 13 days (D13) with serum free culture and feeding.

Fig. 3A-3B illustrate purification and characterization of an exemplary covalently linked delta S-trimer. FIG. 3A shows a sample (loading of 2. Mu.g) and control (chimeric Hu-1S-trimer containing beta (beta) variant RBD, loading of 2. Mu.g) from a delta S-trimer purification process for a reduction SDS-PAGE coomassie brilliant blue staining analysis, in the following order: the cell harvest was depth filtered (HCCF: serum freee medium after depth filtration to remove cell debris), affinity chromatography (AC-E: affinty capture chomatography elution), ultrafiltration (UF/DF-1-F: ultrafiltration/Ultrafiltration 1 Fraction), viral inactivation (VIN: viral inactivation with low pH treatment), intermediate depth filtration (IDF: intermediate Depth Filtration), ion exchange (AEX: anion Exchange Chromatography), nanofiltration (NF: nanofiltration), ultrafiltration (UF/DF-2-F: ultrafiltration/Ultrafiltration 2 Fraction). Fig. 3B is a SEC-HPLC purity analysis with a delta S-trimer purity of 97.22%.

Figures 4A-4B show the receptor binding kinetics of delta S-trimers to ACE 2-Fc. FIG. 4A shows that binding Kd to Hu-1S-trimer and receptor is 5nM. Figure 4B shows that the delta S-trimer binds to the receptor with a Kd of 0.5nM. The delta S-trimer receptor has a higher affinity than the Hu-1S-trimer.

FIG. 5 shows BALB/c mouse SARS-CoV-2Hu-1, alpha (alpha, B.1.1.7), beta (beta, B.1.351), gamma (gamma, P.1), delta (delta, B.1.617.2), mu (mu, B.1.621) and Omicro (O, B.1.1.529) strain pseudovirus neutralizing antibodies EC ₅₀ Data. On day 0 (starter) and day 21(booster) mice were immunized twice with either Hu-1S-trimer or delta S-trimer (n=8/group) with CpG 1018 plus Alum as adjuvant. Mice were bled on day 0, and pseudovirus neutralizing antibodies (FIG. 5) and cell-mediated immunity (CMI) assays (FIGS. 6A-6B) were performed on day 35 with splenocytes and with blood. The Hu-1S-trimer group served as a control group and mice were immunized twice with 150 μg CpG 1018 plus 75 μg Alum as an adjuvant, 3 μg Hu-1S-trimer. The delta S-trimer group was immunized twice with 150 μg CpG 1018 plus 75 μg Alum as an adjuvant to 3 μg delta S-trimer. In the samples after mouse booster vaccination (day 35), the delta S-trimer induced high levels of neutralizing antibody titres to amikates, 10-fold higher than Hu-1S-trimer induced neutralizing antibody titres to amikates.

Fig. 6A-6B show the assessment of Cell Mediated Immunity (CMI) in mice immunized twice with starter and booster by ELISpot. Mouse spleen cells harvested on day 35 of Hu-1S-trimer or delta S-trimer group were stimulated with Hu-1 strain S1 peptide library or Hu-1 strain S2 peptide library and Th1 cytokines (IL-2 and IFNγ) or Th2 cytokines (IL-4 and IL-5) were detected in mouse spleen cells by ELISPot. Fig. 6A shows ELISpot results (n=8/group mean) of Hu-1 strain S1 peptide library stimulation. Fig. 6B shows ELISpot results (n=8/group mean) of Hu-1 strain S2 peptide library stimulation. The vertical axis is the number of ELISpot per 25 ten thousand splenocytes.

Figures 7A-7G show VOC neutralizing antibodies in the 3 rd vaccinated boost mice. FIG. 7A is a schematic representation of a three immunization and pseudovirus neutralizing antibody test. BALB/c mice were immunized twice on day 0 (dose 1) and on day 21 (dose 2) with 150. Mu.g CpG 1018 plus 75. Mu.g Alum as adjuvant, 3. Mu.g Hu-1S-trimer. On study day 57, animals were divided into three groups (n=10 per group) and either did not receive or did not receive Hu-1S-trimer or delta S-trimer as dose 3 vaccination. Serum was collected on study day 56 (D-1 PD 3) and on study day 71 (D14 PD 3) for pseudovirus neutralizing antibody testing. Group 1 received no dose 3 vaccination as a control group; group 2: vaccine with 150 μg CpG 1018 plus 75 μg Alum as adjuvant and 3 μg Hu-1S-trimer as dose 3 Inoculating; group 3: 3. Mu.g of delta S-trimer with 150. Mu.g CpG 1018 plus 75. Mu.g Alum as adjuvant was vaccinated as dose 3. FIGS. 7B-7G are, respectively, hu-1, alpha, beta, gamma, delta, and Omikovia strain pseudovirus neutralizing antibodies (EC ₅₀ ) Data. Dots represent data for individual animals; the horizontal line represents the Geometric Mean Titer (GMT) ±sem for each group. Limit of detection (LOD) titer (EC ₅₀ ) 20. The bottom of each column is labeled with the group number. The fold increase in neutralizing antibody titer after dose 3 (D14 PD 3) per VOC compared to the data before dose 3 vaccination is labeled "x".

Detailed Description

Provided herein are immunogenic compositions, methods, and uses of fusion peptides and proteins comprising coronavirus antigens or immunogens for the treatment (e.g., prophylactic, therapeutic) of coronavirus infections. In some embodiments, compositions and methods of use of recombinant soluble surface antigens from RNA viruses in covalently linked trimeric form are disclosed. In some embodiments, the resulting fusion proteins are secreted as disulfide-linked homotrimers, which are more structurally stable, while retaining the conformation of the natural-like trimeric viral antigen, and thus can be used as more effective vaccines against these dangerous pathogens.

In some embodiments, disclosed herein are methods of preventing viral infection using a viral antigen trimer as a vaccine or as part of a multivalent vaccine, without or with an adjuvant, or with more than one adjuvant, optionally by intramuscular injection or intranasal administration. The virus antigen trimer may be used in an initial agent, an additional agent, and/or a booster. Independently, the initial agent, additional agent, and/or any one or more of the boosters may be absent or used as an adjuvant. If an adjuvant is used, optional adjuvants may include: aluminum-containing adjuvants, such as alum and/or aluminum hydroxide-containing adjuvants; an oligonucleotide-containing adjuvant, such as a CpG oligodeoxynucleotide (CpG-ODN) -containing adjuvant; an adjuvant comprising a TLR9 agonist; adjuvants comprising metabolisable oil, alpha-tocopherol, and/or polyoxyethylene sorbitan monooleate (tween-80), for example adjuvants comprising squalene, alpha-tocopherol, and tween-80 and/or Span 85 in the form of an oil in water emulsion; or any one of the adjuvant combinations.

In some embodiments, disclosed herein are methods of using virus antigen trimers as antigens for diagnosing a virus infection by detecting antibodies (e.g., igM or IgG) that recognize the virus antigen (e.g., neutralizing antibodies).

In some embodiments, disclosed herein are methods of using virus antigen trimers as antigens to generate polyclonal or monoclonal antibodies useful for passive immunization (e.g., neutralizing mabs for treatment of coronavirus infection).

In some embodiments, disclosed herein are virus antigen trimers as vaccines or as part of multivalent vaccines, wherein the vaccine comprises a plurality of trimeric subunit vaccines comprising virus antigens of the same protein of a virus, or virus antigens of two or more different proteins of one or more viruses or virus antigens of one or more strains of the same virus.

In some embodiments, disclosed herein are monovalent vaccines comprising the virus antigen trimers disclosed herein. In some embodiments, disclosed herein are bivalent vaccines comprising the virus antigen trimers disclosed herein. In some embodiments, disclosed herein are trivalent vaccines comprising the virus antigen trimers disclosed herein. In some embodiments, disclosed herein are tetravalent vaccines comprising the virus antigen trimers disclosed herein.

In some embodiments, disclosed herein are monovalent vaccines comprising the S-trimers disclosed herein. In some embodiments, disclosed herein are bivalent vaccines comprising the S-trimers disclosed herein. In some embodiments, disclosed herein are bivalent vaccines comprising at least one S-trimer comprising a first S-protein antigen and at least one S-trimer comprising a second S-protein antigen. In some embodiments, the first and second S protein antigens are from the same S protein of one or more viral species or strains/subtypes, or two or more different S proteins from one or more viral species or one or more strains/subtypes of the same viral species. In some embodiments, disclosed herein are trivalent vaccines comprising the S-trimers disclosed herein. In some embodiments, disclosed herein are trivalent vaccines comprising at least one S-trimer comprising a first S protein antigen, at least one S-trimer comprising a second S protein antigen, and at least one S-trimer comprising a third S protein antigen. In some embodiments, the first, second, and third S protein antigens are from the same S protein of one or more viral species or strains/subtypes, or two, three, or more different S proteins from one or more viral species or one or more strains/subtypes of the same viral species. In some embodiments, disclosed herein are tetravalent vaccines comprising the S-trimers disclosed herein. In some embodiments, disclosed herein are tetravalent vaccines comprising at least one S-trimer comprising a first S protein antigen, at least one S-trimer comprising a second S protein antigen, at least one S-trimer comprising a third S protein antigen, and at least one S-trimer comprising a fourth S protein antigen. In some embodiments, the first, second, third, and fourth S protein antigens are from the same S protein of one or more viral species or strains/subtypes, or two, three, four, or more different S proteins from one or more viral species or one or more strains/subtypes of the same viral species.

Proteins, including recombinant polypeptides and fusion proteins, provided herein comprising coronavirus antigens and immunogens can be used to effectively and safely treat (e.g., therapeutically, prophylactically) coronavirus infections. For example, the proteins comprising coronavirus antigens and immunogens provided herein treat coronavirus infection without mediated vaccine-induced disease enhancement (VED) and/or antibody-dependent enhancement (ADE). In addition, proteins comprising coronavirus antigens and immunogens provided herein are readily produced and exhibit stability under highly stressed conditions such as high temperature, extreme pH, high osmotic pressure, and low osmotic pressure. Thus, the proteins and immunogenic compositions provided herein circumvent and meet the production, stability, safety, and efficacy issues that hinder the development of coronavirus vaccines.

In some aspects, the coronavirus antigens and immunogens provided herein include coronavirus spike (S) proteins or peptides, particularly SARS-CoV or SARS-CoV-2S proteins. The spikes of SARS-CoV and SARS-CoV-2 consist of S protein trimers belonging to the group of class I viral fusion glycoproteins, which also include HIV glycoprotein 160 (Env), influenza Hemagglutinin (HA), paramyxovirus F and Ebola virus glycoproteins. The SARS-CoV and SARS-CoV-2S proteins each encode a surface glycoprotein precursor and the amino terminus and the majority of the protein are predicted to be located on the cell surface or outside of the viral particle. The S protein includes a signal peptide at the N-terminus, an extracellular domain, a transmembrane domain, and an intracellular domain. Similar to other coronaviruses, the S proteins of SARS-CoV and SARS-CoV-2 can be cleaved by proteases into S1 and S2 subunits. In particular, SARS-CoV-2 contains furin (furin) -like cleavage sites that are absent from other SARS-like CoVs.

In some embodiments, provided herein are recombinant S ectodomain trimers. In some embodiments, the recombinant S ectodomain trimer includes a recombinant S ectodomain protomer from an alpha-coronavirus (e.g., NL63-CoV or 229E-CoV). In some embodiments, the recombinant S ectodomain trimer includes S ectodomain protomers from a beta-coronavirus (e.g., OC 43-CoV, SARS-CoV-2, MERS-CoV, HKU1-CoV, WIV1-CoV, mouse Hepatitis Virus (MHV), or HKU 9-CoV).

Like other enveloped RNA viruses (e.g., HIV, RSV, and influenza), coronaviruses, including SARS-CoV-2, all have trimeric surface antigens on their viral envelope to enter different host cells through specific cell surface receptors during infection. Like SARS-CoV-1, SARS-CoV-2 utilizes its trimeric viral surface antigen S protein to bind to its specific cell surface receptor ACE2 and then enter the host cell of the mammalian respiratory system. A prerequisite for the production of an effective recombinant subunit vaccine is the ability to produce a virus S antigen that resembles its natural, in particular maintaining its trimeric conformation, so as to cause a sufficient number of antibodies to bind to the Receptor Binding Domain (RBD) of the virus S protein, thereby preventing the virus from binding to the ACE2 receptor and thus eliminating the virus infection.

In some embodiments, a protein comprising a coronavirus antigen or immunogen (e.g., a SARS-CoV or SARS-CoV-2S protein peptide) is capable of generating an immune response, e.g., an immune response to a SARS-CoV or SARS-CoV-2S protein peptide. In some embodiments, the immune response inhibits or reduces replication of a coronavirus in a subject (e.g., patient). In some embodiments, the immune response includes the production of one or more neutralizing antibodies, e.g., polyclonal and/or monoclonal antibodies. In some embodiments, the neutralizing antibody inhibits or reduces replication of the coronavirus in the subject (e.g., patient). In some embodiments, for example, administration of the protein to a subject as an immunogenic composition does not result in an increased Antibody Dependence (ADE) in the subject due to prior exposure to coronavirus. In some aspects, proteins comprising coronavirus antigens and immunogens are used as vaccines.

In some embodiments, coronavirus antigens and immunogens (e.g., SARS-CoV or SARS-CoV-2S protein peptide) are linked to proteins or peptides to form fusion proteins or recombinant polypeptides. In some embodiments, a protein or peptide linked to a coronavirus antigen or immunogen is capable of binding, e.g., covalently or non-covalently linked, to a protein or peptide (e.g., a fusion protein or recombinant polypeptide protein or peptide). Thus, in some cases, the protein or peptide linked to the coronavirus antigen or immunogen is a multimeric domain.

In some embodiments, the coronavirus antigen and immunogen (e.g., coronavirus S protein peptide) are linked to a collagen propeptide (e.g., at the C-terminus of the collagen propeptide) to form a fusion peptide or recombinant polypeptide. Thus, in some embodiments, the proteins provided herein include a recombinant polypeptide comprising a coronavirus antigen and an immunogen (e.g., a coronavirus S protein peptide or fragment or epitope thereof), linked to a C-terminal propeptide of collagen. In some embodiments, the collagen propeptide is derived from a human C-propeptide of α1 collagen and is capable of self-trimerization upon expression.

In some embodiments, the ability of the protein to mount an immune response is aided by the attachment of coronavirus antigens and immunogens (e.g., coronavirus S protein peptides) to the pro-peptide of collagen (e.g., at the C-terminus of the pro-peptide of collagen). For example, the production of recombinant proteins may preserve the tertiary and quaternary structure of the coronavirus S protein peptide, which may be important for the stability of the natural conformation of the coronavirus S protein peptide, whereas the availability of antigenic sites on the protein surface in turn is capable of eliciting an immune response, such as neutralizing antibodies. Furthermore, attachment of the coronavirus S protein peptide to a protein or peptide capable of self-trimerization causes the recombinant protein to aggregate, thereby mimicking the native homotrimeric structure of the coronavirus S protein peptide on the viral envelope.

In some embodiments, ligating the coronavirus S protein peptide to the C-terminal propeptide of collagen results in a self-trimerized recombinant polypeptide. In some embodiments, the proteins provided herein include a plurality of self-trimerized coronavirus S protein peptides and pro-peptides of collagen recombinant polypeptides. In some embodiments, the trimeric nature of the recombinant protein contributes to the stability of the protein. In some embodiments, the trimeric nature of the recombinant protein contributes to the ability of the protein to mount an immune response. In some embodiments, the trimeric nature of the recombinant protein and/or the macrostructure of the plurality of self-trimerized recombinant proteins contributes to the ability of the protein to generate an immune response.

Also provided herein are immunogenic compositions comprising the proteins provided herein, methods of producing the proteins provided herein, methods of treating a subject with the proteins and compositions provided herein, and kits.

All publications, including patent documents, scientific articles and databases, mentioned in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication was individually incorporated by reference. If a definition set forth herein is contrary to or inconsistent with a definition set forth in the patents, applications, published applications and other publications that are incorporated herein by reference, the definition set forth herein takes precedence over the definition set forth herein by reference. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

I. Viral antigens and immunogens

Proteins provided herein include coronavirus antigens and immunogens. Coronavirus antigens and immunogens contemplated herein are capable of promoting or stimulating cell-mediated responses and/or humoral responses. In some embodiments, the response (e.g., cell-mediated or humoral response) includes the production of antibodies (e.g., neutralizing antibodies). In some embodiments, the coronavirus antigen or immunogen is a coronavirus spike protein peptide.

Coronaviruses are a family of plus-sense single-stranded RNA viruses that are known to cause severe respiratory diseases. They possess the largest genome (26-32 kb) of known RNA viruses, phylogenetically divided into four genera (α, β, γ, δ), with β -coronaviruses being further subdivided into four lineages (A, B, C, D). It is currently known that viruses of the coronavirus family that infect humans are derived from alpha-coronaviruses and beta-coronaviruses. Furthermore, it is believed that gamma-coronaviruses and delta-coronaviruses may infect humans in the future. Non-limiting examples of beta-coronaviruses include the middle east respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), human coronavirus HKU1 (HKU 1-CoV), human coronavirus OC43 (OC 43-CoV), murine hepatitis virus (MHV-CoV), bat SARS-like coronavirus WIV1 (WIV 1-CoV), and human coronavirus HKU9 (HKU 9-CoV). Non-limiting examples of alpha-coronaviruses include human coronavirus 229E (229E-CoV), human coronavirus NL63 (NL 63-CoV), porcine Epidemic Diarrhea Virus (PEDV), and transmissible gastroenteritis coronavirus (TGEV). A non-limiting example of a delta-coronavirus is porcine delta-coronavirus (SDCV).

Disclosed herein is a list of severe acute respiratory syndrome-associated coronaviruses:

■bat coronavirus Cp/YUNNan2011

■Bat coronavirus RaTG13

■Bat coronavirus Rp/Shaanaxi 2011

○Bat SARS coronavirus HKU3

■Bat SARS coronavirus HKU3-1

■Bat SARS coronavirus HKU3-10

■Bat SARS coronavirus HKU3-11

■Bat SARS coronavirus HKU3-12

■Bat SARS coronavirus HKU3-13

■Bat SARS coronavirus HKU3-2

■Bat SARS coronavirus HKU3-3

■Bat SARS coronavirus HKU3-4

■Bat SARS coronavirus HKU3-5

■Bat SARS coronavirus HKU3-6

■Bat SARS coronavirus HKU3-7

■Bat SARS coronavirus HKU3-8

■Bat SARS coronavirus HKU3-9

■Bat SARS coronavirus Rp1

■Bat SARS coronavirus Rp2

○Bat SARS CoV Rf1/2004

■Bat CoV 273/2005

○Bat SARS CoV Rm1/2004

■ Bat (Bat)CoV 279/2005

■Bat SARS CoV Rp3/2004

■Bat SARS-like coronavirus

■Bat SARS-like coronavirus Rs3367

■Bat SARS-like coronavirus RsSHC014

■Bat SARS-like coronavirus WIV1

■Bat SARS-like coronavirus YNLF_31C

■Bat SARS-like coronavirus YNLF_34C

■BtRf-BetaCoV/HeB2013

■BtRf-BetaCoV/JL2012

■BtRf-BetaCoV/SX2013

■BtRs-BetaCoV/GX2013

■BtRs-BetaCoV/HuB2013

■BtRs-BetaCoV/YN2013

■Civet SARS CoV 007/2004

■Civet SARS CoV SZ16/2003

■Civet SARS CoV SZ3/2003

○Recombinant SARSr-CoV

■SARS coronavirus ExoN1

■SARS coronavirus MA15

■SARS coronavirus MA15 ExoN1

■SARS coronavirus wtic-MB

■Chinese chrysanthemum bata coronavirus

■SARS bat coronavirus

■SARS coronavirus A001

■SARS coronavirus A013

■SARS coronavirus A021

■SARS coronavirus A022

■SARS coronavirus A030

■SARS coronavirus A031

■SARS coronavirus AS

■SARS coronavirus B012

■SARS coronavirus B024

■SARS coronavirus B029

■SARS coronavirus B033

■SARS coronavirus B039

■SARS coronavirus B040

■SARS coronavirus BJ01

■SARS coronavirus BJ02

■SARS coronavirus BJ03

■SARS coronavirus BJ04

■SARS coronavirus BJ162

■SARS coronavirus BJ182-12

■SARS coronavirus BJ182-4

■SARS coronavirus BJ182-8

■SARS coronavirus BJ182a

■SARS coronavirus BJ182b

■SARS coronal diseaseToxic BJ202

■SARS coronavirus BJ2232

■SARS coronavirus BJ302

■SARS coronavirus C013

■SARS coronavirus C014

■SARS coronavirus C017

■SARS coronavirus C018

■SARS coronavirus C019

■SARS coronavirus C025

■SARS coronavirus C028

■SARS coronavirus C029

■SARS coronavirus CDC#200301157

■SARS coronavirus civet010

■SARS coronavirus civet014

■SARS coronavirus civet019

■SARS coronavirus civet020

■SARS coronavirus CS21

■SARS coronavirus CS24

■SARS coronavirus CUHK-AG01

■SARS coronavirus CUHK-AG02

■SARS coronavirus CUHK-AG03

■SARS coronavirus CUHK-L2

■SARS coronavirus CUHK-Su10

■SARS coronavirus CUHK-W1

■SARS coronavirus cw037

■SARS coronavirus cw049

■SARS coronavirus ES191

■SARS coronavirus ES260

■SARS coronavirus FRA

○SARS coronavirus Frankfurt1

■SARS coronavirus Frankfurt1-v01

■SARS coronavirus GD01

■SARS coronavirus GD03T0013

■SARS coronavirus GD322

■SARS coronavirus GD69

■SARS coronavirus GDH-BJH01

■SARS coronavirus GZ-A

■SARS coronavirus GZ-B

■SARS coronavirus GZ-C

■SARS coronavirus GZ-D

■SARS coronavirus GZ02

■SARS coronavirus GZ0401

■SARS coronavirus GZ0402

■SARS coronavirus GZ0403

■SARS coronavirus GZ43

■SARS coronavirus GZ50

■SARS coronavirus GZ60

■SARS coronavirus HB

■SARS coronavirus HC/SZ/61/03

■SARS coronavirus HGZ L1-A

■SARS coronavirus HGZ L1-B

■SARS coronavirus HGZ L2

■SARS coronavirus HHS-2004

■SARS coronavirus HKU-36871

■SARS coronavirus HKU-39849

■SARS coronavirus HKU-65806

■SARS coronavirus HKU-66078

■SARS coronavirus Hong Kong/03/2003

■SARS coronavirus HPZ-2003

■SARS coronavirus HSR 1

■SARS coronavirus HSZ-A

■SARS coronavirus HSZ-Bb

■SARS coronavirus HSZ-Bc

■SARS coronavirus HSZ-Cb

■SARS coronavirus HSZ-Cc

■SARS coronavirus HSZ2-A

■SARS coronavirus HZS2-Bb

■SARS coronavirus HZS2-C

■SARS coronavirus HZS2-D

■SARS coronavirus HZS2-E

■SARS coronavirus HZS2-Fb

■SARS coronavirus HZS2-Fc

■SARS coronavirus JMD

■SARS coronavirus LC1

■SARS coronavirus LC2

■SARS coronavirus LC3

■SARS coronavirus LC4

■SARS coronavirus LC5

■SARS coronavirus LLJ-2004

■SARS coronavirus NS-1

■SARS coronavirus P2

■SARS coronavirus PC4-115

■SARS coronavirus PC4-127

■SARS coronavirus PC4-13

■SARS coronavirus PC4-136

■SARS coronavirus PC4-137

■SARS coronavirus PC4-145

■SARS coronavirus PC4-199

■SARS coronavirus PC4-205

■SARS coronavirus PC4-227

■SARS coronavirus PC4-241

■SARS coronavirus PUMC01

■SARS coronavirus PUMC02

■SARS coronavirus PUMC03

■SARS coronavirus Rs_672/2006

■SARS coronavirus sf098

■SARS coronavirus sf099

■SARS coronavirus ShanghaiQXC1

■SARS coronavirus ShanghaiQXC2

■SARS coronavirus Shanhgai LY

■SARS coronavirus Sin0409

■SARS coronavirus Sin2500

■SARS coronavirus Sin2677

■SARS coronavirus Sin2679

■SARS coronavirus Sin2748

■SARS coronavirus Sin2774

■SARS coronavirus Sin3408

■SARS coronavirus Sin3408L

■SARS coronavirus Sin3725V

■SARS coronavirus Sin3765V

■SARS coronavirus Sin842

■SARS coronavirus Sin845

■SARS coronavirus Sin846

■SARS coronavirus Sin847

■SARS coronavirus Sin848

■SARS coronavirus Sin849

■SARS coronavirus Sin850

■SARS coronavirus Sin852

■SARS coronavirus sin_WNV

■SARS coronavirus Sino1-11

■SARS coronavirus Sino3-11

■SARS coronavirus SinP1

■SARS coronavirus SinP2

■SARS coronavirus SinP3

■SARS coronavirus SinP4

■SARS coronavirus SinP5

■SARS coronavirus SoD

■SARS coronavirus SZ1

■SARS coronavirus SZ13

■SARS coronavirus Taiwan

■SARS coronavirus Taiwan JC-2003

■SARS coronavirus Taiwan TC1

■SARS coronavirus Taiwan TC2

■SARS coronavirus Taiwan TC3

■SARS coronavirus TJ01

■SARS coronavirus TJF

■SARS coronavirus Torr 2

○SARS coronavirus TW

■SARS coronavirus TW-GD1

■SARS coronavirus TW-GD2

■SARS coronavirus TW-GD3

■SARS coronavirus TW-GD4

■SARS coronavirus TW-GD5

■SARS coronavirus TW-HP1

■SARS coronavirus TW-HP2

■SARS coronavirus TW-HP3

■SARS coronavirus TW-HP4

■SARS coronavirus TW-JC2

■SARS coronavirus TW-KC1

■SARS coronavirus TW-KC3

■SARS coronavirus TW-PH1

■SARS coronavirus TW-PH2

■SARS coronavirus TW-YM1

■SARS coronavirus TW-YM2

■SARS coronavirus TW-YM3

■SARS coronavirus TW-YM4

■SARS coronavirus TW1

■SARS coronavirus TW10

■SARS coronavirus TW11

■SARS coronavirus TW2

■SARS coronavirus TW3

■SARS coronavirus TW4

■SARS coronavirus TW5

■SARS coronavirus TW6

■SARS coronavirus TW7

■SARS coronavirus TW8

■SARS coronavirus TW9

■SARS coronavirus TWC

■SARS coronavirus TWC2

■SARS coronavirus TWC3

■SARS coronavirus TWH

■SARS coronavirus TWJ

■SARS coronavirus TWK

■SARS coronavirus TWS

■SARS coronavirus TWY

■SARS coronavirus Urbani

■SARS coronavirus Vietnam

■SARS coronavirus WF188

■SARS coronavirus WH20

■SARS coronavirus WHU

■SARS coronavirus xw002

■SARS coronavirus ZJ01

■SARS coronavirus ZJ02

■SARS coronavirus ZJ0301

■SARS coronavirus ZMY 1

■SARS coronavirus ZS-A

■SARS coronavirus ZS-B

■SARS coronavirus ZS-C

■SARS related bat coronavirus RsSHC014

■SARS-associated beta-coronavirus Rp3/2004

■Severe acute respiratory syndrome coronavirus 2

The following table shows exemplary SARS CoV-2 strains.

The coronavirus genome is capped (capped), polyadenylation and covered by nucleocapsid proteins. Coronavirus particles comprise a viral envelope comprising a fusion glycoprotein of type I called spike (S) protein. Most coronaviruses share a common genomic structure in which the replicase gene is contained in the 5 'part of the genome and the structural gene is contained in the 3' part of the genome.

Coronavirus spike (S) protein is a class I fusion glycoprotein initially synthesized as a precursor protein. The individual precursor S polypeptides form homotrimers, which are glycosylated and processed in the golgi apparatus to remove signal peptides, and are cleaved by cellular proteases to produce separate S1 and S2 polypeptide chains, which remain bound as S1/S2 protomers in the homotrimers and are thus heterodimeric trimers. The S1 subunit is located distally to the viral membrane and comprises a Receptor Binding Domain (RBD) that mediates the attachment of the virus to its host receptor. The S2 subunit comprises fusion protein mechanisms (machinery), such as fusion peptides, two heptad repeats (HR 1 and HR 2) and a central helix, a transmembrane domain and a cytosolic tail domain that are unique to fusion glycoproteins (cytosolic tail domain).

In some cases, the coronavirus antigen or immunogen is a coronavirus S protein peptide in a pre-fusion conformation, which is the structural conformation adopted after the extracellular domain of the coronavirus S protein is processed into a mature coronavirus S protein in the secretory system and before triggering a fusion event that causes a transition of coronavirus S to a post-fusion conformation. The three-dimensional structure of an exemplary coronavirus S protein (HKU 1-CoV) in a Pre-fusion conformation is provided in Kirchdoerfer et al, "Pre-fusion structure of a human coronavirus spike protein," Nature,531:118-121,2016, incorporated by reference in its entirety for all purposes.

In some cases, a coronavirus antigen or immunogen comprises one or more amino acid substitutions, deletions, or insertions compared to the native coronavirus S sequence, which provides increased pre-fusion conformational retention as compared to coronavirus S ectodomain trimers formed from the corresponding native coronavirus S sequence. "stabilization" of the pre-fusion conformation by one or more amino acid substitutions, deletions or insertions may be, for example, energy stabilization (e.g., reducing the energy of the pre-fusion conformation relative to the post-fusion open conformation) and/or kinetic stabilization (e.g., reducing the conversion rate from the pre-fusion conformation to the post-fusion conformation). Furthermore, stabilization of the coronavirus S ectodomain trimer in the pre-fusion conformation may include increased resistance to denaturation as compared to the corresponding native coronavirus S sequence. Provided herein are methods of determining whether a coronavirus S ectodomain trimer is in a pre-fusion conformation, including, but not limited to, negative staining electron microscopy and antibody binding analysis using pre-fusion conformation specific antibodies.

In some cases, the coronavirus antigen or immunogen is a fragment of an S protein peptide. In some embodiments, the antigen or immunogen is an epitope of an S protein peptide. Epitopes include antigenic determinant chemical groups or peptide sequences on molecules that are antigenic, thereby eliciting a specific immune response, e.g., epitopes are the antigenic regions of B-cells and/or T-cells that respond. Antibodies may bind to specific epitopes, such as epitopes on the S ectodomain of coronavirus. Epitopes can be formed by either contiguous or non-contiguous amino acids juxtaposed by tertiary folding of the protein. In some embodiments, the coronavirus epitope is a linear epitope. In some embodiments, the coronavirus epitope is a conformational epitope. In some embodiments, the coronavirus epitope is a neutralizing epitope site. In some embodiments, all neutralizing epitopes of the coronavirus S protein peptide or fragment thereof are present as antigens or immunogens.

In some cases, for example, when the viral antigen or immunogen is a fragment of an S protein peptide, only a single subunit of the S protein peptide is present and the single subunit of the S protein peptide is trimerized. In some embodiments, the viral antigen or immunogen comprises a signal peptide, an S1 subunit peptide, an S2 subunit peptide, or any combination thereof. In some embodiments, the viral antigen or immunogen comprises a signal peptide, a Receptor Binding Domain (RBD) peptide, a Receptor Binding Motif (RBM) peptide, a Fusion Peptide (FP), a heptad repeat 1 (HR 1) peptide, or a heptad repeat 2 (HR 2) peptide, or any combination thereof. In some embodiments, the viral antigen or immunogen comprises the Receptor Binding Domain (RBD) of the S protein. In some embodiments, the viral antigen or immunogen comprises an S1 subunit and an S2 subunit of an S protein. In some embodiments, the viral antigen or immunogen comprises the S1 subunit of the S protein, but does not comprise the S2 subunit. In some embodiments, the viral antigen or immunogen comprises the S2 subunit of the S protein, but does not comprise the S1 subunit. In some embodiments, the viral antigen or immunogen is free of Transmembrane (TM) domain peptides and/or Cytoplasmic (CP) domain peptides.

In some embodiments, the viral antigen or immunogen comprises a protease cleavage site, wherein the protease is optionally furin (furin), trypsin, factor Xa, or cathepsin L.

In some embodiments, the viral antigen or immunogen does not contain a protease cleavage site, wherein the protease is optionally furin (furin), trypsin, factor Xa, or cathepsin L, or comprises a mutated protease cleavage site that is not cleavable by a protease.

In some embodiments, the viral antigen or immunogen is a SARS-CoV-2 antigen comprising at least one SARS-CoV-2 protein or fragment thereof. In some embodiments, the SARS-CoV-2 antigen is recognized by SARS-CoV-2 reactive antibody and/or T cells. In some embodiments, the SARS-CoV-2 antigen is an inactivated whole virus. In some embodiments, the SARS-CoV-2 antigen comprises a subunit of a virus. In some embodiments, the SARS-CoV-2 antigen comprises a structural protein of SARS-CoV-2 or a fragment thereof. In some embodiments, the structural protein of SARS-CoV-2 comprises one or more of the group consisting of spike (S) protein, membrane (M) protein, nucleocapsid (N) protein and envelope (E) protein. In some embodiments, the SARS-CoV-2 antigen comprises or further comprises a nonstructural protein of SARS-CoV-2 or a fragment thereof. The nucleotide sequence of a representative SARS-CoV-2 isolate (isolate) (Hu-1) is described in GenBank accession number MN908947.3 (Wu et al, nature,579:265-269,2020, incorporated by reference in its entirety for all purposes).

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in any one of SEQ ID NOS: 81-84. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence that has at least or about 80%, 85%, 90%, 92%, 95%, 97%, or 99% sequence identity to SEQ ID NO 83 as shown below. In some embodiments, the viral antigen or immunogen comprises an RBD trimer, e.g., SARS-CoV-2RBD sequence linked to any of SEQ ID No. 67-80.

SEQ ID NO:83：

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 55. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 85%, 90%, 92%, 95%, or 97% sequence identity to SEQ ID NO 55 (underlined sequence indicates the Receptor Binding Motif (RBM) within the Receptor Binding Domain (RBD) of Thr333-Gly526 (bold)). In some embodiments, the viral antigen or immunogen comprises an RBD trimer, e.g., SARS-CoV-2RBD sequence linked to any of SEQ ID No. 67-80.

SEQ ID NO:55：

In some embodiments, the viral antigen or immunogen comprises the spike glycoprotein sequence of Hu-1 coronavirus (e.g., NC 045512). In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.526 lineage. In some embodiments, the viral antigen or immunogen comprises the spike glycoprotein sequence of a Cluster 5 (ΔFVI-spike) virus. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.1.7 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.1.207 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.1.317 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.1.318 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the p.1 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.351 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.429/cal.20c lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.525 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.526 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.617 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.617.2 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.618 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.620 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the p.2 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the P.3 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.1.143 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the a.23.1 lineage. In some embodiments, the viral antigen or immunogen comprises a spike glycoprotein sequence of a virus in the b.1.617 lineage. In some embodiments, the viral antigen or immunogen comprises a sequence derived from any two or more (in any suitable combination) spike glycoproteins selected from the group consisting of a virus in the marchand-Hu-1, b.1.526 lineage, a virus in the b.1.1.7 lineage, a virus in the p.1 lineage, a virus in the b.1.351 lineage, a virus in the p.2 lineage, a virus in the b.1.1.143 lineage, a virus in the a.23.1 lineage, and a virus in the b.1.617 lineage.

In some embodiments, the viral antigen or immunogen comprises T95I, G142D, Δ143-145, and/or T478K, e.g., as in the b.1.617.2 delta and/or b.1.1.529 omnikov variety.

In some embodiments, the viral antigen or immunogen comprises E484K and/or S477N, e.g., as in variant b.1.526. In some embodiments, the viral antigen or immunogen comprises Δ400-402 (Δfvi), e.g., as in the Cluster 5 (Δfvi-spike) variant. In some embodiments, the viral antigen or immunogen comprises Δ69-70 (Δhv), Δ144 (Δy), N501Y, A570D, D G, P681H, T716I, S982A and/or D1118H, e.g., as in variant b.1.1.7. In some embodiments, the viral antigen or immunogen comprises P681H, e.g., as in variant b.1.1.207. In some embodiments, the viral antigen or immunogen comprises L18F, T20N, P S, D35138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, T1027I and/or V1176F, e.g., as in the p.1 variant. In some embodiments, the viral antigen or immunogen comprises E484K, e.g., as in the p.2 variant. In some embodiments, the viral antigen or immunogen comprises E484K and/or N501Y, e.g., as in variant P.3. In some embodiments, the viral antigen or immunogen comprises L18F, D80A, D G, Δ242-244 (Δlal), R246I, K417N, E484K, N501Y, D G, and/or a701V, e.g., as in variant b.1.351. In some embodiments, the viral antigen or immunogen comprises S13I, W C and/or L452R, e.g., as in the b.1.429/cal.20C variant. In some embodiments, the viral antigen or immunogen comprises Δ69-70 (Δhv), E484K, and/or F888L, e.g., as in variant b.1.525. In some embodiments, the viral antigen or immunogen comprises G142D, L452R, E484Q and/or P681R, e.g., as in variant b.1.617. In some embodiments, the viral antigen or immunogen comprises G142D, L452R and/or P681R, e.g., as in variant b.1.617.2. In some embodiments, the viral antigen or immunogen comprises E484K, e.g., as in variant b.1.618. In some embodiments, the viral antigen or immunogen may comprise a fusion polypeptide (protomer) comprising any one or more of the foregoing mutations in any suitable combination. In some embodiments, the viral antigen or immunogen may comprise a trimer of three fusion polypeptides, and any of the three protomer fusion polypeptides may comprise any one or more of the foregoing mutations in any suitable combination. In some embodiments, two or all three of the three protomer fusion polypeptides that form a trimer may include different mutations and/or different combinations of mutations in each protomer. In some embodiments, the viral antigen or immunogen may comprise a mixture of trimers, and each trimer may comprise different mutations and/or different combinations of mutations.

In some embodiments, the viral antigen or immunogen comprises any one, two, three, four, five or more mutations selected from the group consisting of mutations (e.g., substitutions, deletions and/or insertions) at amino acid positions 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118 and 1176 of SEQ ID No. 55. In some embodiments, the viral antigen or immunogen comprises any one, two, three, four, five, six, seven, eight, or all mutations selected from the group consisting of mutations (e.g., substitutions, deletions, and/or insertions) at amino acid positions 440, 452, 477, 484, 501, 614, 655, 681, and 701. In some embodiments, the viral antigen or immunogen comprises a chimeric polypeptide comprising sequences from different viruses, such as one or more mutations from a first variant of a coronavirus and one or more mutations from a second variant of a coronavirus different from the first variant. In some embodiments, such chimeric viral antigens or immunogens (or combinations of chimeric viral antigens or immunogens) can be used to elicit a broad immune response against the first and second variants of coronavirus.

In some embodiments, the viral antigen or immunogen comprises a polypeptide selected from the group consisting of T95I, G142D, Δ143-145, T478K, S13I, L18F, T6323 26S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F. In some embodiments, the viral antigen or immunogen comprises any one, two, three, four, five or more mutations selected from the group consisting of N440K, L452R, S477G, S477N, E484Q, N501Y, D614G, H655 69 681H, P681R and a 701V.

In some embodiments, the SARS-CoV-2 antigen comprises a truncated S protein lacking a signal peptide, the transmembrane and cytoplasmic domains of a full-length S protein. In some embodiments, the SARS-CoV-2 antigen is a recombinant protein, while in other embodiments, the SARS-CoV-2 antigen is purified from the viral particle. In some preferred embodiments, the SARS-CoV-2 antigen is an isolated antigen.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 27. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:27, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 27, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 28. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 28, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID No. 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 28, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 29. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 29, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID No. 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 29, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 30. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:30, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 30, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 31. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:31, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO:31, a variant of the method of the invention, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 32. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 32, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID No. 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 32, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 33. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 33, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID No. 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO:33, and a variant of the above-mentioned method, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 34. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:34, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises a variant of SEQ ID NO 34, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452R, S487 477G, E484G, E501, 570G, E614G, E655G, E681G, E681G, E681G, E683G, E685G, E701G, E888G, E982 527 521118H, and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 35. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:35, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 35, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 36. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:36, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 36, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 37. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:37, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 37, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 38. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:38, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 38, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 39. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:39, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO:39 of the above-mentioned variant of the invention, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 40. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 40, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID No. 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 40, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 41. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 41, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO. 55). In some embodiments, the viral antigen or immunogen comprises a variant of SEQ ID NO 41, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452R, S487 477G, E484G, E501, 570G, E614G, E655G, E681G, E681G, E681G, E683G, E685G, E701G, E888G, E982 527 521118H, and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 42. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:42, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 42, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 43. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 43, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID No. 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 43, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 44. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:44, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 44, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 45. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 45, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID No. 55). In some embodiments, the viral antigen or immunogen comprises a variant of SEQ ID NO 45, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452R, S487 477G, E484G, E501, 570G, E614G, E655G, E681G, E681G, E681G, E683G, E685G, E701G, E888G, E982 527 521118H, and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 46. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 46, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID No. 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 46, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 47. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:47, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 47, which is described in detail in the following, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 48. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:48, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 48, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 49. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 49, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID No. 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 49, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 50. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:50, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 50, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 51. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:51, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 51, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 52. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 52.

In some embodiments, the viral antigen or immunogen comprises a signal peptide. In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 53. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 53. In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 54. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 54.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 55. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 55, including sequences comprising substitutions, deletions, and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176. In some embodiments, the viral antigen or immunogen comprises SEQ ID NO: a variant of 55, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 56. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:56, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions selected from the group consisting of 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and 1176 (with respect to amino acid positions of SEQ ID NO: 55). In some embodiments, the viral antigen or immunogen comprises SEQ ID NO:56, a variant of which, and variants include those selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), and any one, two, three, four, five or more mutations of the group consisting of K417T, K417N, N K, L452R, S477N, S477G, E484G, E484G, E570G, E614G, E655G, E681G, E681G, E682G, E683G, E716G, E52888G, E982G, E1027G, E1118H and V1176F.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 57. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 57, including sequences comprising substitutions, deletions, and/or insertions at one or more amino acid positions of SEQ ID NO. 57.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 58. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 58, including sequences comprising substitutions, deletions, and/or insertions at one or more amino acid positions of SEQ ID NO. 58.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 59. In some embodiments, the viral antigen or immunogen comprises a sequence comprising substitutions, deletions and/or insertions at one or more amino acid positions of SEQ ID NO. 59. In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 60. In some embodiments, the viral antigen or immunogen comprises a sequence comprising substitutions, deletions and/or insertions at one or more amino acid positions of SEQ ID NO. 60.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 61. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 61, including sequences comprising substitutions, deletions, and/or insertions at one or more amino acid positions of SEQ ID NO. 61.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 62. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 62, including sequences comprising substitutions, deletions, and/or insertions at one or more amino acid positions of SEQ ID NO. 62.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 63. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 63, including sequences comprising substitutions, deletions, and/or insertions at one or more amino acid positions of SEQ ID NO. 63.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 64. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 64, including sequences comprising substitutions, deletions, and/or insertions at one or more amino acid positions of SEQ ID NO. 64.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 65. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 65, including sequences comprising substitutions, deletions, and/or insertions at one or more amino acid positions of SEQ ID NO. 65.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 81. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 81, including sequences comprising substitutions, deletions, and/or insertions at one or more amino acid positions of SEQ ID NO. 81.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 82. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 82, including sequences comprising substitutions, deletions, and/or insertions at one or more amino acid positions of SEQ ID NO. 82.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 83. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 83, including sequences comprising substitutions, deletions, and/or insertions at one or more amino acid positions of SEQ ID NO. 83.

In some embodiments, the viral antigen or immunogen comprises the sequence set forth in SEQ ID NO. 84. In some embodiments, a viral antigen or immunogen comprises an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO. 84, including sequences comprising substitutions, deletions, and/or insertions at one or more amino acid positions of SEQ ID NO. 84.

In some embodiments, the viral antigen or immunogen does not include a transmembrane domain such as SEQ ID NO:66 or a portion thereof. In some embodiments, the coronavirus antigen or immunogen comprises a soluble S protein peptide. In some embodiments, the soluble S protein peptide lacks a TM domain peptide and a CP domain peptide. In some embodiments, the soluble S protein peptide is not bound to a lipid bilayer, such as a membrane or viral envelope.

In some embodiments, the S protein peptide is produced from a codon optimized nucleic acid sequence. In some embodiments, the S protein peptide is produced from a nucleic acid sequence that is not codon optimized.

In some embodiments, a viral antigen or immunogen referred to herein may comprise a recombinant polypeptide or fusion peptide comprising the viral antigen or immunogen. The term viral antigen or immunogen may be used to refer to a protein comprising a coronavirus antigen or immunogen. In certain instances, the coronavirus antigen or immunogen is a coronavirus protein peptide provided herein. The viral antigens or immunogens mentioned herein may be used in the initial, additional, and/or booster agents. Independently, the initial agent, additional agent, and/or any one or more of the boosters may be absent or used as an adjuvant. If an adjuvant is used, optional adjuvants may include: aluminum-containing adjuvants, such as alum and/or aluminum hydroxide-containing adjuvants; an oligonucleotide-containing adjuvant, such as a CpG oligodeoxynucleotide (CpG-ODN) -containing adjuvant; an adjuvant comprising a TLR9 agonist; adjuvants comprising metabolisable oil, alpha-tocopherol, and/or polyoxyethylene sorbitan monooleate (tween-80), for example adjuvants comprising squalene, alpha-tocopherol, and tween-80 and/or Span 85 in the form of an oil in water emulsion; or any one of the adjuvant combinations.

Recombinant peptides and proteins

It is contemplated that coronavirus antigens and immunogens provided herein, e.g., S protein peptides (see section I), can be combined, e.g., linked, with other proteins or peptides to form recombinant polypeptides, including fusion peptides. In some embodiments, individual recombinant polypeptides (e.g., monomers) provided herein are combined to form multimers, e.g., trimers, of the recombinant polypeptides. In some embodiments, the binding of the individual recombinant polypeptide monomers occurs by covalent interactions. In some embodiments, the binding of the individual recombinant polypeptide monomers occurs by non-covalent interactions. In some embodiments, the interaction (e.g., covalent or non-covalent) is effected by a protein or peptide that links a coronavirus antigen or immunogen (e.g., an S protein peptide). In some embodiments, for example, when the coronavirus antigen or immunogen is an S protein peptide as described herein, the protein or peptide to which it is attached may be selected so that the native homotrimeric structure of the glycoprotein is preserved. This may be advantageous for eliciting a strong and potent immunogenic response to the S protein peptide. For example, the retention and/or maintenance of the native conformation of a coronavirus antigen or immunogen (e.g., an S protein peptide) may improve or allow access to antigenic sites capable of generating an immune response. In some cases, a recombinant polypeptide comprising an S protein peptide described herein (e.g., see section I) is alternatively referred to herein as a recombinant S antigen, a recombinant S immunogen, or a recombinant S protein.

It is further contemplated that in some cases, the recombinant polypeptide or multimeric recombinant polypeptide thereof aggregates or can aggregate to form a protein or complex comprising a plurality of coronavirus antigens and/or immunogenic recombinant polypeptides. The formation of such proteins may be advantageous in generating a strong and potent immunogenic response to coronavirus antigens and/or immunogens. For example, the formation of a protein comprising a plurality of recombinant polypeptides, thereby forming a plurality of coronavirus antigens, e.g., coronavirus S protein peptides, may preserve the tertiary and/or quaternary structure of the virus antigen, allowing for eliciting an (mount) immune response against the native structure. In some cases, aggregation may confer structural stability to the coronavirus antigen or immunogen, which in turn may provide access to potential antigenic sites capable of promoting an immune response.

1. Fusion peptides and recombinant polypeptides

In some embodiments, coronavirus antigens or immunogens may be linked at their C-terminus (C-terminal linkage) to a trimerization domain to facilitate trimerization of monomers. In some embodiments, trimerization stabilizes membrane proximal aspects of coronavirus antigens or immunogens (e.g., coronavirus S protein peptides) in a trimeric configuration.

Non-limiting examples of exogenous multimeric domains that promote stable trimerization of soluble recombinant proteins include: GCN4 leucine zipper (Harbury et al 1993 Science 262:1401-1407), the trimerization motif of the lung surfactant Protein (Hoppe et al 1994 FEBS Lett 344:191-195), collagen (McAlinden et al 2003J Biol Chem 278:42200-42207) and phage T4 fibritin Foldon (Miroshnikov et al 1998 Protein Eng 11:329-414), any of which may be linked to a coronavirus antigen or immunogen as described herein (e.g., by linking to the C-terminus of the S peptide) to facilitate trimerization of the recombinant virus antigen or immunogen, the above documents being incorporated by reference in their entirety for all purposes. See also U.S. patent nos. 7,268,116, 7,666,837, 7,691,815, 10,618,949, 10,906,944 and 10,960,070, and US 2020/0009244, which are incorporated herein by reference in their entirety for all purposes.

In some embodiments, one or more peptide linkers (e.g., glycine-serine linkers, e.g., 10 amino acid glycine-serine peptide linkers) can be used to link the recombinant viral antigen or immunogen to the multimerization domain. A trimer may include any of the stabilizing mutations provided herein (or combinations thereof) so long as the recombinant viral antigen or immunogenic trimer retains the desired properties (e.g., pre-fusion conformation). In some embodiments, the recombinant polypeptide or fusion protein comprises a first sequence as set forth in any one of SEQ ID NOS.27-66 and 81-84 linked to a second sequence as set forth in any one of SEQ ID NOS.67-80, wherein the C-terminus of the first sequence is directly linked to the N-terminus of the second sequence. In some embodiments, the recombinant polypeptide or fusion protein comprises a first sequence as set forth in any one of SEQ ID NOS.27-66 and 81-84 linked to a second sequence as set forth in any one of SEQ ID NOS.67-80, wherein the C-terminal end of the first sequence is linked to the N-terminal end of the second sequence, such as by a linker. In some embodiments, the linker comprises a sequence comprising a glycine-X-Y repeat sequence.

To be therapeutically viable, the trimerized protein fraction required for biopharmaceutical design should meet the following criteria. Ideally, it should be part of a naturally secreted protein, such as an immunoglobulin Fc, which is also abundant in the circulation (non-toxic), of human origin (lack of immunogenicity), relatively stable (long half-life), and capable of efficient self-trimerization, which is enhanced by inter-chain covalent disulfide bonds, so that trimerized coronavirus antigens or immunogens are structurally stable.

Collagen is a family of fibrin, which is the major component of the extracellular matrix. It is the most abundant protein in mammals, accounting for nearly 25% of the total protein in the body. Collagen plays an important structural role in the formation of bone, tendons, skin, cornea, cartilage, blood vessels and teeth. Both fibrillar types of collagen I, II, III, IV, V and XI are synthesized as larger trimeric precursors, called procollagens, in which a central uninterrupted triple-helical domain consisting of hundreds of "G-X-Y" repeats (or glycine repeats) is flanked by non-collagenous domains (NC), N-propeptides and C-propeptides. Both the C-terminal and N-terminal extensions are proteolytically processed following procollagen secretion, an event that triggers the assembly of the mature protein into collagen fibrils, forming an insoluble cellular matrix. BMP-1 is a protease that recognizes a specific peptide sequence of procollagen near the junction between glycine repeat sequence and C-prodomain of collagen and is responsible for removal of the procollagen. The concentration of the shedding trimer C-propeptide of type I collagen was found in human serum of normal adults in the range of 50-300ng/mL, with higher levels in children, indicating active bone formation. In the familial high serum concentration population of C-propeptide of type I collagen, levels can be as high as 1-6 μg/mL without significant abnormalities, indicating that the C-propeptide is non-toxic. Structural studies of the trimeric C-propeptide of collagen have shown that it is a trefoil structure, with all three subunits clustered together at a junction near its N-terminus, linked to the remainder of the procollagen molecule. Fusion of this protruding protein geometry in one direction is similar to Fc dimers.

Type I, iv, V and XI collagens are assembled predominantly into a heterotrimeric form consisting of two alpha-1 chains and one alpha-2 chain (for type I, iv, V) or three different chains (for type XI), which are highly homologous in sequence. Both type II and type III collagens are homotrimers of the alpha-1 chain. For type I collagen (the most abundant form of collagen), stable alpha (I) homotrimers are also formed and are present at variable levels in different tissues. When overexpressed alone in cells, most of these collagen C-propeptide chains can self-assemble into homotrimers. Although the N-propeptide domain is first synthesized, the molecular assembly of trimeric collagen begins with the registered binding of the C-propeptide. It is believed that the C-propeptide complex is stabilized by inter-chain disulfide bond formation, but the necessity of disulfide bond formation for proper chain registration is not yet clear. The triple helical repetition of glycine then propagates from the associated C-terminus to the N-terminus in a zipper-like manner. This knowledge creates a collagen matrix of non-native type by exchanging the C-propeptides of the different collagen chains using recombinant DNA technology. Non-collagen proteins (e.g., cytokines and growth factors) have also been fused to the N-terminus of procollagen or mature collagen to form a new collagen matrix, the purpose of which is to allow slow release of the non-collagen proteins from the cell matrix. However, in both cases, the C-propeptide needs to be cleaved before the recombinant collagen fibers are assembled into an insoluble cellular matrix.

Although other protein trimerization domains (such as those of GCN4 from the yeast fibrillin (fibritin) of bacteriophage T4 and aspartate transcarbamylase of E.coli) have been previously described as allowing trimerization of heterologous proteins, none of these trimeric proteins are of human nature nor are they naturally secreted proteins. Thus, any trimeric fusion protein must be synthesized in the cell, which not only can lead to misfolding of the naturally secreted protein (e.g., soluble receptor), but also makes it difficult to purify such fusion proteins from thousands of other intracellular proteins. Furthermore, a fatal disadvantage of using such non-human protein trimerization domains (e.g., from yeast, bacteriophage, and bacteria) in trimeric biopharmaceutical design is their putative immunogenicity in humans, rendering such fusion proteins ineffective shortly after injection into humans.

Thus, there are many advantages to using collagen in the recombinant polypeptides described herein, including: (1) Collagen is the most abundant protein secreted by mammals and accounts for nearly 25% of the total protein in the body; (2) The main form of collagen occurs naturally in the form of a trimeric helix, the globular C-propeptide of which is responsible for the initiation of trimerization; (3) Trimeric C-propeptide of collagen released from proteolysis of mature collagen naturally occurs at sub-microgram/milliliter levels in mammalian blood and is not known to be toxic to the body; (4) The linear triple helical region of collagen can be included as a linker, predicting the spacing of each residue as Or excluded as part of the fusion protein, so that the distance between the protein to be trimerized and the C-propeptide of the collagen can be precisely adjusted to achieve optimal biological activity; (5) The recognition site of BMP1 that cleaves C-propeptide from procollagen can be mutated or deleted to prevent disruption of the trimeric fusion protein; (6) The C-propeptide domain is self-trimerized by disulfide bonds and it provides a universal affinity tag that can be used to purify any secreted fusion proteins produced. In some embodiments, the C-propeptide of collagen, which is conjugated to a coronavirus antigen and an immunogen (e.g., an S protein peptide), is capable of recombinantly producing a soluble, covalently linked homotrimeric fusion protein.

In some embodiments, a coronavirus antigen or immunogen is linked to the C-terminal propeptide of collagen to form a recombinant polypeptide. In some embodiments, the C-terminal propeptide of a recombinant polypeptide forms an inter-polypeptide disulfide bond. In some embodiments, the recombinant protein forms a trimer. In some embodiments, the coronavirus antigen or immunogen is an S protein peptide as described in section I.

For example, a fusion polypeptide comprising the signal peptide MFVFLVLLPLVSS (SEQ ID NO: 54) on the N-terminal end of the fusion polypeptide of SEQ ID NO:1 may be produced by inter-polypeptide disulfide bonding (Cys residues which may form inter-polypeptide disulfide bonding are shown in bold) and trimerized.

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In some embodiments, the inter-polypeptide disulfide bonds may include one or more or all of Cys15-136, cys131-166, cys 291-301, cys379-432, cys336-361, cys391-525, cys480-488, cys538-590, cys617-649, cys662-671, cys743-749, cys738-760, cys840-851, cys1032-1043, and Cys1082-1126, in any suitable combination. In some embodiments, the fusion polypeptide in a trimer may include one or more glycosylation sites (e.g., asn-linked), e.g., at one or more or all Asn residues at 17, 61, 122, 149, 165, 234, 282, 331, 343, 603, 616, 657, 709, 717, 801, 1074, 1098, and 1134, in any suitable combination.

In some embodiments, the C-terminal propeptide is human collagen. In some embodiments, the C-terminal pro-peptide comprises a C-terminal polypeptide of proα1 (I), proα1 (II), proα1 (III), proα1 (V), proα1 (XI), proα2 (I), proα2 (V), proα2 (XI), or proα3 (XI), or fragment thereof. In some embodiments, the C-terminal propeptide is or comprises a C-terminal polypeptide of pro α1 (I).

In some embodiments, the C-terminal propeptide is or comprises the amino acid sequence set forth in SEQ ID NO. 67. In some embodiments, the C-terminal propeptide is an amino acid sequence with at least or about 85%, 90%, 92%, 95%, or 97% sequence identity with SEQ ID NO. 67. In some embodiments, the C-terminal propeptide is or comprises the amino acid sequence set forth in SEQ ID NO. 68. In some embodiments, the C-terminal propeptide is an amino acid sequence with at least or about 85%, 90%, 92%, 95%, or 97% sequence identity with SEQ ID NO. 68. In some embodiments, the C-terminal propeptide is or is the amino acid sequence shown in SEQ ID NO. 69. In some embodiments, the C-terminal propeptide exhibits an amino acid sequence with at least or about 85%, 90%, 92%, 95%, or 97% sequence identity with SEQ ID NO: 69. In some embodiments, the C-terminal propeptide is or comprises the amino acid sequence set forth in SEQ ID NO. 70. In some embodiments, the C-terminal propeptide is an amino acid sequence with at least or about 85%, 90%, 92%, 95%, or 97% sequence identity with SEQ ID NO. 70. In some embodiments, the C-terminal propeptide is or comprises the amino acid sequence of SEQ ID NO. 71. In some embodiments, the C-terminal propeptide is an amino acid sequence with at least or about 85%, 90%, 92%, 95%, or 97% sequence identity with SEQ ID NO. 71.

In some embodiments, the C-terminal propeptide is or comprises the amino acid sequence set forth in SEQ ID NO. 72. In some embodiments, the C-terminal propeptide is an amino acid sequence with at least or about 85%, 90%, 92%, 95%, or 97% sequence identity with SEQ ID NO. 72. In some embodiments, the C-terminal propeptide is or comprises the amino acid sequence of SEQ ID NO. 73. In some embodiments, the C-terminal propeptide is an amino acid sequence with at least or about 85%, 90%, 92%, 95%, or 97% sequence identity with SEQ ID NO. 73. In some embodiments, the C-terminal propeptide is or is the amino acid sequence shown in SEQ ID NO. 74. In some embodiments, the C-terminal propeptide exhibits an amino acid sequence with at least or about 85%, 90%, 92%, 95%, or 97% sequence identity with SEQ ID NO. 74. In some embodiments, the C-terminal propeptide is or comprises the amino acid sequence set forth in SEQ ID NO. 75. In some embodiments, the C-terminal propeptide is an amino acid sequence with at least or about 85%, 90%, 92%, 95%, or 97% sequence identity to SEQ ID NO. 75. In some embodiments, the C-terminal propeptide is or comprises the amino acid sequence of SEQ ID NO. 76. In some embodiments, the C-terminal propeptide is an amino acid sequence with at least or about 85%, 90%, 92%, 95%, or 97% sequence identity with SEQ ID NO. 76.

In some embodiments, the C-terminal propeptide is or comprises the amino acid sequence of SEQ ID NO. 77. In some embodiments, the C-terminal propeptide is an amino acid sequence with at least or about 85%, 90%, 92%, 95%, or 97% sequence identity with SEQ ID NO. 77. In some embodiments, the C-terminal propeptide is or comprises the amino acid sequence set forth in SEQ ID NO. 78. In some embodiments, the C-terminal propeptide is an amino acid sequence with at least or about 85%, 90%, 92%, 95%, or 97% sequence identity with SEQ ID NO. 78. In some embodiments, the C-terminal propeptide is or is the amino acid sequence shown in SEQ ID NO. 79. In some embodiments, the C-terminal propeptide exhibits an amino acid sequence with at least or about 85%, 90%, 92%, 95%, or 97% sequence identity to SEQ ID NO. 79. In some embodiments, the C-terminal propeptide is or comprises the amino acid sequence set forth in SEQ ID NO. 80. In some embodiments, the C-terminal propeptide is an amino acid sequence with at least or about 85%, 90%, 92%, 95%, or 97% sequence identity with SEQ ID NO. 80.

In some embodiments, the C-terminal propeptide is or comprises the amino acid sequence of a collagen trimerization domain (e.g., the C-propeptide of human α1 (I) collagen) with an aspartic acid (D) to asparagine (N) substitution at the BMP-1 site, e.g., as shown in SEQ ID NO:68, wherein RA DMutation to RAN. In some embodiments, the C-terminal propeptide is or comprises the amino acid sequence of a collagen trimerization domain (e.g., the C-propeptide of human α1 (I) collagen) with alanine (A) to asparagine (N) substitution at the BMP-1 site, e.g., as shown in SEQ ID NO:69, wherein RAD mutation to RND. In some embodiments, the C-terminal propeptide herein may include a mutated BMP-1 site, e.g., RSAN instead of DDAN. In some embodiments, the C-terminal propeptide herein may include a BMP-1 site, e.g., comprising RAD (e.g.,RADDAN) sequences other than sequences of RANs (e.g., RANDANs) or RNDs (e.g., RNDDAN) (e.g., SEQ ID NO:68 or 69) may be used in the fusion polypeptides disclosed herein. For example, SEQ ID NO 27 (underlined) or a fragment, variant or mutant thereof may be directly or indirectly linked to SEQ ID NO 67 (italics) or a fragment, variant or mutant thereof, e.g., to form the following fusion proteins:

QCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDN PVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEF RVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGI NITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVE KGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPT KLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNL KPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNK CVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQ DVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVAS QSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNR ALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCL GDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLY ENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQI DRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVP AQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPEL DSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKRSANVVRDRDLEVDTTLKSLSQQIENIRSPEG SRKNPARTCRDLKMCHSDWKSGEYWIDPNQGCNLDAIKVFCNMETGETCVYPTQPSVAQKNWYISKNPKDKRHVWFGESMTD GFQFEYGGQGSDPADVAIQLTFLRLMSTEASQNITYHCKNSVAYMDQQTGNLKKALLLQGSNEIEIRAEGNSRFTYSVTVDG CTSHTGAWGKTVIEYKTTKTSRLPIIDVAPLDVGAPDQEFGFDVGPVCFL

in some embodiments, the C-terminal propeptide is or comprises an amino acid sequence that is a fragment of any one of SEQ ID NOS 67-80.

In some embodiments, the C-terminal propeptide may include a sequence comprising a glycine-X-Y repeat sequence wherein X and Y are independently any amino acid, or an amino acid sequence that is at least 85%, 90%, 92%, 95%, or 97% identical thereto, capable of forming an inter-polypeptide disulfide bond and trimerizing a recombinant polypeptide. In some embodiments, X and Y are independently proline or hydroxyproline.

In some cases where the S protein peptide is linked to a C-terminal propeptide to form a recombinant polypeptide, the recombinant polypeptide forms a trimer, thereby forming a homotrimer of the S protein peptide. In some embodiments, the S protein peptide of the trimerized recombinant polypeptide is in a pre-fusion conformation. In some embodiments, the S protein peptide of the trimerized recombinant polypeptide is in a post-fusion conformation. In some embodiments, the confirmation state allows access to different antigenic sites on the S protein peptide. In some embodiments, the antigenic site is an epitope, such as a linear epitope or a conformational epitope. The advantage of having such trimerized recombinant polypeptides is that an immune response can be directed against a wide variety of potential and diverse antigenic sites.

In some embodiments, the trimerized recombinant polypeptide comprises a single recombinant polypeptide comprising the same viral antigen or immunogen. In some embodiments, the trimerized recombinant polypeptide comprises a single recombinant polypeptide, each comprising a viral antigen or immunogen that is different from the other recombinant polypeptides. In some embodiments, the trimerized recombinant polypeptide comprises a single recombinant polypeptide, wherein one of the single recombinant polypeptides comprises a viral antigen or immunogen that is different from the other recombinant polypeptides. In some embodiments, the trimerized recombinant polypeptide comprises a single recombinant polypeptide, wherein two of the single recombinant polypeptide comprise the same viral antigen or immunogen, and the viral antigen or immunogen is different from the viral antigen or immunogen comprised in the remaining recombinant polypeptides.

In some embodiments, the recombinant polypeptide comprises any coronavirus antigen or immunogen described in section I. In some embodiments, the recombinant polypeptide comprises any coronavirus antigen or immunogen as described in section I linked to a C-terminal propeptide of collagen as described herein.

In some embodiments, the immunogen comprises a recombinant SARS-CoV or SARS-CoV-2S ectodomain trimer, e.g., a SARS-CoV-2 delta b.1.617.2 coronavirus S ectodomain trimer, comprising a protomer comprising one or more (e.g., two, e.g., two consecutive) proline substitutions at or near the boundary between the HR1 domain and the central helical domain that stabilize the S ectodomain trimer in a pre-fusion conformation. In some such embodiments, one or more (e.g., two, e.g., two consecutive) proline substitutions in the S ectodomain in the pre-fusion conformation are located between the N-terminus of amino acid 15 of the C-terminal residue of HR1 and the C-terminus of amino acid 5 of the N-terminal residue of the central helix.

In some embodiments, one or more (e.g., two, e.g., two consecutive) proline substitutions stabilize coronavirus (e.g., SARS-CoV or SARS-CoV-2) S ectodomain trimer in a pre-fusion conformation, e.g., SARS-CoV-2 delta b.1.617.2 coronavirus S ectodomain trimer. In some embodiments, the SARS-CoV-2S protein peptide comprises a 986K/987V to 986P/987P mutation.

In some embodiments, the stabilized recombinant coronavirus (e.g., SARS-CoV or SARS-CoV-2) S ectodomain trimer in the pre-fusion conformation includes single-stranded S ectodomain protomers comprising mutations at S1/S2 and/or S2' protease cleavage sites to prevent protease cleavage at these sites. In some embodiments, the SARS-CoV-2S protein peptide comprises a mutation of 685R to 685A. Exemplary protease cleavage sites for various viruses are shown below:

coronavirus	S1/S2, site 1	S1/S2, site 2	S2’
				2019-nCoV	SPRRAR↓SVAS	IAY↓TMS	SKPSKR↓SF
CoV-ZX21	TASILR↓STGQ	IAY↓TMS	SKPSKR↓SF
				Bat-AC45	TASIIR↓STGQ	IAY↓TMS	SKPSKR↓SF
SARS-CoV	TVSLLR↓STGQ	IAY↓TMS	LKPTKR↓SF
				BM48-31	SSTLVR↓SGGH	LAY↓TMS	LKPTKR↓SF
HKU9-1	ADSLPR↓LQLV	VNY↓DPL	GATTYR↓SA
				MERS-CoV	TPRSCR↓SVPG		GSRSAR↓SA
HKUI	SRRKRR↓SISA		CGSSSR↓SF
				HCoV-OC43	KNRRSR↓GAITT		SKASSR↓SA
HCoV-229E	IAVQPR↓NVSYD		SRVAGR↓SA
				HCoV-NL63	IPVRPR↓NSSDN		SRIAGR↓SA

In some embodiments, the protomer of the recombinant coronavirus (e.g., SARS-CoV or SARS-CoV-2) S ectodomain trimer that is stabilized in the pre-fusion conformation by one or more proline substitutions (e.g., 986P/987P substitutions) includes additional modifications for stabilization in the pre-fusion conformation, such as mutations at protease cleavage sites to prevent protease cleavage.

Reference is made to SEQ ID NO:55, the extracellular domain comprises a Signal Peptide (SP) that is removed during cell processing; an N-terminal domain (NTD); receptor Binding Domains (RBDs); one or more S1/S2 cleavage sites; fusion Peptide (FP); an Internal Fusion Peptide (IFP); heptad repeat 1/2 (HR 1/2) and transmembrane domain (TM). Exemplary sources of sequences can be found on ncbi.nlm.nih.gov/nuccore/MN908947.3, ncbi.nlm.nih.gov/nuccore/MN908947, ncbi.nlm.nih.gov/nuccore/MN 908947.2. Additional sequences can be found on ncbi.nlm.nih.gov/genbank/sams-cov-2-seqs/including the complete genome of pneumovirus isolate Hu-1.

In some embodiments, a pre-fusion stable protomer of a SARS-CoV-2S ectodomain trimer, e.g., a SARS-CoV-2 delta b.1.617.2 protomer of a coronavirus S ectodomain trimer, may have a C-terminal residue of NTD, RBD, S1 (at S1/S2 position 1 or S1/S2 position 2), FP, IFP, HR1, HR2, or a C-terminal residue of an ectodomain (which may be linked to, e.g., a trimerization domain or a transmembrane domain). The position numbering of the S protein may vary between SARS-CoV strains, but the sequences can be aligned to define the relevant domains and cleavage sites. It will be appreciated that some residues (e.g., up to 10) on the N-and C-termini of any ectodomain fragment can be removed or modified in the disclosed immunogens without reducing the utility of the S ectodomain trimer as an immunogen.

In some embodiments, the recombinant polypeptide is or comprises an NTD peptide of SARS-CoV or SARS-CoV-2S protein. In some embodiments, the recombinant polypeptide is or comprises an RBD peptide of SARS-CoV or SARS-CoV-2S protein. In some embodiments, the recombinant polypeptides are or include NTD peptides and RBD peptides of SARS-CoV or SARS-CoV-2S protein. In some embodiments, the recombinant polypeptide is or comprises an S1 domain peptide of a SARS-CoV or SARS-CoV-2S protein. In some embodiments, the recombinant polypeptide is or comprises an S2 domain peptide of a SARS-CoV or SARS-CoV-2S protein.

Exemplary SARS-CoV-1S recombinant polypeptides without signal peptide are provided in SEQ ID NO. 26 (1491 aa):

the SARS-CoV-1S recombinant polypeptide can comprise the N-terminal signal peptide provided in SEQ ID NO. 53.

Exemplary SARS-CoV-2S recombinant polypeptides are provided in SEQ ID NO. 1 that are devoid of signal peptide:

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the SARS-CoV-2S recombinant polypeptide can comprise the N-terminal signal peptide provided in SEQ ID NO. 54.

Exemplary SARS-CoV-2S recombinant polypeptides without signal peptide are provided in SEQ ID NO. 85 (1507 aa):

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the SARS-CoV-2S recombinant polypeptide can comprise the N-terminal signal peptide provided in SEQ ID NO. 54 (MFVFLVLLPLVSS).

Exemplary SARS-CoV-2S recombinant polypeptides without signal peptide are provided in SEQ ID NO. 86 (1507 aa):

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Exemplary SARS-CoV-2S recombinant polypeptides without signal peptide are provided in SEQ ID NO. 87 (1507 aa):

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Exemplary SARS-CoV-2S recombinant polypeptides without signal peptide are provided in SEQ ID NO 88 (1507 aa):

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In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 1. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID No. 1, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118 and/or 1176 (amino acid positions with respect to SEQ ID No. 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO 1, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 2. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 2, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID No. 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO 2, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E9837 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 3. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:3, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118 and/or 1176 (amino acid positions with respect to SEQ ID NO: 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO:3, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 4. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 4, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID No. 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO 4, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E9837 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 5. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:5, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID NO: 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO 5, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 6. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 6, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID No. 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO 6, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E9837 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 7. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:7, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID NO: 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO:7, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 8. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 8, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID No. 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO 8, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E9837 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 9. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:9, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID NO: 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO 9, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 10. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID No. 10, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118 and/or 1176 (amino acid positions with respect to SEQ ID No. 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO 10, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E9837 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 11. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:11, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118 and/or 1176 (amino acid positions with respect to SEQ ID NO: 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO. 11, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 12. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:12, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID NO: 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO:12, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 13. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:13, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID NO: 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO 13, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 14. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:14, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID NO: 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO 14, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 15. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:15, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID NO: 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO 15, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E9837 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 16. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 16, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID No. 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO. 16, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 17. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:17, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID NO: 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO 17, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 18. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:18, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID NO: 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO:18, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452R, S N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 19. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 19, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID No. 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO:19, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 20. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:20, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID NO: 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO:20, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 21. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 21, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID No. 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO. 21, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452R, S N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 22. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 22, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID No. 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO. 22, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 23. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 23, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID No. 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO. 23, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 24. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:24, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID NO: 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO:24, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 25. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID No. 25, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions (e.g., 13, 18, 20, 26, 69, 70, 80, 138, 142, 144, 152, 190, 215, 242, 243, 244, 246, 400, 401, 402, 417, 440, 452, 477, 484, 501, 570, 614, 655, 681, 682, 683, 684, 685, 701, 716, 888, 982, 1027, 1118, and/or 1176 (amino acid positions with respect to SEQ ID No. 55), or any combination thereof. In some embodiments, the recombinant polypeptide is or comprises a variant of SEQ ID NO 25, and the variant comprises any one, two, three, four, five or more mutations selected from the group consisting of S13I, L18F, T N, P S, Δ69-70 (ΔHV), D80A, D138Y, G D, Δ144 (ΔY), W152C, R190S, D G, Δ242-244 (ΔLAL), R246I, Δ400-402 (ΔFVI), K417T, K417N, N440K, L452 477N, S477G, E484G, E501, 570G, E614 655G, E681G, E681G, E681G, E682 683G, E685G, E701G, E D, G, E888 982G, E1027 521118H, and V1176F, or any combination thereof.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 26. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO. 26, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions of SEQ ID NO. 26.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 85. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO. 26, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions of SEQ ID NO. 85.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 86. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID No. 86, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions of SEQ ID No. 86.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 87. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID No. 87, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions of SEQ ID No. 87.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 88. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID No. 88, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions of SEQ ID No. 88.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 89. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID No. 89, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions of SEQ ID No. 89.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 90. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID No. 90, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions of SEQ ID No. 90.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 91. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO. 91, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions of SEQ ID NO. 91.

In some embodiments, the recombinant polypeptide is or includes the sequence set forth in SEQ ID NO. 92. In some embodiments, the recombinant polypeptide is or includes an amino acid sequence having at least or about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID No. 92, including sequences comprising substitutions, deletions and/or insertions at one or more amino acid positions of SEQ ID No. 92.

As described above, in some embodiments, the recombinant polypeptides provided herein not only bind to form trimers, but can also aggregate or be aggregated to produce proteins comprising a variety of recombinant polypeptides. In some embodiments, the formed protein has a macrostructure. In some cases, the macrostructures can confer structural stability to the coronavirus antigen or immunogenic recombinant polypeptide, which in turn can provide access to potential antigenic sites capable of promoting an immune response.

In some embodiments, the trimerized recombinant polypeptide aggregates to form a protein comprising a plurality of trimerized recombinant polypeptides. In some embodiments, the plurality of trimerized recombinant polypeptides form a protein having a macrostructure.

In some embodiments, the proteins described herein comprising a plurality of recombinant polypeptides are immunogens. In some embodiments, a protein comprising a plurality of recombinant polypeptides described herein is contained in a nanoparticle. For example, in some embodiments, the protein is directly attached to the nanoparticle, e.g., a protein nanoparticle. In some embodiments, the protein is indirectly linked to the nanoparticle. In some embodiments, the proteins described herein comprising a plurality of recombinant polypeptides are contained in a virus-like particle (VLP).

In some embodiments, provided herein are complexes comprising a recombinant polypeptide selected from the group consisting of SEQ ID NOS: 1-26 and 85-92, or fragments, variants, or mutants thereof, in any suitable combination. In some embodiments, provided herein are complexes comprising a trimer of a recombinant polypeptide selected from the group consisting of SEQ ID NOS: 1-26 and 85-92, or a fragment, variant or mutant thereof, wherein the recombinant polypeptide is trimerized by inter-polypeptide disulfide bonds to form a trimer.

In some embodiments, provided herein are fusion proteins comprising a plurality of recombinant polypeptides, each recombinant polypeptide comprising, from amino to carboxy terminus: a) A first region comprising a portion of a coronavirus spike protein extracellular domain preceding a coronavirus spike protein Receptor Binding Domain (RBD) in a non-chimeric coronavirus spike protein of a first coronavirus; b) A second region comprising a coronavirus spike-protein Receptor Binding Domain (RBD) of a second coronavirus different from the first coronavirus; and C) a C-terminal propeptide of collagen, wherein the C-terminal propeptide of the recombinant polypeptide forms an inter-polypeptide disulfide bond. In some embodiments, the fusion protein further comprises a third region between the second region and the C-terminal propeptide of collagen. In some embodiments, the third region comprises the S1 domain of a third coronavirus, wherein the third coronavirus is the same as or different from the first coronavirus or the second coronavirus. In some embodiments, the third region comprises the S2 domain of a fourth coronavirus, wherein the fourth coronavirus is the same as or different from the first, second, or fourth coronavirus. In some embodiments, the first region comprises an N-terminal domain (NTD) of the first coronavirus. In some embodiments, the first region comprises one or more amino acid residues that are different from the corresponding amino acid residues in the second coronavirus. In some embodiments, the second region comprises one or more amino acid residues that are different from the corresponding amino acid residues in the first coronavirus. In some embodiments, the first and second coronaviruses are different varieties or strains of the same coronavirus. In some embodiments, the first region comprises the NTD of a first coronavirus, the second region comprises the RBD of a second coronavirus, and the first and second coronaviruses are different varieties of SARS-CoV-2. In some embodiments, the first coronavirus and the second coronavirus are independently selected from the group consisting of SARS-CoV-2 viruses of the b.1.1.529, b.1.617.2, b.1.526, b.1.1.143, p.2, b.1.351, p.1, b.1.1.7, b.1.617, and a.23.1 lineages.

In some embodiments, provided herein are trimeric fusion proteins comprising three recombinant polypeptides, each comprising, from amino to carboxy terminus: a) A first region comprising the coronavirus spike-protein N-terminal domain (NTD) of SARS-CoV-2 of b.1.526 lineage; b) A second region comprising the coronavirus spike-protein Receptor Binding Domain (RBD) of SARS-CoV-2 of b.1.351 lineage; and C) a C-terminal propeptide of collagen, wherein the C-terminal propeptide of the recombinant polypeptide forms an inter-polypeptide disulfide bond. In some embodiments, provided herein are trimeric fusion proteins comprising three recombinant polypeptides, each comprising, from amino to carboxy terminus: a) A first region comprising the coronavirus spike-protein N-terminal domain (NTD) of SARS-CoV-2 of b.1.617.2 lineage; b) A second region comprising the coronavirus spike-protein Receptor Binding Domain (RBD) of SARS-CoV-2 of b.1.617.2 lineage or non-b.1.617.2 lineage; and C) a C-terminal propeptide of collagen, wherein the C-terminal propeptide of the recombinant polypeptide forms an inter-polypeptide disulfide bond. In some embodiments, provided herein are trimeric fusion proteins comprising three recombinant polypeptides, each comprising, from amino to carboxy terminus: a) A first region comprising the coronavirus spike-protein N-terminal domain (NTD) of SARS-CoV-2 of b.1.617.2 lineage or non-b.1.617.2 lineage; b) A second region comprising the coronavirus spike-protein Receptor Binding Domain (RBD) of SARS-CoV-2 of b.1.617.2 lineage; and C) a C-terminal propeptide of collagen, wherein the C-terminal propeptide of the recombinant polypeptide forms an inter-polypeptide disulfide bond.

In some embodiments, provided herein are methods for preventing coronavirus infection in a mammal, comprising immunizing a mammal with an effective amount of the fusion protein disclosed herein. In some embodiments, neutralizing antibodies are generated against the first and second coronaviruses in a mammal. In some embodiments, the first and second coronaviruses are different varieties of SARS-CoV-2, and the neutralizing antibodies produced in the mammal neutralize two or more SARS-CoV-2 viruses of the b.1.1.529, b.1.617.2, b.1.526, b.1.1.143, p.2, b.1.351, p.1, b.1.1.7, b.1.617, and a.23.1 lineages. In some embodiments, neutralizing antibodies produced in the mammal neutralize three or more SARS-CoV-2 viruses of the b.1.1.529, b.1.617.2, b.1.526, b.1.1.143, p.2, b.1.351, p.1, b.1.1.7, b.1.617, and a.23.1 lineages. In some embodiments, the method comprises immunizing a mammal with two or more doses of the fusion protein. In some embodiments, the fusion protein is administered with a second booster after one or more doses of immunogen (including spike protein peptides comprising NTD and RBD from the same SARS-CoV-2 variant).

In some embodiments, provided herein are engineered fusion polypeptides derived from or modified from spike (S) glycoproteins of coronaviruses including SARS-CoV-1 and SARS-CoV-2. In some embodiments, the fusion polypeptides disclosed herein can be stabilized in a pre-fusion conformation as compared to a wild-type S protein sequence of a coronavirus. In some embodiments, fusion with the trimerization domain may prevent the S protein peptide in the fusion protein from forming a straight helix (e.g., similar to what happens during membrane fusion). For example, the frozen EM structure of the S-trimer subunit candidate vaccine suggests that it adopts mainly a tightly closed pre-fusion state, unlike the full-length wild-type spike protein, which forms pre-and post-fusion states in the presence of detergent. Ma et aJ Virol (2021) doi:10.1128/JVi.00194-21, incorporated herein by reference in its entirety for all purposes. In some embodiments, the fusion protein may include an altered soluble S sequence with modifications that inactivate the S1/S2 cleavage site; mutations in the corner region between the heptad repeat 1 (HR 1) region and the Central Helix (CH) region, preventing HR1 and CH from forming a straight helix; and/or truncation of the heptad repeat region 2 (HR 2) in addition to stabilizing mutations. In some embodiments, fusion proteins herein may, but need not, include one or more mutations, such as K986G/V987G, K986P/V987P, K986G/V987P or K986P/V987G, which are believed to stabilize the spike protein in a pre-fusion state. In some embodiments, mutations such as K986G/V987G, K986P/V987P, K986G/V987P or K986P/V987G are useful for stabilizing the protein-containing trimerization disclosed herein ^TM Fusion polypeptides of trimerization domains are not necessary.

In some of these embodiments, the mutation that inactivates the S1/S2 cleavage site may comprise a substitution of RRAR (682-685 in SEQ ID NO: 55) with GSAG (SEQ ID NO: 60), and the mutation in the corner region may comprise the double mutation K986G/V987G, K986P/V987P, K986G/V987P or K986P/V987G. In some embodiments, the truncation of HR2 entails deletion of one or more of the residues shown in SEQ ID NO. 65 at the C-terminus of the wild-type soluble S sequence. In some embodiments, the immunogenic polypeptide may further comprise (a) one or more proline or glycine substitutions in the HR1 region that interact with HR2, and/or (b) an insertion of one or more amino acid residues. In some of these embodiments, the immunogenic polypeptide may have one or more substitutions selected from a942P, S943P, A944P, A942G, S943G and a 944G. In some of these embodiments, the insertion may be a G or GS insertion between any of the residues in A942-A944.

The recombinant polypeptides mentioned herein, or fragments, variants or mutants thereof, in any suitable combination, including trimers of recombinant polypeptides selected from the group consisting of SEQ ID NOs 1-26 and 85-92, or fragments, variants or mutants thereof, wherein the recombinant polypeptides trimerize by inter-polypeptide disulfide bonds to form trimers, may be used in the starter and/or booster. Independently, the initial agent and/or any one or more of the boosters may be absent or used as an adjuvant. If an adjuvant is used, optional adjuvants may include: aluminum-containing adjuvants, such as alum and/or aluminum hydroxide-containing adjuvants; an oligonucleotide-containing adjuvant, such as a CpG oligodeoxynucleotide (CpG-ODN) -containing adjuvant; an adjuvant comprising a TLR9 agonist; adjuvants comprising metabolisable oil, alpha-tocopherol, and/or polyoxyethylene sorbitan monooleate (tween-80), for example adjuvants comprising squalene, alpha-tocopherol, and tween-80 and/or Span 85 in the form of an oil in water emulsion; or any one of the adjuvant combinations.

2. Polynucleotide and vector

Also provided are polynucleotides (nucleic acid molecules) encoding the coronavirus antigens or immunogens and recombinant polypeptides provided herein, as well as vectors for genetically engineering cells to express such coronavirus antigens or immunogens and recombinant polypeptides.

In some embodiments, polynucleotides encoding the recombinant polypeptides provided herein are provided. In some aspects, the polynucleotide comprises a single nucleic acid sequence, e.g., a nucleic acid sequence encoding a recombinant polypeptide. In other examples, the polynucleotide comprises a first nucleic acid sequence encoding a recombinant polypeptide, particularly a coronavirus antigen or immunogen, and a second nucleic acid sequence encoding a recombinant polypeptide comprising a different coronavirus antigen or immunogen.

In some embodiments, the polynucleotide encoding the recombinant polypeptide comprises at least one promoter operably linked to control expression of the recombinant polypeptide. In some embodiments, the polynucleotide comprises two, three, or more promoters operably linked to control expression of the recombinant polypeptide.

In some embodiments, for example, when the polynucleotide comprises two or more nucleic acid coding sequences, e.g., sequences encoding recombinant polypeptides comprising different coronavirus antigens or immunogens, at least one promoter is operably linked to control the expression of the two or more nucleic acid sequences. In some embodiments, the polynucleotide comprises two, three, or more promoters operably linked to control expression of the recombinant polypeptide.

In some embodiments, expression of the recombinant polypeptide is inducible or conditional. Thus, in some aspects, the polynucleotide encoding the recombinant polypeptide comprises a conditional promoter, enhancer, or transactivator. In some such aspects, the conditional promoter, enhancer, or transactivator is an inducible promoter, enhancer, or transactivator or is a repressible promoter, enhancer, or transactivator. For example, in some embodiments, inducible or conditional promoters can be used to limit expression of the recombinant polypeptide to a particular microenvironment. In some embodiments, expression driven by an inducible or conditional promoter is modulated by exposure to an exogenous agent (e.g., heat, radiation, or a drug).

Where the polynucleotide comprises more than one nucleic acid sequence encoding a recombinant polypeptide, the polynucleotide may further comprise a nucleic acid sequence encoding a peptide between one or more nucleic acid sequences. In some cases, the nucleic acid located between the nucleic acid sequences encodes a peptide that separates the translation products of the nucleic acid sequences during or after translation. In some embodiments, the peptide comprises an Internal Ribosome Entry Site (IRES), a self-cleaving peptide, or a peptide that causes ribosome jump (skip), such as a T2A peptide.

In some embodiments, polynucleotides encoding recombinant polypeptides are introduced into compositions containing cultured cells (e.g., host cells), such as by retroviral transduction, transfection, or transformation. In some embodiments, this may allow expression (e.g., production) of the recombinant polypeptide. In some embodiments, the expressed recombinant polypeptide is purified.

In some embodiments, a polynucleotide (nucleic acid molecule) provided herein encodes a coronavirus antigen or immunogen as described herein. In some embodiments, a polynucleotide (nucleic acid molecule) provided herein encodes a recombinant polypeptide comprising a coronavirus antigen or immunogen (e.g., coronavirus S protein peptide) as described herein.

Vectors or constructs comprising the nucleic acid molecules as described herein are also provided. In some embodiments, the vector or construct comprises one or more promoters operably linked to a nucleic acid molecule encoding a recombinant polypeptide to drive expression thereof. In some embodiments, the promoter is operably linked to one or more nucleic acid molecules, e.g., nucleic acid molecules encoding recombinant polypeptides containing different coronavirus antigens or immunogens.

In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is a retroviral vector. In some embodiments, the retroviral vector is a lentiviral vector. In some embodiments, the retroviral vector is a gamma-retroviral vector.

In some embodiments, the vector or construct comprises a single promoter that drives expression of one or more nucleic acid molecules of the polynucleotide. In some embodiments, such promoters may be polycistronic (bicistronic or tricistronic, see, e.g., U.S. patent No. 6,060,273). For example, in some embodiments, the transcriptional unit may be engineered to include an IRES (internal ribosome entry site) bicistronic unit that allows for the co-expression of gene products (e.g., encoding different recombinant polypeptides) by messages from a single promoter. In some embodiments, the vectors provided herein are bicistronic, allowing the vector to contain and express two nucleic acid sequences. In some embodiments, the vectors provided herein are tricistronic, allowing the vectors to contain and express three nucleic acid sequences.

In some embodiments, a single promoter directs the expression of RNAs that contain two or three genes (e.g., encoding chimeric signaling receptors and encoding recombinant receptors) in a single Open Reading Frame (ORF) that are separated from each other by a sequence encoding a self-cleaving peptide (e.g., a 2A sequence) or a protease recognition site (e.g., furin). Thus, the ORF encodes a single polypeptide that is processed into a single protein during translation (for 2A) or post-translation. In some cases, peptides (e.g., T2A) can result in synthesis of a ribosome skip (ribosome skip) 2A element C-terminal peptide bond, resulting in separation between the 2A sequence end and the next peptide downstream (see, e.g., de Felipe Genetic Vaccines and Ther.2:13 (2004) and de Felipe et al traffic 5:616-626 (2004), incorporated by reference in their entirety for all purposes). Many 2A elements are known in the art. Examples of 2A sequences that can be used in the methods and nucleic acids disclosed herein include, but are not limited to, 2A sequences from foot and mouth disease virus (F2A), equine rhinitis a virus (E2A), thosea asigna virus (T2A), and porcine teschovirus (porcine teschovirus) -1 (P2A) as described in U.S. patent publication No. 20070116690.

In some embodiments, the vector is comprised in a virus. In some embodiments, the virus is a pseudovirus. In some embodiments, the virus is a virus-like particle. In some embodiments, the vector is contained in a cell. In some embodiments, the virus or cell comprising the vector comprises a recombinant genome.

Immunogenic compositions and formulations

In some embodiments, provided herein are immunogenic compositions comprising trimers of recombinant polypeptides comprising a sequence selected from the group consisting of SEQ ID NOS: 1-26 and 85-92, or a combination of any two or more trimers. In some embodiments, provided herein are immunogenic compositions comprising a trimer of recombinant polypeptides having the sequences set forth in SEQ ID NO. 1. An immunogenic composition as referred to herein comprising a trimer of a recombinant polypeptide selected from the group consisting of SEQ ID NOs 85-92 or fragments, variants or mutants thereof, wherein the recombinant polypeptide trimerizes by inter-polypeptide disulfide bonds to form a trimer, which may be used in an initiator and/or booster. Independently, the initial agent and/or any one or more of the boosters may be absent or used as an adjuvant. If an adjuvant is used, optional adjuvants may include: aluminum-containing adjuvants, such as alum and/or aluminum hydroxide-containing adjuvants; an oligonucleotide-containing adjuvant, such as a CpG oligodeoxynucleotide (CpG-ODN) -containing adjuvant; an adjuvant comprising a TLR9 agonist; adjuvants comprising metabolisable oil, alpha-tocopherol, and/or polyoxyethylene sorbitan monooleate (tween-80), for example adjuvants comprising squalene, alpha-tocopherol, and tween-80 and/or Span 85 in the form of an oil in water emulsion; or any one of the adjuvant combinations.

In some embodiments, a unit dose of the immunogenic composition may comprise from about 10 μg to about 100 μg of SARS-CoV-2 antigen, preferably from about 25 μg to about 75 μg of SARS-CoV-2 antigen, preferably from about 40 μg to about 60 μg of SARS-CoV-2 antigen or about 50 μg of SARS-CoV-2 antigen. In some embodiments, the dose comprises 3 μg of SARS-CoV-2 antigen. In other embodiments, the dose comprises 9 μg of SARS-CoV-2 antigen. In a further embodiment, the dose comprises 30 μg of SARS-CoV-2 antigen.

In some cases, it may be desirable to combine the disclosed immunogens with other pharmaceutical products (e.g., vaccines) that induce protective responses to other agents. For example, a composition comprising a recombinant coronavirus S antigen (e.g., trimer or protein) as described herein may be administered simultaneously (typically alone) or sequentially with other vaccines (e.g., influenza vaccine or varicella zoster vaccine) recommended by the consultation of immunopractice committee (ACIP; cdc.gov/vaccines/ACIP/index.html) against the age group of interest (e.g., infants about one to six months old). Thus, the disclosed immunogens comprising the recombinant coronavirus S antigens described herein can be administered simultaneously or sequentially with vaccines against, for example, hepatitis b (HepB), diphtheria, tetanus and pertussis (DTaP), pneumococci (PCV), haemophilus influenzae type b (Hib), polio, influenza and rotavirus.

Multivalent or combination vaccines provide protection against a variety of pathogens. In some aspects, multivalent vaccines can protect against multiple strains of the same pathogen. In some aspects, the multivalent vaccine is resistant to multiple pathogens, such as the combination vaccine Tdap, which is resistant to tetanus, pertussis, and diphtheria strains. Multivalent vaccines are necessary to minimize the number of immunizations required to confer protection against multiple pathogens or pathogenic strains to reduce management costs and improve coverage. This may be particularly useful, for example, when vaccinating infants or children.

In some embodiments, for example, the vaccine comprising the immunogenic composition described herein is a multivalent vaccine. In some embodiments, the antigenic material for incorporation into the multivalent vaccine composition is derived from a coronavirus strain or type, e.g., as described herein (see, e.g., section one). Antigens for incorporation into multivalent vaccine compositions may be derived from a strain or strains (e.g., between two and five strains) of coronavirus to provide a broader range of protection. In one embodiment, the antigen for incorporation into the multivalent vaccine composition is derived from multiple strains of coronavirus. Other useful antigens include live, attenuated and inactivated viruses, such as inactivated poliovirus (Jiang et al, J.biol. Stand., (1986) 14:103-9), attenuated strains of hepatitis A virus (Bradley et al, J.Med. Virol., (1984) 14:373-86), attenuated measles virus (James et al, N.Engl. J.Med., (1995) 332:1262-6), and epitopes of pertussis virus (e.g., ACEL-IMUNE cell-free DTP, wyeth-Lederle vaccine, and Pediatrics), which are incorporated by reference in their entirety for all purposes.

In some aspects, the vaccines provided herein are universal vaccines. In some embodiments, the universal vaccine is a vaccine that protects against multiple strains of the same virus (e.g., multiple strains of coronavirus). Developing an effective universal coronavirus vaccine would reduce cost and labor, such as using seasonal vaccine formulations, and allow for more robust pandemic prevention.

In some embodiments, the immunogens described herein may be used as an initial agent (primary services), an additional agent (additional dose), and/or a homologous or heterologous enhancer (boost), such as a first agent, a second agent, a third agent, a fourth agent, and/or more. In some embodiments, the immunogens described herein can be used as seasonal vaccines. In some embodiments, the immunogens described herein may be used as a first, second, third, fourth, and/or more dose within five years, four years, three years, two years, one year, and/or six months.

In some aspects, a universal vaccine is a vaccine consisting of multiple epitopes derived from different strains. In some aspects, the universal vaccine consists of a single epitope maintained in different strains. For example, a universal vaccine may be based on relatively conserved domains of the S protein.

Immunogenic compositions comprising the disclosed immunogens (e.g., the disclosed recombinant coronavirus S antigens or nucleic acid molecules encoding the disclosed primordial multimers of the recombinant coronavirus S antigens) and a pharmaceutically acceptable carrier are also provided. In some embodiments, an immunogenic composition comprises a trimerized recombinant polypeptide provided herein and optionally a pharmaceutically acceptable carrier. In some embodiments, an immunogenic composition comprises a trimerized recombinant polypeptide provided herein and disodium hydrogen phosphate, e.g., disodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate, e.g., disodium hydrogen phosphate monohydrate, sodium chloride, and tween 80. In some embodiments, 1.0mL of an aqueous immunogenic composition solution comprises 720 μg of the trimerized recombinant polypeptide provided herein and 0.62mg of disodium hydrogen phosphate dihydrate, 0.62mg of disodium hydrogen phosphate monohydrate, 9.0mg of sodium chloride, and 0.2mg of tween 80. In some embodiments, the immunogenic composition comprises a protein comprising a plurality of trimerized recombinant polypeptides provided herein, and optionally a pharmaceutically acceptable carrier. In some embodiments, an immunogenic composition includes a protein nanoparticle provided herein and optionally a pharmaceutically acceptable carrier. In some embodiments, the immunogenic composition comprises a VLP provided herein and optionally a pharmaceutically acceptable carrier. In some embodiments, an immunogenic composition comprises an isolated nucleic acid provided herein and optionally a pharmaceutically acceptable carrier. In some embodiments, the immunogenic composition includes a carrier provided herein and optionally a pharmaceutically acceptable carrier. In some embodiments, the immunogenic composition comprises a virus provided herein and optionally a pharmaceutically acceptable carrier. In some embodiments, the immunogenic composition comprises a pseudovirus provided herein and optionally a pharmaceutically acceptable carrier. In some embodiments, the immunogenic composition comprises the cells provided herein and optionally a pharmaceutically acceptable carrier. In some embodiments, the immunogenic composition as described herein is a vaccine. In some embodiments, the vaccine is a prophylactic vaccine. In some embodiments, the vaccine is a therapeutic vaccine. In some embodiments, the vaccine is a prophylactic vaccine and a therapeutic vaccine. Such pharmaceutical compositions may be administered to a subject by a variety of modes of administration known to those of ordinary skill in the art, e.g., intramuscular, intradermal, subcutaneous, intravenous, intraarterial, intra-articular, intraperitoneal, intranasal, sublingual, tonsillar, oropharyngeal, or other parenteral and mucosal routes. In several embodiments, the pharmaceutical composition comprising one or more of the disclosed immunogens is an immunogenic composition. Practical methods for preparing the administrable compositions are known or obvious to those skilled in the art and are described in more detail in, for example, remingtons Pharmaceutical Sciences,19th Ed, mack Publishing Company, easton, pa., 1995.

Thus, immunogens described herein, e.g., recombinant coronavirus S antigens, e.g., trimers, proteins, can be formulated with pharmaceutically acceptable carriers to help maintain biological activity while also promoting increased stability during storage within an acceptable temperature range. Potential carriers include, but are not limited to, physiological equilibrium media, phosphate buffered saline, water, emulsions (e.g., oil/water or water/oil emulsions), various types of wetting agents, anti-freeze additives or stabilizers, such as proteins, peptides or hydrolysates (e.g., albumin, gelatin), sugars (e.g., sucrose, lactose, sorbitol), amino acids (e.g., sodium glutamate), or other protective agents. The resulting aqueous solution may be packaged for use as is or lyophilized. The lyophilized formulation is mixed with a sterile solution prior to single or multi-dose administration.

The formulation composition, particularly a liquid formulation, may contain a bacteriostatic agent to prevent or minimize degradation during storage, including but not limited to benzyl alcohol, phenol, m-cresol, chlorobutanol, methyl and/or propyl p-hydroxybenzoates at effective concentrations (typically 1% w/v). Some patients may disable the bacteriostatic agent; thus, the lyophilized formulation may be reconstituted in a solution with or without such ingredients.

The immunogenic compositions of the invention may comprise pharmaceutically acceptable carrier materials required to approximate physiological conditions, such as pH modifiers andbuffers, tonicity adjusting agents, wetting agents and the like, such as sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate and triethanolamine oleate. The immunogenic composition may optionally include an adjuvant to enhance the immune response of the host. Suitable adjuvants are, for example, toll-like receptor (TLR) agonists, alum, alPO ₄ Hydrogels, lipid-a, derivatives or variants thereof, oil emulsions, saponins, neutral liposomes, liposomes containing vaccines and cytokines, nonionic block copolymers and chemokines. Nonionic block polymers containing Polyoxyethylene (POE) and polyoxypropylene (POP) among many other suitable adjuvants well known in the art may be used as adjuvants, such as POE-POP-POE block copolymers, MPL ^TM (3-O-deacylated monophosphoryl lipid A; corixa, hamilton, ind.) and IL-12 (Genetics Institute, cambridge, mass.) (Newman et al 1998,Critical Reviews in Therapeutic Drug Carrier Systems 15:89-142, incorporated by reference in its entirety for all purposes). An advantage of these adjuvants is that they help to stimulate the immune system in a non-specific manner, thereby enhancing the immune response to the pharmaceutical product. In some embodiments, the immunogenic compositions of the invention may include or be administered with more than one adjuvant. In some embodiments, the immunogenic compositions of the invention may include or be administered with two adjuvants. In some embodiments, the immunogenic compositions of the invention may include or be administered with a variety of adjuvants. For example, in some cases, a vaccine, e.g., comprising an immunogenic composition provided herein, can include or be administered in combination with a variety of adjuvants.

Examples of suitable adjuvants for vaccine compositions include, for example, aluminium hydroxide, lecithin, freund's adjuvant, MPL ^TM And IL-1, one or a combination of any of which may be used in combination with a trimer comprising a recombinant polypeptide selected from the group consisting of SEQ ID NOS: 85-92, or a fragment, variant or mutant thereof. In some embodiments, the vaccine compositions or nanoparticle immunogens disclosed herein (e.g., SARS-COV-2 vaccine compositions) can be formulated in controlled or sustained release formulations. This can be done byCompositions containing slow release polymers are either achieved by microcapsule delivery systems or bioadhesive gels. The various pharmaceutical compositions may be prepared according to standard procedures well known in the art.

In some embodiments, immunogenic compositions of the invention comprise a trimer of a recombinant polypeptide selected from the group consisting of SEQ ID NOS 85-92, or fragments, variants or mutants thereof, wherein the recombinant polypeptide is trimerized by inter-polypeptide disulfide bonds to form a trimer, may comprise an adjuvant formulation comprising a metabolizable oil (e.g., squalene) and an alpha-tocopherol (e.g., DL-alpha-tocopherol) in the form of an oil in water emulsion, and polyoxyethylene sorbitan monooleate (Tween-80). In some embodiments, the adjuvant formulation may include from about 2% to about 10% squalene, from about 2% to about 10% alpha-tocopherol (e.g., D-alpha-tocopherol), and from about 0.3% to about 3% polyoxyethylene sorbitan monooleate. In some embodiments, the adjuvant formulation may include about 5% squalene, about 5% tocopherol, and about 0.4% polyoxyethylene sorbitan monooleate. In some embodiments, the immunogenic compositions of the invention may comprise 3O-acylated monophosphate a (3D-MPL) and an adjuvant in the form of an oil in water emulsion comprising a metabolizable oil, alpha-tocopherol, and polyoxyethylene sorbitan monooleate. In some embodiments, the immunogenic compositions of the invention may comprise QS21 (Quillaja saponaria Molina extract: component 21), 3D-MPL and an oil-in-water emulsion, wherein the oil-in-water emulsion comprises a metabolizable oil, alpha-tocopherol, and polyoxyethylene sorbitan monooleate. In some embodiments, the immunogenic compositions of the invention may comprise QS21, 3D-MPL and an oil-in-water emulsion, wherein the oil-in-water emulsion has the following composition: metabolizable oils such as squalene, alpha-tocopherol, and tween-80 and/or Span 85. In some embodiments, the immunogenic compositions of the invention may comprise an adjuvant in the form of a liposome composition.

In some embodiments, immunogenic compositions of the invention comprise a trimer of a recombinant polypeptide selected from the group consisting of SEQ ID NOs 85-92, or fragments, variants or mutants thereof, wherein the recombinant polypeptide forms a trimer by inter-polypeptide disulfide trimerization, may comprise an adjuvant formulation comprising a metabolizable oil (e.g., squalene), alpha-tocopherol, polyoxyethylene sorbitan monooleate (Tween-80), and/or Span 85. In some embodiments, the adjuvant formulation may include about 5% (w/v) squalene, about 5% (w/v) alpha-tocopherol, about 0.5% (w/v) polyoxyethylene sorbitan monooleate, and/or about 0.5% (w/v) Span 85.

In some embodiments, immunogenic compositions of the invention comprise a trimer of a recombinant polypeptide selected from the group consisting of SEQ ID NOs 85-92, or fragments, variants or mutants thereof, wherein the recombinant polypeptide forms a trimer by inter-polypeptide disulfide trimerization, may comprise an adjuvant formulation comprising Quillaja (Quillaja) saponin, cholesterol and a phospholipid, e.g., in the form of a nanoparticle composition. In some embodiments, the immunogenic compositions of the invention may comprise a mixture of separately purified Quillaja saponaria Molina fractions, which are subsequently formulated with cholesterol and phospholipids.

In some embodiments, the immunogenic compositions of the invention comprise a trimer of a recombinant polypeptide selected from the group consisting of SEQ ID NOS: 85-92, or fragments, variants or mutants thereof, wherein the recombinant polypeptide trimerizes by inter-polypeptide disulfide bond to form a trimer, may comprise a polypeptide selected from the group consisting of MF59 ^TM 、Matrix-A ^TM 、Matrix-C ^TM 、Matrix-M ^TM Adjuvants of the group consisting of AS01, AS02, AS03 and AS 04. Alternative adjuvants include O' Hagan et al, the history ofadjuvant:a phoenix that arose from the ashes,Expert Review of Vaccines, DOI:10.1586/ERV.12.140(2013)；/>et al,Development and evaluation of AS03,an Adjuvant System containingα-tocopherol and squalene in an oil-in-water emulsion,Expert Review of Vaccines,11(3),349-366(2012)；Morel et al.,Adjuvant System AS03 containingα- tocopherol modulates innate immune response and leads to improved adaptive immunity, vaccine, doi 10.1016/j.vaccine.2011.01.011 (2011), which is incorporated herein by reference in its entirety for all purposes.

In some embodiments, an immunogenic composition of the invention comprises a trimer of a recombinant polypeptide selected from the group consisting of SEQ ID NOs 85-92, or fragments, variants, or mutants thereof, wherein the recombinant polypeptide is trimerized by inter-polypeptide disulfide bonds to form a trimer, may comprise a toll-like receptor 9 (TLR 9) agonist, wherein the TLR9 agonist is an oligonucleotide 8 to 35 nucleotides in length, comprises an unmethylated cytidine-phospho-guanosine (also known as CpG or cytosine-phospho-guanosine) motif, and the SARS-CoV-2 antigen and oligonucleotide are present in the immunogenic composition in an amount effective to stimulate an immune response against the SARS-CoV-2 antigen in a mammalian subject (e.g., a human subject in need of the SARS-CoV-2 antigen and the oligonucleotide). TLR9 (CD 289) recognizes an unmethylated cytidine-phosphate-guanosine (CpG) motif found in microbial DNA, which can be mimicked using synthetic CpG-containing oligodeoxynucleotides (CpG-ODNs). CpG-ODNs are known to enhance antibody production and stimulate T helper 1 (Th 1) cell responses (Coffman et al, immunity, 33:492-503,2010, incorporated by reference in their entirety for all purposes). The best oligonucleotide TLR9 agonists typically comprise a palindromic sequence of the general formula: 5 '-purine-CG-pyrimidine-3' or 5 '-purine-CG-pyrimidine-CG-3'. U.S. patent No. 6,589,940, which is incorporated herein by reference in its entirety. In some embodiments, the CpG oligonucleotide is linear. In other embodiments, the CpG oligonucleotide is circular or includes a hairpin loop. CpG oligonucleotides can be single stranded or double stranded. In some embodiments, the CpG oligonucleotide may comprise a modification. Modifications include, but are not limited to, modifications of 3'oh or 5' oh groups, modifications of nucleotide bases, modifications of sugar components, and modifications of phosphate groups. Modified bases can be included in the palindromic sequence of a CpG oligonucleotide so long as the modified bases remain the same specificity for their natural complement by Watson-Crick base pairing (e.g., the palindromic portion remains self-complementary). In some embodiments, the CpG oligonucleotide includes a non-classical base. In some embodiments, the CpG oligonucleotide comprises a modified nucleoside. In some embodiments, the modified nucleoside is selected from the group consisting of 2'-deoxy-7-deazaguanosine (2' -deoxy-7-deazaguanosine), 2 '-deoxy-6-thioguanosine, arabino-guanosine (arabinogalactanosine), 2' -deoxy-2 '-substituted-arabino-guanosine, and 2' -O-substituted-arabino-guanosine. CpG oligonucleotides may contain modifications of the phosphate group. For example, in addition to phosphodiester linkages, phosphate modifications include, but are not limited to, methyl phosphonate, phosphorothioate, phosphoramide (bridging or non-bridging), phosphotriester, and phosphorodithioate, and may be used in any combination. Other non-phosphate linkages may also be used. In some embodiments, the oligonucleotide comprises only phosphorothioate backbones. In some embodiments, the oligonucleotide comprises only a phosphodiester backbone. In some embodiments, the oligonucleotide comprises a combination of phosphate linkages in the phosphate backbone, such as a combination of phosphodiester linkages and phosphorothioate linkages. Oligonucleotides with phosphorothioate backbones may be more immunogenic than oligonucleotides with phosphodiester backbones and appear to be more resistant to degradation after injection into a host (Braun et al, J Immunol,141:2084-2089,1988; and Latime et al, mol Immunol, 32:1057-1064,1995, incorporated by reference in their entirety for all purposes). The CpG oligonucleotides of the invention include at least one, two or three internucleotide phosphorothioate linkages. In some embodiments, when a plurality of CpG oligonucleotide molecules are present in a pharmaceutical composition comprising at least one excipient, two stereoisomers of the phosphorothioate linkage are present in the plurality of CpG oligonucleotide molecules. In some embodiments, all internucleotide linkages of the CpG oligonucleotide are phosphorothioate linkages, or in other words, the CpG oligonucleotide has a phosphorothioate backbone.

Any suitable CpG Oligodeoxynucleotide (ODN) or combination thereof may be used as an adjuvant in the present invention. For example, a K-type ODN (also known as type B) encodes multiple CpG motifs on the phosphorothioate backbone. The K-type ODN may be based on the following sequenceThe use of phosphorothioate nucleotides enhances resistance to nuclease digestion compared to natural phosphodiester nucleotides, resulting in a significant increase in vivo half-life. K-type ODN induces pDC differentiation and TNF- α production, and B cell proliferation and IgM secretion. The type D ODN (also referred to as type a) consists of a mixed phosphodiester/phosphorothioate backbone, containing a single CpG motif flanked by palindromic sequences, and with poly G tails (structural motifs that promote concatemer formation) at the 3 'and 5' ends. The D-ODN can be based on the following sequence GGTGCATCGATGCAGGGGGG. The D-type ODN triggers maturation of pDC and secretion of IFN- α, but has no effect on B cells. Type C ODNs are similar to type K, consisting entirely of phosphorothioate nucleotides, but similar to type D ODNs, contain palindromic CpG motifs. The C-type ODN may be based on the following sequenceSuch ODNs stimulate B cells to secrete IL-6 and pDC to produce IFN- α. The P-type ODN contains two palindromic sequences that enable them to form a higher order structure. The P-type ODN may be based on the following sequence P-type ODNs activate B cells and PDC and induce greater IFN- α production compared to C-type ODNs. In this paragraph, bold letters in the ODN sequence indicate self-complementary palindromic, cpG motifs are underlined.

Exemplary CpG ODNs, such as CpG 7909 (5'-TCGTCGTTTTGTCGTTTTGTCGTT-3') and CpG 1018 (5'-TGACTGTGAACGTTCGAGATGA-3'), are known and disclosed in U.S. patent nos. 7,255,868, 7,491,706, 7,479,285, 7,745,598, 7,785,610, 8,003,115, 8,133,874, 8,114,418, 8,222,398, 8,333,980, 8,597,665, 8,669,237, 9,028,845 and 10,052,378; and Bode et al, "CpG DNA as a vaccine adjuvant", expert Rev Vaccines (2011), 10 (4): 499-511, all of which are incorporated herein by reference in their entirety for all purposes.

One or more adjuvants may be used in combination, including but not limited to alum (aluminum salt), waterOil-in-oil emulsions, water-in-oil emulsions, liposomes and microparticles, for example poly (lactide-co-glycolide) microparticles (Shah et al, methods Mol Biol, 1494:1-14,2017, incorporated by reference in their entirety for all purposes). In some embodiments, the immunogenic composition further comprises an aluminum salt adjuvant that adsorbs SARS-CoV-2 antigen. In some embodiments, the aluminum salt adjuvant comprises one or more of the group consisting of amorphous aluminum hydroxy phosphate sulfate, aluminum hydroxide, aluminum phosphate, and aluminum potassium sulfate. In some embodiments, the aluminum salt adjuvant comprises one or both of aluminum hydroxide and aluminum phosphate. In some embodiments, the aluminum salt adjuvant comprises aluminum hydroxide. In some embodiments, a unit dose of the immunogenic composition comprises about 0.25 to about 0.50mg Al ³⁺ Or about 0.35mg Al ³⁺ . In some embodiments, the immunogenic composition further comprises an additional adjuvant. Other suitable adjuvants include, but are not limited to, squalene emulsions in water (e.g., MF59 or AS 03), TLR3 agonists (e.g., poly IC or poly ICLC), TLR4 agonists (e.g., bacterial lipopolysaccharide derivatives such AS monophosphate ester a (MPL), and/or saponins such AS Quil a or QS-21 such AS01 or AS 02), TLR5 agonists (bacterial flagellin), and TLR7, TLR8, and/or TLR9 agonists (imidazoquinoline derivatives such AS imiquimod and requimod) (Coffman et al, immunity,33:492-503,2010, incorporated herein in their entirety for all purposes). In some embodiments, additional adjuvants include MPL and alum (e.g., AS 04). For veterinary use and for the production of non-human animal antibodies, the mitogenic component (intact and incomplete) of Freund's adjuvant may be used.

In some embodiments, a unit dose of an immunogenic composition may include from about 10 μg to about 1000 μg of one or more adjuvants, preferably from about 25 μg to about 500 μg of one or more adjuvants, preferably from about 50 μg to about 300 μg of one or more adjuvants, preferably from about 100 μg to about 250 μg of one or more adjuvants, preferably from about 150 μg to about 225 μg of one or more adjuvants. In some embodiments, a unit dose of the immunogenic composition may comprise from about 10 μg to about 500 μg of aluminum-containing adjuvant, preferably from about 25 μg to about 250 μg of aluminum-containing adjuvant, preferably from about 50 μg to about 125 μg of aluminum-containing adjuvant, preferably about 75 μg of aluminum-containing adjuvant, e.g., alum. In some embodiments, a unit dose of an immunogenic composition may comprise about 10 μg to about 500 μg of a CpG adjuvant, preferably about 25 μg to about 300 μg of a CpG adjuvant, preferably about 50 μg to about 250 μg of a CpG adjuvant, preferably about 75 μg to about 200 μg of a CpG adjuvant, preferably about 100 μg to about 175 μg of a CpG adjuvant, preferably about 150 μg of a CpG adjuvant, such as CpG 1018A. In some embodiments, a unit dose of an immunogenic composition can include about 10 μg to about 500 μg of an aluminum-containing adjuvant and about 10 μg to about 500 μg of a CpG adjuvant. In some embodiments, a unit dose of the immunogenic composition can include about 25 μg to about 250 μg of the aluminum-containing adjuvant and about 25 μg to about 300 μg of the CpG adjuvant. In some embodiments, a unit dose of an immunogenic composition can include about 50 μg to about 125 μg of an aluminum-containing adjuvant and about 50 μg to about 250 μg of a CpG adjuvant. In some embodiments, a unit dose of an immunogenic composition can include about 50 μg to about 100 μg of an aluminum-containing adjuvant and about 75 μg to about 200 μg of a CpG adjuvant. In some embodiments, a unit dose of an immunogenic composition can include about 50 μg to about 100 μg of an aluminum-containing adjuvant and about 100 μg to about 175 μg of a CpG adjuvant. In some embodiments, a unit dose of an immunogenic composition can include about 75 μg to about 100 μg of an aluminum-containing adjuvant, such as Alum, and about 150 μg of a CpG adjuvant, such as CpG 1018A. In some embodiments, a unit dose of an immunogenic composition may comprise about 10 μg to about 100 μg of a SARS-CoV-2 antigen, e.g., any one or several of the SARS-CoV-2S fusion proteins or S-trimers of the invention, e.g., fusion proteins or S-fusion protein trimers comprising a SARS-CoV-2 coronavirus delta (delta, b.1.617.2) variant S protein peptide or fragment, variant or mutant thereof. In some embodiments, a unit dose of the immunogenic composition may comprise about 20 μg to about 75 μg of SARS-CoV-2S fusion protein or S-trimer, preferably about 25 μg to about 60 μg of SARS-CoV-2S fusion protein or S-trimer, or about 30 μg, about 40 μg, about 50 μg of SARS-CoV-2S fusion protein or S-trimer. In some embodiments, a unit dose of the immunogenic composition may include about 3 μg of SARS-CoV-2S fusion protein or S-trimer. In other embodiments, the dose comprises 9 μg SARS-CoV-2S fusion protein or S-trimer. In a further embodiment, the dose comprises 30 μg SARS-CoV-2S fusion protein or S-trimer. In some embodiments, a unit dose of an immunogenic composition can include about 30 μg of SARS-CoV-2S fusion protein or S-trimer, about 75 μg to about 100 μg of aluminum-containing adjuvant, such as Alum, and about 150 μg of CpG adjuvant, such as CpG 1018A.

In some embodiments, the immunogenic composition includes pharmaceutically acceptable excipients including, for example, solvents, fillers, buffers, tonicity adjusting agents and preservatives (Pramanick et al, pharma Times,45:65-77, 2013, incorporated by reference in its entirety for all purposes). In some embodiments, the immunogenic composition can include excipients that act as one or more of solvents, fillers, buffers, and tonicity modifiers (e.g., sodium chloride in saline can serve as both an aqueous carrier and tonicity modifier).

In some embodiments, the immunogenic composition includes an aqueous carrier as a solvent. Suitable carriers include, for example, sterile water, saline, phosphate buffered saline, and Ringer's solution. In some embodiments, the composition is isotonic.

The immunogenic composition may include a buffer. The buffer controls the pH to inhibit degradation of the active agent during processing, storage, and optionally reconstitution. Suitable buffers include, for example, salts comprising acetate, citrate, phosphate or sulfate. Other suitable buffers include, for example, amino acids such as arginine, glycine, histidine, and lysine. The buffer may further comprise hydrochloric acid or sodium hydroxide. In some embodiments, the buffer maintains the pH of the composition in the range of 6 to 9. In some embodiments, the pH is greater than (lower limit) 6, 7, or 8. In some embodiments, the pH is less than (upper limit) 9, 8, or 7. That is, the pH is in the range of about 6 to 9, with the lower limit being less than the upper limit.

The immunogenic composition may include a tonicity modifier. Suitable tonicity adjusting agents include, for example, dextrose, glycerol (glycerin), sodium chloride, glycerol (glycerin), and mannitol.

The immunogenic composition may include a bulking agent. Bulking agents are particularly useful when the pharmaceutical composition is lyophilized prior to administration. In some embodiments, the filler is a protective agent that helps stabilize and prevent degradation of the active agent during freezing or spray drying and/or during storage. Suitable fillers are sugars (mono-, di-and polysaccharides), such as sucrose, lactose, trehalose, mannitol, sorbitol, glucose and raffinose.

The immunogenic composition may include a preservative. Suitable preservatives include, for example, antioxidants and antibacterial agents. However, in a preferred embodiment, the immunogenic composition is prepared under sterile conditions and in a disposable container, and thus need not contain a preservative.

In some embodiments, the composition may be provided as a sterile composition. Pharmaceutical compositions generally comprise an effective amount of the disclosed immunogens and can be prepared by conventional techniques. Generally, the amount of immunogen per dose of immunogenic composition is selected as the amount that induces an immune response without significant adverse side effects. In some embodiments, the composition may be provided in unit dosage form for inducing an immune response in a subject. The unit dosage form comprises a suitable single preselected dose for administration to a subject, or a suitably marked or measured multiple of two or more preselected unit doses, and/or a metering mechanism for administration of the unit doses or multiples thereof. In other embodiments, the composition further comprises one or more adjuvants.

Method of inducing an immune response

In some embodiments, provided herein are methods for generating an immune response to a coronavirus surface antigen in a subject comprising administering to the subject an effective amount of a complex comprising a recombinant polypeptide selected from the group consisting of SEQ ID NOs 1-26 and 85-92, optionally as a primer (primary services), an additional agent (additional dose), and/or a homologous or heterologous enhancer (boost), e.g., a first agent, a second agent, a third agent, a fourth agent, and/or more, optionally the primer, the additional agent, or the heterologous enhancer is used in combination with any one or more of other recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines. In some embodiments, provided herein are methods for generating an immune response to a coronavirus surface antigen in a subject, wherein the surface antigen comprises an S protein or antigenic fragment thereof, and the method comprises administering to the subject an effective amount of a complex comprising a recombinant polypeptide selected from the group consisting of SEQ ID NOs 1-26 and 85-92, optionally as a primary series, additional agent, and/or a homologous or heterologous booster (boost), e.g., a first agent, a second agent, a third agent, a fourth agent, and/or more agent, optionally in combination with any one or more of the primary, additional agent, or heterologous booster, other recombinant subunit vaccine, nanoparticle vaccine, mRNA vaccine, DNA vaccine, adenovirus vector vaccine, and inactivated virus vaccine. In some embodiments, provided herein are methods for generating an immune response to a coronavirus surface antigen in a subject, wherein the surface antigen comprises a sequence selected from the group consisting of SEQ ID NOs 27-66 and 81-84, and the method comprises administering to the subject an effective amount of a complex comprising a recombinant polypeptide selected from the group consisting of SEQ ID NOs 1-26 and 85-92, optionally as an initial agent (primary services), an additional agent (additional dose), and/or a homologous or heterologous booster (boost) such as a first agent, a second agent, a third agent, a fourth agent, and/or more agent, optionally the initial agent, the additional agent, or the heterologous booster is used in combination with any one or more of other recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines. In some embodiments, provided herein are methods for generating an immune response to a coronavirus surface antigen in a subject, wherein the surface antigen comprises an S protein of a coronavirus or an antigenic fragment thereof, and optionally the surface antigen comprises a sequence selected from the group consisting of SEQ ID NOs 27-66 and 81-84 or an antigenic fragment thereof, and the method comprises administering to the subject an effective amount of a complex comprising a recombinant polypeptide comprising a sequence of any one of SEQ ID NOs 85-92, optionally as an initial agent (primary series), an additional agent (additional dose), and/or a homologous or heterologous booster (boost), e.g., a first agent, a second agent, a third agent, a fourth agent, and/or more agent, optionally in combination with any one or more of other recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated vaccines. Optionally, the adjuvants in any of the initial, additional, and/or reinforcing agents may independently include: aluminum-containing adjuvants, such as alum and/or aluminum hydroxide-containing adjuvants; an oligonucleotide-containing adjuvant, such as a CpG oligodeoxynucleotide (CpG-ODN) -containing adjuvant; an adjuvant comprising a TLR9 agonist; adjuvants comprising metabolisable oil, alpha-tocopherol, and/or polyoxyethylene sorbitan monooleate (tween-80), for example adjuvants comprising squalene, alpha-tocopherol, and tween-80 and/or Span 85 in the form of an oil in water emulsion; or any one of the adjuvant combinations.

In some embodiments, provided herein are methods for generating an immune response to a coronavirus surface antigen in a subject, wherein the surface antigen comprises an S protein or antigenic fragment thereof, and the method comprises administering to the subject an effective amount of a complex comprising a recombinant polypeptide comprising a sequence selected from the group consisting of SEQ ID NOs 1-26 and 85-92, or a combination of any two or more of the complexes, optionally as an initial agent and/or as a booster, e.g., a second and/or third booster injection. In some embodiments, the method comprises administering to the subject an effective amount of a complex comprising a recombinant polypeptide comprising the sequences set forth in SEQ ID NO 85, SEQ ID NO 86, SEQ ID NO 87, and/or SEQ ID NO 88. Optionally, the adjuvants in any of the initial and/or booster agents may independently include: aluminum-containing adjuvants, such as alum and/or aluminum hydroxide-containing adjuvants; an oligonucleotide-containing adjuvant, such as a CpG oligodeoxynucleotide (CpG-ODN) -containing adjuvant; an adjuvant comprising a TLR9 agonist; adjuvants comprising metabolisable oil, alpha-tocopherol, and/or polyoxyethylene sorbitan monooleate (tween-80), for example adjuvants comprising squalene, alpha-tocopherol, and tween-80 and/or Span 85 in the form of an oil in water emulsion; or any one of the adjuvant combinations.

The disclosed immunogens (e.g., recombinant coronavirus S antigens, e.g., S-trimers or S proteins described herein, nucleic acid molecules (e.g., RNA molecules) or vectors encoding the protomers of the disclosed recombinant coronavirus S antigens, or protein nanoparticles or virus-like particles comprising the disclosed recombinant coronavirus S antigens) can be administered to a subject to induce an immune response to the corresponding coronavirus S antigens in the subject. In a particular example, the subject is a human. The immune response may be a protective immune response, e.g. a response that inhibits subsequent infection by the corresponding coronavirus. The eliciting of an immune response may also be used to treat or inhibit infections and diseases associated with the corresponding coronavirus.

The subject may be selected for treatment with or at risk of infection with a coronavirus, for example because of exposure to or potential exposure to a coronavirus. Following administration of the disclosed immunogens, the subject may be monitored for infection or symptoms associated with coronaviruses, or both.

Typical subjects to be treated with the therapies and methods of the invention include humans as well as non-human primates and other animals. To identify a subject for prophylaxis or treatment according to the methods of the invention, an acceptable screening method is employed to determine a risk factor associated with a target or suspected disease or disorder, or to determine the status of an existing disease or disorder in the subject. Such screening methods include, for example, routine examination to determine environmental, familial, occupational, and other such risk factors that may be associated with a target or suspected disease or condition, as well as diagnostic methods, such as various ELISA and other immunoassay methods for detecting and/or characterizing coronavirus infection. These and other conventional methods allow a clinician to select a patient in need of treatment using the methods and pharmaceutical compositions of the present invention. In accordance with these methods and principles, the compositions may be administered in accordance with the teachings herein or other conventional methods, as an independent prophylactic or therapeutic regimen, or as a subsequent, adjunctive or coordinated therapeutic regimen of other treatments.

Administration of the disclosed immunogens (e.g., coronavirus S antigens, e.g., trimers, proteins) can be used for prophylactic or therapeutic purposes. When provided prophylactically, the disclosed therapeutic agents are provided prior to any symptoms, e.g., prior to infection. The prophylactic administration of the disclosed therapeutic agents is useful for preventing or ameliorating any subsequent infection. When provided therapeutically, the disclosed therapeutic agents are provided at the beginning of or after the symptoms of the disease or infection, e.g., after the development of symptoms of a coronavirus infection corresponding to the coronavirus S antigen, or after diagnosis of a coronavirus infection. Thus, the therapeutic agent may be provided prior to the intended exposure to the coronavirus in order to attenuate the intended severity, duration, or extent of the symptoms of the infection and/or related disease after exposure to the virus is or is suspected, or after the actual onset of infection.

The immunogens and immunogenic compositions thereof described herein are provided to a subject, preferably a human, in an amount effective to induce or enhance an immune response against a coronavirus S antigen in the subject. The actual dosage of the disclosed immunogens will vary depending upon factors such as the disease sign and particular state of the subject (e.g., age, size, health condition, degree of symptoms, susceptibility factors, etc., of the subject), the time and route of administration, other drugs or treatments administered concurrently, and the particular pharmacology of the composition eliciting the desired activity or biological response in the subject. The dosage regimen may be adjusted to provide the optimal prophylactic or therapeutic response.

Immunogenic compositions comprising one or more of the disclosed immunogens can be used in a coordinated (or prime-boost) vaccination regimen or combination formulation. In certain embodiments, the novel combination immunogenic compositions and the coordinated immunization schemes employ separate immunogens or formulations, each of which is intended to elicit an antiviral immune response, such as an immune response to the coronavirus S antigen. The individual immunogenic compositions that elicit an antiviral immune response may be combined in a single immunization step in a multivalent immunogenic composition that is administered to a subject, or they may be administered separately (in a monovalent immunogenic composition) in a coordinated (or prime-boost) immunization regimen.

There may be several boosters, each of which may be a different disclosed immunogen. In some examples, the enhancer may be the same immunogen as another enhancer or priming agent. The priming and boosting agents can be administered as a single dose or multiple doses, e.g., two, three, four, five, six or more doses can be administered to the subject over days, weeks or months. Multiple strengthening agents may also be performed, such as one to five times (e.g., 1, 2, 3, 4, or 5 strengthening agents) or more. Different doses can be used for a series of consecutive immunizations. For example, a relatively large dose is used in primary immunization followed by a relatively small dose for boosting.

In some embodiments, the booster may be administered about two weeks, about three to eight weeks, or about four weeks after the priming agent, or about several months after priming. In some embodiments, the enhancer may be administered about 5, about 6, about 7, about 8, about 10, about 12, about 18, about 24 months after the priming agent, or more or less time after the priming agent. Additional boosters can also be used periodically at appropriate time points to enhance the "immune memory" of the subject. Suitability of selected vaccine parameters, e.g., formulation, dose, regimen, etc., can be determined by removing aliquots of serum from the subject and determining antibody titers during the immunization program. In addition, the clinical condition of the subject may be monitored to obtain a desired effect, such as preventing infection or ameliorating a disease state (e.g., reducing viral load). If such monitoring indicates that vaccination is suboptimal, additional doses of the immunogenic composition may be used to boost the subject and vaccination parameters may be improved in a manner that is expected to enhance the immune response.

In some embodiments, the prime-boost method may include DNA-primer and protein-boost vaccination protocols for the subject. The method may comprise two or more administrations of the nucleic acid molecule or protein.

For protein therapy, typically, each human dose will include 1-1000 μg of protein, e.g., from about 1 μg to about 100 μg, e.g., from about 1 μg to about 50 μg, e.g., about 1 μg, about 2 μg, about 5 μg, about 10 μg, about 15 μg, about 20 μg, about 25 μg, about 30 μg, about 40 μg, or about 50 μg.

The amount used in the immunogenic composition is selected based on the population of subjects (e.g., infants or elderly). The optimal amounts of the particular ingredients can be determined by standard studies involving observation of antibody titers and other responses in subjects. It is to be understood that a therapeutically effective amount of the disclosed immunogens (e.g., the disclosed recombinant coronavirus S antigen, e.g., the trimer, protein, viral vector, or nucleic acid molecule in an immunogenic composition) can include an amount that is ineffective at inducing an immune response by a single dose administration but effective at multiple doses administration, e.g., in a prime-boost dosing regimen.

After administration of the immunogens disclosed herein, the subject' S immune system typically responds to the immunogenic composition by producing antibodies specific for the coronavirus S protein peptides contained in the immunogen. This response means that an immunologically effective dose is delivered to the subject.

In some embodiments, the subject's antibody response will be determined in the context of evaluating an effective dose/immunization regimen. In most cases, it is sufficient to evaluate the antibody titer in serum or plasma obtained from the subject. The decision as to whether to administer a re-booster vaccination and/or to alter the amount of therapeutic agent administered to the individual may be based at least in part on the antibody titer level. The antibody titer level can be based, for example, on an immunological binding assay that measures the concentration of antibodies in serum that bind to antigens (including, for example, recombinant coronavirus S antigen, e.g., S-trimer).

The method is effective without completely eliminating, reducing or preventing coronavirus infection. For example, eliciting an immune response to coronavirus with one or more of the disclosed immunogens can reduce or inhibit a desired amount of coronavirus infection, such as at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% (elimination or prevention of detectably infected cells) compared to coronavirus infection in the absence of the immunogen. In further examples, coronavirus replication may be reduced or inhibited by the disclosed methods. The method is effective without completely eliminating coronavirus replication. For example, eliciting an immune response with one or more of the disclosed immunogens can reduce the replication of a desired amount of the corresponding coronavirus, e.g., at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% (elimination or prevention of detectable coronavirus replication) compared to the replication of the coronavirus in the absence of the immune response.

In some embodiments, the disclosed immunogens are administered to a subject concurrently with the administration of an adjuvant. In other embodiments, the disclosed immunogens are administered to a subject after administration of an adjuvant and for a sufficient period of time to induce an immune response.

One method of nucleic acid administration is direct immunization with plasmid DNA, for example, with mammalian expression plasmids. Immunization by nucleic acid constructs is well known in the art and is disclosed, for example, in U.S. Pat. No. 5,643,578 (which describes a method of immunizing a vertebrate by introducing DNA encoding a desired antigen to elicit a cell-mediated or humoral response) and U.S. Pat. Nos. 5,593,972 and 5,817,637 (which describe operably linking a nucleic acid sequence encoding an antigen to regulatory sequences capable of expression). U.S. patent No. 5,880,103 describes several methods of delivering nucleic acids encoding immunogenic peptides or other antigens to organisms. The method comprises nucleic acids (or their own synthetic peptides) and immunostimulatory constructs or ISCOMS ^TM Liposome delivery of ISCOMS ^TM Is cholesterol and Quil A ^TM (saponins) spontaneously form a negatively charged cage structure of 30-40nm size after mixing. Using ISCOMS ^TM Delivery vehicles as antigens have generated protective immunity in experimental models of various infections, including toxoplasmosis and EB virus-induced tumors (Mowat and Donachie, immunol. Today 12:383, 1991). It has been found that as low as 1 μg is encapsulated in ISCOMS ^TM The antigen dose in (a) produces a class I mediated CTL response(Takahashi et al, nature 344:873, 1990), incorporated by reference in its entirety for all purposes.

In some embodiments, plasmid DNA vaccines are used to express the disclosed immunogens in a subject. For example, nucleic acid molecules encoding the disclosed immunogens can be administered to a subject to induce an immune response to coronavirus S antigen. In some embodiments, the nucleic acid molecule may be included on a plasmid vector for DNA immunization, such as a pVRC8400 vector (as described in Barouch et al, j. Virol,79,8828-8834,2005, incorporated by reference in its entirety for all purposes).

In another method of immunization with nucleic acids, the disclosed recombinant coronavirus S antigens (e.g., trimers, proteins) can be expressed by an attenuated viral host or vector or bacterial vector. Recombinant vaccinia virus, adeno-associated virus (AAV), herpes virus, retrovirus, cytomegalovirus (cytogmeglo virus) or other viral vectors may be used to express peptides or proteins, thereby eliciting CTL responses. Vaccinia vectors and methods useful in immune planning are described, for example, in U.S. Pat. No. 4,722,848, which is incorporated by reference in its entirety for all purposes. BCG (Bacillus Calmette Guerin) provides another vector for expression of peptides (see Stover, nature 351:456-460,1991, incorporated by reference in its entirety for all purposes).

In one embodiment, the nucleic acid encoding the disclosed recombinant coronavirus S antigen is introduced directly into the cell. For example, the nucleic acid may be loaded onto gold microspheres by standard methods and passed through HELIOS such as Bio-Rad ^TM A gene gun or the like introduces it into the skin. The nucleic acid may be "naked" and consist of a plasmid under the control of a strong promoter. Typically, the DNA is injected into the muscle, but may be injected directly into other sites. The injected dose is generally about 0.5 μg/kg to about 50mg/kg, and typically about 0.005mg/kg to about 5mg/kg (see, e.g., U.S. Pat. No. 5,589,466).

For example, the nucleic acid may be loaded onto gold microspheres by standard methods and passed through HELIOS such as Bio-Rad ^TM A gene gun or the like introduces it into the skin. The nucleic acid may be "naked" and consist of a plasmid under the control of a strong promoter. Typically, the DNA is injected into the muscle, but may be injected directly into other sites. The injected dose is generally about 0.5 μg/kg to about 50mg/kg, and typically about 0.005mg/kg to about 5mg/kg (see, e.g., U.S. Pat. No. 5,589,466).

In another embodiment, mRNA-based immunization protocols can be used to deliver nucleic acids encoding the disclosed recombinant coronavirus S antigens directly into cells. In some embodiments, mRNA-based nucleic acid vaccines can provide an effective alternative to the foregoing methods. mRNA vaccines eliminate the safety issue of DNA integration into the host genome and can be translated directly in the host cell cytoplasm. Furthermore, simple cell-free in vitro synthesis of RNA avoids manufacturing complications associated with viral vectors. Exemplary forms of two RNA-based vaccines that can be used to deliver nucleic acids encoding the disclosed recombinant coronavirus S antigens include conventional non-amplified mRNA immunization (see, e.g., petsch et al, ", protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection," Nature biotechnology,30 (12): 1210-6, 2012) and Self-amplified mRNA immunization (see, e.g., gel et al, ", nonviral delivery of Self-amplifying RNA vaccines," PNAS,109 (36): 14604-14609, 2012;Magini et al, ", self-Amplifying mRNA Vaccines Expressing Multiple Conserved Influenza Antigens Confer Protection against Homologous and Heterosubtypic Viral Challenge," PLoS One,11 (8): e0161193,2016; and Brito et al, ", self-amplifying mRNA vaccines," Adv gene, 89:179-233,2015). All documents in this paragraph are incorporated by reference in their entirety for all purposes.

In some embodiments, administering a therapeutically effective amount of one or more of the disclosed immunogens to a subject can induce a neutralizing immune response in the subject. To assess neutralization activity, serum can be collected from the subject at appropriate time points after immunization of the subject, frozen and stored for neutralization assays. Methods of assaying for neutralizing activity are known to those of ordinary skill in the art and are further described herein, including but not limited to Plaque Reduction Neutralization (PRNT) assays, micro-neutralization assays, flow cytometry-based assays, single cycle infection assays. In some embodiments, a panel of coronavirus pseudoviruses may be used to determine serum neutralization activity.

In some embodiments, the neutralizing immune response induced by the immunogens disclosed herein results in neutralizing antibodies against coronaviruses (e.g., SARS-CoV-2). In some embodiments, the neutralizing antibodies herein bind to a cellular receptor or co-receptor of a coronavirus (e.g., SARS-CoV-2) or a component thereof. In some embodiments, the viral receptor or co-receptor is a coronavirus receptor or co-receptor, preferably a pneumovirus receptor or co-receptor, more preferably a human coronavirus receptor, such as a SARS-CoV-2 receptor or co-receptor. In some embodiments, the neutralizing antibodies herein modulate, reduce, antagonize, alleviate, block, inhibit, eliminate, and/or interfere with at least one coronavirus (e.g., SARS-CoV-2) activity or binding, or coronavirus (e.g., SARS-CoV-2) receptor activity or binding, e.g., SARS-CoV-2 release, SARS-CoV-2 receptor signaling, membrane SARS-CoV-2 cleavage, SARS-CoV-2 activity, SARS-CoV-2 production, and/or synthesis in vitro, in situ, and/or in vivo. In some embodiments, the immunogens disclosed herein induce neutralizing antibodies against SARS-CoV-2 that modulate, reduce, antagonize, alleviate, block, inhibit, eliminate, and/or interfere with the binding of SARS-CoV-2 to the SARS-CoV-2 receptor or co-receptor, such as angiotensin converting enzyme 2 (ACE 2), dipeptidyl peptidase 4 (DPP 4), dendritic cell specific intercellular adhesion molecule-3-capture non-integrins (DC-SIGN) and/or liver/lymph node-SIGN (L-SIGN).

V. products or kits

Also provided are articles of manufacture or kits comprising the provided recombinant polypeptides, proteins, and immunogenic compositions. The article of manufacture may comprise a container, a label on or associated with the container, or a package insert. Suitable containers include, for example, bottles, vials, syringes, test tubes, IV solution bags, and the like. The container may be formed of various materials, such as glass or plastic. In some embodiments, the container has a sterile access port. Exemplary containers include intravenous solution bags, vials, including containers with stoppers that can be pierced by an injection needle. The article of manufacture or kit may further comprise package insert indicating that the composition is useful for treating a particular disorder, such as the disorders described herein (e.g., coronavirus infection). Alternatively, or in addition, the article of manufacture or kit may further comprise another or the same container comprising a pharmaceutically acceptable buffer. It may further comprise other materials such as other buffers, diluents, filters, needles and/or syringes.

The label or package insert may indicate that the composition is used to treat a coronavirus infection in an individual. A label or package insert on or associated with the container may indicate reconstitution and/or instructions for use of the formulation. The label or package insert may further indicate that the formulation is used or intended for subcutaneous, intravenous, or other modes of administration to treat or prevent coronavirus infection in an individual.

In some embodiments, the container contains a composition that is alone or in combination with another composition effective to treat, prevent, and/or diagnose a condition. The article of manufacture or kit may comprise (a) a first container having a composition (i.e., a first agent) contained therein, wherein the composition comprises an immunogenic composition or a protein or recombinant polypeptide thereof; and (b) a second container having a composition (i.e., a second agent) contained therein, wherein the composition comprises another agent, such as an adjuvant or other therapeutic agent, and the article or kit further comprises instructions on a label or package insert for treating a subject with the second agent in an effective amount.

Terminology

Unless otherwise defined, all terms of art, terminology and other technical and scientific terms (term) or terminology) used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or ease of reference, and such definitions contained herein do not necessarily represent substantial differences from what is commonly understood in the art.

The terms "polypeptide" and "protein" are used interchangeably to refer to a polymer of amino acid residues and are not limited to a minimum length. Polypeptides (including provided receptors and other polypeptides, such as linkers or peptides) may include amino acid residues, including natural and/or unnatural amino acid residues. The term also includes post-expression modifications of the polypeptide, such as glycosylation, sialylation, acetylation, and phosphorylation. In some aspects, the polypeptide may comprise modifications to the native (native) or natural (natural) sequence so long as the protein retains the desired activity. These modifications may be deliberate, such as by site-directed mutagenesis, or occasional, such as by mutation of the host producing the protein or by errors due to PCR amplification.

As used herein, a "subject" is a mammal, such as a human or other animal, and is typically a human. In some embodiments, the subject (e.g., patient) to whom the one or more agents, cells, cell populations, or compositions are administered is a mammal, typically a primate, e.g., a human. In some embodiments, the primate is a monkey or ape. The subject may be male or female, and may be of any suitable age group, including infant, juvenile, adolescent, adult and geriatric subjects. In some embodiments, the subject is a non-primate mammal, such as a rodent.

As used herein, "treatment" (and grammatical variants thereof, such as "treatment") or "treatment") refers to the complete or partial amelioration or reduction of a disease, condition, or disorder, or a symptom, adverse effect, or outcome, or phenotype associated therewith. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of a disease, alleviating symptoms, alleviating any direct or indirect pathological consequences of a disease, preventing metastasis, reducing the rate of disease progression, improving or alleviating a disease state, and alleviating or improving prognosis. The term does not mean to cure the disease entirely or to eliminate any symptoms entirely or to affect all symptoms or results.

As used herein, "delay of progression of a disease" refers to delaying, impeding, slowing, stabilizing, inhibiting, and/or delaying the progression of a disease (e.g., cancer). The length of time to delay may vary depending on the history of the disease and/or the individual being treated. In some embodiments, sufficient or significant delay may actually comprise prophylaxis, as the individual will not develop a disease. For example, advanced cancers, such as metastasis, may be delayed in their progression.

As used herein, "preventing" includes providing prophylaxis against disease occurrence or recurrence in a subject who may be susceptible to disease but has not yet been diagnosed with disease. In some embodiments, the provided cells and compositions are used to delay the progression of a disease or to slow the progression of a disease.

As used herein, "inhibiting" a function or activity refers to reducing the function or activity when compared to the same condition other than the condition or parameter of interest or to another condition. For example, cells that inhibit tumor growth reduce the growth rate of a tumor compared to the growth rate of a tumor in the absence of cells.

In the case of administration, an "effective amount" of an agent (e.g., a pharmaceutical formulation, cell, or composition) refers to an effective amount of dosage/amount and period of time required to achieve a desired effect (e.g., therapeutic or prophylactic effect).

A "therapeutically effective amount" of an agent (e.g., a pharmaceutical formulation or cell) refers to an effective amount of a dose and period of time required to achieve a desired therapeutic effect (e.g., for treating a disease, condition, or disorder) and/or a pharmacokinetic or pharmacodynamic effect of the treatment. The therapeutically effective amount can vary depending on factors such as the disease state, age, sex and weight of the subject, the population of cells being administered, and the like. In some embodiments, provided methods involve administering cells and/or compositions in an effective amount (e.g., a therapeutically effective amount).

"prophylactically effective amount" refers to an effective amount of dosage and period of time required to achieve the desired prophylactic effect. Typically, but not necessarily, because a prophylactic dose is administered to a subject at a pre-or early stage of the disease, the prophylactically effective amount will be less than the therapeutically effective amount. In cases where the tumor burden is low, some aspects of the prophylactically effective amount will be greater than the therapeutically effective amount. The vaccine or other agent is in an amount effective to produce a desired response, such as reducing or eliminating signs or symptoms of the disorder or disease, such as pneumonia. For example, this may be an amount necessary to inhibit viral replication or to measurably alter the external symptoms of a viral infection. In general, this amount will be sufficient to measurably inhibit viral (e.g., SARS-CoV-2) replication or infectivity. When administered to a subject, the dosage typically used will reach a target tissue concentration that has been demonstrated to effect inhibition of viral replication in vitro. In some embodiments, an "effective amount" is an amount that treats (including prevents) one or more symptoms and/or underlying causes of any disorder or disease, e.g., for treating a coronavirus infection. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, an effective amount is an amount that prevents the development of one or more signs or symptoms of a particular disease or disorder, such as one or more signs or symptoms associated with a coronavirus infection.

As used herein, the term "antigen" or "immunogen" is used interchangeably to refer to a substance, typically a protein, capable of inducing an immune response in a subject. The term also refers to an immunologically active protein, i.e., capable of eliciting an immune response against a humoral and/or cellular type of the protein upon administration to a subject (either directly or by administering to the subject a nucleotide sequence or vector encoding the protein). The term "vaccine immunogen" is used interchangeably with "protein antigen" or "immunogenic polypeptide" unless otherwise indicated.

The term "conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acids do not encode an amino acid sequence, essentially identical sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For polypeptide sequences, "conservatively modified variants" refers to variants having conservative amino acid substitutions, where the amino acid residue is replaced by another amino acid residue having a side chain with a similar charge. The art has defined families of amino acid residues with side chains having similar charges. These families include those with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

Epitope refers to an antigenic determinant. These are specific chemical groups or peptide sequences on the antigenic molecule, so they elicit a specific immune response, e.g., an epitope is an antigenic region of a B-cell and/or T-cell response. Epitopes can be formed by either contiguous or non-contiguous amino acids juxtaposed by tertiary folding of the protein.

Unless otherwise indicated, fusion proteins are recombinant proteins comprising the amino acid sequences of at least two unrelated proteins linked together by peptide bonds to form a single protein. Thus, it does not comprise a naturally occurring coronavirus surface antigen, i.e., the fusion (F) protein described herein. The unrelated amino acid sequences may be directly linked to each other or they may be linked using a linker sequence. As used herein, a protein is irrelevant if the amino acid sequences of the protein are not normally linked together by peptide bonds in their natural environment (e.g., within a cell). For example, the amino acid sequence of a viral antigen and the amino acid sequence of collagen or procollagen are not typically linked together by peptide bonds.

An immunogen is a protein or a portion thereof that is capable of inducing an immune response in a mammal, such as a mammal infected by or at risk of being infected by a pathogen. Administration of the immunogen may result in protective and/or active immunity against the pathogen of interest.

An immunogenic composition refers to a composition comprising an immunogenic polypeptide that induces a measurable CTL response against a virus expressing the immunogenic polypeptide, or induces a measurable B-cell response (e.g., antibody production) against the immunogenic polypeptide.

Sequence identity or similarity between two or more nucleic acid sequences or two or more amino acid sequences is expressed in terms of identity or similarity between the sequences. Sequence identity can be measured in terms of percent identity; the higher the percentage, the more identical the sequence. Two sequences are "substantially identical" (i.e., 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% identity over a specified region, or over the entire sequence if not specified) when compared and aligned for maximum correspondence by a comparison window or using one of the following sequence comparison algorithms or by manual alignment and visual inspection of the specified region. Alternatively, identity exists over a region of at least about 50 nucleotides (or 10 amino acids) in length, or more preferably over a region of 100 to 500 or 1000 or more nucleotides (or 20, 50, 200 or more amino acids) in length.

A vaccine refers to a pharmaceutical composition that elicits a prophylactic or therapeutic immune response in a subject. In some cases, the immune response is a protective immune response. Typically, vaccines elicit antigen-specific immune responses against antigens of pathogens (e.g., viral pathogens) or cellular components associated with pathological conditions. A vaccine may include a polynucleotide (e.g., a nucleic acid encoding a disclosed antigen), a peptide or polypeptide (e.g., a disclosed antigen), a virus, a cell, or one or more cellular components. In some embodiments, the vaccine or vaccine immunogen or vaccine composition is expressed from the fusion construct and self-assembles into nanoparticles that display the immunogenic polypeptide or protein on the surface.

Viroid particles (VLPs) refer to non-replicable viral capsids derived from any of several viruses. VLPs are typically composed of one or more viral proteins, such as, but not limited to, proteins known as capsids, coatings, envelopes, surfaces and/or envelope proteins, or particle-forming polypeptides derived from these proteins. VLPs may spontaneously form upon recombinant expression of the protein in a suitable expression system. Methods for producing specific VLPs are known in the art. The presence of VLPs following recombinant expression of viral proteins can be detected using conventional techniques known in the art, e.g., by electron microscopy, biophysical characterization, and the like. See, e.g., baker et al (1991) Biophys.J.60:1445-1456; and Hagense et al (1994) J.Virol.68:4503-4505, incorporated by reference in its entirety for all purposes. For example, VLPs may be isolated by density gradient centrifugation and/or identified by characteristic density bands. Alternatively, a cryogenic electron microscope can be performed on a vitrified aqueous sample prepared from the VLP in question, and the image recorded under appropriate exposure conditions.

The term "about" as used herein refers to the usual error range for individual values as readily known to those of skill in the art. References herein to "about/about" a value or parameter include (and describe) embodiments directed to the value or parameter itself.

As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, "a" or "an" means "at least one" or "one or more".

Various aspects of the claimed subject matter are presented herein in a range format. It is to be understood that the description of the range format is merely for convenience and brevity and should not be interpreted as an inflexible limitation on the scope of the claimed subject matter. Accordingly, the description of a range should be considered to have specifically disclosed all possible sub-ranges and individual values within that range. For example, where a range of values is provided, it is to be understood that each intervening value, to the extent that any other stated or intervening value in that stated range, between the upper and lower limit of that range is encompassed within the claimed subject matter, may be independently included in the lower range and subject to any specifically excluded limit in the stated range. If the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the claimed subject matter. This applies to any range of widths.

As used herein, a composition refers to any mixture of two or more products, substances, or compounds (including cells). It may be a solution, suspension, liquid, powder, paste, aqueous, non-aqueous, or any combination thereof.

The term "vector" as used herein refers to a nucleic acid molecule capable of transmitting another nucleic acid to which it is linked. The term includes vectors that are self-replicating nucleic acid structures and that are incorporated into the genome of a host cell into which the vector has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors".

Exemplary embodiment I

Embodiment 1. A protein comprising a plurality of recombinant polypeptides, each recombinant polypeptide comprising a coronavirus SARS-CoV-2 delta (b.1.617.2) surface antigen linked to a C-terminal propeptide of collagen, wherein the C-terminal propeptide of the recombinant polypeptide forms an inter-polypeptide disulfide bond.

Embodiment 2. The protein according to embodiment 1, wherein the coronavirus infection is a SARS-coronavirus 2 (SARS-CoV-2) infection.

Embodiment 3. The protein according to embodiment 1 or 2, wherein the surface antigen comprises a coronavirus spike (S) protein or a fragment or epitope thereof, wherein the epitope is optionally a linear epitope or a conformational epitope, and wherein the protein comprises three recombinant polypeptides.

Embodiment 4. The protein of embodiment 3 wherein the surface antigen comprises a signal peptide, an S1 subunit peptide, an S2 subunit peptide, or any combination thereof.

Embodiment 5. The protein of embodiment 3 wherein the surface antigen comprises a signal peptide, a Receptor Binding Domain (RBD) peptide, a Receptor Binding Motif (RBM) peptide, a Fusion Peptide (FP), a heptad repeat 1 (HR 1) peptide, or a heptad repeat 2 (HR 2) peptide, or any combination thereof.

Embodiment 6. The protein of any of embodiments 3-5, wherein the surface antigen comprises a Receptor Binding Domain (RBD) of an S protein.

Embodiment 7. The protein according to any of embodiments 3-6, wherein the surface antigen comprises the S1 subunit and the S2 subunit of the S protein.

Embodiment 8. The protein according to any of embodiments 3-7, wherein the surface antigen does not comprise a Transmembrane (TM) domain peptide and/or a Cytoplasmic (CP) domain peptide.

Embodiment 9. The protein according to any of embodiments 3-8, wherein the surface antigen comprises a protease cleavage site, wherein the protease is optionally furin (furin), trypsin, factor Xa, thrombin or cathepsin L.

Embodiment 10. The protein according to any of embodiments 3-8, wherein the surface antigen does not comprise a protease cleavage site, wherein the protease is optionally furin (furin), trypsin, factor Xa, thrombin or cathepsin L.

Embodiment 11. The protein according to any of embodiments 1-10, wherein the surface antigen is soluble or not directly bound to a lipid bilayer, such as a membrane or viral envelope.

Embodiment 12. The protein according to any of embodiments 1-11, wherein the surface antigens are the same or different in the recombinant polypeptide of the protein.

Embodiment 13. The protein according to any of embodiments 1-12, wherein the surface antigen is fused directly to the C-terminal propeptide or is linked to the C-terminal propeptide by a linker (e.g., a linker comprising a glycine-X-Y repeat sequence), wherein X and Y are independently any amino acid, and optionally proline or hydroxyproline.

Embodiment 14. The protein according to any of embodiments 1-13, which is soluble or not directly bound to a lipid bilayer, such as a membrane or a viral envelope.

Embodiment 15. The protein according to any of embodiments 1-14, wherein the protein is capable of binding to a cell surface receptor of a subject, optionally wherein the subject is a mammal, e.g., a primate, e.g., a human.

Embodiment 16. The protein of embodiment 15 wherein the cell surface receptor is angiotensin converting enzyme 2 (ACE 2), dipeptidyl peptidase 4 (DPP 4), dendritic cell-specific intercellular adhesion molecule-3-grasping non-integrin (DC-SIGN) or liver/lymph node-SIGN (L-SIGN).

Embodiment 17 the protein according to any one of embodiments 1-16, wherein the C-terminal propeptide is human collagen.

Embodiment 18. The protein according to any of embodiments 1-17, wherein the C-terminal propeptide comprises a C-terminal polypeptide of pro α1 (I), pro α1 (II), pro α1 (III), pro α1 (V), pro α1 (XI), pro α2 (I), pro α2 (V), pro α2 (XI) or pro α3 (XI), or a fragment thereof.

Embodiment 19. The protein according to any of embodiments 1 to 18, wherein the C-terminal propeptide is the same or different in the recombinant polypeptide.

Embodiment 20. The protein according to any of embodiments 1-19, wherein the C-terminal propeptide comprises any one of SEQ ID NOS: 67-80 or an amino acid sequence at least 90% identical thereto, capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

Embodiment 21. The protein according to any of embodiments 1-20, wherein the C-terminal propeptide comprises SEQ ID NO 67 or an amino acid sequence at least 90% identical thereto that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

Embodiment 22. The protein according to any of embodiments 1-20, wherein the C-terminal propeptide comprises SEQ ID NO. 68 or an amino acid sequence at least 90% identical thereto that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

Embodiment 23. The protein according to any of embodiments 1 to 20, wherein the C-terminal propeptide comprises SEQ ID NO 69 or an amino acid sequence at least 90% identical thereto that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

Embodiment 24. The protein according to any of embodiments 1-20, wherein the C-terminal propeptide comprises SEQ ID NO 70 or an amino acid sequence at least 90% identical thereto that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

Embodiment 25. The protein according to any of embodiments 1-20, wherein the C-terminal propeptide comprises SEQ ID NO 71 or an amino acid sequence at least 90% identical thereto that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

Embodiment 26. The protein according to any of embodiments 1-20, wherein the C-terminal propeptide comprises SEQ ID NO 72 or an amino acid sequence at least 90% identical thereto that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

Embodiment 27. The protein according to any of embodiments 1 to 20, wherein the C-terminal propeptide comprises SEQ ID NO 73 or an amino acid sequence at least 90% identical to it that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

Embodiment 28. The protein according to any of embodiments 1-20, wherein the C-terminal propeptide comprises SEQ ID NO 74 or an amino acid sequence at least 90% identical thereto that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

Embodiment 29 the protein according to any one of embodiments 1-20, wherein the C-terminal propeptide comprises SEQ ID NO 75 or SEQ ID NO 76 or an amino acid sequence that is at least 90% identical to it that is capable of forming inter-polypeptide disulfide bonds and trimerizing recombinant polypeptides.

Embodiment 30. The protein according to any of embodiments 1-29, wherein the C-terminal propeptide comprises a sequence comprising a glycine-X-Y repeat sequence linked to the N-terminus of any of SEQ ID NOs 67-80, wherein X and Y are independently any amino acid, and optionally proline or hydroxyproline, or an amino acid sequence that is at least 90% identical thereto, capable of forming an inter-polypeptide disulfide bond and trimerizing a recombinant polypeptide.

Embodiment 31 the protein according to any one of embodiments 1-30, wherein the surface antigen in each recombinant polypeptide is in a pre-fusion conformation or a post-fusion conformation.

Embodiment 32. The protein according to any of embodiments 1 to 31, wherein the surface antigen in each recombinant polypeptide comprises any of SEQ ID NOs 27 to 66 and 81 to 84 or an amino acid sequence at least 80% identical thereto.

Embodiment 33. The protein according to any of embodiments 1 to 32, wherein the recombinant polypeptide comprises any of SEQ ID NOs 1 to 26 and 85 to 92 or an amino acid sequence at least 80% identical thereto.

Embodiment 34. An immunogen comprising the protein of any one of embodiments 1 to 33, optionally for use as a vaccine starter and/or as a booster, e.g. a second and/or third booster injection.

Embodiment 35 a protein nanoparticle comprising the protein of any one of embodiments 1-33, directly or indirectly attached to the nanoparticle, optionally for use as a vaccine starter and/or as a booster, e.g. a second and/or third dose booster injection.

Embodiment 36 a virus-like particle (VLP) comprising a protein of any one of embodiments 1-33, optionally for use as a vaccine starter and/or as a booster, e.g. a second and/or third booster injection.

Embodiment 37 an isolated nucleic acid encoding one, two, three or more of the recombinant polypeptides of the protein according to any one of embodiments 1-33.

Embodiment 38 the isolated nucleic acid of embodiment 37, wherein the polypeptide encoding the surface antigen is fused in frame to a polypeptide encoding a C-terminal propeptide of collagen.

Embodiment 39 the isolated nucleic acid according to embodiment 37 or 38 operably linked to a promoter.

Embodiment 40 the isolated nucleic acid according to any of embodiments 37-39, which is a DNA molecule.

Embodiment 41 the isolated nucleic acid according to any of embodiments 37-39 which is an RNA molecule, optionally an mRNA molecule, e.g.a nucleoside modified mRNA, a non-amplified mRNA, a self-amplified mRNA or a trans-amplified mRNA.

Embodiment 42. A vector comprising an isolated nucleic acid according to any one of embodiments 37-41.

Embodiment 43 the vector according to embodiment 42, which is a viral vector.

Embodiment 44. A virus, pseudovirus or cell comprising the vector according to embodiment 42 or 43, optionally wherein the virus or cell has a recombinant genome.

Embodiment 45 an immunogenic composition comprising a protein, immunogen, protein nanoparticle, VLP, isolated nucleic acid, vector, virus, pseudovirus or cell according to any one of embodiments 1-44 and a pharmaceutically acceptable carrier.

Embodiment 46. A vaccine comprising the immunogenic composition according to embodiment 45 and optionally an adjuvant, wherein the vaccine is optionally a subunit vaccine, and/or optionally wherein the vaccine is a prophylactic and/or therapeutic vaccine, optionally for use as a prime and/or as a booster, e.g. a second and/or third booster injection.

Embodiment 47. The vaccine of embodiment 46, wherein the vaccine comprises a plurality of different adjuvants.

Embodiment 48. A method of producing a protein comprising: expressing an isolated nucleic acid or vector according to any of embodiments 37-43 in a host cell to produce a protein according to any of embodiments 1-33; and purifying the protein.

Embodiment 49. A protein produced by the method of embodiment 48.

Embodiment 50. A method for generating an immune response to a coronavirus surface antigen in a subject comprising administering to the subject an effective amount of the protein, immunogen, protein nanoparticle, VLP, isolated nucleic acid, vector, virus, pseudovirus, cell, immunogenic composition or vaccine of any one of embodiments 1-47 and 49 to generate an immune response.

Embodiment 51. The method according to embodiment 50, for treating or preventing coronavirus infection.

Embodiment 52. The method of embodiment 50 or 51, wherein the generation of an immune response inhibits or reduces coronavirus replication in the subject.

Embodiment 53 the method according to any one of embodiments 50-52, wherein the immune response comprises a cell-mediated response and/or a humoral response, optionally comprising the production of one or more neutralizing antibodies, such as polyclonal antibodies or monoclonal antibodies.

Embodiment 54 the method according to any one of embodiments 50-53, wherein the immune response is directed against a surface antigen of a coronavirus but not against a C-terminal propeptide.

Embodiment 55. The method according to any one of embodiments 50-54, wherein the administration does not result in an increased Antibody Dependence (ADE) in the subject due to prior exposure to one or more coronaviruses.

Embodiment 56. The method according to any one of embodiments 50-55, wherein administration does not result in an Antibody Dependent Enhancement (ADE) in the subject when subsequently exposed to one or more coronaviruses.

Embodiment 57. The method according to any of embodiments 50-56, further comprising a priming step and/or a strengthening step.

Embodiment 58 the method according to any of embodiments 50-57, wherein the administering step is performed by topical, transdermal, subcutaneous, intradermal, oral, intranasal (e.g., intranasal spray), intratracheal, sublingual, buccal, rectal, vaginal, inhalation, intravenous (e.g., intravenous), intraarterial, intramuscular (e.g., intramuscular injection), intracardiac, intraosseous, intraperitoneal, transmucosal, intravitreal, subretinal, intra-articular, periarticular, topical, or applied skin (epikutaneous) administration.

Embodiment 59. The method according to any one of embodiments 50-58, wherein the effective amount is administered in a single dose or a series of doses having one interval or more intervals.

Embodiment 60. The method according to any one of embodiments 50-59, wherein the effective amount is administered in the absence of an adjuvant.

Embodiment 61. The method according to any one of embodiments 50 to 59, wherein the effective amount is administered with an adjuvant or adjuvants.

Embodiment 62. A method comprising administering to a subject an effective amount of a protein according to any one of embodiments 1-33 to produce neutralizing antibodies or neutralizing antisera to coronavirus in the subject.

Embodiment 63 the method according to embodiment 62, wherein the subject is a mammal, optionally a human or non-human primate.

Embodiment 64 the method according to embodiment 62 or 63, further comprising isolating neutralizing antibodies or neutralizing antisera from the subject.

Embodiment 65 the method according to embodiment 64, further comprising administering to the human subject an effective amount of an isolated neutralizing antibody or neutralizing antisera to prevent or treat the coronavirus infection by passive immunization.

Embodiment 66. The method according to any of embodiments 62-65, wherein the neutralizing antibody or neutralizing antiserum comprises a polyclonal antibody directed against a coronavirus surface antigen, optionally wherein the neutralizing antibody or neutralizing antiserum is free or substantially free of antibodies directed against a C-terminal pro-peptide of collagen.

Embodiment 67. The method according to any of embodiments 62-65, wherein the neutralizing antibody comprises a monoclonal antibody directed against a coronavirus surface antigen, optionally wherein the neutralizing antibody is free or substantially free of antibodies directed against a C-terminal propeptide of collagen.

Embodiment 68 the protein, immunogen, protein nanoparticle, VLP, isolated nucleic acid, vector, virus, pseudovirus, cell, immunogenic composition or vaccine of any one of embodiments 1-47 and 49 for use in inducing an immune response to coronavirus and/or treating or preventing coronavirus infection in a subject.

Embodiment 69 the use of a protein, immunogen, protein nanoparticle, VLP, isolated nucleic acid, vector, virus, pseudovirus, cell, immunogenic composition or vaccine according to any one of embodiments 1-47 and 49 for inducing an immune response to coronavirus in a subject and/or for treating or preventing coronavirus infection.

Embodiment 70 the use of a protein, immunogen, protein nanoparticle, VLP, isolated nucleic acid, vector, virus, pseudovirus, cell, immunogenic composition or vaccine according to any one of embodiments 1-47 and 49 for the manufacture of a medicament or prophylactic agent for inducing an immune response to coronavirus in a subject and/or for treating or preventing coronavirus infection.

Embodiment 71. A method for analyzing a sample, comprising: contacting the sample with a protein of any of embodiments 1-33, and detecting binding between the protein and an analyte capable of specifically binding to a coronavirus surface antigen.

Embodiment 72. The method of embodiment 71 wherein the analyte is an antibody, receptor or cell that recognizes a surface antigen.

Embodiment 73. The method according to embodiment 71 or 72, wherein binding indicates the presence of an analyte in the sample, and/or the presence of a coronavirus infection in the subject from which the sample was derived.

Embodiment 74. A kit comprising the protein of any of embodiments 1-33 and a substrate, plate or vial containing or immobilizing the protein, optionally wherein the kit is an ELISA or lateral flow assay kit (lateral flow assay kit).

Exemplary embodiment II

Embodiment 1. A method for preventing coronavirus infection in a mammal, the method comprising immunizing a mammal with an effective amount of a recombinant subunit vaccine comprising a soluble coronavirus SARS-CoV-2 delta (delta, b.1.617.2) surface antigen or fragment, variant or mutant thereof linked by in-frame fusion to a C-terminal portion of collagen to form a disulfide-linked trimeric fusion protein.

Embodiment 2. The method according to embodiment 1, wherein the coronavirus infection is a Severe Acute Respiratory Syndrome (SARS) -coronavirus 2 (SARS-CoV-2) infection.

Embodiment 3. The method according to embodiment 1 or 2, wherein the coronavirus surface antigen comprises a coronavirus spike (S) protein or fragment or epitope thereof.

Embodiment 4. The method according to any of embodiments 1-3, wherein the coronavirus surface antigen comprises a SARS-CoV-2 spike (S) ectodomain peptide or fragment or epitope thereof, optionally the S ectodomain peptide or fragment or epitope thereof comprises a SARS-CoV-2 delta (delta, B.1.617.2) variant S ectodomain peptide or fragment, variant or mutant thereof, e.g., a chimeric sequence comprising a delta variant Receptor Binding Domain (RBD) and a Hu-1 or other variant S protein peptide sequence.

Embodiment 5. The method of any of embodiments 1-4, wherein the coronavirus surface antigen comprises a SARS-CoV-2 spike (S) N-terminal domain (NTD) peptide or fragment or epitope thereof, optionally the NTD peptide is a SARS-CoV-2Hu-1, alpha, beta, gamma, delta, muir, or omimetic NTD peptide or fragment, variant or mutant thereof.

Embodiment 6. The method of any of embodiments 1-5, wherein the coronavirus surface antigen comprises a SARS-CoV-2 spike (S) Receptor Binding Domain (RBD) peptide or fragment or epitope thereof, optionally the RBD peptide is a SARS-CoV-2 delta (delta, B.1.617.2) variant RBD peptide or fragment, variant or mutant thereof.

Embodiment 7. The method of any of embodiments 1-6, wherein the coronavirus surface antigen comprises a SARS-CoV-2 spike (S) S1 peptide or fragment or epitope thereof, optionally the S1 peptide is a SARS-CoV-2 delta (delta, B.1.617.2) variant S1 peptide or fragment, variant or mutant thereof.

Embodiment 8 the method according to any one of embodiments 1-7, wherein the coronavirus surface antigen comprises a SARS-CoV-2 spike (S) S2 peptide or fragment or epitope thereof, optionally the S2 peptide is a SARS-CoV-2 Hu-1, alpha, beta, gamma, delta, muir, or omnikov S2 peptide or fragment, variant or mutant thereof.

Embodiment 9. The method of any of embodiments 1-8, wherein the coronavirus surface antigen comprises a SARS-CoV-2 spike (S) ectodomain peptide or fragment or epitope thereof having a mutation.

Embodiment 10. The method of embodiment 9, wherein the mutation comprises a furin cleavage site mutation, optionally the mutation is a deletion, substitution, or addition of one or more amino acids such that the furin cleavage site no longer has activity as a furin cleavage site, optionally the mutation is located at any one or more of positions 682-685, optionally the mutation comprises 685r→685A.

Embodiment 11. The method according to embodiment 9 or 10, wherein the mutation comprises a mutation at or near the junction of the heptad repeat HR1 and the central helix, optionally the mutation comprises a proline substitution, e.g. 986k→986P and/or 987v→987P.

Embodiment 12. The method of any of embodiments 9-11, wherein the mutation comprises a contiguous amino acid substitution, e.g., 986K→986P and 987V→987P.

Embodiment 13. The method according to any of embodiments 1 to 12, wherein the recombinant subunit vaccine comprises the sequence set forth in any of SEQ ID NOS: 81 to 92 or an amino acid sequence having at least or about 80%, 85%, 90%, 92%, 95%, 97%, 99% sequence identity to the sequence set forth in any of SEQ ID NOS: 81 to 92.

Embodiment 14. The method according to any of embodiments 1 to 13, wherein the recombinant subunit vaccine comprises SEQ ID NO. 85 or an amino acid sequence having at least or about 80%, 85%, 90%, 92%, 95%, 97%, 99% sequence identity to SEQ ID NO. 85.

Embodiment 15. The method according to any of embodiments 1 to 14, wherein the recombinant subunit vaccine comprises SEQ ID NO. 86 or an amino acid sequence having at least or about 80%, 85%, 90%, 92%, 95%, 97%, 99% sequence identity to SEQ ID NO. 86.

Embodiment 16. The method according to any of embodiments 1 to 15, wherein the recombinant subunit vaccine comprises SEQ ID NO. 87 or an amino acid sequence having at least or about 80%, 85%, 90%, 92%, 95%, 97%, 99% sequence identity to SEQ ID NO. 87.

Embodiment 17. The method according to any of embodiments 1 to 16, wherein the recombinant subunit vaccine comprises SEQ ID NO. 88 or an amino acid sequence having at least or about 80%, 85%, 90%, 92%, 95%, 97%, 99% sequence identity to SEQ ID NO. 88.

Embodiment 18. The method according to any of embodiments 1 to 17, wherein the recombinant subunit vaccine comprises the sequence set forth in any of SEQ ID NOS: 89-92 or an amino acid sequence having at least or about 80%, 85%, 90%, 92%, 95%, 97%, 99% sequence identity to the sequence set forth in any of SEQ ID NOS: 89-92.

Embodiment 19. The method according to any of embodiments 1 to 18, wherein the recombinant subunit vaccine comprises SEQ ID NO. 91 or an amino acid sequence having at least or about 80%, 85%, 90%, 92%, 95%, 97%, 99% sequence identity to SEQ ID NO. 91.

Embodiment 20. The method according to any of embodiments 1 to 19, wherein the recombinant subunit vaccine comprises a first sequence according to any of SEQ ID NOS: 81 to 84 linked to a second sequence according to any of SEQ ID NOS: 67 to 80, wherein the C-terminus of the first sequence is directly or indirectly linked to the N-terminus of the second sequence.

Embodiment 21. The method of any one of embodiments 1-20, wherein the recombinant subunit vaccine is administered by intramuscular injection.

Embodiment 22. The method of any of embodiments 1-21, wherein the recombinant subunit vaccine is administered by intranasal spray.

Embodiment 23. The method of any of embodiments 1-22, wherein the recombinant subunit vaccine is administered in a single dose or in a series of doses spaced apart by weeks or months.

Embodiment 24. The method according to any of embodiments 1-23, wherein the recombinant subunit vaccine is administered without an adjuvant, optionally the recombinant subunit vaccine is used as an initial agent (primary services), an additional agent (additional dose), and/or a homologous or heterologous booster (boost) such as a first agent, a second agent, a third agent, a fourth agent, and/or more, optionally the initial agent, the additional agent, or the heterologous booster is used in combination with any one or several of other recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines.

The method according to any one of embodiments 1-24, wherein the recombinant subunit vaccine is administered with an adjuvant, optionally the recombinant subunit vaccine is used as an initial agent (primary services), an additional agent (additional dose), and/or a homologous or heterologous booster (boost dose), e.g., a first agent, a second agent, a third agent, a fourth agent, and/or more agents, optionally the initial agent, the additional agent, or the heterologous booster is used in combination with any one or several of other recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines, optionally the initial agent, the additional agent, and/or the adjuvant in the homologous or heterologous booster may independently comprise: aluminum-containing adjuvants, such as alum and/or aluminum hydroxide-containing adjuvants; an oligonucleotide-containing adjuvant, such as a CpG oligodeoxynucleotide (CpG-ODN) -containing adjuvant; an adjuvant comprising a TLR9 agonist; adjuvants comprising metabolisable oil, alpha-tocopherol, and/or polyoxyethylene sorbitan monooleate (tween-80), for example adjuvants comprising squalene, alpha-tocopherol, and tween-80 and/or Span 85 in the form of an oil in water emulsion; or any one of the adjuvant combinations.

Embodiment 26. The method according to any one of embodiments 1-25, wherein the recombinant subunit vaccine is administered with one or more adjuvants, optionally the recombinant subunit vaccine is used as an initial agent (primary services), an additional agent (additional dose), and/or a homologous or heterologous booster (boost) such as a first agent, a second agent, a third agent, a fourth agent, and/or more agents, optionally the initial agent, the additional agent, or the heterologous booster is used in combination with any one or more of other recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines, optionally the adjuvants in the initial agent, additional agent, and/or homologous or heterologous booster may independently comprise: aluminum-containing adjuvants, such as alum and/or aluminum hydroxide-containing adjuvants; an oligonucleotide-containing adjuvant, such as a CpG oligodeoxynucleotide (CpG-ODN) -containing adjuvant; an adjuvant comprising a TLR9 agonist; adjuvants comprising metabolisable oil, alpha-tocopherol, and/or polyoxyethylene sorbitan monooleate (tween-80), for example adjuvants comprising squalene, alpha-tocopherol, and tween-80 and/or Span 85 in the form of an oil in water emulsion; or any one of the adjuvant combinations.

Embodiment 27. A method for detecting coronavirus antibodies from mammalian serum, the method comprising the step of contacting the serum with a soluble coronavirus SARS-CoV-2 delta (B.1.617.2) surface antigen that is linked to the C-terminal portion of collagen by in-frame fusion to form a disulfide-linked trimeric fusion protein.

Embodiment 28. The method of embodiment 27, wherein the soluble coronavirus surface antigen is an S protein or peptide.

Embodiment 29. A method of using a recombinant subunit vaccine comprising a soluble surface antigen from the coronavirus SARS-CoV-2 delta (b.1.617.2) linked by in-frame fusion to the C-terminal portion of collagen to form a disulfide-linked trimeric fusion protein, the method comprising: immunizing a mammal, purifying the resulting neutralizing antibodies, and using the neutralizing antibodies to treat a patient infected with the coronavirus by passive immunotherapy.

Embodiment 30. The method of embodiment 29, wherein the neutralizing antibody comprises a polyclonal antibody.

Embodiment 31. The method of embodiment 29, wherein the neutralizing antibody is a monoclonal antibody.

Embodiment 32. The method of embodiment 29, wherein the neutralizing antibody is a monoclonal antibody to an S protein or peptide.

Embodiment 33. The method of embodiment 29, wherein the neutralizing antibody is a monoclonal antibody to the S protein of SARS-CoV-2.

Embodiment 34 the method of claim 29 wherein the neutralizing antibody is a monoclonal antibody to SARS-CoV-2 Hu-1, alpha, beta, gamma, delta, muir, omnix and/or other strain S protein.

Embodiment 35. The method of embodiment 29, wherein the neutralizing antibody is a monoclonal antibody to the S protein of SARS-CoV-2 delta (B.1.617.2).

Embodiment 36A complex comprising a recombinant polypeptide selected from the group consisting of SEQ ID NOS: 85-92.

Embodiment 37. A complex comprising a trimer of a recombinant polypeptide selected from the group consisting of SEQ ID NOS: 85-92, wherein the recombinant polypeptide is trimerized by inter-polypeptide disulfide bonds to form a trimer.

Embodiment 38. An immunogenic composition comprising a trimer of a recombinant polypeptide comprising a sequence selected from the group consisting of SEQ ID NOS: 85-92 or a combination of any two or more trimers.

Embodiment 39. The immunogenic composition according to embodiment 38, comprising a trimer of recombinant polypeptides having the sequence set forth in SEQ ID NO. 91.

Embodiment 40. A method for generating an immune response to a coronavirus surface antigen in a subject, the method comprising administering to the subject an effective amount of a complex comprising a recombinant polypeptide selected from the group consisting of SEQ ID NOs 85-92, optionally the complex being used as a primer (primary series), an additional agent (additional dose), and/or a homologous or heterologous booster (boost), e.g., a first agent, a second agent, a third agent, a fourth agent, and/or a further agent, optionally the primer, the additional agent, or the heterologous booster being used in combination with any one or more of other recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines.

Embodiment 41A method for generating an immune response to a coronavirus surface antigen in a subject,

wherein the surface antigen comprises S protein or an antigenic fragment thereof, and

the method comprises administering to the subject an effective amount of a complex comprising a recombinant polypeptide selected from the group consisting of SEQ ID NOs 85-92, optionally as a primer (primary services), an additional agent (additional dose), and/or a homologous or heterologous booster (boost dose), e.g., a first agent, a second agent, a third agent, a fourth agent, and/or more agents, optionally in combination with any one or more of the other recombinant subunit vaccine, nanoparticle vaccine, mRNA vaccine, DNA vaccine, adenoviral vector vaccine, and inactivated viral vaccine.

Embodiment 42. A method for generating an immune response to a coronavirus surface antigen in a subject,

wherein the surface antigen comprises a sequence selected from the group consisting of SEQ ID NOS 27-66 and 81-84, and

Embodiment 43A method for generating an immune response to a coronavirus surface antigen in a subject,

wherein the surface antigen comprises the S protein of a coronavirus or an antigenic fragment thereof, and optionally the surface antigen comprises a sequence selected from the group consisting of SEQ ID NOS 27-66 and 81-84, or an antigenic fragment thereof, and

The method comprises administering to the subject an effective amount of a complex comprising a recombinant polypeptide comprising the sequence of any one of SEQ ID NOs 85-92, optionally the complex is used as an initial agent (primary services), an additional agent (additional dose), and/or a homologous or heterologous booster (boost) such as a first agent, a second agent, a third agent, a fourth agent, and/or more agents, optionally the initial agent, the additional agent, or the heterologous booster is used in combination with any one or more of other recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines.

Embodiment 44. A method for generating an immune response to a coronavirus surface antigen in a subject,

the method comprises administering to the subject an effective amount of a complex or a combination of any two or more complexes comprising a recombinant polypeptide comprising a sequence selected from the group consisting of SEQ ID NOs 85-92, optionally the complex or combination of complexes as an initial agent (primary services), an additional agent (additional dose), and/or a homologous or heterologous booster (boost dose), e.g., a first agent, a second agent, a third agent, a fourth agent, and/or more agents, optionally the initial agent, the additional agent, or the heterologous booster is used in combination with any one or more of other recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines.

Embodiment 45. The method of embodiment 44, wherein the method comprises administering to the subject an effective amount of a complex comprising a recombinant polypeptide comprising the sequences set forth in SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87 and/or SEQ ID NO: 88.

Embodiment 46. A fusion protein comprising a plurality of recombinant polypeptides, each recombinant polypeptide comprising, from amino to carboxy terminus:

a) A first region comprising a portion of a coronavirus spike protein extracellular domain preceding a coronavirus spike protein Receptor Binding Domain (RBD) in a non-chimeric coronavirus spike protein of a first coronavirus;

b) A second region comprising a coronavirus spike-protein Receptor Binding Domain (RBD) of a second coronavirus different from said first coronavirus; and

c) A C-terminal propeptide of collagen, wherein the C-terminal propeptide of the recombinant polypeptide forms an inter-polypeptide disulfide bond, wherein at least one of the first coronavirus and the second coronavirus is SARS-CoV-2 delta (b.1.617.2), optionally the fusion protein is used as a primer (primary services), an additional agent (additional dose), and/or a homologous or heterologous enhancer (boost), such as a first agent, a second agent, a third agent, a fourth agent, and/or a further agent, optionally the primer, the additional agent, or the heterologous enhancer is used in combination with any one or more of other recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines.

Embodiment 47. The fusion protein of embodiment 46, further comprising a third region between the second region and the C-terminal propeptide of the collagen.

Embodiment 48. The fusion protein according to embodiment 47, wherein the third region comprises the S1 domain of a third coronavirus, wherein the third coronavirus is the same as or different from the first coronavirus or the second coronavirus.

Embodiment 49. The fusion protein according to embodiment 47 or 48, wherein the third region comprises the S2 domain of a fourth coronavirus, wherein the fourth coronavirus is the same as or different from the first, second or fourth coronavirus.

Embodiment 50. The fusion protein according to any of embodiments 46-49, wherein the first region comprises the N-terminal domain (NTD) of the first coronavirus.

Embodiment 51. The fusion protein according to any of embodiments 46-50, wherein the first region comprises one or more amino acid residues that are different from the corresponding amino acid residues in the second coronavirus.

Embodiment 2. The fusion protein according to any of embodiments 46-51, wherein the second region comprises one or more amino acid residues different from the corresponding amino acid residues in the first coronavirus.

Embodiment 53. The fusion protein according to any one of embodiments 46-52, wherein the first and second coronaviruses are different variants or strains of the same coronavirus.

Embodiment 54. The fusion protein of embodiment 53, wherein the first region comprises the NTD of the first coronavirus, the second region comprises the RBD of the second coronavirus, and the first and second coronaviruses are different varieties of SARS-CoV-2.

Embodiment 55. The fusion protein according to any of embodiments 46-54, wherein the first coronavirus and the second coronavirus are independently selected from the group consisting of the SARS-CoV-2 viruses of the B.1.1.529, B.1.617.2, B.1.526, B.1.1.143, P.2, B.1.351, P.1, B.1.1.7, B.1.617 and A.23.1 lineages.

Embodiment 56A trimeric fusion protein comprising three recombinant polypeptides, each recombinant polypeptide comprising, from amino to carboxy terminus:

a) A first region comprising the coronavirus spike-protein N-terminal domain (NTD) of SARS-CoV-2 of b.1.617.2 lineage;

b) A second region comprising the coronavirus spike-protein Receptor Binding Domain (RBD) of SARS-CoV-2 of b.1.617.2 lineage; and

c) A C-terminal propeptide of collagen, wherein the C-terminal propeptide of the recombinant polypeptide forms an inter-polypeptide disulfide bond, optionally the fusion protein is used as a starter (primary series), an additional agent (additional dose), and/or a homologous or heterologous enhancer (boost dose), e.g., a first agent, a second agent, a third agent, a fourth agent, and/or more agent, optionally the starter, the additional agent, or the heterologous enhancer is used in combination with any one or more of other recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines.

Embodiment 57. A method for preventing a coronavirus infection in a mammal, the method comprising immunizing a mammal with an effective amount of the fusion protein of any one of claims 46-56.

Embodiment 58. The method of embodiment 57, wherein neutralizing antibodies to the first and second coronaviruses are produced in the mammal.

Embodiment 59. The method of embodiment 58, wherein the first and second coronaviruses are different varieties of SARS-CoV-2, and the neutralizing antibodies produced in the mammal neutralize two or more SARS-CoV-2 viruses of the B.1.1.529, B.1.617.2, B.1.526, B.1.1.143, P.2, B.1.351, P.1, B.1.1.7, B.1.617 and A.23.1 lineages.

Embodiment 60. The method of embodiment 59, wherein the neutralizing antibody produced in the mammal neutralizes three or more SARS-CoV-2 viruses of the B.1.1.529, B.1.617.2, B.1.526, B.1.1.143, P.2, B.1.351, P.1, B.1.1.7, B.1.617 and A.23.1 lineages.

Embodiment 61 the method of any one of embodiments 57-60, comprising immunizing a mammal with two or more doses of the fusion protein, at least one of the two or more doses of the fusion protein comprising a SARS-CoV-2 delta (b.1.617.2) spike protein amino acid sequence, optionally the at least one dose of the fusion protein comprising the sequence of any one of SEQ ID NOs 81-92 or an amino acid sequence having at least or about 80%, 85%, 90%, 92%, 95%, 97%, 99% sequence identity to the sequence of any one of SEQ ID NOs 81-92.

Embodiment 62. The method of any of embodiments 57-61, wherein the fusion protein is administered as a re-booster following one or more doses of an immunogen comprising spike protein peptides comprising NTD and RBD from the same or different SARS-CoV-2 variants, optionally the one or more doses of an immunogen comprising the sequence of any of SEQ ID NOS 27-66 and 81-84 or an amino acid sequence having at least or about 80%, 85%, 90%, 92%, 95%, 97%, 99% sequence identity to the sequence of any of SEQ ID NOS 27-66 and 81-92, optionally the booster fusion protein comprises the sequence of any of SEQ ID NOS 81-92 or an amino acid sequence having at least or about 80%, 85%, 90%, 92%, 95%, 97%, 99% sequence identity to the sequence of any of SEQ ID NOS 81-92.

Examples

The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

Example 1: production of recombinant disulfide-linked SARS-CoV-2S-trimer fusion proteins

A secreted recombinant disulfide-linked polypeptide is produced comprising a SARS-CoV-2 protein peptide fused to a trimerization domain as a candidate protein subunit vaccine. In one embodiment, the extracellular domain of spike protein from SARS-CoV2, including its Signal Peptide (SP), S1 and S2 domains, is fused in-frame at the C-terminus to a mammalian expression vector encoding the human C-propeptide of alpha 1 collagen, such that the secreted trimeric S-trimer fusion antigen is expressed, e.g., as shown in FIGS. 1A-1B.

Protein trimerization is used for rapid expression of S-trimeric antigens ^TM Technique (Liu et al, scientific Reports,7 (1): 8953,2017). cDNA encoding the extracellular domain of SARS-CoV-2 spike (S) protein was subcloned into pTRIMER mammalian expression vector to allow in-frame fusion to protein trimerization ^TM Tag, protein trimerization ^TM The tag is capable of self-trimerization through disulfide bonds. After stable transfection into CHO cells followed by screening of high titer production clones and extensive process optimization, a fed-batch serum-free cell culture process in a bioreactor was developed, resulting in high level expression of S-trimer as secreted protein. Liang et al, nat.Comms.,12:1346, 2021; richmond et al, lancet,397:682-694,2021, incorporated by reference in its entirety for all purposes.

To obtain high purity forms of S-trimer for vaccine research, protein trimerization is utilized ^TM The advantage of high binding affinity between the tag and Endo180 developed an affinity purification scheme, endo180 being a collagen receptor capable of binding to the C-terminal region of type 1 procollagen and maturing the collagen. Endo180-Fc fusion proteins were loaded onto a protein A column and captured by the resin through high affinity binding between protein A and the human IgG1 Fc domain of Endo 180-Fc. Serum-free cell culture medium containing S-trimer secreted by CHO cells was then loaded onto a protein a column with pre-captured Endo 180-Fc. After washing away any unbound contaminating Host Cell Proteins (HCP) and other impurities, bound S-trimer is purified to near homogeneity in one step using mild salt elution without isolating Endo180-Fc from the protein a column. The S-trimer is further purified by low pH for prophylactic Viral Inactivation (VI), anion exchange chromatography to remove host cell DNA and any residual endotoxin, nanofiltration as a prophylactic Viral Removal (VR) step, and final UF/DF to concentrate the S-trimer to the desired concentration in the formulation buffer, thereby obtaining the active Drug (DS) of the S-trimer subunit candidate vaccine. Stability analysis of the purified S-trimer showed that the S-trimer was stable in liquid solution formulations at 2-8deg.C.

SDS-PAGE analysis under non-reducing and reducing conditions confirmed that the purified S-trimer was disulfide-linked trimer and was partially cleaved at the S1/S2 boundary by furin produced by CHO cells. Under non-reducing conditions, S-trimer occurs in a variety of high molecular weight forms, possibly as a result of partial cleavage of antigen, releasing non-covalently linked and cleaved S1 during sample processing.

Production and characterization of spike antigens based on Hu-1 and VOC strains

By protein trimerisation ^TM The technology (Liang et al, nat. Comms.,12:1346, 2021) produces spike antigen covalent trimers based on Hu-1 and VOC strains. High level expression of the S-trimer fusion protein is shown in FIG. 2. S-trimer expression in fed-batch serum-free CHO cell cultures was analyzed by 8% SDS-PAGE in a 10L bioreactor. 10. Mu.L of cell-free conditioned medium from day 9 to day 13 was analyzed under reducing conditions and then subjected to Coomassie brilliant blue staining. FIG. 3A shows a sample and control reduction SDS-PAGE Coomassie brilliant blue staining analysis of the delta S-trimer purification process and FIG. 3B shows a SEC-HPLC purity analysis, the delta S-trimer purity being 97.22%.

The binding affinity of purified S-trimer antigen to human ACE2 receptor was assessed by Fortebio BioLayer interferometry using a protein a sensor. In FIGS. 4A-4B, the delta S-trimer has a higher receptor affinity for ACE2-Fc than the Hu-1S-trimer.

Example 2: immunogenicity of SARS-CoV-2 vaccine containing adjuvant

Immunogenicity of S-trimer in BALB/c mice was assessed. In a two dose prime-boost regimen (day 0 and day 21), mice were injected with S-trimer twice intramuscularly. The effect of the adjuvant on humoral immunogenicity is evident, as at the corresponding antigen dose level, the S-trimer binding antibody titres, ACE2 competitive titres and neutralizing antibody titres of the adjuvanted group are significantly higher than for the unadjuvanted vaccine. S-trimers with different adjuvants elicit ACE 2-competitive and pseudovirus-neutralizing antibody titers similar to or higher than those observed in human convalescent serum samples. Similar results were observed in S-trimer immunized rats.

S-trimer antigen specific Cell Mediated Immunity (CMI) was studied by collecting splenocytes from immunized mice that were sacrificed, then stimulated with S-trimer antigen and assayed for Th1 (IL-2 and IFNγ) and Th2 (IL-4 and IL-5) cytokines by ELISPot. The adjuvanted group appears to induce a stronger overall CMI response than the unadjuvanted S-trimer. A Th 1-biased cell-mediated immune response was observed in the non-adjuvanted and some adjuvanted S-trimer groups, whereas a mixed Th1-Th2 distribution was observed in the other adjuvanted groups. CMI appears to be independent of antigen dose.

Pseudovirus neutralization assay

SARS-CoV-2 pseudovirus neutralization assays were performed on Hu-1 strains and variant strains. To evaluate the neutralizing activity of the antiserum against SARS-CoV-2 pseudovirus, the sample was first heat-inactivated for 30 minutes and serially diluted (3-fold) to an equivalent of 650TCID ₅₀ Pseudoviruses were incubated at 37℃for 1 hour, while using virus alone (positive control) and cells alone (negative control). Fresh, trypsinized ACE2 over-expressing-293 cells were then added to each well at 20000 cells/well. At 5% CO ₂ After incubation for 24 hours at 37℃in an incubator, the cells were lysed according to the manufacturer's protocol and luciferase activity was determined by a luciferase assay system (Beyotime). EC of a given serum sample ₅₀ Neutralizing antibody titer was defined as the reciprocal of the dilution in which the samples showed a 50% reduction in Relative Light Units (RLU) compared to the virus control wells alone. FIG. 5 shows BALB/c mouse SARS-CoV-2Hu-1, alpha (alpha, B.1.1.7), beta (beta, B.1.351), gamma (gamma, P.1), delta (delta, B.1.617.2), mu (mu, B.1.621) and Omicro (O, B.1.1.529) strain pseudovirus neutralizing antibodies EC ₅₀ Data.

Splenocyte stimulation and ELISpot assay

To detect antigen-specific T-cell responses, th1 cytokines (IFN-. Gamma., IL-2) and Th2 cytokines (IL-4, IL-5) were measured using the ELISPot kit (Mabtech) according to the manufacturer's instructions. At 2 weeks after the third immunization, spleen cells of immunized mice or PBMCs of immunized mice were collected. 5X 10 in vitro stimulation with 2. Mu.g/mL SARS-CoV-2Hu-1 S1 peptide library, hu-1 S2 peptide library ⁵ Spleen cells (96 well plate). Phorbol 12-myristate 13-acetate (PMA) and ionomycin were added as non-specific stimuli to positive control wells, while negative control wells received no stimulus. Incubation for 24-48 hoursAfter that, the ELISPot kit and biotinylated detection antibody in SA-ALP/SA-HRP were added. Spots were formed by adding BCIP/NBT or AEC substrate solutions and developed after incubation in the dark for 5-30 minutes. IFN-. Gamma., IL-2, IL-4 and IL-5 Spot Forming Cells (SFCs) were counted using an automated ELISPot reader (CTL). Fig. 6A shows ELISpot results (n=8/group mean) of Hu-1 strain S1 peptide library stimulation. Fig. 6B shows ELISpot results (n=8/group mean) of Hu-1 strain S2 peptide library stimulation. The vertical axis is the number of ELISpot per 25 ten thousand splenocytes.

Example 3: immunogenicity of delta strain-based SARS-CoV-2 vaccine

Construction and production of pseudoviruses

The SARS-CoV-2 variant spike protein (S) gene is optimized with mammalian codon, synthesized by Genscript and cloned into pcDNA3.1 (+) eukaryotic expression vector. Plasmids encoding the S glycoproteins of the SARS-CoV-2 variant strains Hu-1, alpha (Alpha ), beta (Beta ), gamma (gamma ), delta (delta ), muu (mu, mu), and Omicron (Omicron ) were constructed. Lentiviral packaging plasmid psPAX2 and pLVX-AcGFP-N1-Fluc lentiviral reporter plasmid expressing GFP and luciferase were from HororGene (Ornogen, china). Pseudoviruses were generated by co-transfecting HEK 293T cells with psPAX2, pLVX-AcGFP-N1-Fluc and plasmids encoding the various S genes using Lipofectamine 3000 (Invitrogen, L3000-015). Supernatants were harvested 24.+ -. 2 hours after transfection, centrifuged at 1500rpm for 5 minutes to remove cell debris and then stored at-80 ℃. Pseudovirus reservoirs were titrated by infection of 293T-ACE2 cells, and incubated at 37℃with 5% CO by addition of Bright-Glo luciferase assay System (Promega, E2650) ₂ After an incubation period of 44 to 48 hours under conditions, luciferase activity was measured using a microplate reader (TECAN, spark). Then according to Reed-Muench method Quantification of SARS-CoV-2 neutralizing antibody by a pseudotyped virus based assay.Nie J.et al.DOI 10.21203/rs.3.Pex-941/v11, incorporated by reference in its entirety for all purposes) calculates the TCID of a pseudovirus ₅₀ 。

Neutralization test

An aliquot of the test serum sample was first heat inactivated at 56 ℃ for 30 minutes and then centrifuged at 10,000rcf for 5 minutes for clarification. Serial dilution (3-fold) of the sample with detection medium (100 ml), with 650TCID ₅₀ The pseudoviruses (50 ml) of (i) were incubated at 37 ℃ for 1 hour while using untreated controls (virus alone) and cells alone (background control) for virus infection. Fresh, trypsinized 293T-ACE2 cells were then added to each well at 20000 cells/well of 100 mcL. After incubation at 37℃for 44 to 48 hours in a 5% CO2 incubator at 37℃cells were lysed and luciferase activity was determined by the Bright-Glo luciferase assay system (Promega) according to the manufacturer's protocol. IC for a given serum sample ₅₀ Neutralizing antibody titer was defined as serum dilution, where the samples showed a 50% reduction in Relative Light Units (RLU) compared to virus infected control wells. Detailed method is based onQuantification of SARS-CoV-2 neutralizing antibody by a pseudotyped virus based assay.Nie J.et al.DOI 10.21203/rs.3.Pex-941/v 11.

Expression and purification of high-interest Variant (VOC) S-trimer fusion proteins

cDNA encoding the extracellular domain of the delta-derived SARS-CoV-2 spike (S) protein was genosynthesized by GenScript using a codon of Cricetulus griseus (Chinese hamster) preference. The cDNA was subcloned into pTRIMER expression vector (GenHunter) at HindIII and Bgl II sites to allow fusion of soluble S protein in frame to protein trimerization ^TM Tags (amino acid residues 1156-1406 from human type I (alpha) collagen), as described previously. Expression vectors were transiently transfected into HEK-293F cell line (cover Biopharma) using PEI (Polyscience) and grown in OPM-293CD05 medium (OPM) and OPM-293pro feed supplement (OPM). Protein trimerization ^TM The S-trimer protein was purified to homogeneity from the conditioned medium by a tag-specific affinity column (cover Biopharma).

Results

Protein trimerization based on the delta (b.1.617.2) strain was constructed and produced ^TM Tag subunit vaccine and was administered as a third dose boost vaccine to Hu-1S-trimer vaccine primed/boosted mice, compared to other VOC candidate vaccines to observe its ability to further boost the broad coverage of neutralizing antibodies. BALB/c mice (females) were first immunized with two doses of Hu-1S-trimer vaccine (3 μg) adjuvanted with CpG (150 μg) plus Alum (75 μg) intramuscular Injection (IM) on study day 0 and day 21. The mice were then divided into 3 groups (10 per group) on day 57, either as a control group without boosting (group 1), or with 3 μg of different candidate vaccines, including Hu-1S-trimer (group 2), delta S-trimer vaccine (group 3), all with CpG (150 μg) plus Alum (75 μg) as adjuvant. Serum was collected before dose 3 boosting (D56, D-1PD 3) and 14 days after dose 3 (D71, D14 PD 3) and tested for neutralizing antibodies against multiple variant pseudoviruses.

The delta candidate vaccine (group 3) significantly enhanced neutralizing antibodies to Hu-1, beta, gamma, delta, and omnikom VOCs, including omnikom (12.1 fold enhancement) (fig. 7A-7G). Enhancement of neutralizing antibody titers and widths (neutralizing antibody breadth) were also observed in the Hu-1S-trimer group (group 2) with Alum/CpG as an adjuvant. The enhancement of neutralizing antibodies to certain VOCs (Hu-1, alpha, delta, and Omikovia) by the complete adjuvant Hu-1S-trimer (group 2) was not apparent. This may be due to the shorter time interval (36 days) between the last two doses of vaccination, resulting in insufficient time to generate more memory responses.

The present invention is not intended to be limited in scope to the particular disclosed embodiments, which are provided, for example, to illustrate various aspects of the invention. Various modifications to the compositions and methods will be apparent from the description and teachings herein. Such changes may be made without departing from the true scope and spirit of the invention and are intended to fall within the scope of the invention.

Sequence(s)

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SEQUENCE LISTING

<110> Sichuan clover biopharmaceutical Co., ltd

<120> coronavirus vaccine compositions, methods and uses thereof

<130> SCB-13.0CN

<140> 2022102942223

<141> 2022-03-24

<160> 92

<170> PatentIn version 3.5

<210> 1

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 1

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

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

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 2

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 2

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

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

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 3

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 3

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

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

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 4

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 4

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

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

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 5

<211> 836

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 5

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

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

515 520 525

Gly Leu Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly

530 535 540

Asp Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

545 550 555 560

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro

565 570 575

Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp

580 585 590

Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu Lys

595 600 605

Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser Arg

610 615 620

Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His Ser Asp

625 630 635 640

Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly Cys Asn Leu

645 650 655

Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu Thr Cys Val

660 665 670

Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp Tyr Ile Ser Lys

675 680 685

Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly Glu Ser Met Thr Asp

690 695 700

Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly Ser Asp Pro Ala Asp Val

705 710 715 720

Ala Ile Gln Leu Thr Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln

725 730 735

Asn Ile Thr Tyr His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln

740 745 750

Thr Gly Asn Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile

755 760 765

Glu Ile Arg Ala Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr Val

770 775 780

Asp Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

785 790 795 800

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala Pro

805 810 815

Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro

820 825 830

Val Cys Phe Leu

835

<210> 6

<211> 979

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 6

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

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

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Ser Asn Gly

660 665 670

Leu Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

675 680 685

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro

690 695 700

Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro

705 710 715 720

Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp Ala

725 730 735

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

740 745 750

Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser Arg Lys

755 760 765

Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His Ser Asp Trp

770 775 780

Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly Cys Asn Leu Asp

785 790 795 800

Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu Thr Cys Val Tyr

805 810 815

Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp Tyr Ile Ser Lys Asn

820 825 830

Pro Lys Asp Lys Arg His Val Trp Phe Gly Glu Ser Met Thr Asp Gly

835 840 845

Phe Gln Phe Glu Tyr Gly Gly Gln Gly Ser Asp Pro Ala Asp Val Ala

850 855 860

Ile Gln Leu Thr Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn

865 870 875 880

Ile Thr Tyr His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr

885 890 895

Gly Asn Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu

900 905 910

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

915 920 925

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr

930 935 940

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

945 950 955 960

Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro Val

965 970 975

Cys Phe Leu

<210> 7

<211> 837

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 7

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

1 5 10 15

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

20 25 30

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

35 40 45

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

50 55 60

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

65 70 75 80

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

85 90 95

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

100 105 110

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

115 120 125

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

130 135 140

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

145 150 155 160

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

165 170 175

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

180 185 190

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

195 200 205

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

210 215 220

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

225 230 235 240

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

245 250 255

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

260 265 270

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

275 280 285

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

290 295 300

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

305 310 315 320

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

325 330 335

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

340 345 350

Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

355 360 365

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

370 375 380

Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly

385 390 395 400

Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His

405 410 415

Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr

420 425 430

Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val

435 440 445

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

450 455 460

Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp

465 470 475 480

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

485 490 495

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

500 505 510

Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser

515 520 525

Asn Gly Leu Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr

530 535 540

Gly Asp Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly

545 550 555 560

Pro Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

565 570 575

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn

580 585 590

Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu

595 600 605

Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser

610 615 620

Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His Ser

625 630 635 640

Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly Cys Asn

645 650 655

Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu Thr Cys

660 665 670

Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp Tyr Ile Ser

675 680 685

Lys Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly Glu Ser Met Thr

690 695 700

Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly Ser Asp Pro Ala Asp

705 710 715 720

Val Ala Ile Gln Leu Thr Phe Leu Arg Leu Met Ser Thr Glu Ala Ser

725 730 735

Gln Asn Ile Thr Tyr His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln

740 745 750

Gln Thr Gly Asn Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu

755 760 765

Ile Glu Ile Arg Ala Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr

770 775 780

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

785 790 795 800

Glu Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

805 810 815

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly

820 825 830

Pro Val Cys Phe Leu

835

<210> 8

<211> 827

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 8

Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser

1 5 10 15

Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val Thr Thr Glu Ile Leu

20 25 30

Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys Thr Met Tyr Ile Cys

35 40 45

Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe

50 55 60

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

65 70 75 80

Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr

85 90 95

Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro

100 105 110

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

115 120 125

Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp

130 135 140

Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe

145 150 155 160

Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala

165 170 175

Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr

180 185 190

Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe Ala Met Gln Met Ala

195 200 205

Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu Asn

210 215 220

Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln

225 230 235 240

Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly Lys Leu Gln Asp Val

245 250 255

Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser

260 265 270

Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser Arg

275 280 285

Leu Asp Lys Val Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr Gly

290 295 300

Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala

305 310 315 320

Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser Glu

325 330 335

Cys Val Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr

340 345 350

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

355 360 365

His Val Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro

370 375 380

Ala Ile Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe

385 390 395 400

Val Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

405 410 415

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp

420 425 430

Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

435 440 445

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His

450 455 460

Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser

465 470 475 480

Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys

485 490 495

Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu

500 505 510

Gln Tyr Ile Lys Arg Ser Asn Gly Leu Pro Gly Pro Ile Gly Pro Pro

515 520 525

Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly Pro Val Gly Pro Pro Gly

530 535 540

Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Ser Ala Gly Phe Asp

545 550 555 560

Phe Ser Phe Leu Pro Gln Pro Pro Gln Glu Lys Ala His Asp Gly Gly

565 570 575

Arg Tyr Tyr Arg Ala Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu

580 585 590

Glu Val Asp Thr Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile

595 600 605

Arg Ser Pro Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp

610 615 620

Leu Lys Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp

625 630 635 640

Pro Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

645 650 655

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln

660 665 670

Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp

675 680 685

Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln

690 695 700

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

705 710 715 720

Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His Cys Lys Asn Ser

725 730 735

Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu Lys Lys Ala Leu Leu

740 745 750

Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg Ala Glu Gly Asn Ser Arg

755 760 765

Phe Thr Tyr Ser Val Thr Val Asp Gly Cys Thr Ser His Thr Gly Ala

770 775 780

Trp Gly Lys Thr Val Ile Glu Tyr Lys Thr Thr Lys Thr Ser Arg Leu

785 790 795 800

Pro Ile Ile Asp Val Ala Pro Leu Asp Val Gly Ala Pro Asp Gln Glu

805 810 815

Phe Gly Phe Asp Val Gly Pro Val Cys Phe Leu

820 825

<210> 9

<211> 707

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 9

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

1 5 10 15

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

20 25 30

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

35 40 45

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

50 55 60

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

65 70 75 80

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

85 90 95

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

100 105 110

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

115 120 125

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

130 135 140

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

145 150 155 160

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

165 170 175

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

180 185 190

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

195 200 205

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg

210 215 220

Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser

225 230 235 240

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

245 250 255

Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala

260 265 270

His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe

275 280 285

Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn

290 295 300

Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn

305 310 315 320

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

325 330 335

Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly

340 345 350

Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile

355 360 365

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

370 375 380

Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly

385 390 395 400

Leu Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

405 410 415

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro

420 425 430

Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro

435 440 445

Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp Ala

450 455 460

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

465 470 475 480

Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser Arg Lys

485 490 495

Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His Ser Asp Trp

500 505 510

Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly Cys Asn Leu Asp

515 520 525

Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu Thr Cys Val Tyr

530 535 540

Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp Tyr Ile Ser Lys Asn

545 550 555 560

Pro Lys Asp Lys Arg His Val Trp Phe Gly Glu Ser Met Thr Asp Gly

565 570 575

Phe Gln Phe Glu Tyr Gly Gly Gln Gly Ser Asp Pro Ala Asp Val Ala

580 585 590

Ile Gln Leu Thr Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn

595 600 605

Ile Thr Tyr His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr

610 615 620

Gly Asn Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu

625 630 635 640

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

645 650 655

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr

660 665 670

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

675 680 685

Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro Val

690 695 700

Cys Phe Leu

705

<210> 10

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 10

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Asn Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 11

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 11

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Asn Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 12

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 12

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Asn Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 13

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 13

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Asn Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 14

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 14

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

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

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

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Ser Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Thr Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu Tyr Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

Ala Asn Leu Ala Ala Ile Lys Met Ser Glu Cys Val Leu Gly Gln

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 15

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 15

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

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

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

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Ser Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Thr Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu Tyr Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

Ala Asn Leu Ala Ala Ile Lys Met Ser Glu Cys Val Leu Gly Gln

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 16

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 16

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

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

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

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Ser Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Thr Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu Tyr Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

Ala Asn Leu Ala Ala Ile Lys Met Ser Glu Cys Val Leu Gly Gln

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 17

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 17

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

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

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

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Ser Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Thr Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu Tyr Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

Ala Asn Leu Ala Ala Ile Lys Met Ser Glu Cys Val Leu Gly Gln

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 18

<211> 1507

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 18

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile Ser Gly Thr Asn Gly Thr Lys Arg Phe

50 55 60

Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr

65 70 75 80

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

85 90 95

Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val

100 105 110

Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val

115 120 125

Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

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

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

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

305 310 315 320

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

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

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

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

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

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser His Arg Arg Ala Ala Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

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

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

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

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

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

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

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

965 970 975

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

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

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

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

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

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu Pro Gly

1190 1195 1200

Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly

1205 1210 1215

Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly

1220 1225 1230

Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro

1235 1240 1245

Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp

1250 1255 1260

Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu

1265 1270 1275

Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly

1280 1285 1290

Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys

1295 1300 1305

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

1310 1315 1320

Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr

1325 1330 1335

Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys

1340 1345 1350

Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp

1355 1360 1365

Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly

1370 1375 1380

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

1385 1390 1395

Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His Cys

1400 1405 1410

Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu Lys

1415 1420 1425

Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg Ala

1430 1435 1440

Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr Val Asp Gly Cys

1445 1450 1455

Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr Lys

1460 1465 1470

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

1475 1480 1485

Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro

1490 1495 1500

Val Cys Phe Leu

1505

<210> 19

<211> 1507

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 19

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile Ser Gly Thr Asn Gly Thr Lys Arg Phe

50 55 60

Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr

65 70 75 80

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

85 90 95

Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val

100 105 110

Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val

115 120 125

Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

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

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

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

305 310 315 320

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

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

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

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

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

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser His Arg Arg Ala Arg Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

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

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

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

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

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

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

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

965 970 975

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

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

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

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

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

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu Pro Gly

1190 1195 1200

Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly

1205 1210 1215

Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly

1220 1225 1230

Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro

1235 1240 1245

Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp

1250 1255 1260

Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu

1265 1270 1275

Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly

1280 1285 1290

Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys

1295 1300 1305

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

1310 1315 1320

Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr

1325 1330 1335

Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys

1340 1345 1350

Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp

1355 1360 1365

Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly

1370 1375 1380

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

1385 1390 1395

Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His Cys

1400 1405 1410

Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu Lys

1415 1420 1425

Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg Ala

1430 1435 1440

Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr Val Asp Gly Cys

1445 1450 1455

Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr Lys

1460 1465 1470

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

1475 1480 1485

Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro

1490 1495 1500

Val Cys Phe Leu

1505

<210> 20

<211> 1507

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 20

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile Ser Gly Thr Asn Gly Thr Lys Arg Phe

50 55 60

Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr

65 70 75 80

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

85 90 95

Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val

100 105 110

Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val

115 120 125

Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

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

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

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

305 310 315 320

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

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

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

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

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

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser His Arg Arg Ala Arg Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

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

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

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

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

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

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val

965 970 975

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

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

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

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

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

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu Pro Gly

1190 1195 1200

Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly

1205 1210 1215

Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly

1220 1225 1230

Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro

1235 1240 1245

Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp

1250 1255 1260

Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu

1265 1270 1275

Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly

1280 1285 1290

Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys

1295 1300 1305

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

1310 1315 1320

Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr

1325 1330 1335

Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys

1340 1345 1350

Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp

1355 1360 1365

Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly

1370 1375 1380

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

1385 1390 1395

Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His Cys

1400 1405 1410

Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu Lys

1415 1420 1425

Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg Ala

1430 1435 1440

Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr Val Asp Gly Cys

1445 1450 1455

Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr Lys

1460 1465 1470

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

1475 1480 1485

Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro

1490 1495 1500

Val Cys Phe Leu

1505

<210> 21

<211> 1507

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 21

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile Ser Gly Thr Asn Gly Thr Lys Arg Phe

50 55 60

Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr

65 70 75 80

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

85 90 95

Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val

100 105 110

Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val

115 120 125

Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

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

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

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

305 310 315 320

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

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

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

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

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

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser His Arg Arg Ala Ala Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

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

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

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

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

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

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val

965 970 975

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

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

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

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

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

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu Pro Gly

1190 1195 1200

Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly

1205 1210 1215

Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly

1220 1225 1230

Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro

1235 1240 1245

Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp

1250 1255 1260

Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu

1265 1270 1275

Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly

1280 1285 1290

Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys

1295 1300 1305

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

1310 1315 1320

Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr

1325 1330 1335

Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys

1340 1345 1350

Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp

1355 1360 1365

Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly

1370 1375 1380

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

1385 1390 1395

Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His Cys

1400 1405 1410

Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu Lys

1415 1420 1425

Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg Ala

1430 1435 1440

Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr Val Asp Gly Cys

1445 1450 1455

Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr Lys

1460 1465 1470

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

1475 1480 1485

Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro

1490 1495 1500

Val Cys Phe Leu

1505

<210> 22

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 22

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 23

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 23

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 24

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 24

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 25

<211> 1509

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 25

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu

1190 1195 1200

Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp

1205 1210 1215

Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1220 1225 1230

Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

1235 1240 1245

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala

1250 1255 1260

Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

1265 1270 1275

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro

1280 1285 1290

Glu Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys

1295 1300 1305

Met Cys His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro

1310 1315 1320

Asn Gln Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met

1325 1330 1335

Glu Thr Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala

1340 1345 1350

Gln Lys Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His

1355 1360 1365

Val Trp Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr

1370 1375 1380

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

1385 1390 1395

Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr

1400 1405 1410

His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn

1415 1420 1425

Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile

1430 1435 1440

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

1445 1450 1455

Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

1460 1465 1470

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

1475 1480 1485

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val

1490 1495 1500

Gly Pro Val Cys Phe Leu

1505

<210> 26

<211> 1491

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 26

Ser Asp Leu Asp Arg Cys Thr Thr Phe Asp Asp Val Gln Ala Pro Asn

1 5 10 15

Tyr Thr Gln His Thr Ser Ser Met Arg Gly Val Tyr Tyr Pro Asp Glu

20 25 30

Ile Phe Arg Ser Asp Thr Leu Tyr Leu Thr Gln Asp Leu Phe Leu Pro

35 40 45

Phe Tyr Ser Asn Val Thr Gly Phe His Thr Ile Asn His Thr Phe Asp

50 55 60

Asn Pro Val Ile Pro Phe Lys Asp Gly Ile Tyr Phe Ala Ala Thr Glu

65 70 75 80

Lys Ser Asn Val Val Arg Gly Trp Val Phe Gly Ser Thr Met Asn Asn

85 90 95

Lys Ser Gln Ser Val Ile Ile Ile Asn Asn Ser Thr Asn Val Val Ile

100 105 110

Arg Ala Cys Asn Phe Glu Leu Cys Asp Asn Pro Phe Phe Ala Val Ser

115 120 125

Lys Pro Met Gly Thr Gln Thr His Thr Met Ile Phe Asp Asn Ala Phe

130 135 140

Asn Cys Thr Phe Glu Tyr Ile Ser Asp Ala Phe Ser Leu Asp Val Ser

145 150 155 160

Glu Lys Ser Gly Asn Phe Lys His Leu Arg Glu Phe Val Phe Lys Asn

165 170 175

Lys Asp Gly Phe Leu Tyr Val Tyr Lys Gly Tyr Gln Pro Ile Asp Val

180 185 190

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

195 200 205

Leu Pro Leu Gly Ile Asn Ile Thr Asn Phe Arg Ala Ile Leu Thr Ala

210 215 220

Phe Leu Pro Ala Gln Asp Thr Trp Gly Thr Ser Ala Ala Ala Tyr Phe

225 230 235 240

Val Gly Tyr Leu Lys Pro Thr Thr Phe Met Leu Lys Tyr Asp Glu Asn

245 250 255

Gly Thr Ile Thr Asp Ala Val Asp Cys Ser Gln Asn Pro Leu Ala Glu

260 265 270

Leu Lys Cys Ser Val Lys Ser Phe Glu Ile Asp Lys Gly Ile Tyr Gln

275 280 285

Thr Ser Asn Phe Arg Val Val Pro Ser Arg Asp Val Val Arg Phe Pro

290 295 300

Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Lys

305 310 315 320

Phe Pro Ser Val Tyr Ala Trp Glu Arg Lys Arg Ile Ser Asn Cys Val

325 330 335

Ala Asp Tyr Ser Val Leu Tyr Asn Ser Thr Phe Phe Ser Thr Phe Lys

340 345 350

Cys Tyr Gly Val Ser Ala Thr Lys Leu Asn Asp Leu Cys Phe Ser Asn

355 360 365

Val Tyr Ala Asp Ser Phe Val Val Lys Gly Asp Asp Val Arg Gln Ile

370 375 380

Ala Pro Gly Gln Thr Gly Val Ile Ala Asp Tyr Asn Tyr Lys Leu Pro

385 390 395 400

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

405 410 415

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

420 425 430

Gly Lys Leu Arg Pro Phe Glu Arg Asp Ile Ser Asn Val Pro Phe Ser

435 440 445

Pro Asp Gly Lys Pro Cys Thr Pro Pro Ala Leu Asn Cys Tyr Trp Pro

450 455 460

Leu Asn Asp Tyr Gly Phe Tyr Thr Thr Thr Gly Ile Gly Tyr Gln Pro

465 470 475 480

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

485 490 495

Val Cys Gly Pro Lys Leu Ser Thr Asp Leu Ile Lys Asn Gln Cys Val

500 505 510

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

515 520 525

Ser Lys Arg Phe Gln Pro Phe Gln Gln Phe Gly Arg Asp Val Ser Asp

530 535 540

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

545 550 555 560

Ser Pro Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn

565 570 575

Ala Ser Ser Glu Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Asp

580 585 590

Val Ser Thr Ala Ile His Ala Asp Gln Leu Thr Pro Ala Trp Arg Ile

595 600 605

Tyr Ser Thr Gly Asn Asn Val Phe Gln Thr Gln Ala Gly Cys Leu Ile

610 615 620

Gly Ala Glu His Val Asp Thr Ser Tyr Glu Cys Asp Ile Pro Ile Gly

625 630 635 640

Ala Gly Ile Cys Ala Ser Tyr His Thr Val Ser Leu Leu Arg Ser Thr

645 650 655

Ser Gln Lys Ser Ile Val Ala Tyr Thr Met Ser Leu Gly Ala Asp Ser

660 665 670

Ser Ile Ala Tyr Ser Asn Asn Thr Ile Ala Ile Pro Thr Asn Phe Ser

675 680 685

Ile Ser Ile Thr Thr Glu Val Met Pro Val Ser Met Ala Lys Thr Ser

690 695 700

Val Asp Cys Asn Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ala Asn

705 710 715 720

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

725 730 735

Ser Gly Ile Ala Ala Glu Gln Asp Arg Asn Thr Arg Glu Val Phe Ala

740 745 750

Gln Val Lys Gln Met Tyr Lys Thr Pro Thr Leu Lys Asp Phe Gly Gly

755 760 765

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

770 775 780

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

785 790 795 800

Gly Phe Met Lys Gln Tyr Gly Glu Cys Leu Gly Asp Ile Asn Ala Arg

805 810 815

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

820 825 830

Leu Leu Thr Asp Asp Met Ile Ala Ala Tyr Thr Ala Ala Leu Val Ser

835 840 845

Gly Thr Ala Thr Ala Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

850 855 860

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

865 870 875 880

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

885 890 895

Asn Lys Ala Ile Ser Gln Ile Gln Glu Ser Leu Thr Thr Thr Ser Thr

900 905 910

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

915 920 925

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

930 935 940

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

945 950 955 960

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

965 970 975

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

980 985 990

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg

995 1000 1005

Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln

1010 1015 1020

Ala Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro

1025 1030 1035

Ser Gln Glu Arg Asn Phe Thr Thr Ala Pro Ala Ile Cys His Glu

1040 1045 1050

Gly Lys Ala Tyr Phe Pro Arg Glu Gly Val Phe Val Phe Asn Gly

1055 1060 1065

Thr Ser Trp Phe Ile Thr Gln Arg Asn Phe Phe Ser Pro Gln Ile

1070 1075 1080

Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val

1085 1090 1095

Ile Gly Ile Ile Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu

1100 1105 1110

Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His

1115 1120 1125

Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala

1130 1135 1140

Ser Val Val Asn Ile Gln Glu Glu Ile Asp Arg Leu Asn Glu Val

1145 1150 1155

Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly

1160 1165 1170

Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu Pro Gly Pro

1175 1180 1185

Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly Pro

1190 1195 1200

Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro

1205 1210 1215

Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro Gln

1220 1225 1230

Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp Ala

1235 1240 1245

Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu Lys

1250 1255 1260

Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser

1265 1270 1275

Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His

1280 1285 1290

Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly

1295 1300 1305

Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly

1310 1315 1320

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

1325 1330 1335

Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp Phe

1340 1345 1350

Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln

1355 1360 1365

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

1370 1375 1380

Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His Cys Lys

1385 1390 1395

Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu Lys Lys

1400 1405 1410

Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg Ala Glu

1415 1420 1425

Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr Val Asp Gly Cys Thr

1430 1435 1440

Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr Lys Thr

1445 1450 1455

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

1460 1465 1470

Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro Val

1475 1480 1485

Cys Phe Leu

1490

<210> 27

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 27

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

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

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 28

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 28

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

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

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 29

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 29

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

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

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 30

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 30

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

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

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 31

<211> 525

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 31

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys

515 520 525

<210> 32

<211> 668

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 32

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

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

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro

660 665

<210> 33

<211> 523

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 33

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

1 5 10 15

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

20 25 30

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

35 40 45

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

50 55 60

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

65 70 75 80

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

85 90 95

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

100 105 110

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

115 120 125

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

130 135 140

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

145 150 155 160

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

165 170 175

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

180 185 190

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

195 200 205

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

210 215 220

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

225 230 235 240

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

245 250 255

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

260 265 270

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

275 280 285

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

290 295 300

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

305 310 315 320

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

325 330 335

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

340 345 350

Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

355 360 365

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

370 375 380

Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly

385 390 395 400

Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His

405 410 415

Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr

420 425 430

Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val

435 440 445

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

450 455 460

Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp

465 470 475 480

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

485 490 495

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

500 505 510

Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln

515 520

<210> 34

<211> 513

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 34

Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser

1 5 10 15

Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val Thr Thr Glu Ile Leu

20 25 30

Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys Thr Met Tyr Ile Cys

35 40 45

Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe

50 55 60

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

65 70 75 80

Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr

85 90 95

Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro

100 105 110

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

115 120 125

Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp

130 135 140

Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe

145 150 155 160

Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala

165 170 175

Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr

180 185 190

Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe Ala Met Gln Met Ala

195 200 205

Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu Asn

210 215 220

Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln

225 230 235 240

Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly Lys Leu Gln Asp Val

245 250 255

Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser

260 265 270

Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser Arg

275 280 285

Leu Asp Lys Val Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr Gly

290 295 300

Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala

305 310 315 320

Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser Glu

325 330 335

Cys Val Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr

340 345 350

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

355 360 365

His Val Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro

370 375 380

Ala Ile Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe

385 390 395 400

Val Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

405 410 415

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp

420 425 430

Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

435 440 445

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His

450 455 460

Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser

465 470 475 480

Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys

485 490 495

Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu

500 505 510

Gln

<210> 35

<211> 393

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 35

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

1 5 10 15

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

20 25 30

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

35 40 45

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

50 55 60

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

65 70 75 80

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

85 90 95

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

100 105 110

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

115 120 125

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

130 135 140

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

145 150 155 160

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

165 170 175

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

180 185 190

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

195 200 205

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg

210 215 220

Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser

225 230 235 240

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

245 250 255

Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala

260 265 270

His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe

275 280 285

Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn

290 295 300

Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn

305 310 315 320

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

325 330 335

Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly

340 345 350

Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile

355 360 365

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

370 375 380

Leu Gln Glu Leu Gly Lys Tyr Glu Gln

385 390

<210> 36

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 36

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Asn Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 37

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 37

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Asn Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 38

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 38

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Asn Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 39

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 39

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Asn Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 40

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 40

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

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

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

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Ser Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Thr Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu Tyr Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

Ala Asn Leu Ala Ala Ile Lys Met Ser Glu Cys Val Leu Gly Gln

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 41

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 41

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

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

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

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Ser Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Thr Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu Tyr Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

Ala Asn Leu Ala Ala Ile Lys Met Ser Glu Cys Val Leu Gly Gln

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 42

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 42

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

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

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

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Ser Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Thr Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu Tyr Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

Ala Asn Leu Ala Ala Ile Lys Met Ser Glu Cys Val Leu Gly Gln

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 43

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 43

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

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

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

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Ser Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Thr Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Lys Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu Tyr Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

Ala Asn Leu Ala Ala Ile Lys Met Ser Glu Cys Val Leu Gly Gln

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 44

<211> 1193

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 44

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile Ser Gly Thr Asn Gly Thr Lys Arg Phe

50 55 60

Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr

65 70 75 80

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

85 90 95

Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val

100 105 110

Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val

115 120 125

Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

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

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

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

305 310 315 320

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

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

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

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

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

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser His Arg Arg Ala Arg Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

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

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

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

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

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

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

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

965 970 975

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

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

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

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

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

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln

1190

<210> 45

<211> 1193

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 45

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile Ser Gly Thr Asn Gly Thr Lys Arg Phe

50 55 60

Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr

65 70 75 80

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

85 90 95

Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val

100 105 110

Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val

115 120 125

Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

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

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

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

305 310 315 320

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

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

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

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

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

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser His Arg Arg Ala Arg Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

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

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

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

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

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

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val

965 970 975

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

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

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

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

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

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln

1190

<210> 46

<211> 1193

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 46

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile Ser Gly Thr Asn Gly Thr Lys Arg Phe

50 55 60

Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr

65 70 75 80

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

85 90 95

Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val

100 105 110

Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val

115 120 125

Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

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

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

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

305 310 315 320

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

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

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

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

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

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser His Arg Arg Ala Ala Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

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

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

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

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

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

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

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

965 970 975

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

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

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

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

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

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln

1190

<210> 47

<211> 1193

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 47

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile Ser Gly Thr Asn Gly Thr Lys Arg Phe

50 55 60

Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr

65 70 75 80

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

85 90 95

Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val

100 105 110

Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val

115 120 125

Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

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

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

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

305 310 315 320

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

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Tyr Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

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

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

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

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser His Arg Arg Ala Ala Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

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

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

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

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

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

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val

965 970 975

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

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

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

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

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

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln

1190

<210> 48

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 48

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 49

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 49

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

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

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 50

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 50

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 51

<211> 1195

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 51

Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

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

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe

130 135 140

Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln

145 150 155 160

Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu

165 170 175

Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser

180 185 190

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

195 200 205

Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg

210 215 220

Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp

225 230 235 240

Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr

245 250 255

Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile

260 265 270

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

275 280 285

Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn

290 295 300

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

305 310 315 320

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

325 330 335

Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr

340 345 350

Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly

355 360 365

Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala

370 375 380

Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly

385 390 395 400

Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe

405 410 415

Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val

420 425 430

Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu

435 440 445

Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser

450 455 460

Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln

465 470 475 480

Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg

485 490 495

Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys

500 505 510

Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe

515 520 525

Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys

530 535 540

Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr

545 550 555 560

Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro

565 570 575

Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser

580 585 590

Asn Gln Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro

595 600 605

Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser

610 615 620

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

625 630 635 640

Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly

645 650 655

Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Ala

660 665 670

Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala

675 680 685

Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn

690 695 700

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

705 710 715 720

Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys

725 730 735

Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg

740 745 750

Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val

755 760 765

Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe

770 775 780

Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser

785 790 795 800

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

805 810 815

Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala

820 825 830

Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu

835 840 845

Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu

850 855 860

Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala

865 870 875 880

Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile

885 890 895

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

900 905 910

Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr

915 920 925

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

930 935 940

Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile

945 950 955 960

Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala

965 970 975

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

980 985 990

Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser

995 1000 1005

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

1010 1015 1020

Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser

1025 1030 1035

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

1040 1045 1050

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

1055 1060 1065

Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val

1070 1075 1080

Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu

1085 1090 1095

Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys

1100 1105 1110

Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu

1115 1120 1125

Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe

1130 1135 1140

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

1145 1150 1155

Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu

1160 1165 1170

Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln

1175 1180 1185

Glu Leu Gly Lys Tyr Glu Gln

1190 1195

<210> 52

<211> 1177

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 52

Ser Asp Leu Asp Arg Cys Thr Thr Phe Asp Asp Val Gln Ala Pro Asn

1 5 10 15

Tyr Thr Gln His Thr Ser Ser Met Arg Gly Val Tyr Tyr Pro Asp Glu

20 25 30

Ile Phe Arg Ser Asp Thr Leu Tyr Leu Thr Gln Asp Leu Phe Leu Pro

35 40 45

Phe Tyr Ser Asn Val Thr Gly Phe His Thr Ile Asn His Thr Phe Asp

50 55 60

Asn Pro Val Ile Pro Phe Lys Asp Gly Ile Tyr Phe Ala Ala Thr Glu

65 70 75 80

Lys Ser Asn Val Val Arg Gly Trp Val Phe Gly Ser Thr Met Asn Asn

85 90 95

Lys Ser Gln Ser Val Ile Ile Ile Asn Asn Ser Thr Asn Val Val Ile

100 105 110

Arg Ala Cys Asn Phe Glu Leu Cys Asp Asn Pro Phe Phe Ala Val Ser

115 120 125

Lys Pro Met Gly Thr Gln Thr His Thr Met Ile Phe Asp Asn Ala Phe

130 135 140

Asn Cys Thr Phe Glu Tyr Ile Ser Asp Ala Phe Ser Leu Asp Val Ser

145 150 155 160

Glu Lys Ser Gly Asn Phe Lys His Leu Arg Glu Phe Val Phe Lys Asn

165 170 175

Lys Asp Gly Phe Leu Tyr Val Tyr Lys Gly Tyr Gln Pro Ile Asp Val

180 185 190

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

195 200 205

Leu Pro Leu Gly Ile Asn Ile Thr Asn Phe Arg Ala Ile Leu Thr Ala

210 215 220

Phe Leu Pro Ala Gln Asp Thr Trp Gly Thr Ser Ala Ala Ala Tyr Phe

225 230 235 240

Val Gly Tyr Leu Lys Pro Thr Thr Phe Met Leu Lys Tyr Asp Glu Asn

245 250 255

Gly Thr Ile Thr Asp Ala Val Asp Cys Ser Gln Asn Pro Leu Ala Glu

260 265 270

Leu Lys Cys Ser Val Lys Ser Phe Glu Ile Asp Lys Gly Ile Tyr Gln

275 280 285

Thr Ser Asn Phe Arg Val Val Pro Ser Arg Asp Val Val Arg Phe Pro

290 295 300

Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Lys

305 310 315 320

Phe Pro Ser Val Tyr Ala Trp Glu Arg Lys Arg Ile Ser Asn Cys Val

325 330 335

Ala Asp Tyr Ser Val Leu Tyr Asn Ser Thr Phe Phe Ser Thr Phe Lys

340 345 350

Cys Tyr Gly Val Ser Ala Thr Lys Leu Asn Asp Leu Cys Phe Ser Asn

355 360 365

Val Tyr Ala Asp Ser Phe Val Val Lys Gly Asp Asp Val Arg Gln Ile

370 375 380

Ala Pro Gly Gln Thr Gly Val Ile Ala Asp Tyr Asn Tyr Lys Leu Pro

385 390 395 400

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

405 410 415

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

420 425 430

Gly Lys Leu Arg Pro Phe Glu Arg Asp Ile Ser Asn Val Pro Phe Ser

435 440 445

Pro Asp Gly Lys Pro Cys Thr Pro Pro Ala Leu Asn Cys Tyr Trp Pro

450 455 460

Leu Asn Asp Tyr Gly Phe Tyr Thr Thr Thr Gly Ile Gly Tyr Gln Pro

465 470 475 480

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

485 490 495

Val Cys Gly Pro Lys Leu Ser Thr Asp Leu Ile Lys Asn Gln Cys Val

500 505 510

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

515 520 525

Ser Lys Arg Phe Gln Pro Phe Gln Gln Phe Gly Arg Asp Val Ser Asp

530 535 540

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

545 550 555 560

Ser Pro Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn

565 570 575

Ala Ser Ser Glu Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Asp

580 585 590

Val Ser Thr Ala Ile His Ala Asp Gln Leu Thr Pro Ala Trp Arg Ile

595 600 605

Tyr Ser Thr Gly Asn Asn Val Phe Gln Thr Gln Ala Gly Cys Leu Ile

610 615 620

Gly Ala Glu His Val Asp Thr Ser Tyr Glu Cys Asp Ile Pro Ile Gly

625 630 635 640

Ala Gly Ile Cys Ala Ser Tyr His Thr Val Ser Leu Leu Arg Ser Thr

645 650 655

Ser Gln Lys Ser Ile Val Ala Tyr Thr Met Ser Leu Gly Ala Asp Ser

660 665 670

Ser Ile Ala Tyr Ser Asn Asn Thr Ile Ala Ile Pro Thr Asn Phe Ser

675 680 685

Ile Ser Ile Thr Thr Glu Val Met Pro Val Ser Met Ala Lys Thr Ser

690 695 700

Val Asp Cys Asn Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ala Asn

705 710 715 720

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

725 730 735

Ser Gly Ile Ala Ala Glu Gln Asp Arg Asn Thr Arg Glu Val Phe Ala

740 745 750

Gln Val Lys Gln Met Tyr Lys Thr Pro Thr Leu Lys Asp Phe Gly Gly

755 760 765

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

770 775 780

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

785 790 795 800

Gly Phe Met Lys Gln Tyr Gly Glu Cys Leu Gly Asp Ile Asn Ala Arg

805 810 815

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

820 825 830

Leu Leu Thr Asp Asp Met Ile Ala Ala Tyr Thr Ala Ala Leu Val Ser

835 840 845

Gly Thr Ala Thr Ala Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

850 855 860

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

865 870 875 880

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

885 890 895

Asn Lys Ala Ile Ser Gln Ile Gln Glu Ser Leu Thr Thr Thr Ser Thr

900 905 910

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

915 920 925

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

930 935 940

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

945 950 955 960

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

965 970 975

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

980 985 990

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg

995 1000 1005

Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln

1010 1015 1020

Ala Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro

1025 1030 1035

Ser Gln Glu Arg Asn Phe Thr Thr Ala Pro Ala Ile Cys His Glu

1040 1045 1050

Gly Lys Ala Tyr Phe Pro Arg Glu Gly Val Phe Val Phe Asn Gly

1055 1060 1065

Thr Ser Trp Phe Ile Thr Gln Arg Asn Phe Phe Ser Pro Gln Ile

1070 1075 1080

Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val

1085 1090 1095

Ile Gly Ile Ile Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu

1100 1105 1110

Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His

1115 1120 1125

Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala

1130 1135 1140

Ser Val Val Asn Ile Gln Glu Glu Ile Asp Arg Leu Asn Glu Val

1145 1150 1155

Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly

1160 1165 1170

Lys Tyr Glu Gln

1175

<210> 53

<211> 13

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 53

Met Phe Ile Phe Leu Leu Phe Leu Thr Leu Thr Ser Gly

1 5 10

<210> 54

<211> 13

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 54

Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser

1 5 10

<210> 55

<211> 1273

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 55

Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val

1 5 10 15

Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe

20 25 30

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

35 40 45

His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp

50 55 60

Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp

65 70 75 80

Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu

85 90 95

Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser

100 105 110

Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile

115 120 125

Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr

130 135 140

Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr

145 150 155 160

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

165 170 175

Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe

180 185 190

Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr

195 200 205

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

210 215 220

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

225 230 235 240

Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser

245 250 255

Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro

260 265 270

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

275 280 285

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

290 295 300

Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val

305 310 315 320

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

325 330 335

Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala

340 345 350

Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu

355 360 365

Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro

370 375 380

Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe

385 390 395 400

Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly

405 410 415

Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys

420 425 430

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

435 440 445

Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe

450 455 460

Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys

465 470 475 480

Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly

485 490 495

Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val

500 505 510

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

515 520 525

Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn

530 535 540

Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu

545 550 555 560

Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val

565 570 575

Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe

580 585 590

Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val

595 600 605

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

610 615 620

His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser

625 630 635 640

Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val

645 650 655

Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala

660 665 670

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

675 680 685

Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser

690 695 700

Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile

705 710 715 720

Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val

725 730 735

Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu

740 745 750

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

755 760 765

Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln

770 775 780

Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe

785 790 795 800

Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser

805 810 815

Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly

820 825 830

Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp

835 840 845

Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu

850 855 860

Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly

865 870 875 880

Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile

885 890 895

Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr

900 905 910

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

915 920 925

Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala

930 935 940

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

945 950 955 960

Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val

965 970 975

Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln

980 985 990

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

995 1000 1005

Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

1010 1015 1020

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1025 1030 1035

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1040 1045 1050

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

1055 1060 1065

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1070 1075 1080

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1085 1090 1095

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1100 1105 1110

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1115 1120 1125

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1130 1135 1140

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1145 1150 1155

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

1160 1165 1170

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1175 1180 1185

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1190 1195 1200

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

1205 1210 1215

Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr Ile Met

1220 1225 1230

Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly Cys Cys

1235 1240 1245

Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser Glu Pro

1250 1255 1260

Val Leu Lys Gly Val Lys Leu His Tyr Thr

1265 1270

<210> 56

<211> 1208

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 56

Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val

1 5 10 15

Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe

20 25 30

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

35 40 45

His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp

50 55 60

Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp

65 70 75 80

Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu

85 90 95

Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser

100 105 110

Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile

115 120 125

Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr

130 135 140

Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val Tyr

145 150 155 160

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

165 170 175

Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe

180 185 190

Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr

195 200 205

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

210 215 220

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

225 230 235 240

Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser

245 250 255

Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro

260 265 270

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

275 280 285

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

290 295 300

Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val

305 310 315 320

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

325 330 335

Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala

340 345 350

Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu

355 360 365

Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro

370 375 380

Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe

385 390 395 400

Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly

405 410 415

Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys

420 425 430

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

435 440 445

Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe

450 455 460

Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys

465 470 475 480

Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly

485 490 495

Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val

500 505 510

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

515 520 525

Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn

530 535 540

Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu

545 550 555 560

Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val

565 570 575

Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe

580 585 590

Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val

595 600 605

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

610 615 620

His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser

625 630 635 640

Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val

645 650 655

Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala

660 665 670

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

675 680 685

Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser

690 695 700

Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile

705 710 715 720

Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val

725 730 735

Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu

740 745 750

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

755 760 765

Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln

770 775 780

Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe

785 790 795 800

Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser

805 810 815

Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly

820 825 830

Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp

835 840 845

Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu

850 855 860

Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly

865 870 875 880

Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile

885 890 895

Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr

900 905 910

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

915 920 925

Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala

930 935 940

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

945 950 955 960

Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val

965 970 975

Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln

980 985 990

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

995 1000 1005

Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

1010 1015 1020

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1025 1030 1035

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1040 1045 1050

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

1055 1060 1065

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1070 1075 1080

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1085 1090 1095

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1100 1105 1110

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1115 1120 1125

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1130 1135 1140

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1145 1150 1155

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

1160 1165 1170

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1175 1180 1185

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1190 1195 1200

Gly Lys Tyr Glu Gln

1205

<210> 57

<211> 290

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 57

Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser

1 5 10 15

Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val

20 25 30

Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr

35 40 45

Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe

50 55 60

Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr

65 70 75 80

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

85 90 95

Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val

100 105 110

Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val

115 120 125

Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

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

275 280 285

Lys Ser

290

<210> 58

<211> 192

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 58

Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr

1 5 10 15

Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys

20 25 30

Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe

35 40 45

Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr

50 55 60

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

65 70 75 80

Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu

85 90 95

Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu

100 105 110

Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg

115 120 125

Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr

130 135 140

Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr

145 150 155 160

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

165 170 175

Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro

180 185 190

<210> 59

<211> 4

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 59

Arg Arg Ala Arg

1

<210> 60

<211> 4

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 60

Gly Ser Ala Gly

1

<210> 61

<211> 18

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 61

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

1 5 10 15

Gly Phe

<210> 62

<211> 78

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 62

Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile

1 5 10 15

Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser

20 25 30

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

35 40 45

Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly

50 55 60

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

65 70 75

<210> 63

<211> 50

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 63

Lys Val Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu

1 5 10 15

Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu

20 25 30

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

35 40 45

Leu Gly

50

<210> 64

<211> 66

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 64

Thr Thr Ala Pro Ala Ile Cys His Asp Gly Lys Ala His Phe Pro Arg

1 5 10 15

Glu Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg

20 25 30

Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser

35 40 45

Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp

50 55 60

Pro Leu

65

<210> 65

<211> 59

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 65

Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp

1 5 10 15

Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys

20 25 30

Glu Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu

35 40 45

Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln

50 55

<210> 66

<211> 23

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 66

Trp Pro Trp Tyr Ile Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile

1 5 10 15

Val Met Val Thr Ile Met Leu

20

<210> 67

<211> 244

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 67

Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu Lys

1 5 10 15

Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser Arg

20 25 30

Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His Ser Asp

35 40 45

Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly Cys Asn Leu

50 55 60

Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu Thr Cys Val

65 70 75 80

Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp Tyr Ile Ser Lys

85 90 95

Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly Glu Ser Met Thr Asp

100 105 110

Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly Ser Asp Pro Ala Asp Val

115 120 125

Ala Ile Gln Leu Thr Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln

130 135 140

Asn Ile Thr Tyr His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln

145 150 155 160

Thr Gly Asn Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile

165 170 175

Glu Ile Arg Ala Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr Val

180 185 190

Asp Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

195 200 205

Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala Pro

210 215 220

Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro

225 230 235 240

Val Cys Phe Leu

<210> 68

<211> 309

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 68

Asn Gly Leu Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr

1 5 10 15

Gly Asp Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly

20 25 30

Pro Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

35 40 45

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn

50 55 60

Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu

65 70 75 80

Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser

85 90 95

Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His Ser

100 105 110

Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly Cys Asn

115 120 125

Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu Thr Cys

130 135 140

Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp Tyr Ile Ser

145 150 155 160

Lys Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly Glu Ser Met Thr

165 170 175

Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly Ser Asp Pro Ala Asp

180 185 190

Val Ala Ile Gln Leu Thr Phe Leu Arg Leu Met Ser Thr Glu Ala Ser

195 200 205

Gln Asn Ile Thr Tyr His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln

210 215 220

Gln Thr Gly Asn Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu

225 230 235 240

Ile Glu Ile Arg Ala Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr

245 250 255

Val Asp Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile

260 265 270

Glu Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

275 280 285

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly

290 295 300

Pro Val Cys Phe Leu

305

<210> 69

<211> 309

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 69

Asn Gly Leu Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr

1 5 10 15

Gly Asp Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly

20 25 30

Pro Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

35 40 45

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Asn Asp

50 55 60

Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu

65 70 75 80

Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser

85 90 95

Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His Ser

100 105 110

Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly Cys Asn

115 120 125

Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu Thr Cys

130 135 140

Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp Tyr Ile Ser

145 150 155 160

Lys Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly Glu Ser Met Thr

165 170 175

Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly Ser Asp Pro Ala Asp

180 185 190

Val Ala Ile Gln Leu Thr Phe Leu Arg Leu Met Ser Thr Glu Ala Ser

195 200 205

Gln Asn Ile Thr Tyr His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln

210 215 220

Gln Thr Gly Asn Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu

225 230 235 240

Ile Glu Ile Arg Ala Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr

245 250 255

Val Asp Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile

260 265 270

Glu Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala

275 280 285

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly

290 295 300

Pro Val Cys Phe Leu

305

<210> 70

<211> 311

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 70

Arg Ser Asn Gly Leu Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly

1 5 10 15

Arg Thr Gly Asp Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro

20 25 30

Pro Gly Pro Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu

35 40 45

Pro Gln Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg

50 55 60

Ala Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

65 70 75 80

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu

85 90 95

Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys

100 105 110

His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly

115 120 125

Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu

130 135 140

Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp Tyr

145 150 155 160

Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly Glu Ser

165 170 175

Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly Ser Asp Pro

180 185 190

Ala Asp Val Ala Ile Gln Leu Thr Phe Leu Arg Leu Met Ser Thr Glu

195 200 205

Ala Ser Gln Asn Ile Thr Tyr His Cys Lys Asn Ser Val Ala Tyr Met

210 215 220

Asp Gln Gln Thr Gly Asn Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser

225 230 235 240

Asn Glu Ile Glu Ile Arg Ala Glu Gly Asn Ser Arg Phe Thr Tyr Ser

245 250 255

Val Thr Val Asp Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr

260 265 270

Val Ile Glu Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp

275 280 285

Val Ala Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp

290 295 300

Val Gly Pro Val Cys Phe Leu

305 310

<210> 71

<211> 311

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 71

Gly Ser Asn Gly Leu Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly

1 5 10 15

Arg Thr Gly Asp Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro

20 25 30

Pro Gly Pro Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu

35 40 45

Pro Gln Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg

50 55 60

Ala Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

65 70 75 80

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu

85 90 95

Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys

100 105 110

His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly

115 120 125

Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu

130 135 140

Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp Tyr

145 150 155 160

Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly Glu Ser

165 170 175

Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly Ser Asp Pro

180 185 190

Ala Asp Val Ala Ile Gln Leu Thr Phe Leu Arg Leu Met Ser Thr Glu

195 200 205

Ala Ser Gln Asn Ile Thr Tyr His Cys Lys Asn Ser Val Ala Tyr Met

210 215 220

Asp Gln Gln Thr Gly Asn Leu Lys Lys Ala Leu Leu Leu Gln Gly Ser

225 230 235 240

Asn Glu Ile Glu Ile Arg Ala Glu Gly Asn Ser Arg Phe Thr Tyr Ser

245 250 255

Val Thr Val Asp Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr

260 265 270

Val Ile Glu Tyr Lys Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp

275 280 285

Val Ala Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp

290 295 300

Val Gly Pro Val Cys Phe Leu

305 310

<210> 72

<211> 244

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 72

Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu Lys

1 5 10 15

Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser Arg

20 25 30

Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His Ser Asp

35 40 45

Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly Cys Asn Leu

50 55 60

Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu Thr Cys Val

65 70 75 80

Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp Tyr Ile Ser Lys

85 90 95

Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly Glu Ser Met Thr Asp

100 105 110

Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly Ser Asp Pro Ala Asp Val

115 120 125

Ala Ile Gln Leu Thr Phe Leu Arg Leu Met Ser Thr Glu Ala Ser Gln

130 135 140

Asn Ile Thr Tyr His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln Gln

145 150 155 160

Thr Gly Asn Leu Lys Lys Ala Leu Leu Leu Lys Gly Ser Asn Glu Ile

165 170 175

Glu Ile Arg Ala Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr Val

180 185 190

Asp Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu

195 200 205

Tyr Lys Thr Thr Lys Ser Ser Arg Leu Pro Ile Ile Asp Val Ala Pro

210 215 220

Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro

225 230 235 240

Val Cys Phe Leu

<210> 73

<211> 309

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 73

Asn Gly Leu Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr

1 5 10 15

Gly Asp Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly

20 25 30

Pro Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

35 40 45

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn

50 55 60

Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu

65 70 75 80

Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser

85 90 95

Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His Ser

100 105 110

Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly Cys Asn

115 120 125

Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu Thr Cys

130 135 140

Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp Tyr Ile Ser

145 150 155 160

Lys Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly Glu Ser Met Thr

165 170 175

Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly Ser Asp Pro Ala Asp

180 185 190

Val Ala Ile Gln Leu Thr Phe Leu Arg Leu Met Ser Thr Glu Ala Ser

195 200 205

Gln Asn Ile Thr Tyr His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln

210 215 220

Gln Thr Gly Asn Leu Lys Lys Ala Leu Leu Leu Lys Gly Ser Asn Glu

225 230 235 240

Ile Glu Ile Arg Ala Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr

245 250 255

Val Asp Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile

260 265 270

Glu Tyr Lys Thr Thr Lys Ser Ser Arg Leu Pro Ile Ile Asp Val Ala

275 280 285

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly

290 295 300

Pro Val Cys Phe Leu

305

<210> 74

<211> 309

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 74

Asn Gly Leu Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr

1 5 10 15

Gly Asp Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly

20 25 30

Pro Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln

35 40 45

Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Asn Asp

50 55 60

Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu

65 70 75 80

Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser

85 90 95

Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His Ser

100 105 110

Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly Cys Asn

115 120 125

Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu Thr Cys

130 135 140

Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp Tyr Ile Ser

145 150 155 160

Lys Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly Glu Ser Met Thr

165 170 175

Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly Ser Asp Pro Ala Asp

180 185 190

Val Ala Ile Gln Leu Thr Phe Leu Arg Leu Met Ser Thr Glu Ala Ser

195 200 205

Gln Asn Ile Thr Tyr His Cys Lys Asn Ser Val Ala Tyr Met Asp Gln

210 215 220

Gln Thr Gly Asn Leu Lys Lys Ala Leu Leu Leu Lys Gly Ser Asn Glu

225 230 235 240

Ile Glu Ile Arg Ala Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr

245 250 255

Val Asp Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile

260 265 270

Glu Tyr Lys Thr Thr Lys Ser Ser Arg Leu Pro Ile Ile Asp Val Ala

275 280 285

Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly

290 295 300

Pro Val Cys Phe Leu

305

<210> 75

<211> 311

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 75

Arg Ser Asn Gly Leu Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly

1 5 10 15

Arg Thr Gly Asp Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro

20 25 30

Pro Gly Pro Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu

35 40 45

Pro Gln Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg

50 55 60

Ala Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

65 70 75 80

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu

85 90 95

Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys

100 105 110

His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly

115 120 125

Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu

130 135 140

Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp Tyr

145 150 155 160

Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly Glu Ser

165 170 175

Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly Ser Asp Pro

180 185 190

Ala Asp Val Ala Ile Gln Leu Thr Phe Leu Arg Leu Met Ser Thr Glu

195 200 205

Ala Ser Gln Asn Ile Thr Tyr His Cys Lys Asn Ser Val Ala Tyr Met

210 215 220

Asp Gln Gln Thr Gly Asn Leu Lys Lys Ala Leu Leu Leu Lys Gly Ser

225 230 235 240

Asn Glu Ile Glu Ile Arg Ala Glu Gly Asn Ser Arg Phe Thr Tyr Ser

245 250 255

Val Thr Val Asp Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr

260 265 270

Val Ile Glu Tyr Lys Thr Thr Lys Ser Ser Arg Leu Pro Ile Ile Asp

275 280 285

Val Ala Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp

290 295 300

Val Gly Pro Val Cys Phe Leu

305 310

<210> 76

<211> 311

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 76

Gly Ser Asn Gly Leu Pro Gly Pro Ile Gly Pro Pro Gly Pro Arg Gly

1 5 10 15

Arg Thr Gly Asp Ala Gly Pro Val Gly Pro Pro Gly Pro Pro Gly Pro

20 25 30

Pro Gly Pro Pro Gly Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu

35 40 45

Pro Gln Pro Pro Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg

50 55 60

Ala Asn Asp Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr

65 70 75 80

Thr Leu Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu

85 90 95

Gly Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys

100 105 110

His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly

115 120 125

Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu

130 135 140

Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp Tyr

145 150 155 160

Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly Glu Ser

165 170 175

Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly Ser Asp Pro

180 185 190

Ala Asp Val Ala Ile Gln Leu Thr Phe Leu Arg Leu Met Ser Thr Glu

195 200 205

Ala Ser Gln Asn Ile Thr Tyr His Cys Lys Asn Ser Val Ala Tyr Met

210 215 220

Asp Gln Gln Thr Gly Asn Leu Lys Lys Ala Leu Leu Leu Lys Gly Ser

225 230 235 240

Asn Glu Ile Glu Ile Arg Ala Glu Gly Asn Ser Arg Phe Thr Tyr Ser

245 250 255

Val Thr Val Asp Gly Cys Thr Ser His Thr Gly Ala Trp Gly Lys Thr

260 265 270

Val Ile Glu Tyr Lys Thr Thr Lys Ser Ser Arg Leu Pro Ile Ile Asp

275 280 285

Val Ala Pro Leu Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp

290 295 300

Val Gly Pro Val Cys Phe Leu

305 310

<210> 77

<211> 234

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 77

Asp Glu Ile Met Thr Ser Leu Lys Ser Val Asn Gly Gln Ile Glu Ser

1 5 10 15

Leu Ile Ser Pro Asp Gly Ser Arg Lys Asn Pro Ala Arg Asn Cys Arg

20 25 30

Asp Leu Lys Phe Cys His Pro Glu Leu Lys Ser Gly Glu Tyr Trp Val

35 40 45

Asp Pro Asn Gln Gly Cys Lys Leu Asp Ala Ile Lys Val Phe Cys Asn

50 55 60

Met Glu Thr Gly Glu Thr Cys Ile Ser Ala Asn Pro Leu Asn Val Pro

65 70 75 80

Arg Lys His Trp Trp Thr Asp Ser Ser Ala Glu Lys Lys His Val Trp

85 90 95

Phe Gly Glu Ser Met Asp Gly Gly Phe Gln Phe Ser Tyr Gly Asn Pro

100 105 110

Glu Leu Pro Glu Asp Val Leu Asp Val Gln Leu Ala Phe Leu Arg Leu

115 120 125

Leu Ser Ser Arg Ala Ser Gln Asn Ile Thr Tyr His Cys Lys Asn Ser

130 135 140

Ile Ala Tyr Met Asp Gln Ala Ser Gly Asn Val Lys Lys Ala Leu Lys

145 150 155 160

Leu Met Gly Ser Asn Glu Gly Glu Phe Lys Ala Glu Gly Asn Ser Lys

165 170 175

Phe Thr Tyr Thr Val Leu Glu Asp Gly Cys Thr Lys His Thr Gly Glu

180 185 190

Trp Ser Lys Thr Val Phe Glu Tyr Arg Thr Arg Lys Ala Val Arg Leu

195 200 205

Pro Ile Val Asp Ile Ala Pro Tyr Asp Ile Gly Gly Pro Asp Gln Glu

210 215 220

Phe Gly Val Asp Val Gly Pro Val Cys Phe

225 230

<210> 78

<211> 244

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 78

Glu Pro Met Asp Phe Lys Ile Asn Thr Asp Glu Ile Met Thr Ser Leu

1 5 10 15

Lys Ser Val Asn Gly Gln Ile Glu Ser Leu Ile Ser Pro Asp Gly Ser

20 25 30

Arg Lys Asn Pro Ala Arg Asn Cys Arg Asp Leu Lys Phe Cys His Pro

35 40 45

Glu Leu Lys Ser Gly Glu Tyr Trp Val Asp Pro Asn Gln Gly Cys Lys

50 55 60

Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu Thr Cys

65 70 75 80

Ile Ser Ala Asn Pro Leu Asn Val Pro Arg Lys His Trp Trp Thr Asp

85 90 95

Ser Ser Ala Glu Lys Lys His Val Trp Phe Gly Glu Ser Met Asp Gly

100 105 110

Gly Phe Gln Phe Ser Tyr Gly Asn Pro Glu Leu Pro Glu Asp Val Leu

115 120 125

Asp Val Gln Leu Ala Phe Leu Arg Leu Leu Ser Ser Arg Ala Ser Gln

130 135 140

Asn Ile Thr Tyr His Cys Lys Asn Ser Ile Ala Tyr Met Asp Gln Ala

145 150 155 160

Ser Gly Asn Val Lys Lys Ala Leu Lys Leu Met Gly Ser Asn Glu Gly

165 170 175

Glu Phe Lys Ala Glu Gly Asn Ser Lys Phe Thr Tyr Thr Val Leu Glu

180 185 190

Asp Gly Cys Thr Lys His Thr Gly Glu Trp Ser Lys Thr Val Phe Glu

195 200 205

Tyr Arg Thr Arg Lys Ala Val Arg Leu Pro Ile Val Asp Ile Ala Pro

210 215 220

Tyr Asp Ile Gly Gly Pro Asp Gln Glu Phe Gly Val Asp Val Gly Pro

225 230 235 240

Val Cys Phe Leu

<210> 79

<211> 245

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 79

Ser Glu Pro Met Asp Phe Lys Ile Asn Thr Asp Glu Ile Met Thr Ser

1 5 10 15

Leu Lys Ser Val Asn Gly Gln Ile Glu Ser Leu Ile Ser Pro Asp Gly

20 25 30

Ser Arg Lys Asn Pro Ala Arg Asn Cys Arg Asp Leu Lys Phe Cys His

35 40 45

Pro Glu Leu Lys Ser Gly Glu Tyr Trp Val Asp Pro Asn Gln Gly Cys

50 55 60

Lys Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu Thr

65 70 75 80

Cys Ile Ser Ala Asn Pro Leu Asn Val Pro Arg Lys His Trp Trp Thr

85 90 95

Asp Ser Ser Ala Glu Lys Lys His Val Trp Phe Gly Glu Ser Met Asp

100 105 110

Gly Gly Phe Gln Phe Ser Tyr Gly Asn Pro Glu Leu Pro Glu Asp Val

115 120 125

Leu Asp Val Gln Leu Ala Phe Leu Arg Leu Leu Ser Ser Arg Ala Ser

130 135 140

Gln Asn Ile Thr Tyr His Cys Lys Asn Ser Ile Ala Tyr Met Asp Gln

145 150 155 160

Ala Ser Gly Asn Val Lys Lys Ala Leu Lys Leu Met Gly Ser Asn Glu

165 170 175

Gly Glu Phe Lys Ala Glu Gly Asn Ser Lys Phe Thr Tyr Thr Val Leu

180 185 190

Glu Asp Gly Cys Thr Lys His Thr Gly Glu Trp Ser Lys Thr Val Phe

195 200 205

Glu Tyr Arg Thr Arg Lys Ala Val Arg Leu Pro Ile Val Asp Ile Ala

210 215 220

Pro Tyr Asp Ile Gly Gly Pro Asp Gln Glu Phe Gly Val Asp Val Gly

225 230 235 240

Pro Val Cys Phe Leu

245

<210> 80

<211> 246

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 80

Arg Ser Glu Pro Met Asp Phe Lys Ile Asn Thr Asp Glu Ile Met Thr

1 5 10 15

Ser Leu Lys Ser Val Asn Gly Gln Ile Glu Ser Leu Ile Ser Pro Asp

20 25 30

Gly Ser Arg Lys Asn Pro Ala Arg Asn Cys Arg Asp Leu Lys Phe Cys

35 40 45

His Pro Glu Leu Lys Ser Gly Glu Tyr Trp Val Asp Pro Asn Gln Gly

50 55 60

Cys Lys Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu

65 70 75 80

Thr Cys Ile Ser Ala Asn Pro Leu Asn Val Pro Arg Lys His Trp Trp

85 90 95

Thr Asp Ser Ser Ala Glu Lys Lys His Val Trp Phe Gly Glu Ser Met

100 105 110

Asp Gly Gly Phe Gln Phe Ser Tyr Gly Asn Pro Glu Leu Pro Glu Asp

115 120 125

Val Leu Asp Val Gln Leu Ala Phe Leu Arg Leu Leu Ser Ser Arg Ala

130 135 140

Ser Gln Asn Ile Thr Tyr His Cys Lys Asn Ser Ile Ala Tyr Met Asp

145 150 155 160

Gln Ala Ser Gly Asn Val Lys Lys Ala Leu Lys Leu Met Gly Ser Asn

165 170 175

Glu Gly Glu Phe Lys Ala Glu Gly Asn Ser Lys Phe Thr Tyr Thr Val

180 185 190

Leu Glu Asp Gly Cys Thr Lys His Thr Gly Glu Trp Ser Lys Thr Val

195 200 205

Phe Glu Tyr Arg Thr Arg Lys Ala Val Arg Leu Pro Ile Val Asp Ile

210 215 220

Ala Pro Tyr Asp Ile Gly Gly Pro Asp Gln Glu Phe Gly Val Asp Val

225 230 235 240

Gly Pro Val Cys Phe Leu

245

<210> 81

<211> 1196

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 81

Gln Cys Val Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Asp Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Gly Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu

305 310 315 320

Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser Arg Arg Arg Ala Arg Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

Ala Leu Gly Lys Leu Gln Asn Val Val Asn Gln Asn Ala Gln Ala Leu

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val

965 970 975

Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln Tyr Ile Lys

1190 1195

<210> 82

<211> 1196

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 82

Gln Cys Val Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Asp Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Gly Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu

305 310 315 320

Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser Arg Arg Arg Ala Ala Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

Ala Leu Gly Lys Leu Gln Asn Val Val Asn Gln Asn Ala Gln Ala Leu

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val

965 970 975

Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln Tyr Ile Lys

1190 1195

<210> 83

<211> 1196

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 83

Gln Cys Val Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Asp Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Gly Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu

305 310 315 320

Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser Arg Arg Arg Ala Ala Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

Ala Leu Gly Lys Leu Gln Asn Val Val Asn Gln Asn Ala Gln Ala Leu

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val

965 970 975

Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln Tyr Ile Lys

1190 1195

<210> 84

<211> 1196

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 84

Gln Cys Val Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Asp Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Gly Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu

305 310 315 320

Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser Arg Arg Arg Ala Arg Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

Ala Leu Gly Lys Leu Gln Asn Val Val Asn Gln Asn Ala Gln Ala Leu

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val

965 970 975

Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln Tyr Ile Lys

1190 1195

<210> 85

<211> 1507

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 85

Gln Cys Val Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Asp Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Gly Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu

305 310 315 320

Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser Arg Arg Arg Ala Arg Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

Ala Leu Gly Lys Leu Gln Asn Val Val Asn Gln Asn Ala Gln Ala Leu

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val

965 970 975

Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu Pro Gly

1190 1195 1200

Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly

1205 1210 1215

Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly

1220 1225 1230

Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro

1235 1240 1245

Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp

1250 1255 1260

Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu

1265 1270 1275

Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly

1280 1285 1290

Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys

1295 1300 1305

His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln

1310 1315 1320

Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr

1325 1330 1335

Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys

1340 1345 1350

Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp

1355 1360 1365

Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly

1370 1375 1380

Gln Gly Ser Asp Pro Ala Asp Val Ala Ile Gln Leu Thr Phe Leu

1385 1390 1395

Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His Cys

1400 1405 1410

Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu Lys

1415 1420 1425

Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg Ala

1430 1435 1440

Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr Val Asp Gly Cys

1445 1450 1455

Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr Lys

1460 1465 1470

Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala Pro Leu

1475 1480 1485

Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro

1490 1495 1500

Val Cys Phe Leu

1505

<210> 86

<211> 1507

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 86

Gln Cys Val Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Asp Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Gly Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu

305 310 315 320

Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser Arg Arg Arg Ala Ala Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

Ala Leu Gly Lys Leu Gln Asn Val Val Asn Gln Asn Ala Gln Ala Leu

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val

965 970 975

Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu Pro Gly

1190 1195 1200

Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly

1205 1210 1215

Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly

1220 1225 1230

Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro

1235 1240 1245

Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp

1250 1255 1260

Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu

1265 1270 1275

Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly

1280 1285 1290

Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys

1295 1300 1305

His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln

1310 1315 1320

Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr

1325 1330 1335

Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys

1340 1345 1350

Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp

1355 1360 1365

Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly

1370 1375 1380

Gln Gly Ser Asp Pro Ala Asp Val Ala Ile Gln Leu Thr Phe Leu

1385 1390 1395

Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His Cys

1400 1405 1410

Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu Lys

1415 1420 1425

Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg Ala

1430 1435 1440

Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr Val Asp Gly Cys

1445 1450 1455

Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr Lys

1460 1465 1470

Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala Pro Leu

1475 1480 1485

Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro

1490 1495 1500

Val Cys Phe Leu

1505

<210> 87

<211> 1507

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 87

Gln Cys Val Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Asp Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Gly Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu

305 310 315 320

Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser Arg Arg Arg Ala Ala Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

Ala Leu Gly Lys Leu Gln Asn Val Val Asn Gln Asn Ala Gln Ala Leu

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val

965 970 975

Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu Pro Gly

1190 1195 1200

Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly

1205 1210 1215

Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly

1220 1225 1230

Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro

1235 1240 1245

Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp

1250 1255 1260

Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu

1265 1270 1275

Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly

1280 1285 1290

Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys

1295 1300 1305

His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln

1310 1315 1320

Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr

1325 1330 1335

Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys

1340 1345 1350

Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp

1355 1360 1365

Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly

1370 1375 1380

Gln Gly Ser Asp Pro Ala Asp Val Ala Ile Gln Leu Thr Phe Leu

1385 1390 1395

Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His Cys

1400 1405 1410

Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu Lys

1415 1420 1425

Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg Ala

1430 1435 1440

Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr Val Asp Gly Cys

1445 1450 1455

Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr Lys

1460 1465 1470

Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala Pro Leu

1475 1480 1485

Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro

1490 1495 1500

Val Cys Phe Leu

1505

<210> 88

<211> 1507

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 88

Gln Cys Val Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr

1 5 10 15

Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser

20 25 30

Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn

35 40 45

Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys

50 55 60

Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala

65 70 75 80

Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr

85 90 95

Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn

100 105 110

Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu

115 120 125

Asp Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Gly Val

130 135 140

Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe

145 150 155 160

Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu

165 170 175

Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His

180 185 190

Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu

195 200 205

Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln

210 215 220

Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser

225 230 235 240

Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln

245 250 255

Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp

260 265 270

Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu

275 280 285

Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg

290 295 300

Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu

305 310 315 320

Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr

325 330 335

Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val

340 345 350

Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser

355 360 365

Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser

370 375 380

Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr

385 390 395 400

Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly

405 410 415

Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly

420 425 430

Asn Tyr Asn Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro

435 440 445

Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro

450 455 460

Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr

465 470 475 480

Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val

485 490 495

Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro

500 505 510

Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe

515 520 525

Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe

530 535 540

Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala

545 550 555 560

Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser

565 570 575

Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln

580 585 590

Val Ala Val Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala

595 600 605

Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly

610 615 620

Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His

625 630 635 640

Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys

645 650 655

Ala Ser Tyr Gln Thr Gln Thr Asn Ser Arg Arg Arg Ala Arg Ser Val

660 665 670

Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn

675 680 685

Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr

690 695 700

Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser

705 710 715 720

Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn

725 730 735

Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu

740 745 750

Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala

755 760 765

Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly

770 775 780

Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg

785 790 795 800

Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala

805 810 815

Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg

820 825 830

Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro

835 840 845

Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala

850 855 860

Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln

865 870 875 880

Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val

885 890 895

Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe

900 905 910

Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser

915 920 925

Ala Leu Gly Lys Leu Gln Asn Val Val Asn Gln Asn Ala Gln Ala Leu

930 935 940

Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser

945 950 955 960

Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val

965 970 975

Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr

980 985 990

Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn

995 1000 1005

Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys

1010 1015 1020

Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro

1025 1030 1035

Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val

1040 1045 1050

Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His

1055 1060 1065

Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn

1070 1075 1080

Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln

1085 1090 1095

Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val

1100 1105 1110

Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro

1115 1120 1125

Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn

1130 1135 1140

His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn

1145 1150 1155

Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu

1160 1165 1170

Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu

1175 1180 1185

Gly Lys Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu Pro Gly

1190 1195 1200

Pro Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly

1205 1210 1215

Pro Val Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly

1220 1225 1230

Pro Pro Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro

1235 1240 1245

Gln Glu Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp

1250 1255 1260

Ala Asn Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu

1265 1270 1275

Lys Ser Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly

1280 1285 1290

Ser Arg Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys

1295 1300 1305

His Ser Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln

1310 1315 1320

Gly Cys Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr

1325 1330 1335

Gly Glu Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys

1340 1345 1350

Asn Trp Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp

1355 1360 1365

Phe Gly Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly

1370 1375 1380

Gln Gly Ser Asp Pro Ala Asp Val Ala Ile Gln Leu Thr Phe Leu

1385 1390 1395

Arg Leu Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His Cys

1400 1405 1410

Lys Asn Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu Lys

1415 1420 1425

Lys Ala Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg Ala

1430 1435 1440

Glu Gly Asn Ser Arg Phe Thr Tyr Ser Val Thr Val Asp Gly Cys

1445 1450 1455

Thr Ser His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr Lys

1460 1465 1470

Thr Thr Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala Pro Leu

1475 1480 1485

Asp Val Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro

1490 1495 1500

Val Cys Phe Leu

1505

<210> 89

<211> 1520

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 89

Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val

1 5 10 15

Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe

20 25 30

Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu

35 40 45

His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp

50 55 60

Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp

65 70 75 80

Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu

85 90 95

Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser

100 105 110

Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile

115 120 125

Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Asp Val Tyr

130 135 140

Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Gly Val Tyr Ser Ser

145 150 155 160

Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu Met Asp

165 170 175

Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe Val Phe

180 185 190

Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr Pro Ile

195 200 205

Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu Pro Leu

210 215 220

Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr Leu Leu

225 230 235 240

Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp

245 250 255

Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr

260 265 270

Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val Asp

275 280 285

Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe

290 295 300

Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln Pro

305 310 315 320

Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe

325 330 335

Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn

340 345 350

Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn

355 360 365

Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys

370 375 380

Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile

385 390 395 400

Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile

405 410 415

Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile

420 425 430

Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn

435 440 445

Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg

450 455 460

Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro Cys Asn Gly

465 470 475 480

Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln

485 490 495

Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser

500 505 510

Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser

515 520 525

Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu

530 535 540

Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe

545 550 555 560

Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp

565 570 575

Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly

580 585 590

Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val

595 600 605

Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala Ile His Ala

610 615 620

Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val

625 630 635 640

Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn Asn

645 650 655

Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr

660 665 670

Gln Thr Gln Thr Asn Ser Arg Arg Arg Ala Arg Ser Val Ala Ser Gln

675 680 685

Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala

690 695 700

Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val

705 710 715 720

Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys

725 730 735

Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu

740 745 750

Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile

755 760 765

Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys

770 775 780

Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe

785 790 795 800

Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Phe Ile

805 810 815

Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile

820 825 830

Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile

835 840 845

Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr

850 855 860

Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile

865 870 875 880

Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe

885 890 895

Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn

900 905 910

Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala

915 920 925

Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly

930 935 940

Lys Leu Gln Asn Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu

945 950 955 960

Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn

965 970 975

Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln Ile Asp

980 985 990

Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln

995 1000 1005

Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala

1010 1015 1020

Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val

1025 1030 1035

Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser

1040 1045 1050

Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala

1055 1060 1065

Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly

1070 1075 1080

Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr

1085 1090 1095

His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile

1100 1105 1110

Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile

1115 1120 1125

Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu

1130 1135 1140

Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr

1145 1150 1155

Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser

1160 1165 1170

Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala

1175 1180 1185

Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys

1190 1195 1200

Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu Pro Gly Pro Ile

1205 1210 1215

Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly Pro Val

1220 1225 1230

Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro

1235 1240 1245

Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro Gln Glu

1250 1255 1260

Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp Ala Asn

1265 1270 1275

Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu Lys Ser

1280 1285 1290

Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser Arg

1295 1300 1305

Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His Ser

1310 1315 1320

Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly Cys

1325 1330 1335

Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu

1340 1345 1350

Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp

1355 1360 1365

Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly

1370 1375 1380

Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly

1385 1390 1395

Ser Asp Pro Ala Asp Val Ala Ile Gln Leu Thr Phe Leu Arg Leu

1400 1405 1410

Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His Cys Lys Asn

1415 1420 1425

Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu Lys Lys Ala

1430 1435 1440

Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg Ala Glu Gly

1445 1450 1455

Asn Ser Arg Phe Thr Tyr Ser Val Thr Val Asp Gly Cys Thr Ser

1460 1465 1470

His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr Lys Thr Thr

1475 1480 1485

Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala Pro Leu Asp Val

1490 1495 1500

Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro Val Cys

1505 1510 1515

Phe Leu

1520

<210> 90

<211> 1520

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 90

Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val

1 5 10 15

Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe

20 25 30

Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu

35 40 45

His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp

50 55 60

Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp

65 70 75 80

Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu

85 90 95

Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser

100 105 110

Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile

115 120 125

Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Asp Val Tyr

130 135 140

Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Gly Val Tyr Ser Ser

145 150 155 160

Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu Met Asp

165 170 175

Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe Val Phe

180 185 190

Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr Pro Ile

195 200 205

Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu Pro Leu

210 215 220

Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr Leu Leu

225 230 235 240

Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp

245 250 255

Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr

260 265 270

Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val Asp

275 280 285

Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe

290 295 300

Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln Pro

305 310 315 320

Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe

325 330 335

Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn

340 345 350

Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn

355 360 365

Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys

370 375 380

Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile

385 390 395 400

Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile

405 410 415

Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile

420 425 430

Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn

435 440 445

Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg

450 455 460

Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro Cys Asn Gly

465 470 475 480

Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln

485 490 495

Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser

500 505 510

Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser

515 520 525

Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu

530 535 540

Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe

545 550 555 560

Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp

565 570 575

Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly

580 585 590

Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val

595 600 605

Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala Ile His Ala

610 615 620

Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val

625 630 635 640

Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn Asn

645 650 655

Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr

660 665 670

Gln Thr Gln Thr Asn Ser Arg Arg Arg Ala Ala Ser Val Ala Ser Gln

675 680 685

Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala

690 695 700

Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val

705 710 715 720

Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys

725 730 735

Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu

740 745 750

Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile

755 760 765

Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys

770 775 780

Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe

785 790 795 800

Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Phe Ile

805 810 815

Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile

820 825 830

Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile

835 840 845

Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr

850 855 860

Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile

865 870 875 880

Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe

885 890 895

Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn

900 905 910

Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala

915 920 925

Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly

930 935 940

Lys Leu Gln Asn Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu

945 950 955 960

Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn

965 970 975

Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val Gln Ile Asp

980 985 990

Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln

995 1000 1005

Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala

1010 1015 1020

Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val

1025 1030 1035

Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser

1040 1045 1050

Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala

1055 1060 1065

Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly

1070 1075 1080

Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr

1085 1090 1095

His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile

1100 1105 1110

Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile

1115 1120 1125

Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu

1130 1135 1140

Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr

1145 1150 1155

Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser

1160 1165 1170

Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala

1175 1180 1185

Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys

1190 1195 1200

Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu Pro Gly Pro Ile

1205 1210 1215

Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly Pro Val

1220 1225 1230

Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro

1235 1240 1245

Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro Gln Glu

1250 1255 1260

Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp Ala Asn

1265 1270 1275

Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu Lys Ser

1280 1285 1290

Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser Arg

1295 1300 1305

Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His Ser

1310 1315 1320

Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly Cys

1325 1330 1335

Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu

1340 1345 1350

Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp

1355 1360 1365

Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly

1370 1375 1380

Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly

1385 1390 1395

Ser Asp Pro Ala Asp Val Ala Ile Gln Leu Thr Phe Leu Arg Leu

1400 1405 1410

Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His Cys Lys Asn

1415 1420 1425

Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu Lys Lys Ala

1430 1435 1440

Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg Ala Glu Gly

1445 1450 1455

Asn Ser Arg Phe Thr Tyr Ser Val Thr Val Asp Gly Cys Thr Ser

1460 1465 1470

His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr Lys Thr Thr

1475 1480 1485

Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala Pro Leu Asp Val

1490 1495 1500

Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro Val Cys

1505 1510 1515

Phe Leu

1520

<210> 91

<211> 1520

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 91

Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val

1 5 10 15

Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe

20 25 30

Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu

35 40 45

His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp

50 55 60

Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp

65 70 75 80

Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu

85 90 95

Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser

100 105 110

Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile

115 120 125

Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Asp Val Tyr

130 135 140

Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Gly Val Tyr Ser Ser

145 150 155 160

Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu Met Asp

165 170 175

Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe Val Phe

180 185 190

Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr Pro Ile

195 200 205

Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu Pro Leu

210 215 220

Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr Leu Leu

225 230 235 240

Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp

245 250 255

Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr

260 265 270

Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val Asp

275 280 285

Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe

290 295 300

Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln Pro

305 310 315 320

Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe

325 330 335

Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn

340 345 350

Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn

355 360 365

Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys

370 375 380

Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile

385 390 395 400

Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile

405 410 415

Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile

420 425 430

Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn

435 440 445

Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg

450 455 460

Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro Cys Asn Gly

465 470 475 480

Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln

485 490 495

Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser

500 505 510

Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser

515 520 525

Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu

530 535 540

Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe

545 550 555 560

Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp

565 570 575

Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly

580 585 590

Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val

595 600 605

Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala Ile His Ala

610 615 620

Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val

625 630 635 640

Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn Asn

645 650 655

Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr

660 665 670

Gln Thr Gln Thr Asn Ser Arg Arg Arg Ala Ala Ser Val Ala Ser Gln

675 680 685

Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala

690 695 700

Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val

705 710 715 720

Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys

725 730 735

Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu

740 745 750

Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile

755 760 765

Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys

770 775 780

Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe

785 790 795 800

Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Phe Ile

805 810 815

Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile

820 825 830

Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile

835 840 845

Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr

850 855 860

Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile

865 870 875 880

Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe

885 890 895

Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn

900 905 910

Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala

915 920 925

Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly

930 935 940

Lys Leu Gln Asn Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu

945 950 955 960

Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn

965 970 975

Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val Gln Ile Asp

980 985 990

Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln

995 1000 1005

Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala

1010 1015 1020

Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val

1025 1030 1035

Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser

1040 1045 1050

Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala

1055 1060 1065

Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly

1070 1075 1080

Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr

1085 1090 1095

His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile

1100 1105 1110

Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile

1115 1120 1125

Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu

1130 1135 1140

Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr

1145 1150 1155

Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser

1160 1165 1170

Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala

1175 1180 1185

Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys

1190 1195 1200

Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu Pro Gly Pro Ile

1205 1210 1215

Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly Pro Val

1220 1225 1230

Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro

1235 1240 1245

Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro Gln Glu

1250 1255 1260

Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp Ala Asn

1265 1270 1275

Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu Lys Ser

1280 1285 1290

Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser Arg

1295 1300 1305

Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His Ser

1310 1315 1320

Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly Cys

1325 1330 1335

Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu

1340 1345 1350

Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp

1355 1360 1365

Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly

1370 1375 1380

Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly

1385 1390 1395

Ser Asp Pro Ala Asp Val Ala Ile Gln Leu Thr Phe Leu Arg Leu

1400 1405 1410

Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His Cys Lys Asn

1415 1420 1425

Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu Lys Lys Ala

1430 1435 1440

Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg Ala Glu Gly

1445 1450 1455

Asn Ser Arg Phe Thr Tyr Ser Val Thr Val Asp Gly Cys Thr Ser

1460 1465 1470

His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr Lys Thr Thr

1475 1480 1485

Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala Pro Leu Asp Val

1490 1495 1500

Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro Val Cys

1505 1510 1515

Phe Leu

1520

<210> 92

<211> 1520

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic construct

<400> 92

Met Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys Val

1 5 10 15

Asn Leu Arg Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser Phe

20 25 30

Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val Leu

35 40 45

His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr Trp

50 55 60

Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe Asp

65 70 75 80

Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu

85 90 95

Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser

100 105 110

Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile

115 120 125

Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Asp Val Tyr

130 135 140

Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Gly Val Tyr Ser Ser

145 150 155 160

Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe Leu Met Asp

165 170 175

Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu Phe Val Phe

180 185 190

Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His Thr Pro Ile

195 200 205

Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu Pro Leu

210 215 220

Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr Leu Leu

225 230 235 240

Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser Gly Trp

245 250 255

Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln Pro Arg Thr

260 265 270

Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp Ala Val Asp

275 280 285

Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu Lys Ser Phe

290 295 300

Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg Val Gln Pro

305 310 315 320

Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys Pro Phe

325 330 335

Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn

340 345 350

Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn

355 360 365

Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro Thr Lys

370 375 380

Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser Phe Val Ile

385 390 395 400

Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile

405 410 415

Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly Cys Val Ile

420 425 430

Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn

435 440 445

Tyr Arg Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe Glu Arg

450 455 460

Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Lys Pro Cys Asn Gly

465 470 475 480

Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly Phe Gln

485 490 495

Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val Val Leu Ser

500 505 510

Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser

515 520 525

Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe Asn Gly Leu

530 535 540

Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe Leu Pro Phe

545 550 555 560

Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val Arg Asp

565 570 575

Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe Gly Gly

580 585 590

Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val Ala Val

595 600 605

Leu Tyr Gln Gly Val Asn Cys Thr Glu Val Pro Val Ala Ile His Ala

610 615 620

Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly Ser Asn Val

625 630 635 640

Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His Val Asn Asn

645 650 655

Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys Ala Ser Tyr

660 665 670

Gln Thr Gln Thr Asn Ser Arg Arg Arg Ala Arg Ser Val Ala Ser Gln

675 680 685

Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser Val Ala

690 695 700

Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile Ser Val

705 710 715 720

Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val Asp Cys

725 730 735

Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn Leu Leu Leu

740 745 750

Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu Thr Gly Ile

755 760 765

Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala Gln Val Lys

770 775 780

Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly Phe Asn Phe

785 790 795 800

Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser Phe Ile

805 810 815

Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly Phe Ile

820 825 830

Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp Leu Ile

835 840 845

Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu Leu Thr

850 855 860

Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala Gly Thr Ile

865 870 875 880

Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln Ile Pro Phe

885 890 895

Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val Thr Gln Asn

900 905 910

Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe Asn Ser Ala

915 920 925

Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala Leu Gly

930 935 940

Lys Leu Gln Asn Val Val Asn Gln Asn Ala Gln Ala Leu Asn Thr Leu

945 950 955 960

Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val Leu Asn

965 970 975

Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val Gln Ile Asp

980 985 990

Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr Val Thr Gln

995 1000 1005

Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn Leu Ala

1010 1015 1020

Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys Arg Val

1025 1030 1035

Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro Gln Ser

1040 1045 1050

Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val Pro Ala

1055 1060 1065

Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His Asp Gly

1070 1075 1080

Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn Gly Thr

1085 1090 1095

His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln Ile Ile

1100 1105 1110

Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val Ile

1115 1120 1125

Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu

1130 1135 1140

Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr

1145 1150 1155

Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser

1160 1165 1170

Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala

1175 1180 1185

Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys

1190 1195 1200

Tyr Glu Gln Tyr Ile Lys Arg Ser Asn Gly Leu Pro Gly Pro Ile

1205 1210 1215

Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly Pro Val

1220 1225 1230

Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro

1235 1240 1245

Ser Ala Gly Phe Asp Phe Ser Phe Leu Pro Gln Pro Pro Gln Glu

1250 1255 1260

Lys Ala His Asp Gly Gly Arg Tyr Tyr Arg Ala Asn Asp Ala Asn

1265 1270 1275

Val Val Arg Asp Arg Asp Leu Glu Val Asp Thr Thr Leu Lys Ser

1280 1285 1290

Leu Ser Gln Gln Ile Glu Asn Ile Arg Ser Pro Glu Gly Ser Arg

1295 1300 1305

Lys Asn Pro Ala Arg Thr Cys Arg Asp Leu Lys Met Cys His Ser

1310 1315 1320

Asp Trp Lys Ser Gly Glu Tyr Trp Ile Asp Pro Asn Gln Gly Cys

1325 1330 1335

Asn Leu Asp Ala Ile Lys Val Phe Cys Asn Met Glu Thr Gly Glu

1340 1345 1350

Thr Cys Val Tyr Pro Thr Gln Pro Ser Val Ala Gln Lys Asn Trp

1355 1360 1365

Tyr Ile Ser Lys Asn Pro Lys Asp Lys Arg His Val Trp Phe Gly

1370 1375 1380

Glu Ser Met Thr Asp Gly Phe Gln Phe Glu Tyr Gly Gly Gln Gly

1385 1390 1395

Ser Asp Pro Ala Asp Val Ala Ile Gln Leu Thr Phe Leu Arg Leu

1400 1405 1410

Met Ser Thr Glu Ala Ser Gln Asn Ile Thr Tyr His Cys Lys Asn

1415 1420 1425

Ser Val Ala Tyr Met Asp Gln Gln Thr Gly Asn Leu Lys Lys Ala

1430 1435 1440

Leu Leu Leu Gln Gly Ser Asn Glu Ile Glu Ile Arg Ala Glu Gly

1445 1450 1455

Asn Ser Arg Phe Thr Tyr Ser Val Thr Val Asp Gly Cys Thr Ser

1460 1465 1470

His Thr Gly Ala Trp Gly Lys Thr Val Ile Glu Tyr Lys Thr Thr

1475 1480 1485

Lys Thr Ser Arg Leu Pro Ile Ile Asp Val Ala Pro Leu Asp Val

1490 1495 1500

Gly Ala Pro Asp Gln Glu Phe Gly Phe Asp Val Gly Pro Val Cys

1505 1510 1515

Phe Leu

1520

Claims

1. A trimeric fusion protein comprising a soluble coronavirus SARS-CoV-2 delta (b.1.617.2) surface antigen or a fragment, variant or mutant thereof, linked to a C-terminal portion of collagen, which C-terminal portion forms a disulfide-linked trimer, thereby forming the trimeric fusion protein.

2. The trimeric fusion protein of claim 1, comprising a recombinant polypeptide selected from the group consisting of SEQ ID NOs 85-92.

3. A trimeric fusion protein according to claim 1 or 2, for use in the prevention of coronavirus infection, optionally comprising infection with any one or more of SARS-CoV-2Hu-1, alpha, beta, gamma, delta, muir, omnikom and other strains of SARS-CoV-2.

4. The trimeric fusion protein according to any of claims 1-3, which is optionally administered without an adjuvant as an initial agent (primary series), an additional agent (additive series), and/or a homologous or heterologous enhancer (boost) e.g. a first agent, a second agent, a third agent, a fourth agent, and/or more agents, optionally the initial agent, the additional agent, or the heterologous enhancer is used in combination with any one or several of other recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines,

Alternatively the trimeric fusion protein is used as an initial agent, comprising a first needle and a second needle,

optionally the trimeric fusion protein is used without an adjuvant as an additional agent comprising a third needle, a fourth needle, and/or more needles,

alternatively the trimeric fusion protein is used as a homologous or heterologous enhancer comprising a third needle, a fourth needle, and/or more needles, without an adjuvant.

5. A trimeric fusion protein according to any one of claims 1-3, wherein the trimeric fusion protein is administered together with an adjuvant, optionally the trimeric fusion protein is used as an initial agent (primary services), an additional agent (additional dose), and/or a homologous or heterologous booster (boost dose), e.g. a first agent, a second agent, a third agent, a fourth agent, and/or more agents, optionally the initial agent, the additional agent, or the heterologous booster is used in combination with any one or several of other recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines, optionally the adjuvant in the initial agent, the additional agent, and/or the homologous or heterologous booster may independently comprise: aluminum-containing adjuvants, such as alum and/or aluminum hydroxide-containing adjuvants; an oligonucleotide-containing adjuvant, such as a CpG oligodeoxynucleotide (CpG-ODN) -containing adjuvant; an adjuvant comprising a TLR9 agonist; adjuvants comprising metabolisable oil, alpha-tocopherol, and/or polyoxyethylene sorbitan monooleate (tween-80), for example adjuvants comprising squalene, alpha-tocopherol, and tween-80 and/or Span 85 in the form of an oil in water emulsion; or a combination of any of the above adjuvants,

Optionally the trimeric fusion protein is used as a starter with an adjuvant comprising a first needle and a second needle, the adjuvant comprising Alum and an adjuvant comprising CpG oligodeoxynucleotides (CpG-ODN) and/or an adjuvant comprising squalene, alpha-tocopherol, and Tween-80 and/or Span 85 in the form of an oil in water emulsion,

optionally the trimeric fusion protein is used as an additional agent comprising a third needle, a fourth needle, and/or more needles, together with an adjuvant comprising Alum and CpG-containing oligodeoxynucleotides (CpG-ODN) and/or an adjuvant comprising squalene, alpha-tocopherol, and Tween-80 and/or Span 85 in the form of an oil in water emulsion,

optionally the trimeric fusion protein is used as a homologous or heterologous enhancer comprising a third needle, a fourth needle, and/or more needles together with an adjuvant comprising Alum and CpG-containing oligodeoxynucleotides (CpG-ODN) and/or an adjuvant comprising squalene, alpha-tocopherol, and Tween-80 and/or Span 85 in the form of an oil in water emulsion.

6. A trimeric fusion protein according to any one of claims 1-3, wherein the trimeric fusion protein is administered together with one or more adjuvants, optionally the trimeric fusion protein is used as an initial agent (primary services), an additional agent (additional dose), and/or a homologous or heterologous enhancer (boost) such as a first agent, a second agent, a third agent, a fourth agent, and/or more agents, optionally the initial agent, the additional agent, or the heterologous enhancer is used in combination with any one or more of other recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines, optionally the adjuvants in the initial agent, additional agent, and/or homologous or heterologous enhancer may independently comprise: aluminum-containing adjuvants, such as alum and/or aluminum hydroxide-containing adjuvants; an oligonucleotide-containing adjuvant, such as a CpG oligodeoxynucleotide (CpG-ODN) -containing adjuvant; an adjuvant comprising a TLR9 agonist; adjuvants comprising metabolisable oil, alpha-tocopherol, and/or polyoxyethylene sorbitan monooleate (tween-80), for example adjuvants comprising squalene, alpha-tocopherol, and tween-80 and/or Span 85 in the form of an oil in water emulsion; or a combination of any of the foregoing adjuvants.

7. A trimeric fusion protein according to any one of claims 1-3, for use as a starter agent for immunization of a mammal, optionally comprising a first needle and a second needle.

8. The trimeric fusion protein according to claim 7, the first needle and/or the second needle being devoid of an adjuvant.

9. The trimeric fusion protein according to claim 7, the adjuvant of the first needle and/or the second needle comprising: aluminum-containing adjuvants, such as alum and/or aluminum hydroxide-containing adjuvants; and/or an oligonucleotide-containing adjuvant, such as a CpG oligodeoxynucleotide (CpG-ODN) -containing adjuvant.

10. The trimeric fusion protein according to claim 7, the adjuvant of the first needle and/or the second needle comprising: adjuvants containing metabolisable oil, alpha-tocopherol, and/or polyoxyethylene sorbitan monooleate (tween-80), for example adjuvants containing squalene, alpha-tocopherol, and tween-80 and/or Span 85 in the form of an oil in water emulsion.

11. The trimeric fusion protein of any one of claims 1-10, as a third needle, a fourth needle, and/or a further needle additive for immunization of a mammal.

12. The trimeric fusion protein according to any one of claims 1-11, as a third needle, a fourth needle, and/or a further needle booster for immunization of a mammal,

Optionally the enhancer is devoid of an adjuvant,

optionally adjuvants for the enhancer include: aluminum-containing adjuvants, such as alum and/or aluminum hydroxide-containing adjuvants; and/or an oligonucleotide-containing adjuvant, such as a CpG oligodeoxynucleotide (CpG-ODN) -containing adjuvant,

optionally adjuvants for the enhancer include adjuvants comprising metabolisable oil, alpha-tocopherol, and/or polyoxyethylene sorbitan monooleate (tween-80), for example adjuvants comprising squalene, alpha-tocopherol, and tween-80 and/or Span85 in the form of an oil in water emulsion.

13. The trimeric fusion protein of any one of claims 1-12, for use in combination with one or more other vaccines independently selected from the group consisting of recombinant subunit vaccines, nanoparticle vaccines, mRNA vaccines, DNA vaccines, adenovirus vector vaccines, and inactivated virus vaccines.

14. The trimeric fusion protein according to any one of claims 13, wherein the trimeric fusion protein is used as a starter agent and the other vaccine or vaccines are used as a booster agent.

15. The trimeric fusion protein according to any one of claims 13, wherein said other vaccine or vaccines are used as a starter agent and said trimeric fusion protein is used as a booster agent.