CN117715930A

CN117715930A - Antibodies to

Info

Publication number: CN117715930A
Application number: CN202280025767.2A
Authority: CN
Inventors: G·斯克里顿; J·蒙哥沙巴亚
Original assignee: Ruiqiao Biotechnology Co ltd
Current assignee: Ruiqiao Biotechnology Co ltd
Priority date: 2021-02-04
Filing date: 2022-02-04
Publication date: 2024-03-15
Also published as: CN117337301A

Abstract

The present invention relates to antibodies capable of binding to the spike protein of coronavirus SARS-CoV-2, and methods and uses thereof in the prevention, treatment and/or diagnosis of coronavirus infection, and diseases and/or complications associated with coronavirus infection, including COVID-19.

Description

Antibodies to

Technical Field

The present invention relates to antibodies useful in the prevention, treatment and/or diagnosis of coronavirus infection and diseases and/or complications associated with coronavirus infection, including covd-19.

Background

The pathogen SARS-CoV-2 of COVID-19 is a beta coronavirus, which is associated with SARS-CoV-1 and MERS coronavirus, both of which cause severe respiratory syndrome.

Since several months after the identification of SARS-CoV-2 as the causative agent of COVID-19, our understanding of the disease and virus has made tremendous progress. There are many established therapies, including dexamethasone and tolizumab (Tocilizumab) and monoclonal antibodies (mAbs), which have been shown to be effective in both prophylactic and therapeutic settings (Baum et al 2020, science [ science ]369, 1014-1018). Despite these advances, pandemics remain far uncontrolled, resulting in a continual wave of infection.

Coronaviruses have four structural proteins: nucleocapsid proteins, envelope proteins, membrane proteins, and spike (S) proteins. Spike proteins are the most important surface proteins. It has an elongated trimeric structure and is responsible for engaging the target cell and triggering fusion of the virus with the host membrane. Spike proteins from both SARS-CoV-2 and SARS-CoV-1 use angiotensin converting enzyme 2 (ACE 2) as a cell surface receptor. ACE2 is expressed in many tissues, including epithelial cells of the upper and lower respiratory tract.

The S protein consists of two subunits, S1, which mediate receptor binding, and S2, which is responsible for fusion of the viral and host cell membranes. It is a dynamic structure that can be converted to a post-fusion state by cleavage between S1 and S2 following receptor binding or trypsin treatment. In some SARS-CoV-2 sequences, a furin cleavage site is inserted between the S1 and S2 subunits, and mutation of the cleavage site reduces disease in animal models. The S1 fragment occupies the membrane distal tip of S and can be subdivided into an N-terminal domain (NTD) and a Receptor Binding Domain (RBD). While both regions are immunogenic, RBD contains an interactive surface for ACE2 binding. While the RBD is typically pressed down against the top of S2, it can swing up to engage ACE2. Monoclonal antibodies (mabs) recognize one or both of an "up" and "down" conformation. The S protein is relatively conserved between SARS-CoV-2 and SARS-CoV-1 (76%), but the degree of conservation of RBD and NTD (74% and 50%, respectively) is lower than that of the S2 domain (90%). The degree of conservation for MERS-CoV and seasonal human coronaviruses is much lower (19-21%). Overall, the SARS-CoV-2 antibody shows limited cross-reactivity even with SARS-CoV-1.

Binding to ACE2 is mediated by a 25 amino acid patch at the S-tip in the S1 Receptor Binding Domain (RBD). Analysis of the large number of mabs generated from SARS-CoV-2 infected individuals showed that the mabs bound to multiple epitopes on S1 and S2. Most mabs, while capable of binding S with high affinity, show little or no neutralizing activity. Genome monitoring of SARS-CoV-2 has identified thousands of mutations in structural and non-structural proteins. However, at the end of 2020, virus variants are described as rapidly becoming the local dominant strain and causing global spread and are designated as variants of interest (VoC).

Alpha (b.1.1.7) was first identified in the uk and the transmission rate increased. B.1.1.7 there are 9 amino acid changes in the spike, including N501Y in the ACE2 interacting surface. Beta (501Y.V2, also known as B.1.351) was first reported in south Africa. Gamma (P.1, 501Y.V2) was first reported in Brazil to have 10 and 12 amino acid changes in spike proteins, respectively. Delta was first reported in india and now has spread globally, causing outbreaks in multiple countries.

All of these variants contain multiple mutations in S and include RBD, variation in NTD, and in some cases a furin cleavage site between S1 and S2. The RBD mutations found in Alpha (N501Y), beta (K417N, E484K, N501Y), gamma (K417T, E484K, N501Y) and Delta (L452R, T478K) are located in or in close proximity to the ACE2 interacting surface where they potentially modulate ACE2 interactions or disrupt neutralizing antibody binding. The affinity increase of ACE2 interactions is mainly directed to Alpha, beta, gamma and Delta (7, 19, 2 fold, respectively) and may play a role in increasing viral transmissibility.

SARS-CoV-2 assay kits using monoclonal antibodies have also been developed. Examples include lateral flow tests by, for example, innova (rapid qualitative test for SARS-CoV-2 antigen) and Quidel (Sofia 2SARS antigen FIA). However, these tests are reported to be very inaccurate.

All SARS-CoV-2 vaccines currently approved are designed to induce antibody (and T cells) responses to S and contain the S sequence found in the original strain. Thus, particular attention is paid to whether the S mutation in VoC causes immune escape, resulting in vaccine failure or susceptibility to repeated infection in previously infected individuals.

It has been reported that in many studies vaccine efficacy against Beta is reduced, which corresponds to a significant reduction in the neutralization titer of Beta using serum obtained from early pandemic cases or vaccines when compared to neutralization of early pandemic strains (Zhou et al 2021). The RBD mutation present in Beta (K417N, E484K, E484K, N501Y) disrupts the binding of many potent neutralizing mabs, including some mabs being developed for clinical use, and possibly together with changes in NTD accounts for the antigen distance between Beta and early SARS-CoV-2.

The object of the present invention is to identify further improved antibodies useful for the prevention, treatment and/or diagnosis of coronavirus infections and diseases and/or complications associated with coronavirus infections, including covd-19, especially Beta and unidentified variants with additional mutations in RBD in the spike protein of SARS-CoV-2.

Disclosure of Invention

The inventors identified 28 human monoclonal antibodies (mabs) that recognized spike proteins of SARS-CoV-2 (see table 2). These antibodies showed potent neutralizing activity against SARS-CoV-2. Some of the antibodies in Table 2 show potent neutralization that is broadly effective against hCoV-19/Wuhan/WIV04/2019 strains as well as SARS-CoV-2 strains from various lineages, such as A.23.1, B.1.1.7 (alpha), B.1.351 (beta), B.1.258, B.1.526.2, B.1.616, B.1.617.1 (kappa), B.1.617.2 (delta), C36.3, C.37 (lambda), P.1 (gamma) and/or B.1.1.529 (omicron) strains. In addition, some of the antibodies in Table 2 show potent neutralization of specific mutations (e.g., 501Y, 484K, 417N/T) in RBD against spike protein of SARS-CoV-2.

Many mabs in table 2 use a common V gene (V gene common to most populations) and have few mutations relative to the germline. The inventors generated additional antibodies by exchanging the light and heavy chains of the antibodies of tables 1 and 2 derived from the same common V gene. Antibodies derived from the same public V gene have been found to provide particularly useful mixed chain antibodies. For example, some of the resulting mixed chain antibodies exhibited potent neutralization that was widely effective against the hCoV-19/Wuhan/WIV/2019 strain as well as SARS-CoV-2 strains from various lineages, such as A.23.1, B.1.351 (beta), B.1.258, B.1.526.2, B.1.616, B.1.617.1 (kappa), C36.3 and/or C.37 (lambda) strains.

Specifically, the inventors found that antibodies Beta-27, beta-47, beta-48, beta-49, beta-50, beta-53, beta-56, beta-47H/55L, beta-47H/Beta-25L, beta-47H/165L, beta-47H/253L, beta-47H/318L, 253H/Beta-47L, beta-27H/150L, beta-27H/222L, beta-27H/269L and 150H/Beta-27L exhibited potent neutralization that was broadly effective against Victoria, south Africa (B.1.351; beta) and Delta strains without loss of potency.

Furthermore, the inventors identified potent cross-lineage neutralizing antibodies Beta-49 and Beta-50 binding to a conformation of spike protein not previously observed, and this conformation was referred to herein as the "downward and outward" conformation. The "downward and outward conformation" is similar to the conventional downward (receptor inaccessible) conformation except there is no direct contact between the Receptor Binding Domains (RBDs) in the spike protein trimer, except for contact with the N-glycosylation site at amino acid position 343 of the spike protein relative to the hCoV-19/Wuhan/WIV04/2019 strain. The epitope that Beta-49 and Beta-50 bind extends through both subunits of the spike protein trimer and enables the antibody to lock the trimer in the "downward and outward conformation", which is receptor inaccessible. The epitopes bound by Beta-49 and Beta-50 are well conserved across the various lineages of SARS-CoV-2. Although mutations have been observed in the epitopes bound by antibodies Beta-49 and Beta-50, particularly SARS-CoV-2 variants, these mutations surprisingly do not affect the neutralizing properties of antibodies Beta-49 and Beta-50. Thus, antibodies that bind the same epitope as Beta-49 and Beta-50 are expected to have broad cross-lineage neutralizing properties.

Accordingly, in one aspect the invention provides an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, wherein: (a) The antibody comprises at least three CDRs of antibody Beta-47 or any one of the 27 antibodies in table 2; (b) The antibody is capable of binding to the same epitope on the spike protein as the antibody Beta-49 or Beta-50, or competing with the antibody Beta-49 or Beta-50; or (c) the antibody is capable of locking the spike protein in a downward and outward conformation, wherein the downward and outward conformation is characterized by spike trimers comprising three spike proteins, with the exception of contact between the Receptor Binding Domains (RBDs) of the spike proteins without direct contact via the N-glycosylation site at amino acid position 343 of the spike protein relative to the hCoV-19/Wuhan/WIV04/2019 strain.

The invention also provides an antibody combination comprising two or more antibodies according to the invention.

The invention also provides an antibody combination comprising (a) an antibody according to the invention; and (b) an antibody comprising at least three CDRs of the antibody in table 1. For example, the antibody of (b) comprises: (i) At least four, five, or all six CDRs of an antibody in table 1; (ii) A heavy chain variable domain comprising or consisting of an amino acid sequence having at least 80% sequence identity to a heavy chain variable domain of an antibody in table 1; (iii) A light chain variable domain comprising or consisting of an amino acid sequence having at least 80% sequence identity to a light chain variable domain of an antibody in table 1; and/or (iv) a heavy chain variable domain and a light chain variable domain comprising or consisting of an amino acid sequence having at least 80% identity to the heavy chain variable domain and the light chain variable domain, respectively, of an antibody in table 1.

The invention also provides one or more polynucleotides encoding an antibody according to the invention, one or more vectors comprising said polynucleotides or a host cell comprising said vectors.

The invention also provides a method for producing an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, comprising culturing the host cell of the invention and isolating the antibody from said culturing.

The invention also provides a pharmaceutical composition comprising: (a) An antibody or combination of antibodies according to the invention, and (b) at least one pharmaceutically acceptable diluent or carrier.

The invention also provides an antibody, antibody combination or pharmaceutical composition according to the invention for use in a method of treatment of the human or animal body by therapy.

The invention also provides an antibody, antibody combination or pharmaceutical composition according to the invention for use in a method of treating or preventing a disease or complication associated with a coronavirus infection.

The invention also provides a method of treating or preventing a coronavirus infection or a disease or complication associated with a coronavirus infection, the method comprising administering to the subject a therapeutically effective amount of an antibody, antibody combination or pharmaceutical composition according to the invention.

The invention also provides a method of identifying the presence of a coronavirus or fragment thereof in a sample, the method comprising: (i) Contacting the sample with an antibody or combination of antibodies according to the invention, and (ii) detecting the presence or absence of an antibody-antigen complex, wherein the presence of the antibody-antigen complex is indicative of the presence of coronavirus or fragment thereof in the sample.

The invention also provides a method of treating or preventing a coronavirus infection or a disease or complication associated therewith in a subject, the method comprising identifying the presence of a coronavirus according to the method of the invention and treating the subject with an antibody or combination, antiviral or anti-inflammatory agent according to the invention.

The invention also provides an antiviral or anti-inflammatory agent for use in a method of treating or preventing a coronavirus infection or a disease or complication associated therewith in a subject, wherein the method comprises identifying the presence of a coronavirus according to the method of the invention and treating the subject with a therapeutically effective amount of the antiviral or anti-inflammatory agent.

The invention also provides the use of an antibody, antibody combination or pharmaceutical composition according to the invention for the prevention, treatment and/or diagnosis of a coronavirus infection or a disease or complication associated therewith.

The invention also provides the use of an antibody, antibody combination or pharmaceutical composition according to the invention in the manufacture of a medicament for the treatment or prophylaxis of a coronavirus infection or a disease or complication associated therewith.

The invention also provides an antibody, combination or pharmaceutical composition of the invention for use in a method of preventing, treating or diagnosing a coronavirus infection caused by a SARS-CoV-2 strain comprising a substitution at position 417, 484, 501, 452 and/or 478 in the spike protein relative to the spike protein of the hCoV-19/Wuhan/WIV/2019 strain, e.g. it is a member of lineage alpha, beta, gamma or delta.

The invention also provides a method of producing an antibody capable of binding to a spike protein of SARS-CoV-2, comprising producing an antibody directed against a modified spike protein locked in a downward and outward conformation, wherein the downward and outward conformation is characterized by a lack of direct contact between the three Receptor Binding Domains (RBDs) of the spike protein trimer, except for contact with the N-glycosylation site at amino acid position 343 of the spike protein relative to the hCoV-19/Wuhan/WIV/2019 strain.

Drawings

FIG. 1 isolation and characterization of beta SARS-CoV-2 specific mAb. (A) Comparison of Beta neutralization and S binding ELISA was performed by convalescence plasma from a donor diagnosed with Beta SARS-CoV-2 infection. FRNT50 >Plasma samples of 1:250 are highlighted and correspond to the case shown in D. (B) Neutralization titers against SARS-CoV-2 strain Victoria and Beta variants of 5 selected plasma samples with potent neutralization properties were analyzed using Wilcoxon paired symbol rank test and double tail p-values were calculated; the geometric mean is indicated above each column. (C) A schematic diagram of the Beta separation strategy is shown. (D) Antigen-specific single B cells were isolated using the labeled recombinant S protein as a bait. Measurement of S-reactive IgG by FACS ⁺ Frequency of B cells. (E) Epitope mapping of Beta-specific mabs against S and RBD was assessed by ELISA. (F) Neutralization potency (IC 50) between anti-S (non-RBD) and anti-RBD mabs against authentic Beta was obtained using the focus-reduced neutralization test (focus reduction neutralization test, FRNT). (G) Comparison of IC50 values for ACE2 binding with FRNT50 titers of selected mabs.

FIG. 2. Cross-reactivity of beta-specific mAbs. Neutralization assays were performed with selected Beta-specific mabs against Victoria, alpha (N501Y), beta (K417N, E484K, N501Y), gamma (K417T, E484K, N501Y), delta (L452R, T478K), alpha+e484K (E484K, N501Y) and b.1.525 (E484K) live virus isolates. Titration curves are shown and mabs are grouped according to cross-reactivity pattern between virus variants. Potential binding determinants of mabs that showed differential neutralization between isolates are indicated. (a) a fully cross-reactive mAb, (B) an N501Y-dependent mAb, (C) an E484K-dependent mAb, (D) a K417N/T-dependent mAb, (E) an L452R/T478K-dependent mAb, and (F) an NTD-binding mAb. FRNT50 is reported in table 10.

FIG. 3 mAb therapy after use and exposure of genes for SARS-CoV-2Beta VoC in K18-hACE2 mice. (A) IgVH and IgVL genes of the selected mAbs were used. (B) amino acid substitutions in IGHV and IGHL of 27 potent mAbs. (C-F) administration of 10 by intranasal administration to 8 week old female K18-hACE2 transgenic mice ³ SARS-CoV-2Beta strain of FFU. One day later, mice received a single 10mg/kg dose of indicated mAb treatment by intraperitoneal injection. Tissues were collected at 6 dpi. (A) Changes in body weight after infection with SARS-CoV-2 (mean ± SEM; n=6 mice per group, two experiments; one-way ANOVA: P using Dunnett test of area under curve<0.0001). Viral RNA levels in lung (B), nasal wash (C) and brain (D) (line represents median; n=6 mice per group, two experiments; one-way ANOVA: P) using Dunnett's test compared to control mAb<0.01，***P＝0.001，****P<0.0001. The dashed line indicates the detection limit of the assay).

FIG. 4 results of Biological Layer Interferometry (BLI) competition mapping. The average fine position of the antibodies is shown as spheres, the numbers match the antibody definitions in table 10, but the prefix "β" is omitted for clarity. Staining protocols are associated with one aspect of serological properties, e.g., Y501 dependence indicates that potent neutralization is observed only for those viruses bearing Tyr-501. Anatomical terms relate to torso analogy (dejniratisai et al 2021 a). The RBD is shown embedded in the translucent molecular surface of the cartoon. Three views are shown, the outer two views being related by rotation 180 ° about a vertical axis and the central view being related to the "front" view by rotation 90 ° about a horizontal axis.

FIG. 5. The general structure of the Beta-RBD/Beta-S complex with Beta-mAb Fab. (A) Front and rear views of the Beta-RBD/Beta-Fab complex. Fab is shown as a ribbon, heavy chain red and light chain blue, and RBD is shown as a grey surface representation, ACE2 footprint green, mutation site of Beta variant magenta and Delta variant orange. All structures were determined by crystallography, except Beta-26 and Beta-32, which were derived from cryo-EM (cryo-electron microscopy). (B) The heavy chain is red and the light chain is blue Beta-32 Fab crystal structure. (C) Cryo-EM density map of complexes of Beta-S with Beta-6, beta-26, beta-32, beta-44, beta-53 and COVOX-222 Fab. The bound Fab was orange, RBD domain was cyan, and the remaining spikes were grey. Arrows indicate the orientation of the RBD.

FIG. 6. Structural details of IgVH4-30 and IgVH4-39 Beta Fab complexes. (A) interaction of Beta-6 with Beta-RBD. The first set of summaries of the interactions of CDRs from the heavy (magenta) and light (cyan) chains with Beta-RBD (translucent gray surface and side chains are blue bars, mutation sites for Beta and Delta variants are shown as magenta and orange spheres, respectively). The interactions of the H3, H2, H1 and L3 loops are shown in the adjacent figures. (B) Difference in binding orientation between Beta-6 (blue) and Beta-54 (red). (C) A close-up of the junction of CDR-H3 with Tyr-501 (B) is shown. (D) is identical to (C) except that IgVH is overlapped instead of RBD. (E) details of Beta-54 interaction with Beta-RBD. (F) The binding mode of Beta-40 IgVH (green) compared to the binding mode of Beta-6 (blue). (G) detailed interaction of Beta-24 with Beta-RBD. (H) Common features of the joints used for Beta-6 (blue), 24 (cyan) and 54 (red). Y35 of CDR-H1 and Y54 of CDR-2 are conserved among IgVH4-30 and IgVH4-39 Beta-mAbs reported herein.

FIG. 7 engagement of other Beta IgVH Fab with Beta-RBD. (A) In contrast to COVOX-222 (red, PDB ID 7 NXA) and COVOX-150 (gray, PDB ID 7 BEI), CDR-L1 of cross-reactive IgVH3-53 Beta-27 (blue) was conjugated to Tyr-501. (B) Beta-32 (green) binding pattern compared to Beta-6 (blue). (C) Beta-38 directly engages E484K by forming a salt bridge from D94 of CDR-L3 and a hydrogen bond from N32 of CDR-L1. (D) Details of the interaction of Beta-22 are plotted in the same manner as in FIG. 6A. (E) Comparison of binding patterns between Beta-22 and Beta-29. (F) Details of the interaction between Beta-44 and Beta-RBD. (G) Details of the interaction between Beta-47 and Beta-RBD. (H) Beta-26 binds at the left shoulder and contacts K484 and T478 of the RBD. (I) Beta-53 (HC red and LC blue) binds to S309 (HC salmon red and LC light blue; PDB ID 7 BEP) at the same epitope. (J) Binding position and orientation of Beta-53 relative to the receptor ACE 2.

FIG. 8 binding of Beta-43 to plate immobilized Wuhan, alpha, beta and Gamma NTD was determined by ELISA.

Fig. 9. Clustering analysis of paired Biological Layer Interferometry (BLI) competition experiments (see example 16). These points are projected onto two dimensions with minimal information loss. In the trunk analogy, there is a reasonably continuous distribution essentially from one side up across the shoulders, neck, shoulders to the opposite side.

FIG. 10 gold standard Fourier Shell Correlation (FSC) curves for globally and locally refined S-Fab complexes. The partial refinement of RBD, fab and the rest are cyan, orange and light grey, respectively, and the fitted RBD/Fab model is reddish (black outline). The map/model pairs are rotated 180 deg. relative to each other.

FIG. 11 (A) is a table defining mutations in spike proteins from different strains when compared to the Wuhan SARS-CoV-2 spike protein sequence. (B) Shows the IC of selected antibodies against a panel of pseudoviral constructs with mutations when compared to the Wuhan SARS-CoV-2 spike protein sequence in Table 13 ₅₀ Graph of curve.

FIG. 12 binding of Beta-49 and 50Fab and IgG1 to Beta S trimer or Beta RBD, as measured by ELISA, was compared to binding of mAb 222.

FIG. 13.17 Alpha recovery serum was analyzed for FRNT50 titers for Alpha and B.1 (D614G) using the Wilcoxon paired symbol rank sum test and calculated as two-tailed p-value; the geometric mean is indicated above each column.

FIG. 14 (A) shows a cross-correlation matrix of consistency of neutralization titers of antibodies against seven SARS-CoV-2 variants. Each antibody was associated with the vehicle containing residual neutralization titers after subtracting the mean of each variant and normalizing to standard deviation 1. Each point (i, j) in the matrix is colored according to the dot product between the vectors of antibodies i and j. (B) And (3) carrying out singular value decomposition on the matrix in the step (A), and drawing a result of a main variation mode. (C) Results of plotting the primary variation pattern after singular value decomposition of correlation matrices similar to (a) but calculated for Beta antibodies and colored according to their names as full cross-reactivity, 501Y-specific, 484K-specific or 417T-specific antibodies.

FIG. 15 Cryo-EM density plot of Beta-S complex with Beta-43, 49, 50. The bound Fab was orange, RBD domain was cyan, and the remaining spikes were grey. Arrows indicate the orientation of the RBD.

FIG. 16 engagement of other Beta IgVH Fab with Beta-RBD. (A) Beta-49 and Beta-50 (blue and salmon red, respectively) are almost identical to the combinations depicted by the RBD standards. (B) Coverage of the N343 RBD glycans from the S309 (green) (Pinto et al 2020), beta-53 (yellow) and Beta 49 (gray) complexes, in which the side chains are rotated into unfavorable conformations. (C) Top view of Beta-49 Fan and Beta-S cryo-EM complex. S shows the RBD surface in cyan (where the glycan attaches to residue 343 shows magenta), while Beta-49 heavy and light chains show dark pink and blue cartoon, respectively. The heavy chain contacts both RBDs, forming primary (marked with circles) and secondary (marked with ellipses) epitopes. (D) A top view of a typical RBD with all RBDs in Beta-49 binding state in downward spike (PDB 7 NDA). The three fold axes of S are shown. One RBD is superimposed (referenced), and the arrows show the motion in the other RBDs induced on the binding Beta-49. (E) a close-up of a secondary epitope with some RBD residues tagged. (F) close-up of Beta-49 interaction with Beta-S. RBD is shown as rods and surface (except for glycans at residue N343, which is shown as rods only). Fab is shown as a rod stained by chains. (G) is similar to (F), but for Beta-50. Comparison of the attachment of Beta-27 to mabs 150 and 222. RBD is shown as the surface where residue 501 is highlighted. (I) Side view of the right shoulder and neck region (shown as the surface) of the RBD shows Beta-27 and mabs 150 and 222. The transfer caused by repositioning of HC CDR3 is shown with arrows. (J) comparison of Beta-6 and Beta-32 with RBD attachment. The axis on the left graph shows the difference in pose. (K) K484 is shown surrounded by CDR3 of the light and heavy chains of Beta-38.

FIG. 17 details of beta-43 binding to NTD, the standard depiction is that NTD is a gray surface.

FIG. 18 (A) cross-reactivity of Beta 49, 50 with SARS-CoV-1S trimer as measured by ELISA and compared to mAb S309. (B) Neutralization curves for Beta obtained using mAb S309, beta-49, 50, 53.

FIG. 19 gold standard FSC curve of globally and locally refined S-Fab complexes. The partial refinement of RBD, fab and the rest are cyan, orange and light grey, respectively, and the fitted RBD/Fab model is reddish (black outline). The map/model pairs are rotated 180 deg. relative to each other.

FIG. 20 epitopes of antibodies Beta-49 and 50. (A) Beta-49 compares to the binding patterns of Beta-53 and S309. The crystal structure of Beta-49/Beta-RBD is shown below: RBD is a grey surface, three mutation sites are highlighted in magenta, vhVL is a band and N343 glycans is a bar (left panel). The middle panel compares the binding pattern of Beta-49 to Beta-53 (cyan, PDB ID 7PS 2), and the right panel compares it to S309 (blue, PDB ID 7 BEP). (B) Sequences of RBD regions of SARS-CoV-2 (SEQ ID NO: 714) and SARS-CoV-1 (SEQ ID NO: 715). The conserved major epitopes are tagged with cyan, N and C, which tag the ends of the natural sequences in the soluble RBD construct. The secondary structure in SARS-CoV-2 is labeled as above, and the sequence number of SARS-CoV-2 is given.

Fig. 21.Ntd conformational changes. Comparison of the Crystal Structure of Beta-NTD bound to Beta-43 with the Crystal Structure of the original Virus strain. (A) Two Beta-NTD/Beta-43 complexes in the crystal asymmetry unit were compared by overlapping Beta-NTD. Beta-NTD, HC, and LC are green, red, and blue in one complex, and light green, salmon red, and light blue in a second complex. The mutation sites are shown as magenta spheres. The C alpha of residue 241 is orange, after which three residues are deleted in the Beta variant. (B) Overlapping of Beta-NTD (green) with biliverdin-bound NTD (grey, PDB ID 7B 62). The box area shows a large difference between the two structures. (C) Comparison of (D) Beta-NTD/Beta-43 complex (color as (A)) with NTD/N11 Fab complex (C) (NTD, HC and LC are gray, salmon red and bluish, respectively, PDB ID 7E 7X) and NTD/S2M28 Fab complex (D) (color scheme as (C), PDB ID 7LY 3).

Cross-reactivity of beta-specific mabs. Neutralization assays were performed with selected Beta-specific mabs against Victoria, alpha (N501Y), beta (K417N, E484K, N501Y), gamma (K417T, E484K, N Y), delta (L452R, T478K) and Omicron (G339D, S371L, S373P, S F, K417N, N K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y H) live virus isolates. FRNT50 is reported in table 15.

FIG. 23 (A) ternary complex of Omicon-RBD (gray)/Beta-55 (HC red, LC blue)/EY 6A (HC salmon red, LC cyan). (B) Electron density plots show the densities of mutated residues at 446, 498, 501 and 505, and their interactions with CDR-H3 of Beta-55. (C) And (D) comparison of Beta-55 with binding patterns of Beta-24 ((cyan in C)) and Beta-40 ((cyan in D)).

Detailed Description

Antibodies of the invention

The antibodies of the invention specifically bind to the spike protein of SAR-CoV-2. Specifically, it specifically binds to the S1 subunit of spike protein, such as the Receptor Binding Domain (RBD) or the N-terminal domain (NTD).

The antibodies of the invention may comprise at least three CDRs of an antibody in table 2. The antibody may comprise at least four, five, or all six CDRs of an antibody in table 2. The antibody may comprise or consist of a heavy chain variable domain comprising an amino acid sequence having at least 80% sequence identity to the heavy chain variable domain of an antibody in table 2. The antibody may comprise or consist of a light chain variable domain comprising an amino acid sequence having at least 80% sequence identity to the light chain variable domain of the antibody in table 2. The antibody may comprise or consist of an amino acid sequence having at least 80% identity to the heavy chain variable domain and the light chain variable domain of the antibody in table 2, respectively. The antibody may be any of the antibodies in table 2.

Table 2 lists 28 individual antibodies identified from recovered Beta SARS-CoV-2COVID-19 patients. Table 1 lists 42 individual antibodies previously identified from recovered COVID-19 patients [ Dejnigisai, wanwisa et al, "antigen anatomy of The antigenic anatomy ofSARS-CoV-2receptorbinding domain[SARS-CoV-2 receptor binding domain ]" Cell [ Cell ]184 (8) (2021):2183-2200; supasa, piyada et al, "Reduced neutralization ofSARS-CoV-2B.1.1.7variantby convalescent and vaccine sera [ reduction of neutralization of SARS-CoV-2B.1.1.7 variants by convalescence serum and vaccine serum ]" Cell [ Cell ]184 (8) (2021):2201-2211; zhou, daming et al, "Evidence ofescape ofSARS-CoV-2variant B.1.351from natural andvaccine-reduced sera [ SARS-CoV-2variant B.1.351 evidence of escape from natural serum and vaccine-induced serum ]" Cell [ Cell ]184 (9) (2021):2348-2361; dejnirattisai, wanwisa et al, "Antibody evasion by the P.1strain of SARS-CoV-2[ antibody escape of P.1strain of SARS-CoV-2 ]" Cell [ Cell ]184 (11) (2021):2939-2954; liu, chang et al, "Reducedneutralization of SARS-CoV-2B.1.617by vaccine and convalescent serum [ neutralization of SARS-CoV-2B.1.617by vaccine serum and convalescent serum ]" Cell [ Cell ]184 (16) (2021):4220-4236 ]. The antibodies in Table 1 are also referred to herein by the prefix "COVOX", such as COVOX-222. Tables 1 and 2 list the heavy and light chain variable region nucleotide and amino acid sequences of each of the antibodies and the Complementarity Determining Regions (CDRs) of the variable chains.

The antibodies in table 2 may be selected from the group consisting of: beta-22, beta-27, beta-29, beta-40, beta-47, beta-53, beta-54, beta-55, and Beta-56. It has surprisingly been found that these antibodies can retain neutralization of the SARS-CoV-2 variant Omicron (e.g., IC 50.ltoreq.5. Mu.g/ml for Omicron).

The antibodies in table 2 may be selected from the group consisting of: beta-22, beta-29, beta-40, beta-47, beta-53, beta-54, beta-55, and Beta-56. It has surprisingly been found that these antibodies retain a strong neutralization of the SARS-CoV-2 variant Omicron (e.g.IC 50.ltoreq.0.4. Mu.g/ml for Omicron).

The antibodies in table 2 may be selected from the group consisting of: beta-40, beta-47, beta-54 and Beta-55. It was surprisingly found that these antibodies can retain a strong neutralization of the SARS-CoV-2 variant Omicron (e.g.ltoreq.0.11. Mu.g/ml for Omicron) and further retain a strong neutralization of the SARS-CoV-2 variant (Victoria, alpha, beta, gamma and Delta) for all other tests.

The antibodies in table 2 may be selected from the group consisting of: beta-27, beta-47, beta-48, beta-49, beta-50, beta-53, and Beta-56. Surprisingly, it was found that these antibodies can retain strong neutralization of SARS-CoV-2 variant Victoria, B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), B.1.1.7+E484Q, B.1.525, B1.617.1, C.37, B.1.616, B.1.258, C.36.3, B.1.526.2 and A.23.1+E484K, e.g.with an IC50 of +.0.02 μg/ml for most, if not all, of the tested strains (see e.g.tables 10, 12 and 13).

The antibodies in table 2 may be selected from the group consisting of: beta-27, beta-32, beta-47, beta-48, beta-49, beta-50, beta-53, beta-55, and Beta-56. These antibodies were found to have potent cross-lineage neutralization, e.g., they were effective against Victoria, alpha, beta, gamma, delta, alpha +484K and b.1.525 strains (e.g., IC50 less than 0.1 μg/ml as shown in table 10).

The antibodies in Table 2 can be any of Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50, beta-53, beta-06, beta-10, beta-23, beta-24, beta-30, beta-40, beta-54, beta-55, beta-56, and Beta-44. It was surprisingly found that these antibodies showed strong neutralization of SARS-CoV-2 strain comprising a mutation at position 501 of RBD.

The antibodies in Table 2 can be any of Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50, beta-53, beta-26, beta-33, beta-34, beta-38, beta-45, beta-51, and Beta-44. It was surprisingly found that these antibodies showed strong neutralization of the SARS-CoV-2 strain comprising a mutation at position 484 of RBD.

The antibodies in Table 2 can be any of Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50, beta-53, beta-20, beta-22, beta-29, and Beta-44. It was surprisingly found that these antibodies showed strong neutralization of the SARS-CoV-2 strain comprising a mutation at position 417 of the RBD.

The antibodies in Table 2 can be any of Beta-06, beta-10, beta-23, beta-24, beta-30, beta-40, beta-54, beta-55, beta-56, and Beta-44. Surprisingly, these antibodies were found to exhibit strong neutralization of SARS-CoV-2alpha strain.

The antibodies in table 2 may be any of the following: beta-47, beta-27, beta-32, beta-48, beta-49, beta-50, and Beta-53; beta-26, beta-33, beta-34, beta-38, beta-45, beta-51; beta-20, beta-22, beta-29 and Beta-44. Surprisingly, these antibodies were found to exhibit strong neutralization of SARS-CoV-2gamma strain.

The antibodies in Table 2 can be any of Beta-20, beta-24, beta-26, and Beta-27. Surprisingly, these antibodies were found to exhibit strong neutralization of SARS-CoV-2 strain in mice.

Thus, in one embodiment, the antibodies in Table 2 may be Beta-27. Beta-27 was found to neutralize Omacron variants of SARS-CoV-2 (see Table 15, FIG. 22). In one embodiment, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 485, 486 and 487, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 488, 489 and 490, respectively. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-27 (i.e., SEQ ID NO: 482). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the light chain variable domain of antibody Beta-27 (i.e., SEQ ID NO: 484). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy and light chain variable domains of antibody Beta-27 (i.e., SEQ ID NOs: 482 and 484, respectively).

The heavy chain domain of Beta-27 is derived from the IGHV3-53 v region, and the inventors found that converting heavy and light chains between antibodies derived from the same v region can result in antibodies that are particularly useful in the present invention (see further explanation below). Thus, an antibody of the invention may comprise a heavy chain of Beta-27, rather than a light chain of Beta-27. For example, the antibody may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOS 485, 486 and 487, respectively. The antibody may comprise or consist of a heavy chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-27 (i.e., SEQ ID NO: 482). The antibody may comprise or consist of a heavy chain variable domain comprising or consisting of SEQ ID NO 482.

Alternatively, in embodiments of the invention, the antibody may comprise a light chain of Beta-27, rather than a heavy chain of Beta-27. For example, the antibody may comprise CDRL1, CDRL2 and CDRL3 having the amino acid sequences set forth in SEQ ID NOS 488, 489 and 490, respectively. The antibody may comprise or consist of a light chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the light chain variable domain of antibody beta-27 (i.e., SEQ ID NO: 484). The antibody may comprise or consist of a light chain variable domain comprising or consisting of SEQ ID NO 484.

In one embodiment, the antibodies in Table 2 may be Beta-47. Beta-47 was found to strongly neutralize the Omacron variant of SARS-CoV-2 (IC 50 is.ltoreq.0.1. Mu.g/ml; see Table 15, FIG. 22). In one embodiment, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 595, 596 and 597, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 598, 599 and 600, respectively. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-47 (i.e., SEQ ID NO: 592). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the light chain variable domain of antibody Beta-47 (i.e., SEQ ID NO: 594). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy and light chain variable domains of antibody Beta-47 (SEQ ID NO:592 and 594, respectively).

The heavy chain domain of Beta-47 is derived from the IGHV1-58 v region, and the inventors found that converting heavy and light chains between antibodies derived from the same v region can result in antibodies that are particularly useful in the present invention (see further explanation below). Thus, an antibody of the invention may comprise the heavy chain of Beta-47, but not the light chain of Beta-47. For example, the antibody may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 595, 596 and 597, respectively. The antibody may comprise or consist of a heavy chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-47 (i.e., SEQ ID NO: 592). The antibody comprises a heavy chain variable domain comprising or consisting of SEQ ID NO 592.

Alternatively, in embodiments of the invention, the antibody may comprise a light chain of Beta-47, rather than a heavy chain of Beta-47. For example, the antibody may comprise CDRL1, CDRL2 and CDRL3 having the amino acid sequences set forth in SEQ ID NOS 598, 599 and 600, respectively. The antibody may comprise or consist of a light chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the light chain variable domain of antibody Beta-47 (i.e., SEQ ID NO: 594). The antibody may comprise or consist of a light chain variable domain comprising or consisting of SEQ ID NO. 594.

In one embodiment, the antibodies in Table 2 may be Beta-48. In one embodiment, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 605, 606 and 607, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 608, 609 and 610, respectively. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-48 (i.e., SEQ ID NO: 602). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the light chain variable domain of antibody Beta-48 (i.e., SEQ ID NO: 604). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy chain variable domain and the light chain variable domain of antibody Beta-48 (SEQ ID NO:602 and 604, respectively).

The heavy chain domain of Beta-48 is derived from the IGHV3-21 v region, and switching the heavy and light chains between antibodies derived from the same v region can result in antibodies useful in the present invention. Thus, an antibody of the invention may comprise a heavy chain of Beta-48, rather than a light chain of Beta-48. For example, the antibody may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 605, 606 and 607, respectively. The antibody may comprise or consist of a heavy chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-48 (i.e., SEQ ID NO: 602). The antibody may comprise or consist of a heavy chain variable domain comprising or consisting of SEQ ID NO 602.

In embodiments of the invention, the antibody may comprise a light chain of Beta-48, rather than a heavy chain of Beta-48. For example, the antibody may comprise CDRL1, CDRL2 and CDRL3 having the amino acid sequences set forth in SEQ ID NOS 608, 609 and 610, respectively. The antibody may comprise or consist of a light chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the light chain variable domain of antibody Beta-48 (i.e., SEQ ID NO: 604). The antibody may comprise or consist of a light chain variable domain comprising or consisting of SEQ ID NO 604.

In one embodiment, the antibody in Table 2 may be Beta-49. In one embodiment, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 615, 616 and 617, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 618, 619 and 620, respectively. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-49 (i.e., SEQ ID NO: 612). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the light chain variable domain of antibody Beta-49 (i.e., SEQ ID NO: 614). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy and light chain variable domains of antibody Beta-49 (i.e., SEQ ID NOs: 612 and 614, respectively).

The heavy chain domain of Beta-49 is derived from the IGHV 1-69v region, and switching the heavy and light chains between antibodies derived from the same v region can result in antibodies useful in the present invention. Thus, an antibody of the invention may comprise the heavy chain of Beta-49, rather than the light chain of Beta-49. For example, the antibody may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOS 615, 616 and 617, respectively. The antibody may comprise or consist of an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-49 (i.e., SEQ ID NO: 612). The antibody may comprise or consist of SEQ ID NO: 612.

Alternatively, in embodiments of the invention, the antibody may comprise a light chain of Beta-49, rather than a heavy chain of Beta-49. For example, the antibody may comprise CDRL1, CDRL2 and CDRL3 having the amino acid sequences set forth in SEQ ID NOS 618, 619 and 620, respectively. The antibody may comprise or consist of a light chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the light chain variable domain of antibody Beta-49 (i.e., SEQ ID NO: 614). The antibody may comprise or consist of a light chain variable domain comprising or consisting of SEQ ID NO 614.

In one embodiment, the antibodies in Table 2 may be Beta-50. In one embodiment, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences set forth in SEQ ID NOs 625, 626 and 627, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 628, 629 and 630, respectively. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-50 (i.e., SEQ ID NO: 622). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the light chain variable domain of antibody Beta-50 (i.e., SEQ ID NO: 624). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% >, 90% >, 95% >, 96% >, 97% >, 98% >, 99% or 100% sequence identity with the heavy and light chain variable domains of antibody Beta-50 (i.e., SEQ ID NOs: 622 and 624, respectively).

The heavy chain domain of Beta-50 is derived from the IGHV 1-69v region, and switching the heavy and light chains between antibodies derived from the same v region can result in antibodies useful in the present invention. Thus, an antibody of the invention may comprise a heavy chain of Beta-50, rather than a light chain of Beta-50. For example, the antibody may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOS 625, 626 and 627, respectively. The antibody may comprise or consist of a heavy chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-50 (i.e., SEQ ID NO: 622). The antibody may comprise or consist of SEQ ID NO 622.

Alternatively, in embodiments of the invention, the antibody may comprise a light chain of Beta-50, rather than a heavy chain of Beta-50. For example, the antibody may comprise CDRL1, CDRL2 and CDRL3 having the amino acid sequences set forth in SEQ ID NOS 628, 629 and 630, respectively. The antibody may comprise or consist of a light chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the light chain variable domain of antibody Beta-50 (i.e., SEQ ID NO: 624). The antibody may comprise or consist of a light chain variable domain comprising or consisting of SEQ ID NO 624.

In one embodiment, the antibodies in Table 2 may be Beta-49 or Beta-50. As discussed herein and in the examples, the spike protein binds CDRH2 without the need for Beta-50. Thus, in one embodiment, an antibody of the invention may comprise CDRH1 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 615 and 617, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 618, 619 and 620, respectively. In one embodiment, an antibody of the invention may comprise CDRH1 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 625 and 627, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 628, 629 and 630, respectively.

In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence that has 80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.96%,. Gtoreq.97%,. Gtoreq.98%,. Gtoreq.99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-49 (i.e., SEQ ID NO: 612), provided that the residues of the heavy chain variable domain corresponding to residues at positions 1, 3, 5, 23-28, 30-33, 52, 54-55, 57, 75-77 and 99-105 of SEQ ID NO:612 are identical to residues at positions 1, 3, 5, 23-28, 30-33, 52, 54-55, 57, 75-77 and 99-105 of SEQ ID NO: 612. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence that has 80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.96%,. Gtoreq.97%,. Gtoreq.98%,. Gtoreq.99% or 100% sequence identity to the light chain variable domain of antibody Beta-49 (i.e., SEQ ID NO: 614), provided that the residues of the light chain variable domain corresponding to residues at positions 30, 32-33, 50-51, 53-54 and 94-95 of SEQ ID NO:614 are identical to residues at positions 30, 32-33, 50-51, 53-54 and 94-95 of SEQ ID NO: 614. In one embodiment, an antibody of the invention may comprise or consist of a heavy chain variable domain comprising or consisting of amino acid sequences having 80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.96%,. Gtoreq.97%,. Gtoreq.98%,. Gtoreq.99%, 100% sequence identity to the heavy chain variable domain and light chain variable domain of antibody Beta-49 (i.e., SEQ ID NO:612 and 614, respectively), provided that the residues of the heavy chain variable domain corresponding to residues at positions 1, 3, 5, 23-28, 30-33, 52, 54-55, 57, 75-77 and 99-105 of SEQ ID NO:612 are identical to residues at positions 1, 3, 5, 23-28, 30-33, 52, 54-55, 57, 75-77 and 99-105, respectively, and the light chain variable domain corresponding to residues at positions 1, 3, 5, 23-28, 57, 75-77 and 99-105 of SEQ ID NO:612, and residues at positions 54-33, 54-52, 54-55, 57 and 54-33, 54-52, 54-55 and 95-94 of the light chain variable domain corresponding to residues at positions 54-33, 54-52 and 54-52.

In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence that has 80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.96%,. Gtoreq.97%,. Gtoreq.98%,. Gtoreq.99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-50 (i.e., SEQ ID NO: 622), provided that the residues of the heavy chain variable domain corresponding to residues at positions 3, 5, 23-28, 30-33, 75-77 and 100-105 of SEQ ID NO:622 are identical to residues at positions 3, 5, 23-28, 30-33, 75-77 and 100-105 of SEQ ID NO: 622. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence that has 80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.96%,. Gtoreq.97%,. Gtoreq.98%,. Gtoreq.99% or 100% sequence identity to the light chain variable domain of antibody Beta-50 (i.e., SEQ ID NO: 624), provided that the residues of the light chain variable domain corresponding to the residues at positions 31, 33, 50-51, 53-54 and 94-95 of SEQ ID NO:624 are identical to the residues at positions 31, 33, 50-51, 53-54 and 94-95 of SEQ ID NO: 624. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.96%,. Gtoreq.97%,. Gtoreq.98%,. Gtoreq.99%, 100% sequence identity, provided that the residues of the heavy chain variable domain corresponding to the residues at positions 3, 5, 23-28, 30-33, 75-77 and 100-105 of SEQ ID No. 622 are identical to the residues at positions 3, 5, 23-28, 30-33, 75-77 and 100-105 of SEQ ID No. 622, respectively, and the residues of the light chain variable domain corresponding to the residues at positions 31, 33, 50-51, 53-54 and 94 of SEQ ID No. 624 are identical to the residues at positions 31, 33, 50-51, 53-54 and 94 of SEQ ID No. 622, and positions 31-51-54-94 of the light chain variable domain are identical to the residues at positions 3, 5, 23-28, 30-33, 75-77 and 100-105 of SEQ ID No. 622, respectively.

In one embodiment, the antibodies in Table 2 may be Beta-53. Beta-53 was found to strongly neutralize the Omacron variant of SARS-CoV-2 (IC 50 is.ltoreq.0.4. Mu.g/ml; see Table 15, FIG. 22). In one embodiment, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 645, 646 and 647, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 648, 649 and 650, respectively. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-53 (i.e., SEQ ID NO: 642). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the light chain variable domain of antibody Beta-53 (i.e., SEQ ID NO: 644). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy and light chain variable domains of antibody Beta-53 (i.e., SEQ ID NOs: 642 and 644, respectively).

The heavy chain domain of Beta-53 is derived from the IGHV 5-10v region, and switching the heavy and light chains between antibodies derived from the same v region can result in antibodies useful in the present invention. Thus, an antibody of the invention may comprise a heavy chain of Beta-53, rather than a light chain of Beta-53. For example, the antibody may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 645, 646 and 647, respectively. The antibody may comprise or consist of a heavy chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-53 (i.e., SEQ ID NO: 642). The antibody may comprise or consist of SEQ ID NO 642.

Alternatively, in embodiments of the invention, the antibody may comprise a light chain of Beta-53, rather than a heavy chain of Beta-53. For example, the antibody may comprise CDRL1, CDRL2 and CDRL3 having the amino acid sequences set forth in SEQ ID NOS 648, 649 and 670, respectively. The antibody may comprise or consist of a light chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the light chain variable domain of antibody Beta-53 (i.e., SEQ ID NO: 644). The antibody may comprise or consist of a light chain variable domain comprising or consisting of SEQ ID NO 644.

In one embodiment, the antibodies in Table 2 may be Beta-56. Beta-56 was found to strongly neutralize the Omacron variant of SARS-CoV-2 (IC 50 is.ltoreq.0.2. Mu.g/ml; see Table 15, FIG. 22). In one embodiment, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 675, 676 and 677, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 678, 679 and 670, respectively. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-56 (i.e., SEQ ID NO: 672). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the light chain variable domain of antibody Beta-56 (i.e., SEQ ID NO: 674). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy and light chain variable domains of antibody Beta-56 (i.e., SEQ ID NOs 672 and 674, respectively).

The heavy chain domain of Beta-56 is derived from the IGHV 4-31v region, and switching the heavy and light chains between antibodies derived from the same v region can result in antibodies useful in the present invention. Thus, an antibody of the invention may comprise the heavy chain of Beta-56, but not the light chain of Beta-56. For example, the antibody may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOS 675, 676 and 677, respectively. The antibody may comprise or consist of a heavy chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-56 (i.e., SEQ ID NO: 672). The antibody may comprise or consist of SEQ ID NO 672.

Alternatively, in embodiments of the invention, the antibody may comprise a light chain of Beta-56, rather than a heavy chain of Beta-56. For example, the antibody may comprise CDRL1, CDRL2 and CDRL3 having the amino acid sequences set forth in SEQ ID NOS 678, 679 and 680, respectively. The antibody may comprise or consist of a light chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the light chain variable domain of antibody Beta-56 (i.e., SEQ ID NO: 674). The antibody may comprise or consist of a light chain variable domain comprising or consisting of SEQ ID NO. 674.

It was surprisingly found that antibody Beta-32 retained strong neutralization of SARS-CoV-2 variant Victoria, B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), B.1.1.7+E484Q and B.1.525.

Thus, in one embodiment, the antibodies in Table 2 may be Beta-32. In one embodiment, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 515, 516 and 517, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 518, 519 and 520, respectively. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-32 (i.e., SEQ ID NO: 512). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the light chain variable domain of antibody Beta-32 (i.e., SEQ ID NO: 514). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy and light chain variable domains of antibody Beta-32 (i.e., SEQ ID NOs: 512 and 514, respectively).

The heavy chain domain of Beta-32 is derived from the IGHV 1-2v region, and switching the heavy and light chains between antibodies derived from the same v region can result in antibodies useful in the present invention. Thus, an antibody of the invention may comprise a heavy chain of Beta-32, rather than a light chain of Beta-32. For example, the antibody may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOS 515, 516 and 517, respectively. The antibody may comprise or consist of a heavy chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-32 (i.e., SEQ ID NO: 512). The antibody may comprise or consist of SEQ ID NO. 512.

Alternatively, in embodiments of the invention, the antibody may comprise a light chain of Beta-32, rather than a heavy chain of Beta-32. For example, the antibody may comprise CDRL1, CDRL2 and CDRL3 having the amino acid sequences set forth in SEQ ID NOS 518, 519 and 520, respectively. The antibody may comprise or consist of a light chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the light chain variable domain of antibody Beta-32 (i.e., SEQ ID NO: 514). The antibody may comprise or consist of a light chain variable domain comprising or consisting of SEQ ID NO. 514.

In one embodiment, the antibodies in Table 2 may be Beta-22. Beta-22 was found to strongly neutralize Omacron variants of SARS-CoV-2 (IC 50. Ltoreq.0.4. Mu.g/ml), as well as strongly neutralize Alpha, beta and Gamma variants (see Table 15, FIG. 22). In one embodiment, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 435, 436 and 437, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 438, 439 and 440, respectively. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-22 (i.e., SEQ ID NO: 432). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the light chain variable domain of antibody Beta-22 (i.e., SEQ ID NO: 434). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy and light chain variable domains of antibody Beta-22 (i.e., SEQ ID NOs: 432 and 434, respectively).

The heavy chain domain of Beta-22 is derived from the IGHV 3-30v region, and switching the heavy and light chains between antibodies derived from the same v region can result in antibodies useful in the present invention. Thus, an antibody of the invention may comprise a heavy chain of Beta-22, rather than a light chain of Beta-22. For example, the antibody may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 435, 436 and 437, respectively. The antibody may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-22 (i.e., SEQ ID NO: 432). The antibody may comprise or consist of SEQ ID NO. 432.

Alternatively, in embodiments of the invention, the antibody may comprise a light chain of Beta-22, rather than a heavy chain of Beta-22. For example, the antibody may comprise CDRL1, CDRL2 and CDRL3 having the amino acid sequences set forth in SEQ ID NOS 438, 439 and 440, respectively. The antibody may comprise or consist of a light chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the light chain variable domain of antibody Beta-22 (i.e., SEQ ID NO: 434). The antibody may comprise or consist of a light chain variable domain comprising or consisting of SEQ ID NO 434.

In one embodiment, the antibodies in Table 2 may be Beta-27. Beta-27 was found to neutralize the Omacron variant of SARS-CoV-2 (IC 50. Ltoreq.5. Mu.g/ml), as well as strongly neutralize all other tested variants (see Table 15, FIG. 22). In one embodiment, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 485, 486 and 487, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 488, 489 and 490, respectively. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-27 (i.e., SEQ ID NO: 482). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the light chain variable domain of antibody Beta-27 (i.e., SEQ ID NO: 484). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy and light chain variable domains of antibody Beta-27 (i.e., SEQ ID NOs: 482 and 484, respectively).

The heavy chain domain of Beta-27 is derived from the IGHV 3-30v region, and switching the heavy and light chains between antibodies derived from the same v region can result in antibodies useful in the present invention. Thus, an antibody of the invention may comprise a heavy chain of Beta-27, rather than a light chain of Beta-27. For example, the antibody may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOS 485, 486 and 487, respectively. The antibody may comprise or consist of a heavy chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-27 (i.e., SEQ ID NO: 482). The antibody may comprise or consist of SEQ ID NO 482.

In one embodiment, the antibodies in Table 2 may be Beta-40. Beta-40 was found to extremely strongly neutralize the omacron variant of SARS-CoV-2 (IC 50 of 0.012. Mu.g/ml), as well as strongly neutralize all other tested variants (see Table 15, FIG. 22). In one embodiment, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences set forth in SEQ ID NOs 555, 556 and 557, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 558, 559 and 560, respectively. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-40 (i.e., SEQ ID NO: 552). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the light chain variable domain of antibody Beta-40 (i.e., SEQ ID NO: 554). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy and light chain variable domains of antibody Beta-40 (i.e., SEQ ID NOs: 552 and 554, respectively).

The heavy chain domain of Beta-40 is derived from the IGHV 4-39v region, and switching the heavy and light chains between antibodies derived from the same v region can result in antibodies useful in the present invention. Thus, an antibody of the invention may comprise the heavy chain of Beta-40, rather than the light chain of Beta-40. For example, the antibody may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOS 555, 556 and 557, respectively. The antibody may comprise or consist of an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-40 (i.e., SEQ ID NO: 552). The antibody may comprise or consist of SEQ ID NO 552.

Alternatively, in embodiments of the invention, the antibody may comprise a light chain of Beta-40, rather than a heavy chain of Beta-40. For example, the antibody may comprise CDRL1, CDRL2 and CDRL3 having the amino acid sequences set forth in SEQ ID NOS 558, 559 and 560, respectively. The antibody may comprise or consist of a light chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the light chain variable domain of antibody Beta-40 (i.e., SEQ ID NO: 554). The antibody may comprise or consist of a light chain variable domain comprising or consisting of SEQ ID NO 554.

In one embodiment, the antibodies in Table 2 may be Beta-54. Beta-54 was found to strongly neutralize the omacron variant of SARS-CoV-2 (IC 50 of 0.02. Mu.g/ml), as well as strongly neutralize all other tested variants (see Table 15, FIG. 22). In one embodiment, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 655, 656 and 657, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 658, 659 and 660, respectively. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-54 (i.e., SEQ ID NO: 652). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the light chain variable domain of antibody Beta-54 (i.e., SEQ ID NO: 654). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy and light chain variable domains of antibody Beta-54 (i.e., SEQ ID NO:652 and 654, respectively).

The heavy chain domain of Beta-54 is derived from the IGHV 4-39v region, and switching the heavy and light chains between antibodies derived from the same v region can result in antibodies useful in the present invention. Thus, an antibody of the invention may comprise the heavy chain of Beta-54, but not the light chain of Beta-54. For example, the antibody may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 655, 656 and 657, respectively. The antibody may comprise or consist of a heavy chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-54 (i.e., SEQ ID NO: 652). The antibody may comprise or consist of SEQ ID NO 652.

Alternatively, in embodiments of the invention, the antibody may comprise a light chain of Beta-54, rather than a heavy chain of Beta-54. For example, the antibody may comprise CDRL1, CDRL2 and CDRL3 having the amino acid sequences set forth in SEQ ID NOS 658, 659 and 660, respectively. The antibody may comprise or consist of a light chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the light chain variable domain of antibody Beta-54 (i.e., SEQ ID NO: 654). The antibody may comprise or consist of a light chain variable domain comprising or consisting of SEQ ID NO 654.

In one embodiment, the antibodies in Table 2 may be Beta-55. Beta-55 was found to strongly neutralize the omacron variant of SARS-CoV-2 (IC 50 of 0.109. Mu.g/ml), as well as strongly neutralize all other tested variants (see Table 15, FIG. 22). In one embodiment, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 665, 666 and 667, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 668, 669 and 670, respectively. In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-55 (i.e., SEQ ID NO: 662). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the light chain variable domain of antibody Beta-55 (i.e., SEQ ID NO: 664). In one embodiment, an antibody of the invention may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the heavy and light chain variable domains of antibody Beta-55 (i.e., SEQ ID NOs: 662 and 664, respectively).

The heavy chain domain of Beta-55 is derived from the IGHV 4-39v region, and switching the heavy and light chains between antibodies derived from the same v region can result in antibodies useful in the present invention. Thus, an antibody of the invention may comprise the heavy chain of Beta-55, but not the light chain of Beta-55. For example, the antibody may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 665, 646 and 667, respectively. The antibody may comprise or consist of a heavy chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the heavy chain variable domain of antibody Beta-55 (i.e., SEQ ID NO: 662). The antibody may comprise or consist of SEQ ID NO 662.

Alternatively, in embodiments of the invention, the antibody may comprise a light chain of Beta-55, rather than a heavy chain of Beta-55. For example, the antibody may comprise CDRL1, CDRL2 and CDRL3 having the amino acid sequences set forth in SEQ ID NOS 668, 669 and 670, respectively. The antibody may comprise or consist of a light chain variable domain comprising an amino acid sequence having 80% > or more, 90% > or more, 95% > or more, 96% > or more, 97% > or more, 98% > or more, 99% or 100% sequence identity to the light chain variable domain of antibody Beta-55 (i.e., SEQ ID NO: 664). The antibody may comprise or consist of a light chain variable domain comprising or consisting of SEQ ID NO 664.

Mixed chain antibodies of the invention

The antibodies of the invention can comprise a light chain variable domain comprising CDRL1, CDRL2 and CDRL3 from a first antibody in table 1 or 2 and a heavy chain variable domain comprising CDRH1, CDRH2 and CDRH3 from a second antibody in table 1 or 2, provided that the first and second antibodies are different. Such antibodies are referred to herein as mixed chain antibodies.

Examples of mixed chain antibodies useful in the present invention are provided in tables 3A, 3B, 4, 5, 6, 7, 8 and 9. Table 3A shows examples of mixed chain antibodies derived from the same germline heavy chain IGHV 3-53 generated from the antibodies in tables 1 and 2. Table 3B shows examples of mixed chain antibodies derived from the same germline heavy chains IGHV 3-53 and IGHV3-66 produced by the antibodies in tables 1 and 2. Table 4 shows examples of mixed chain antibodies derived from the same germline heavy chain IGHV1-58 produced by the antibodies in tables 1 and 2. Table 5 shows examples of mixed chain antibodies derived from the same germline heavy chain IGHV4-39 produced by the antibodies in tables 1 and 2. Table 6 shows examples of mixed chain antibodies derived from the same germline heavy chain IGHV3-30 produced by the antibodies in tables 1 and 2. Table 7 shows examples of mixed chain antibodies derived from the same germline heavy chain IGHV5-51 produced by the antibodies. Table 8 shows examples of mixed chain antibodies derived from the same germline heavy chain IGHV1-02 produced by the antibodies in tables 1 and 2. Table 9 shows examples of mixed chain antibodies derived from the same germline heavy chain IGHV3-33 generated from the antibodies in tables 1 and 2. Examples of mixed chain antibodies derived from the same germline heavy chain IGHV1-69 are Beta-49H/50L and Beta-50H/49L.

The mixed chain antibodies Beta27H/150L, beta-27H/158L, beta-27H/175L, beta-27H/222L, beta-27H/269L, 150H/Beta-27L, beta-47H/55L, beta-47H/165L, beta-47H/253L, beta-47H/318L, beta-47H/Beta-25L, 55H/Beta-47L, 165H/47L, 253H/Beta-47L, beta-25H/Beta-47L are particularly useful in the present invention. These antibodies were found to have particularly potent cross-lineage neutralization as demonstrated in the examples, see, e.g., tables 12 and 13.

The mixed chain antibodies 150H/222L, 253H/55L, 253H/165L were also found to have particularly potent cross-lineage neutralization as demonstrated in the examples, see, e.g., tables 12 and 13.

Mixed chain antibodies 165H/47L, 253H/Beta-47L, beta-25H/Beta-47L are particularly useful in the present invention. These antibodies were found to have particularly potent cross-lineage neutralization as demonstrated in the examples, see, e.g., tables 12 and 13.

Mixed chain antibodies Beta-49H/50L and Beta-50H/49L are particularly useful in the present invention. These antibodies were found to have particularly potent cross-lineage neutralization as demonstrated in the examples, see, e.g., tables 12 and 13.

Mixed chain antibodies Beta27H/150L, beta-27H/222L, beta-27H/269L, 150H/Beta-27L, beta-47H/55L, beta-47H/165L, beta-47H/253L, beta-47H/318L, beta-47H/Beta-25L and 253H/Beta-47L are particularly useful in the present invention. These antibodies were found to have potent cross-lineage neutralization, e.g., they have IC of 0.1 μg/ml or less against the Victoria, beta and Delta strains of SARS-CoV-2 ₅₀ (see Table 12).

Mixed chain antibodies Beta-47H/55L or Beta-47H/Beta-25L are particularly useful in the present invention. These antibodies were found to have potent cross-lineage neutralization, e.g., they had an IC50 of 0.01 μg/ml or less for most all strains tested (see tables 12 and 13).

Thus, in one embodiment, an antibody of the invention comprises a heavy chain variable domain comprising CDRH1, CDRH2 and CDRH3 from a first antibody in table 1 or 2 and a light chain variable domain comprising CDRL1, CDRL2 and CDRL3 from a second antibody in table 1 or 2, provided that the first and second antibodies are different. The antibody may comprise a heavy chain variable domain amino acid sequence having at least 80% sequence identity to a heavy chain variable domain from a first antibody in table 1 or 2 and a light chain variable domain amino acid sequence having at least 80% sequence identity to a light chain variable domain from a second antibody in table 1 or 2, provided that the first and second antibodies are different. For example, the antibody may comprise or consist of a heavy chain variable domain comprising or consisting of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > 99% or 100% sequence identity to the heavy chain variable domain of an antibody in table 1 or 2, and a light chain variable domain comprising or consisting of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to the light chain variable domain of an antibody in table 1 or 2, provided that the first antibody and the second antibody are different.

The first antibodies may be in table 2 and the second antibodies may be in table 2. The first antibodies may be in table 2 and the second antibodies may be in table 1. The first antibodies may be in table 1 and the second antibodies may be in table 2. The first antibodies may be in table 1 and the second antibodies may be in table 1.

In one embodiment, at least one of the first antibody and the second antibody is an antibody from table 2.

In one embodiment, the first antibody and the second antibody are not both in table 1.

In one embodiment, at least one of the heavy chain variable domain and the light chain variable domain is from table 2.

The antibodies in table 2 may be selected from the group consisting of: beta-27, beta-32, beta-47, beta-48, beta-49, beta-50, beta-53, beta-55, and Beta-56. For example, the antibody in table 2 may be any antibody selected from the group consisting of: beta-27, beta-47, beta-48, beta-49, beta-50, beta-53, and Beta-56.

In one embodiment, both the first antibody and the second antibody are selected from the group consisting of: beta-27, antibody 150, antibody 158, antibody 175, antibody 222, and antibody 269. The heavy chain variable domains of these antibodies are derived from IGHV3-53. The resulting mixed chain antibodies are listed in table 3A. Thus, an antibody of the invention can comprise or consist of all six CDRs (CDRH 1-3 and CDRL 1-3), and/or a heavy chain variable domain and a light chain variable domain, each comprising or consisting of an amino acid sequence having at least 80% sequence identity to a corresponding variable domain of any of the mixed chain antibodies as set forth in table 3A.

Antibodies derived from IGHV3-53 can be used to generate mixed chain antibodies with antibodies derived from IGHV3-66 (e.g., antibodies 40 and 398 in Table 1), "Cell [ Cell ]184 (8) (2021):2183-2200; supasa, piyada et al," Reduced neutralization of SARS-CoV-2B.1.1.7variantby convalescent and vaccine sera [ neutralization of recovery phase serum and vaccine serum to SARS-CoV-2B.1.7 variants ], "Cell [ Cell ]184 (8) (2021):2201-2211 Zhou, damine et al," Evidence of escape of SARS-CoV-2variant B.1.351from natural and vaccine-reduced sera [ SARS-CoV-2variant B.1.351 ] "Cell [ Cell ]184 (9) (2021):2348-2361 ], wajwistisai et al," Wajwist et al, "Cell [ 2.5.1.351 ] and vaccine-induced serum to escape from natural serum," Cell [ Cell ]184 (9) (2021):2348-2361 ], and "Cell [ 2.1.1.7 ] to SARS-2:54, and" Cell [ SARS-2.5.1.7 ] of the vaccine strain [ SARS ]. Thus, in one embodiment, both the first antibody and the second antibody are selected from the group consisting of: beta-27, antibody 150, antibody 158, antibody 175, antibody 222, antibody 269, antibody 40 and antibody 398. The heavy chain variable domains of these antibodies are derived from IGHV3-53 and IGVH3-66. The resulting mixed chain antibodies are listed in table 3B. Thus, an antibody of the invention can comprise or consist of an amino acid sequence having at least 80% (e.g., 80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.96%,. Gtoreq.97%,. Gtoreq.98%,. Gtoreq.99% or 100%) sequence identity to the corresponding variable domain of any of the mixed chain antibodies as listed in table 3B, and/or the heavy chain variable domain and the light chain variable domain of all six CDRs (CDRH 1-3 and CDRL 1-3).

In one embodiment, both the first antibody and the second antibody are selected from the group consisting of: beta-47, beta-25, antibody 55, antibody 165, antibody 253, and antibody 318. The heavy chain variable domains of these antibodies are derived from IGHV 1-58. The resulting mixed chain antibodies are listed in table 4. Thus, an antibody of the invention can comprise or consist of an amino acid sequence having at least 80% (e.g., 80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.96%,. Gtoreq.97%,. Gtoreq.98%,. Gtoreq.99% or 100%) sequence identity to the corresponding variable domain of any of the mixed chain antibodies as listed in table 4, and/or a heavy chain variable domain and a light chain variable domain of all six CDRs (CDRH 1-3 and CDRL 1-3).

In one embodiment, both the first antibody and the second antibody are selected from the group consisting of: beta-06, beta-10, beta-23, beta-40, beta-54, and Beta-55. The heavy chain variable domains of these antibodies are derived from IGHV 4-39. The resulting mixed chain antibodies are listed in table 5. Thus, an antibody of the invention can comprise or consist of an amino acid sequence having at least 80% (e.g., 80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.96%,. Gtoreq.97%,. Gtoreq.98%,. Gtoreq.99%, or 100%) sequence identity to the corresponding variable domain of any of the mixed chain antibodies as listed in table 5, and/or a heavy chain variable domain and a light chain variable domain of all six CDRs (CDRH 1-3 and CDRL 1-3).

In one embodiment, both the first antibody and the second antibody are selected from the group consisting of: beta-22, beta-29 and antibody 159. The heavy chain variable domains of these antibodies are derived from IGHV 3-30. The resulting mixed chain antibodies are listed in table 6. Thus, an antibody of the invention can comprise or consist of an amino acid sequence having at least 80% (e.g., 80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.96%,. Gtoreq.97%,. Gtoreq.98%,. Gtoreq.99%, or 100%) sequence identity to the corresponding variable domain of any of the mixed chain antibodies as listed in table 6, and/or a heavy chain variable domain and a light chain variable domain of all six CDRs (CDRH 1-3 and CDRL 1-3).

In one embodiment, both the first antibody and the second antibody are selected from the group consisting of: beta-38 and antibody 170. The heavy chain variable domains of these antibodies are derived from IGHV 5-51. The resulting mixed chain antibodies are listed in table 7. Thus, an antibody of the invention can comprise or consist of an amino acid sequence having at least 80% (e.g., 80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.96%,. Gtoreq.97%,. Gtoreq.98%,. Gtoreq.99%, or 100%) sequence identity to the corresponding variable domain of any of the mixed chain antibodies as listed in table 7, and/or a heavy chain variable domain and a light chain variable domain of all six CDRs (CDRH 1-3 and CDRL 1-3).

In one embodiment, both the first antibody and the second antibody are selected from the group consisting of: beta-30, beta-32, beta-33, and antibody 316. The heavy chain variable domains of these antibodies are derived from IGHV 1-02. The resulting mixed chain antibodies are listed in table 8. Thus, an antibody of the invention can comprise or consist of an amino acid sequence having at least 80% (e.g., 80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.96%,. Gtoreq.97%,. Gtoreq.98%,. Gtoreq.99%, or 100%) sequence identity to the corresponding variable domain of any of the mixed chain antibodies as listed in table 8, and/or a heavy chain variable domain and a light chain variable domain of all six CDRs (CDRH 1-3 and CDRL 1-3).

In one embodiment, both the first antibody and the second antibody are selected from the group consisting of: beta-20 and Beta-43. The heavy chain variable domains of these antibodies are derived from IGHV 3-33. The resulting mixed chain antibodies are listed in table 9. Thus, an antibody of the invention can comprise or consist of an amino acid sequence having at least 80% (e.g., 80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.96%,. Gtoreq.97%,. Gtoreq.98%,. Gtoreq.99%, or 100%) sequence identity to the corresponding variable domain of any of the mixed chain antibodies as listed in table 9, and/or a heavy chain variable domain and a light chain variable domain of all six CDRs (CDRH 1-3 and CDRL 1-3).

In one embodiment, the first antibody is Beta-47 from table 2 and the second antibody is 55 from table 1. Thus, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 595, 596 and 597, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 68, 69 and 70, respectively. An antibody may comprise or consist of a heavy chain variable domain comprising or consisting of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to SEQ ID No. 592, and a light chain variable domain comprising or consisting of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to SEQ ID No. 64. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO. 592 and a light chain variable domain consisting of SEQ ID NO. 64. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO. 592, a light chain variable domain consisting of SEQ ID NO. 64, and an IgG constant region, i.e., the antibody is Beta-47H/55L.

The Beta-47H/55L antibody was produced from a combination of antibody Beta-47 and antibody 55. These antibodies were relatively potent alone, however, once the heavy chain from antibody beta-47 and the light chain from antibody 55 were combined, the resulting antibodies unexpectedly had improved neutralization and antigen binding. For example, beta-47H/55L provides the strongest neutralization of the strains provided in Table 13. The antibody Beta-47H/Beta-25L was identified in a manner similar to Beta-47H/55L.

In one embodiment, the first antibody is Beta-47 from Table 2 and the second antibody is Beta-25 from Table 2. Thus, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 595, 596 and 597, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 468, 469 and 470, respectively. An antibody may comprise or consist of a heavy chain variable domain comprising or consisting of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to SEQ ID No. 592, and a light chain variable domain comprising or consisting of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to SEQ ID No. 464. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO. 592 and a light chain variable domain consisting of SEQ ID NO. 464. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO. 592, a light chain variable domain consisting of SEQ ID NO. 464, and an IgG constant region, i.e., the antibody is Beta-47H/Beta-25L.

In one embodiment, the first antibody is Beta-47 from table 2 and the second antibody is 165 from table 1. Thus, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 595, 596 and 597, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 188, 189 and 190, respectively. An antibody may comprise or consist of a heavy chain variable domain comprising or consisting of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to SEQ ID No. 592, and a light chain variable domain comprising or consisting of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to SEQ ID No. 184. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO. 592 and a light chain variable domain consisting of SEQ ID NO. 184. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO. 592, a light chain variable domain consisting of SEQ ID NO. 464, and an IgG constant region, i.e., the antibody is Beta-47H/165L.

In one embodiment, the first antibody is Beta-47 from table 2 and the second antibody is 253 from table 1. Thus, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 595, 596 and 597, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 268, 269 and 270, respectively. An antibody may comprise or consist of a heavy chain variable domain comprising or consisting of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to SEQ ID No. 592, and a light chain variable domain comprising or consisting of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to SEQ ID No. 264. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO. 592 and a light chain variable domain consisting of SEQ ID NO. 264. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO. 592, a light chain variable domain consisting of SEQ ID NO. 264, and an IgG constant region, i.e., the antibody is Beta-47H/253L.

In one embodiment, the first antibody is Beta-47 from table 2 and the second antibody is 318 from table 1. Thus, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 595, 596 and 597, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 338, 339 and 340, respectively. An antibody may comprise or consist of a heavy chain variable domain comprising or consisting of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to SEQ ID No. 592, and a light chain variable domain comprising or consisting of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to SEQ ID No. 334. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO. 592 and a light chain variable domain consisting of SEQ ID NO. 334. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO:592, a light chain variable domain consisting of SEQ ID NO:334, and an IgG constant region, i.e., the antibody is Beta-47H/318L.

In one embodiment, the first antibody is 253 from table 1 and the second antibody is Beta-47 from table 2. Thus, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 265, 266 and 267, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 598, 599 and 600, respectively. The antibody may comprise or consist of a heavy chain variable domain comprising or consisting of an amino acid sequence having 80% > or more than 90% > or more than 95% > or more than 96% > or more than 97% > or more than 98% > or more than 99% or 100% sequence identity to SEQ ID NO:262, and a light chain variable domain comprising or consisting of an amino acid sequence having 80% > or more than 90% > or more than 95% > or more than 96% > or more than 97% > or more than 98% > or more than 99% or 100% sequence identity to SEQ ID NO: 594. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO:262 and a light chain variable domain consisting of SEQ ID NO: 594. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO:262, a light chain variable domain consisting of SEQ ID NO:594 and an IgG constant region, i.e., the antibody is 253H/Beta-47L.

In one embodiment, the first antibody is Beta-27 from table 2 and the second antibody is 150 from table 1. Thus, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 485, 486 and 487, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 158, 159 and 160, respectively. The antibody may comprise or consist of a heavy chain variable domain comprising or consisting of an amino acid sequence having 80% > or more than 90% > or more than 95% > or more than 96% > or more than 97% > or more than 98% > or more than 99% or 100% sequence identity to SEQ ID NO. 482 and a light chain variable domain comprising or consisting of an amino acid sequence having 80% > or more than 90% > or more than 95% > or more than 96% > or more than 97% > or more than 98% > or more than 99% or 100% sequence identity to SEQ ID NO. 154. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO. 482 and a light chain variable domain consisting of SEQ ID NO. 154. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO:482 and a light chain variable domain consisting of SEQ ID NO:154 and an IgG constant region, i.e., the antibody is Beta-27H/150L.

In one embodiment, the first antibody is Beta-27 from table 2 and the second antibody is 222 from table 1. Thus, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 485, 486 and 487, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 258, 259 and 260, respectively. An antibody may comprise or consist of a heavy chain variable domain comprising or consisting of an amino acid sequence having 80% > or more than 90% > or more than 95% > or more than 96% > or more than 97% > or more than 98% > or more than 99% or 100% sequence identity to SEQ ID NO 482 and a light chain variable domain comprising or consisting of an amino acid sequence having 80% > or more than 90% > or more than 95% > or more than 96% > or more than 97% > or more than 98% > or more than 99% or 100% sequence identity to SEQ ID NO 254. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO. 482 and a light chain variable domain consisting of SEQ ID NO. 254. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO:482, a light chain variable domain consisting of SEQ ID NO:254 and an IgG constant region, i.e., the antibody is Beta-27H/222L.

In one embodiment, the first antibody is Beta-27 from table 2 and the second antibody is 269 from table 1. Thus, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 485, 486 and 487, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 278, 279 and 280, respectively. The antibody may comprise or consist of a heavy chain variable domain comprising or consisting of an amino acid sequence having 80% > or more than 90% > or more than 95% > or more than 96% > or more than 97% > or more than 98% > or more than 99% or 100% sequence identity to SEQ ID NO 482 and a light chain variable domain comprising or consisting of an amino acid sequence having 80% > or more than 90% > or more than 95% > or more than 96% > or more than 97% > or more than 98% > or more than 99% or 100% sequence identity to SEQ ID NO 274. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO:482 and a light chain variable domain consisting of SEQ ID NO: 274. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO:482 and a light chain variable domain consisting of SEQ ID NO:274 and an IgG constant region, i.e., the antibody is Beta-27H/269L.

In one embodiment, the first antibody is 150 from Table 1 and the second antibody is Beta-27 from Table 2. Thus, an antibody of the invention may comprise CDRH1, CDRH2 and CDRH3 having the amino acid sequences specified in SEQ ID NOs 155, 156 and 157, respectively; and CDRL1, CDRL2 and CDRL3 having the amino acid sequences specified in SEQ ID NOS 488, 489 and 490, respectively. An antibody may comprise or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to SEQ ID NO. 152, and a light chain variable domain comprising or consist of an amino acid sequence having 80% > or 90% > or 95% > or 96% > or 97% > or 98% > or 99% or 100% sequence identity to SEQ ID NO. 484. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO. 152 and a light chain variable domain consisting of SEQ ID NO. 484. The antibody may comprise a heavy chain variable domain consisting of SEQ ID NO. 152 and a light chain variable domain consisting of SEQ ID NO. 484 and an IgG constant region, i.e.the antibody is 150H/Beta-27L.

The first and second antibodies in tables 1 and 2 may be derived from the same germline heavy or light chain v-region (explained further below). The heavy chain v region may be IGHV3-53, IGHV1-58, IGHV4-39, IGHV3-30, IGHV5-51, IGHV1-02 or IGHV3-33. For example, the heavy chain v region may be IGHV3-53, IGHV1-58, or IGHV4-39. For example, the heavy chain v region may be IGHV3-53 or IGHV1-58. The light chain V region may be IG kappa V3-20, IG kappa V1-9, IG kappa V3-1, IG kappa V1-5, IG kappa V3-25, IG kappa V1-12 or IG kappa V1-17. For example, the light chain V region may be IG kappa V3-20 or IG kappa V1-9, such as IG kappa V3-20.

In any of the above embodiments, the first antibody or the second antibody of tables 1 and 2 may be selected from the group consisting of antibodies 58, 222, 253H/55L, beta-22, beta-27, beta-29, beta-40, beta-47, beta-53, beta-54, beta-55, and Beta-56. For example, these antibodies are particularly effective in neutralizing omacron variants of SARS-CoV-2.

Certain antibodies of the invention

The invention also provides an antibody that is a full length antibody of any one of the antibodies in tables 2, 3A, 3B, 4, 5, 6, 7, 8 or 9. In other words, the antibodies of the invention comprise heavy chain variable domains and light chain variable domains consisting of the heavy chain variable domains and light chain variable domains of any of the antibodies in tables 2, 3A, 3B, 4, 5, 6, 7, 8, or 9, respectively, and an IgG (e.g., igG 1) constant region.

For example, the antibody of the invention may be a full length Beta-27, beta-47, beta-48, beta-49, beta-50, beta-53, beta-56, beta-47H/55L, beta-47H/Beta-25L, beta-47H/165L, beta-47H/253L, beta-47H/318L, 253H/Beta-47L, beta-27H/150L, beta-27H/222L, beta-27H/269L or 150H/Beta-27L antibody. These antibodies are highly potent neutralizing mAbs, which have been shown to neutralize, inter alia, at least Victoria, south Africa (B.1.351; beta) and Delta strains without losing efficacy.

The antibodies of the invention may be full length Beta-27, beta-47, beta-48, beta-49, beta-50, beta-53, beta-56, beta-47H/55L or Beta-47H/Beta-25L antibodies.

The antibody of the invention may be a full length Beta-27, beta-47, beta-48, beta-49, beta-50, beta-56, beta-47HC/55LC, beta-47HC/Beta-25LC or Beta-53 antibody. These antibodies exhibit potent neutralization against SARS-CoV-2, see, e.g., table 13.

The antibodies of the invention may be full length Beta-27, beta-47, beta-48, beta-49, beta-50, beta-53, beta-56, beta-47H/55L or Beta-47H/Beta-25L antibodies. These antibodies were found to have potent cross-lineage neutralization, e.g., they were effective against b.1.351, b.1.617.1, c.37, b.1.616, b.1.258, c.36.3, b.1.526.2, and a.23.1+e484K strains (e.g., IC50 less than 0.1 μg/ml, see tables 12 and 13).

The antibodies of the invention may be, for example, full length Beta-47H/55L or Beta-47H/Beta-25L antibodies comprising an IgG1 constant region.

The antibodies of the invention may be, for example, full length Beta-49 or Beta-50 antibodies comprising an IgG1 constant region.

The antibodies of the invention may be full length antibodies Beta-22, beta-27, beta-29, beta-40, beta-47, beta-53, beta-54, beta-55, or Beta-56. For example, these antibodies are particularly effective in neutralizing omacron variants of SARS-CoV-2.

Properties of antibodies of the invention

The antibodies of the invention may be or may comprise modifications of the amino acid sequences of the antibodies from tables 1 to 9, while maintaining the activity and/or function of the antibodies. The modification may be a substitution, deletion and/or addition. For example, the modification may comprise 1, 2, 3, 4, 5, up to 10, up to 20, up to 30 or more amino acid substitutions and/or deletions from the amino acid sequences of the antibodies in tables 1 to 9. For example, the modification may include amino acids substituted with alternative amino acids having similar properties. Some characteristics of the 20 main amino acids that can be used to select suitable substitutions are as follows:

the modification may include derivatized amino acids, such as labeled or unnatural amino acids, provided that the function of the antibody is not significantly adversely affected.

The modification of the antibodies of the invention as described above may be made during the course of synthesis of the antibody or by post-production modification, or when the antibody is in recombinant form, using known site-directed mutagenesis, random mutagenesis or enzymatic cleavage and/or ligation techniques of nucleic acids.

The antibodies of the invention can be modified (e.g., as described above) to increase the potency of the antibodies or to adapt the antibodies to new SARS-CoV-2 variants. These modifications may be amino acid substitutions to adapt the antibody to substitutions in the viral variants. For example, the known binding pattern of an antibody to a spike protein (e.g., by crystal structure measurement or modeling) can be used to identify amino acids of the antibody that interact with substitutions in a viral variant. This information can then be used to identify possible substitutions of the antibody that will compensate for the change in epitope characteristics. For example, substitution of hydrophobic amino acids in the spike protein with negatively charged amino acids can be compensated by substituting amino acids from antibodies that interact with the amino acids in the spike protein with positively charged amino acids. The present disclosure includes methods for identifying residues of an antibody that may be substituted, for example, by determining the structure of an antibody-antigen complex as described herein.

Antibodies of the invention may contain one or more modifications to increase their cross-lineage neutralization properties. For example, spike protein E484, a key residue that mediates interaction with ACE2, was mutated in some strains of SARS-CoV-2 (e.g., victoria strain containing E484, but p.1 and b.1.351 strains contain E484K), resulting in a difference in neutralization of antibodies (see example 24). Thus, antibodies that bind to E484 can be modified to compensate for changes in E484 of the spike protein. For example, E484 was mutated from a positively charged amino acid to a negatively charged amino acid in a SAR-CoV-2 strain of either the B.1.351 or P.1 lineage when compared to the original strain. The binding of the antibody or the amino acid residues near E484 may be mutated to compensate for the change in charge. Examples of such amino acid residues may be G104 and/or K108 in SEQ ID NO:102 of antibody 88 or R52 in SEQ ID NO:372 of antibody 384 (see example 24).

The antibodies of the invention may be isolated antibodies. An isolated antibody is an antibody that is substantially free of other antibodies having different antigen specificities.

The term "antibody" as used herein may refer to whole antibodies (i.e., elements comprising two heavy and two light chains interconnected by disulfide bonds) as well as antigen binding fragments thereof. Antibodies typically comprise an immunologically active portion of an immunoglobulin (Ig) molecule (i.e., a molecule that contains an antigen binding site that specifically binds (immunoreacts with) an antigen. By "specifically bind" or "immunoreact with … …" is meant that the antibody reacts with one or more antigenic determinants of the desired antigen and does not react with other polypeptides. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as HCVR or VH) and at least one heavy chain constant region. Each light chain consists of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The variable regions of the heavy and light chains contain binding domains that interact with antigens. VH and VL regions can be further subdivided into regions of higher variability termed Complementarity Determining Regions (CDRs) with more conserved regions termed Framework Regions (FR) interposed therebetween. Antibodies can include, but are not limited to, polyclonal, monoclonal, chimeric, dAb (domain antibodies), single chain, fab 'and F (ab') 2 fragments, scFv, and Fab expression libraries.

The antibodies of the invention may be monoclonal antibodies. Monoclonal antibodies (mabs) of the invention can be produced by a variety of techniques, including conventional monoclonal antibody methods, such as "Monoclonal Antibodies: a manual oftechniques [ monoclonal antibodies: technical manual ] "(Zola H,1987,CRC Press[CRC press ]) and" Monoclonal Hybridoma Antibodies: techniques and applications [ monoclonal hybridoma antibodies: techniques and applications ] "(Hurrell JGR,1982CRC Press[CRC publishers ]).

Antibodies of the invention may be multispecific, such as bispecific. Bispecific antibodies of the invention bind two different epitopes. These epitopes can be in the same protein (e.g., two epitopes in the spike protein of SARS-CoV-2) or in different proteins (e.g., one epitope in the spike protein of SARS-CoV-2 and one epitope in another protein, such as a coating protein).

In one embodiment, the bispecific antibodies of the invention can bind to two separate epitopes on the spike protein of SARS-CoV-2. Bispecific antibodies can bind to the NTD of spike protein and the RBD of spike protein. Bispecific antibodies can bind to two different epitopes in the RBD of spike proteins.

One or more (e.g., two) antibodies of the invention can be coupled to form a multi-specific (e.g., bispecific) antibody. Methods for preparing multispecific (e.g., bispecific) antibodies are well known in the art.

The antibody may be selected from the group consisting of: single chain antibodies, single chain variable fragments (scFv), variable fragments (Fv), fragment antigen binding regions (Fab), recombinant antibodies, monoclonal antibodies, fusion proteins comprising an antigen binding domain or an aptamer of a natural antibody, single domain antibodies (sdabs) (also known as VHH antibodies), nanobodies (single domain antibodies of Camelid origin), single domain antibody fragments of shark IgNAR origin (known as VNARs), diabodies, triabodies, statins, aptamers (DNA or RNA), and active components or fragments thereof.

The constant region domains (if present) of the antibody molecules of the invention may be selected taking into account the proposed function of the antibody molecule, in particular the effector function that may be required. For example, the constant region domain may be a human IgA, igD, igE, igG or IgM domain. Typically, the constant region is of human origin. Specifically, human IgG (i.e., igG1, igG2, igG3, or IgG 4) constant region domains can be used. Typically, human IgG1 constant regions.

The light chain constant region may be lambda or kappa.

Antibodies of the invention may be monospecific or multispecific (e.g., bispecific). The multispecific antibody comprises at least two different variable domains, wherein each variable domain is capable of binding to a separate antigen or a different epitope on the same antigen.

The antibody of the present invention may be a chimeric antibody, a CDR-grafted antibody, a nanobody, a human antibody or a humanized antibody. Typically, the antibody is a human antibody. Fully human antibodies are those in which the variable and constant regions of the heavy and light chains, if present, are of human origin or are substantially identical to sequences of human origin but not necessarily from the same antibody.

The antibodies of the invention may be full length antibodies.

The antibodies of the invention may be antigen binding fragments. The antigen-binding fragments of the invention bind to the same epitope of the parent antibody (i.e., the antibody from which the antigen-binding fragment is derived). The antigen binding fragments of the invention typically retain the epitope-interacting portion of the parent antibody. Antigen binding fragments typically comprise Complementarity Determining Regions (CDRs) that interact with an antigen, such as one, two, three, four, five, or six CDRs. In some embodiments, the antigen binding fragment further comprises a structural scaffold surrounding CDRs of the parent antibody, such as a variable region domain of the heavy chain and/or light chain. Typically, the antigen binding fragment retains the same or similar binding affinity for the antigen as the parent antibody.

The antigen binding fragment does not necessarily have the same sequence as the parent antibody. In one embodiment, the antigen binding fragment may have ≡70%,. Gtoreq.80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.96%,. Gtoreq.97%,. Gtoreq.98%,. Gtoreq.99%, 100% sequence identity with the corresponding CDR of the parent antibody. In one embodiment, the antigen binding fragment may have greater than or equal to 70%, > or equal to 80%, > or equal to 90%, > or equal to 95%, > or equal to 96%, > or equal to 97%, > or equal to 98%, > or equal to 99%, 100% sequence identity with the corresponding variable region domain of the parent antibody. Typically, the non-identical amino acids of the variable region are not in the CDRs.

The antigen binding fragments of the antibodies of the invention retain the ability to selectively bind to an antigen. Antigen binding fragments of antibodies include single chain antibodies (i.e., full length heavy and light chains); fab, modified Fab, fab ', modified Fab ', F (ab ') 2, fv, fab-dsFv, single domain antibodies (e.g., VH or VL or VHH), scFv.

The antigen binding function of an antibody may be achieved by fragments of full length antibodies. Methods for producing and manufacturing these antibody fragments are well known in the art (see, e.g., verma R et al, 1998, J. Immunol. Methods [ J. Immunol. Methods ],216, 165-181).

Methods for screening antibodies of the invention that do not have 100% amino acid sequence identity to one of the antibodies disclosed herein having the desired specificity, affinity, and functional activity include the methods described herein, such as enzyme-linked immunosorbent assays, biacore, focus reduction neutralization assays (FRNTs), and other techniques known in the art.

Regarding function, the antibodies of the invention may be capable of neutralizing at least one biological activity of SAR-CoV-2 (neutralizing antibodies), in particular neutralizing viral infectivity.

Neutralization may also use ICs ₅₀ Or IC (integrated circuit) ₉₀ The value is determined. For example, the antibody may have an IC of 0.1. Mu.g/ml, 0.05. Mu.g/ml, 0.01. Mu.g/ml, 0.005. Mu.g/ml or 0.002. Mu.g/ml or less ₅₀ Values. In some cases, antibodies of the invention may have an IC of between 0.0001 μg/ml and 0.1 μg/ml, sometimes between 0.0001 μg/ml and 0.05 μg/ml, or even between 0.0001 μg/ml and 0.001 μg/ml ₅₀ Values.

For example, the ICs of some antibodies of tables 2 to 9 (i.e., tables 2, 3A, 3B, 4, 5, 6, 7, 8, and 9) ₅₀ Values are provided in tables 10, 12 and 13.

The ability of an antibody to neutralize viral infectivity can be measured using an appropriate assay, particularly using a cell-based neutralization assay, as shown in the examples. For example, neutralization capacity can be measured in a focal reduction neutralization assay (FRNT), wherein the reduction in the number of cells (e.g., human cells) infected with a virus (e.g., infected at 37 ℃ for 2 hours) in the presence of an antibody is compared to a negative control without antibody addition.

The antibodies of the invention can block the interaction between the spike protein of SAR-CoV-2 and the cell surface receptor angiotensin converting enzyme 2 (ACE 2) of the target cell, for example, by blocking directly or by disrupting the pre-fusion conformation of the spike protein.

The blocking of the interaction between the spike protein and ACE2 may be all or part. For example, the antibodies of the invention may reduce spike protein-ACE 2 formation by ≡50%,. Gtoreq.60%,. Gtoreq.70%,. Gtoreq.80%,. Gtoreq.90%,. Gtoreq.95%,. Gtoreq.99% or 100%. The blocking of spike protein-ACE 2 formation may be measured by any suitable means known in the art, for example by ELISA.

Most antibodies that showed neutralization were also shown to block the interaction between spike protein and ACE 2. (see FIG. 1G). In addition, many non-neutralizing antibodies are good ACE2 blockers.

In terms of binding kinetics, the antibodies of the invention can have an affinity constant (K) for the spike protein of SARS-CoV-2 of < 5nM, < 4nM, < 3nM, < 2nM, < 1nM, < 0.5nM, < 0.4nM, < 0.3nM, < 0.2nM or < 0.1nM _D ) Values.

KD values can be measured by any suitable means known in the art, for example, by ELISA or surface plasmon resonance (Biacore) at 25 ℃.

Binding affinity (K) _D ) Can be determined by determining the dissociation constant (K _d ) And association constant (K) _a ) To quantify. For example, the antibody may have a length of 10000M or more ^-1 s ^-1 、≥50000M ^-1 s ^-1 、≥100000M ^-1 s ^-1 、≥200000M ^-1 s ^-1 Or greater than or equal to 500000M ^-1 s ^-1 Association constant (K) _a ) And/or be less than or equal to 0.001s ^-1 、≤0.0005s ^-1 、≤0.004s ^-1 、≤0.003s ^-1 、≤0.002s ^-1 Or less than or equal to 0.0001s ^-1 Dissociation constant (K) _d )。

The antibodies of the invention are preferably capable of providing in vivo protection in animals infected with coronavirus (e.g., SARS-CoV-2). For example, administration of an antibody of the invention to an animal infected with a coronavirus (e.g., SARS-CoV-2) can result in a survival rate of 30%. Gtoreq.40%,. Gtoreq.50%,. Gtoreq.60%,. Gtoreq.70%,. Gtoreq.80%,. Gtoreq.90%,. Gtoreq.95%, or 100%. Survival rates may be determined using conventional methods.

The antibodies of the invention may have any combination of one or more of the above properties.

The antibodies of the invention can bind to the same epitope as any of the antibodies described herein (i.e., particularly with antibodies having the heavy and light chain variable regions described above), or compete with any of the antibodies described herein for binding to SARS-CoV-2 spike protein. Methods for identifying antibodies that bind to the same epitope or cross-compete with each other are used in the examples and are discussed further below.

Fc region

The antibodies of the invention may or may not comprise an Fc domain.

The antibodies of the invention may be modified in the Fc region in order to improve their stability. Such are known in the art. Modification may improve the stability of the antibody during storage of the antibody. The in vivo half-life of antibodies can be improved by modification of the Fc region.

For example, cysteine residues may be introduced into the Fc region, allowing for inter-chain disulfide bond formation in that region. Homodimeric antibodies thus produced may have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). (see Caron et al, J.exp Med. [ journal of Experimental medicine ],176:1191-1195 (1992) and Shopes, J.Immunol. [ journal of immunology ],148:2918-2922 (1992)). Alternatively, antibodies with dual Fc regions may be engineered, whereby complement lysis and ADCC capacity may be enhanced. (see Stevenson et al, anti-Cancer Drug Design [ anticancer drug design ],3:219-230 (1989)).

For example, the antibodies of the invention may be modified to facilitate the interaction of the Fc domain with FcRn. The Fc domain may be modified to improve the stability of the antibody by affecting Fc and FcRn interactions at low pH (such as in endosomes). The M252Y/S254T/T256E (YTE) mutation can be used to improve the half-life of IgG1 antibodies.

Antibodies can be modified to affect the interaction of the antibody with other receptors, such as fcyri, fcyriia, fcyriib, fcyriii, and fcαr. Such modifications may be used to affect effector functions of the antibody.

In one embodiment, the antibodies of the invention comprise an altered Fc domain as described below. In another preferred embodiment, the antibodies of the invention comprise an Fc domain, but the sequence of the Fc domain has been altered to modify one or more Fc effector functions.

In one embodiment, an antibody of the invention comprises a "silent" Fc region. For example, in one embodiment, the antibodies of the invention do not exhibit effector functions or functions associated with a normal Fc region. The Fc region of the antibodies of the invention does not bind to one or more Fc receptors.

In one embodiment, the antibodies of the invention do not comprise CH ₂ A domain. In one embodiment, the antibodies of the invention do not comprise CH ₃ A domain. In one embodiment, the antibodies of the invention comprise an additional CH ₂ And/or CH ₃ A domain.

In one embodiment, the antibodies of the invention do not bind to Fc receptors. In one embodiment, the antibodies of the invention do not bind complement. In alternative embodiments, the antibodies of the invention do not bind fcγr, but bind complement.

In one embodiment, the antibodies of the invention may generally comprise modifications that alter the serum half-life of the antibody. Thus, in another embodiment, the antibodies of the invention have an Fc region modification that alters the half-life of the antibody. Such modifications may exist as those that alter Fc function. In a preferred embodiment, the antibodies of the invention have modifications that alter the serum half-life of the antibody.

In one embodiment, an antibody of the invention may comprise a human constant region, such as IgA, igD, igE, igG or IgM domain. In particular, when the antibody molecule is intended for therapeutic use where antibody effector function is desired, human IgG constant region domains, particularly IgG1 and IgG3 isotypes, may be used. Alternatively, igG2 and IgG4 isotypes may be used when the antibody molecule is used for therapeutic purposes and antibody effector function is not required.

In one embodiment, the antibody heavy chain comprises CH ₁ Domain, and antibody light chain comprises CL domain (kappa or lambda). In one embodiment, the antibody heavy chain comprises CH ₁ Domain, CH ₂ Domain and CH ₃ Domain, and antibody light chain comprises CL domain (kappa or lambda).

The four human IgG isotypes bind with different affinities to the activated fcγ receptor (fcγri, fcγriia, fcγriic, fcγriiia), the inhibitory fcγriib receptor and the first component of complement (C1 q), thereby generating distinct effector functions (Bruhns p. Et al, 2009.Specificity and affinity of human Fc γ receptors and their polymorphic variants for human IgG subclasses [ the specificity and affinity of human fcγ receptor and polymorphic variants thereof for the human IgG subclass ]. Blood [ Blood ].113 (16): 3716-25), see also Jeffrey b.stavenhagen et al, cancer Research [ Cancer Research ]2007, 9 months 15; 67 (18):8882-90. In one embodiment, the antibodies of the invention do not bind to Fc receptors. In another embodiment of the invention, the antibody does bind to one or more types of Fc receptors.

In one embodiment, the Fc region employed is mutated, particularly as described herein. In one embodiment, the Fc mutation is selected from the group comprising: mutations that remove or enhance binding of the Fc region to Fc receptors, mutations that increase or remove effector function, mutations that increase or decrease half-life of antibodies, and combinations thereof. In one embodiment, when referring to the effect of a modification, it can be demonstrated by comparison with an equivalent antibody lacking the modification.

Some antibodies that selectively bind FcRn at pH 6.0 but not pH 7.4 exhibit longer half-lives in various animal models. Located at CH ₂ And CH (CH) ₃ Several mutations at the interface between domains such as T250Q/M428L (Hinton PR. et al, 2004.Engineered human IgG antibodies with longer serum half-lives in primates [ engineered human IgG antibodies with longer serum half-life in primates ]]J Biol Chem journal of biochemistry]279 (8) 6213-6) and M252Y/S254T/T256 E+H2433K/N434F (Vaccaro C. Et al, 2005.Engineering the Fc region ofimmunoglobulin G to modulate in vivo antibody levels [ engineering the Fc region of immunoglobulin G to modulate antibody levels in vivo) ]NatBiotechnol. [ NatBiotechnology ]]23 (10) 1283-8) has been shown to increase binding affinity for FcRn and the in vivo half-life of IgG 1. Thus, there may be modifications at M252/S254/T256+H244/N434 that alter serum half-life, and in particular there may be M252Y/S254T/T256 E+H2433K/N434F. In one embodiment, it is desirable to increase half-life. In another embodiment, it may actually be desirable to reduce the serum half-life of the antibody, so modifications that reduce serum half-life may be present.

Already in CH of human IgG1 ₂ A number of mutations were made in the domain and in vivoTheir effect on ADCC and CDC was tested externally (Idusogenie EE et al, 2001.Engineered antibodies with increased activity to recruit complement [ engineered antibodies with enhanced complement recruitment activity ]]J Immunol journal of immunology].166 (4):2571-5). Notably, alanine substitutions at position 333 have been reported to increase ADCC and CDC. Thus, in one embodiment, there may be a modification at position 333, particularly a modification that alters the ability to recruit complement. Lazar et al describe a triple mutant (S239D/I332E/a 330L) with higher affinity for fcyriiia and lower affinity for fcyriib, thereby enhancing ADCC (Lazar GA. et al, 2006). Thus, modifications may be present at S239/I332/A330, particularly those that alter the affinity for Fc receptors, particularly S239D/I332E/A330L. An engineered antibody Fc variant with enhanced effector function. PNAS [ Prop of national academy of sciences of the United states ] ]103 (11):4005-4010). Antibody production with increased ADCC using the same mutations (Ryan MC. et al 2007.Antibody targeting of B-cell maturation antigen on malignant plasma cells [ antibody targeting of B cell maturation antigen on malignant plasma cells ]]Mol. Cancer Ther. [ molecular cancer treatment],6:3009-3018). Richards et al studied a slightly different triple mutant (S239D/I332E/G236A) with increased FcgammaRIIIa affinity and FcgammaRIIIb ratio, which mediated enhanced phagocytosis of target cells by macrophages (Richards JO et al 2008.Optimization of antibody binding to Fcgamma RIIa enhances macrophage phagocytosis of tumor cells [ optimization of antibody binding to FcgammaRIIa enhanced phagocytosis of tumor cells by macrophages)]Mol Cancer Ther [ molecular Cancer treatment].7 (8):2517-27). In one embodiment, there may thus be an S239D/I332E/G236A modification.

In another embodiment, the antibodies of the invention may have modified hinge and/or CH1 regions. Alternatively, the employed isoform may be selected because it has a specific hinge region.

Primary public V-zone

The public V region (also described herein as the public V gene) is the V region of the germline heavy and light chain regions in most of the antibody responses found in the population to SARS-CoV-2. In this application, the V region is specifically responsive to the Beta SARS-CoV-2 variant. That is, many individuals will utilize the same v region from their germline v region pool when generating an immune response to a SARS-CoV-2 variant.

As used herein, an antibody "derived from" a particular V region refers to an antibody produced by V (D) J recombination using such germline V region sequences. For example, germline IGHV3-53 v region sequences can undergo somatic recombination and somatic mutation to produce antibodies that specifically bind to the spike protein of SARS-CoV-2. The nucleotide sequence encoding the antibody is unlikely to contain the same sequence as the IGHV3-53 germline sequence, but nevertheless the antibody is derived from the v region. The antibodies of the invention typically comprise no more than 20 non-silent mutations, such as no more than 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 non-silent mutations in the v region when compared to the germline sequence. The antibodies of the invention typically do not contain 2-20 non-silent mutations, such as 3-15, 4-10, and 5-9 non-silent mutations, in the v region when compared to the germline sequence. Germline v-region sequences are well known in the art, and methods for identifying whether a region of an antibody is derived from a particular germline v-region sequence are also well known in the art.

In one embodiment, the antibodies of the invention are derived from the v-region selected from IGHV3-53, IGHV1-58, IGHV3-66, IGHV4-39, IGHV3-30, IGHV5-51, IGHV1-02, or IGHV 3-33. The inventors found that the potent neutralizing antibodies identified herein contained relatively few mutations in the CDRs of the v regions. Thus, in one embodiment, the antibodies of the invention are encoded by a v-region selected from IGHV3-53, IGHV1-58, IGHV3-66, IGHV4-39, IGHV3-30, IGHV5-51, IGHV1-02, or IGHV3-33, and have 3-10 non-silent nucleotide mutations or 2-5 non-silent mutations, such as 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 non-silent mutations when compared to naturally occurring germline sequences. A silent mutation as defined herein is a change in a nucleotide sequence that encodes an amino acid sequence that is unchanged. Thus, a non-silent mutation is a mutation that results in a change in the amino acid sequence encoded by the nucleotide sequence.

The inventors have surprisingly found that the light chain variable regions of two antibodies having the same heavy chain v region can be exchanged to produce a mixed chain antibody comprising the heavy chain variable region of a first antibody and the light chain variable region of a second antibody. For example, both antibodies may comprise a heavy chain variable region derived from IGHV 3-53. Preferably, both antibodies also comprise a light chain variable region derived from the same light chain v region, although this is not required, as for example the light chain of antibody 222 can be matched to any heavy chain variable region derived from IGHV3-53 and produce a potent neutralizing antibody. As described above and in example 7, both antibodies may comprise heavy chain variable regions derived from IGHV3-53 and/or IGHV 3-66.

In one embodiment, the antibodies of the invention comprise CDRs derived from the heavy chain variable domain of an antibody selected from the main public v region of IGHV3-53, IGHV1-58, IGHV3-66, IGHV4-39, IGHV3-30, IGHV5-51, IGHV1-02 or IGHV3-33, such as antibodies Beta-27, 150, 158, 175, 222 and 269 for IGHV3-53, antibodies Beta-47, beta-25, 55, 165, 253 and 318 for IGHV1-58, antibodies Beta-47, beta-25, 55, 165, 253 and 318 for IGHV1-58, antibodies 40 and 398 for IGHV3-66, antibodies Beta-6, beta-10, beta-23, beta-40, beta-54 and Beta-55 for IGHV4-39, antibodies Beta-22, beta-29 and 159 for IGHV3-30, antibodies Beta-38 and 170 for IGHV5-51, antibodies Beta-30, beta-32, beta-33 and 316 for IGHV1-02, or antibodies Beta-20 and Beta-43 for IGHV 3-33. The SEQ ID NOs corresponding to the CDRs of each of these antibodies are shown in tables 1 and 2.

In one embodiment, the antibodies of the invention comprise heavy chain variable domains derived from antibodies selected from the primary public v region of IGHV3-53, IGHV1-58, IGHV3-66, IGHV4-39, IGHV3-30, IGHV5-51, IGHV1-02, or IGHV3-33, such as antibodies Beta-27, 150, 158, 175, 222, and 269 for IGHV3-53, antibodies Beta-47, beta-25, 55, 165, 253, and 318 for IGHV1-58, antibodies Beta-47, beta-25, 55, 165, 253 and 318 for IGHV1-58, antibodies 40 and 398 for IGHV3-66, antibodies Beta-6, beta-10, beta-23, beta-40, beta-54 and Beta-55 for IGHV4-39, antibodies Beta-22, beta-29 and 159 for IGHV3-30, antibodies Beta-38 and 170 for IGHV5-51, antibodies Beta-30, beta-32, beta-33 and 316 for IGHV1-02, or antibodies Beta-20 and Beta-43 for IGHV 3-33. The SEQ ID NOs corresponding to the heavy chain variable domains of each of these antibodies are shown in tables 1 and 2.

In a preferred embodiment, the antibodies of the invention comprise heavy chain CDR 1-3 as set forth in SEQ ID NOS 595 to 597, respectively. In another embodiment, the antibody comprises the heavy chain variable domain of antibody Beta-47 set forth in SEQ ID NO. 592.

Of the v regions identified from a panel of early antibodies (tables 1 and 14), only one of the strong neutralizing antibodies in this panel was from Beta-infected individuals derived from IGHV3-53 (Beta-27) (Table 2). Furthermore, only one neutralizing antibody of the set of novel antibodies was derived from Beta-infected individuals derived from IGHV1-58 (Beta-47) (Table 2), although another antibody with less potent neutralization (Beta-25) also derived from this v-region was also selected for variable domain exchange. The IGHV4-39 v region is highly representative of the set of novel antibodies described herein: beta-6, beta-10, beta-23, beta-40, beta-54, and Beta-55. The other v regions described in tables 6-9 also show v regions in the set of new antibodies and/or shared with the set of early antibodies. By exchanging light chains within these groups, antibodies can be functionally enhanced by an order of magnitude by using an alternative light chain (e.g., by combining the heavy chain variable domain of Beta-47 with the light chain variable domain of Beta-25 or 55).

Furthermore, and as described in the examples, it has surprisingly been shown that antibodies derived from a specific public V region are capable of maintaining or improving neutralization against a broad range of strains when compared to beta strains. Specifically, the antibodies of the invention are derived from IGHV3-53 v region (antibody Beta-27). Specifically, the antibodies of the invention are derived from IGHV1-58v region (antibody Beta-47). In one embodiment, the light chain of an antibody having a heavy chain derived from IGHV1-58 may be exchanged with a light chain of a second antibody also derived from the same heavy chain V region. In one embodiment, the light chain of an antibody having a heavy chain derived from IGHV3-53 may be exchanged with a light chain of a second antibody also derived from the same heavy chain V region. When exchanging the chains of antibodies, the light and heavy chains of each antibody are preferably derived from the same V region. For example, antibodies 55, 165 and 253 all have a heavy chain derived from IGHV1-58v region and a light chain derived from Kappa 3-20. The inventors found that combining the light chain of 55 or 165 with the heavy chain of 253 resulted in a >1log increase in neutralization titer. Other combinations are contemplated because the structures with RBD or spike 253 and 253/55 and 253/165 have been shown to bind the same epitope almost identically and not contact any of the three mutation site residues in the b.1.351 variant.

Thus, in one embodiment, the invention provides a method of producing an antibody that specifically binds to spike protein of SARS-CoV-2 (e.g., SARS-CoV-2 strain of the Alpha, beta, gamma and/or Delta lineage) comprising identifying two or more antibodies derived from the same light chain and/or heavy chain v region, replacing the light chain of a first antibody with the light chain of a second antibody, thereby producing a mixed chain antibody comprising the heavy chain of the first antibody and the light chain of the second antibody. In one embodiment, the method further comprises determining the affinity and/or neutralization of SARS-CoV-2 by the mixed chain antibody. The method may further comprise comparing the affinity of the mixed chain antibody to the affinity of the first and/or second antibody. The method may further comprise selecting mixed chain antibodies having the same affinity as the first and/or second antibodies or greater affinity than them. In some embodiments, the heavy chain v region is IGHV 1-58 and/or the light chain v region is IGLV Kappa 3-20.

In another embodiment, the invention provides an antibody that specifically binds to Beta variants of SARS-CoV-2, wherein the antibody has a v region derived from IGHV 4-39. More specifically, the invention provides an antibody specific for a variant of SARS-CoV-2 comprising amino acid 501Y in the spike protein, wherein the antibody has a v-region derived from IGHV 4-39. Surprisingly, it was found that the antibody response to Beta variants that infect SARS-CoV-2 is severely biased towards antibodies having a heavy chain variable region derived from IGHV 4-39. Most of these antibodies have been shown to be specific for tyrosine at position 501 of the spike protein. Exemplary antibodies include Beta-6, beta-10, beta-23, beta-40, beta-54, beta-55. In one embodiment, such antibodies can be used to neutralize future variants of spike proteins comprising 501Y. In one embodiment, wherein the antibody heavy chain is derived from IGHV4-39, the antibody of the invention comprises CDRH1, CDRH2 and CDRH3 from Beta-6, beta-10, beta-23, beta-40, beta-54 or Beta-55, and CDRL3 from Beta-6, beta-10, beta-23, beta-40, beta-54 or Beta-55. As explained in example 6, it has been demonstrated that the majority of the interactions of antibodies derived from IGHV4-39 with spike proteins occur in the heavy chain, and that the light chain interactions are limited to those from the light chain CDRL3. Furthermore, antibodies derived from IGHV4-39 have been shown to be very representative of the group of antibodies that bind to the Omicron variant of SARS-CoV-2 (i.e., beta-40, beta-54, and Beta-55).

Antibodies that bind to the "downward and outward" conformations of spike proteins

Antibodies Beta-49 and Beta-50 of IgVH1-69 bind to the previously unidentified conformation of the spike protein (see example 18), with the RBD in the downward configuration (FIG. 15), and the heavy chain interacting with both RBDs (FIG. 16C), resulting in translation/rotation of the RBD of the spike protein to the periphery of the spike trimer (the "outward" configuration) (FIG. 16D). The spike protein occurs naturally as a trimer (referred to herein as spike trimer). The "downward" conformation of the spike protein is known to represent a receptor inaccessible state (Cai, y. Et al, 2020.Distinct conformational states ofSARS-CoV-2spike protein[SARS-CoV-2 different conformational states of spike protein ]. Science [ Science ],369 (6511), pages 1586-1592). Antibodies Beta-49 and Beta-50 are believed to "lock" the spike protein in a "down and out" conformation, a novel receptor inaccessible state. Surprisingly, antibodies that bind to the downward and outward conformations of spike proteins strongly neutralize all SARS-CoV-2 variants tested to date. Thus, antibodies that bind to the downward and outward conformations of spike proteins can be used as cross-lineage potent neutralizing antibodies for SARS-CoV-2 variants.

In a typical "downward" conformation, there is direct contact between two adjacent RBDs in the spike trimer. In the downward and outward conformations identified herein, RBD are well separated and there is no direct contact between them except at the N343 glycans. The term "direct contact" refers to disulfide, covalent, salt bridge, and hydrogen bonds (e.g., "lack of direct contact" refers to lack of disulfide, covalent, salt bridge, and hydrogen bonds).

Thus, the present invention provides modified spike proteins of SARS-CoV-2 that lock in both the downward and outward conformations. When the modified spike proteins are in a receptor-inaccessible state and the RBD domain of one spike protein in the spike trimer does not contact the RBD domain of another spike protein in the spike trimer (except via N-glycosylated Asn 343), the modified spike proteins are locked in a downward and outward conformation. In some embodiments, the modified spike protein comprises a cysteine substitution at an amino acid of the RBD and/or NTD domain that is very close in downward and outward conformations such that disulfide bonds are formed between cysteine residues. Methods for engineering disulfide bonds into proteins or identifying residues suitable for introducing cysteine residues into amino acid sequences at positions that allow disulfide bond formation to stabilize the conformation of the protein are well known in the art (see, e.g., gao et al, 2020.Scientific reports [ science report ],10 (1), pages 1-9, and Dombkowski et al, 2014.FEBS letters [ society of european society of biochemistry, journal 588 (2), pages 206-212). In some embodiments, the modified spike protein comprises cysteines at positions corresponding to positions 198 and 463 of the spike protein of the hCoV-19/Wuhan/WIV/2019 strain such that disulfide bonds are formed between the cysteine residues. In one embodiment, the modified spike protein comprises amino acid substitutions D198C and P463C, wherein the amino acid number corresponds to the amino acid number of the spike protein of the hCoV-19/Wuhan/WIV04/2019 strain such that a disulfide bond is formed between cysteine residues. In some embodiments, the invention provides a modified spike protein having at least 80% amino acid identity to the amino acid sequence of SEQ ID NO. 681, wherein the modified spike protein comprises the substitutions D198C and P463C. The resulting spike protein forms a disulfide bond between the amino acids at positions corresponding to 198 and 463 of SEQ ID NO. 681, which locks the spike protein in a "downward and outward" conformation.

Spike proteins locked in both downward and outward conformations can be used to generate antibodies targeting the same epitope as antibodies Beta-49 and Beta-50. Antibodies that bind to this epitope can strongly neutralize variants of SARS-CoV-2. Accordingly, provided herein is a method of producing an antibody capable of binding to a spike protein of SARS-CoV-2, the method comprising producing an antibody directed against a modified spike protein locked in a downward and outward conformation. Methods for producing antibodies are well known in the art. For example, the production of antibodies to spike proteins can be performed by hybridoma technology, phage display technology, or by immunizing an animal with spike proteins. Antibodies may be monoclonal or polyclonal.

The invention also provides a method of screening for antibodies capable of binding to the same epitope as antibodies Beta-49 and/or Beta-50. The method may comprise competition studies with antibodies Beta-49 and/or Beta-50. Competition studies may be performed by any means known to the skilled artisan, such as the biological layer interferometry study exemplified in example 5. The invention also provides an antibody obtained by the method. Similarly, the invention provides an antibody obtainable by the method. The invention also provides an antibody capable of binding to the same epitope on spike protein as antibody Beta 49 or Beta 50. The invention also provides an antibody that competes with antibody Beta 49 or Beta 50 for binding to spike protein.

The skilled artisan can readily determine the binding site (epitope) of an antibody using standard techniques such as those described in the examples of the present application. The skilled artisan can also readily determine whether an antibody binds to the same epitope as an antibody described herein or competes for binding with an antibody described herein by using conventional methods known in the art.

For example, to determine whether a test antibody (i.e., where it is not known whether the test antibody competes with other antibodies for binding to an antigen) binds to the same epitope as an antibody described herein (referred to as a "reference antibody" in the following paragraphs), the reference antibody is allowed to bind to a protein or peptide under saturated conditions. Next, the ability of the test antibodies to bind to the protein or peptide is assessed. If the test antibody is capable of binding to a protein or peptide after saturation binding to the reference antibody, it can be concluded that: the test antibody binds to a different epitope than the reference antibody. In another aspect, if the test antibody is unable to bind to a protein or peptide after saturation binding to the reference antibody, the test antibody may bind to the same epitope as the reference antibody of the invention.

To determine whether an antibody competes for binding with a reference antibody, the above-described binding method is performed in two orientations. In the first orientation, the reference antibody is allowed to bind to the protein/peptide under saturated conditions, followed by assessment of the binding of the test antibody to the protein/peptide molecule. In the second orientation, the test antibody is allowed to bind to the protein/peptide under saturated conditions, followed by assessment of binding of the reference antibody to the protein/peptide. If only the first (saturated) antibody is able to bind the protein/peptide in both orientations, then it can be concluded that: the test antibody and the reference antibody compete for binding to the protein/peptide. As the skilled artisan will appreciate, an antibody that competes for binding with a reference antibody may not necessarily bind the same epitope as the reference antibody, but may spatially block binding of the reference antibody by binding overlapping or adjacent epitopes.

Two antibodies bind to the same or overlapping epitope if each competitively inhibits (blocks) the binding of the other antibody to the antigen. Alternatively, two antibodies have the same epitope if substantially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other antibody. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate the binding of one antibody reduce or eliminate the binding of the other antibody.

Additional routine experimentation (e.g., peptide mutation and binding analysis) can then be performed to confirm whether the observed lack of binding of the test antibody is in fact due to binding or steric blocking (or another phenomenon) of the same epitope as the reference antibody is the cause of the observed lack of binding. Such experiments can be performed using ELISA, RIA, surface plasmon resonance, flow cytometry, or any other quantitative or qualitative antibody binding assay available in the art.

The cross-competing antibodies can be identified using any suitable method in the art, for example, by using a competition ELISA or BIAcore assay, wherein binding of the cross-competing antibodies to a specific epitope on the spike protein prevents binding of the antibodies of the invention, and vice versa. In one embodiment, the antibody produces ≡50%,. Gtoreq.60%,. Gtoreq.70%,. Gtoreq.80%,. Gtoreq.90% or 100% reduction in binding of the specific antibodies disclosed herein.

The antibodies described below in the examples can be used as reference antibodies.

Other techniques that can be used to determine antibody epitopes include hydrogen/deuterium exchange, X-ray crystallography and peptide display libraries (as described in the examples). Combinations of these techniques can be used to determine the epitope of the test antibody.

The methods used herein are equally applicable to other data, such as surface plasmon resonance or ELISA, and provide a general method for rapidly determining position from highly redundant competition experiments.

The numbering of spike proteins, such as modified spike proteins provided herein, is related to the numbering of the hCoV-19/Wuhan/WIV04/2019 (WIV) strain (also provided herein as SEQ ID NO:681 (see also FIG. 20B)), unless otherwise indicated. Spike proteins as used herein may be derived from any variant of SARS-CoV-2. Reference to SEQ ID NO. 681 is to provide a numbering system for identifying amino acid positions in variants in which the absolute numbers differ. For example, in the Beta variant, there is a 3 residue deletion in the NTD, the amino acid position (Asn) corresponding to position 501 of WIV is numbered the same as the amino acid (Tyr) in the same position of Beta, although not the 501 th amino acid in the spike protein sequence of Beta. In some embodiments, the spike protein is the amino acid sequence set forth in SEQ ID NO: 681. When compared to SEQ ID NO. 681, it is a means of a skilled person to use sequence alignment tools to align the amino acid sequences of spike proteins from different variants to determine the corresponding positions of the amino acids in the variants. Thus, the spike protein may have at least 50% amino acid sequence identity to SEQ ID NO:681, such as at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 681.

Antibodies Beta-49 and Beta-50 bind to neoepitopes not previously observed. Beta-49 formation in totalIs +.A spike trimer footprint on one RBD>On the second RBD is +.>Residues 27-28, 30-33, 52, 54-55, 57 and 99-105 of the Beta-49 heavy chain and residues 30, 32-33, 50-51, 53-54 and 94-95 of the Beta-49 light chain interact with residues 332-340, 342-346, 362-368, 527 and 529 of the first RBD; residues 1, 3, 5, 23-26 and 75-77 of the Beta-49 heavy chain interact with 476-478, 486-487 and 489 of the second RBD. The numbering of amino acids in Beta-49 as used herein is the absolute numbering of SEQ ID NOs 612 and 614.

Beta-50 Fab formation in totalIs +.A spike trimer footprint on one RBD>On the second RBD is +.>Residues 27-28, 30-33 and 100-105 of the Beta-50 heavy chain and residues 31, 33, 50, 53-54 and 94-95 of the Beta-50 light chain interact with residues 332-340, 342-345, 362-365, 367-368, 504 and 526-529 of the first RBD; residues 3, 5, 23-27 and 75-77 of the Beta-50 heavy chain interact with residues 475-478, 486-487 and 489 of the second RBD.The numbering of amino acids in Beta-49 as used herein is the absolute numbering of SEQ ID NOs 622 and 624.

Specifically, antibodies Beta-49 and Beta-50 interact in a number of ways with N-glycans at position 343 of the spike protein and aspartate at position 364 of the spike protein. Both of these characteristics are well conserved among SARS-CoV viruses (see FIG. 20) (Sztain et al, 2021.Nature Chemistry [ Nature Chemie ],13 (10), pages 963-968). Furthermore, residues 335-336, 338-342, 363, 365 and 367-368 of spike protein form hydrophobic pockets critical to binding to heavy chain CDR 3. N-terminal residues 333-334 and C-terminal residues 527-529 of RBD form part of an epitope that was not previously observed. Residues 477 and 486-487 of the second RBD are also required for binding.

Accordingly, the present invention provides an antibody capable of binding to an epitope of a spike protein of coronavirus SARS-CoV-2, wherein the epitope comprises N343 and D364 of the spike protein, wherein N343 is N-glycosylated.

The invention also provides an antibody capable of binding to an epitope of the spike protein of coronavirus SARS-CoV-2, wherein the epitope comprises a hydrophobic pocket formed by residues 335-336, 338-342, 363, 365 and 367-368 of the (first) spike protein. The epitope may additionally comprise residues 477 and 486-487 of the second spike protein (i.e., the antibody binds to an epitope formed by two spike protein monomers in a spike trimer). The epitope may additionally comprise residues 333-334 and 527-529 of the (first) spike protein. The epitope may comprise residues 332-340, 342-345, 362-365, 367-368, 527, and 529 of the first spike protein and residues 476-478, 486-487, and 489 of the second spike protein (i.e., wherein the antibody binds to the spike trimer). In any of these antibodies, the amino acid at position 343 can be Asn and is N-glycosylated.

Thus, the present invention also provides an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, wherein the Receptor Binding Domain (RBD) of the spike protein is in a "downward and outward conformation".

Many interactions between spike proteins and antibodies are through backbone interactions. Thus, mutations at undefined positions in the spike protein are well tolerated. Antibodies Beta-49 and Beta-50 potently neutralize all known variants of SARS-CoV-2 due to binding of Beta-49 and Beta-50 to epitopes previously unidentified that contain the invariant residues required to convert SARS-CoV-2 spike from a downward (receptor-inaccessible) to an upward (receptor-accessible) conformation. As shown in the examples and tables herein, although the above epitopes have been identified as comprising residues such as T478 and S477, these are not important for antibody binding, as antibodies Beta-49 and Beta-50 each bind to SARS-CoV-2 variants with substitutions at these positions (e.g., T478K in Delta and S477N in b.1.526.2). Thus, any antibody that binds to the same critical residues (such as those discussed above, as shown in figures 16F and G, or as shown in figure 20B) can also strongly neutralize the various lineages of SARS-CoV-2.

Antibody conjugates

The invention also relates to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or a fragment thereof) or a radioisotope (i.e., a radioactive conjugate). Conjugates of antibodies and cytotoxic agents may be made using a variety of bifunctional protein coupling agents known in the art.

The antibodies of the invention may be conjugated to molecules that modulate or alter serum half-life. The antibodies of the invention may bind to albumin, for example, to modulate serum half-life. In one embodiment, the antibodies of the invention will also include a binding region specific for albumin. In another embodiment, the antibodies of the invention may include a peptide linker that is an albumin binding peptide. Examples of albumin binding peptides are included in WO 2015/197772 and WO 2007/106120, the entire contents of both of which are incorporated by reference.

Polynucleotides, vectors and host cells

The invention also provides one or more isolated polynucleotides (e.g., DNA) encoding an antibody of the invention. In one embodiment, polynucleotide sequences are co-present on more than one polynucleotide, but together they are capable of encoding an antibody of the invention. For example, a polynucleotide may encode the heavy and/or light chain variable regions of an antibody of the invention. The polynucleotide may encode the complete heavy and/or light chain of an antibody of the invention. Typically, one polynucleotide will encode each of the heavy and light chains.

Polynucleotides encoding antibodies of the invention may be obtained by methods well known to those skilled in the art. For example, DNA sequences encoding part or all of the heavy and light chains of an antibody may be synthesized from the corresponding amino acid sequences as desired.

General methods by which vectors can be constructed, transfection methods and culture methods are well known to those skilled in the art. In this respect, reference is made to "Current Protocols in Molecular Biology [ guidelines of molecular biology laboratory ]",1999, F.M. Ausubel (editions), wiley Interscience, new York [ journal database of Willi Press, new York ] and the Maniatis handbook published by Cold spring harbor Press.

The polynucleotides of the invention may be provided in the form of an expression cassette comprising a control sequence operably linked to an insertion sequence, thereby allowing expression of the antibodies of the invention in vivo. Accordingly, the invention also provides one or more expression cassettes encoding one or more polynucleotides encoding the antibodies of the invention. These expression cassettes are in turn typically provided within a vector (e.g., a plasmid or recombinant viral vector). Thus, in one embodiment, the invention provides a vector encoding an antibody of the invention. In another embodiment, the invention provides vectors that collectively encode the antibodies of the invention. These vectors may be cloning vectors or expression vectors. Suitable vectors may be any vector capable of carrying a sufficient amount of genetic information and allowing expression of the polypeptides of the invention.

The polynucleotides, expression cassettes or vectors of the invention are introduced into host cells, for example by transfection. Accordingly, the invention also provides a host cell comprising one or more polynucleotides, expression cassettes or vectors of the invention. The polynucleotides, expression cassettes or vectors of the invention may be introduced transiently or permanently into a host cell, allowing for expression of antibodies from one or more of the polynucleotides, expression cassettes or vectors. Such host cells include transient or preferably stable higher eukaryotic cell lines (such as mammalian cells or insect cells), lower eukaryotic cells (such as yeast) or prokaryotic cells (such as bacterial cells). Specific examples of cells include mammalian HEK293 (such as HEK293F, HEK293T, HEK293S or HEK Expi 293F), CHO, heLa, NS0 and COS cells or any other cell line used herein (such as the cell lines used in the examples). Preferably, the cell line selected will be one that is not only stable but also allows for mature glycosylation.

The invention also provides a process for producing an antibody of the invention comprising culturing a host cell containing one or more vectors of the invention under conditions suitable for expression of the antibody from one or more polynucleotides of the invention, and isolating the antibody from said culturing.

Antibody combinations

The inventors found that certain of the antibodies of table 2 were particularly effective when used in combination, and that certain combinations of the antibodies of table 2 and table 1 (e.g., to minimize loss of activity due to SARS-CoV-2 variants) maximized therapeutic effect and/or increased diagnostic ability. Useful combinations include antibodies that do not cross-compete with each other and/or bind to non-overlapping epitopes.

Thus, the present invention provides a combination of antibodies of the invention, wherein each antibody is capable of binding to the spike protein of coronavirus SARS-CoV-2, wherein each antibody comprises at least three CDRs of any one of the 28 antibodies in Table 2.

The combination may comprise at least two of the following:

(a) Antibodies that interact with tyrosine at position 501 of the receptor binding domain of the spike protein of SARS-Cov-2, such as Beta-6, beta-10, beta-23, beta-24, beta-30, beta-40, beta-54, beta-55, or Beta-56;

(b) Antibodies that interact with a lysine at position 484 of the receptor binding domain of the spike protein of SARS-Cov-2, such as Beta-26, beta-33, beta-34, beta-38, beta-45 or Beta-51;

(c) An antibody that interacts with asparagine or threonine at position 417 of the receptor binding domain of the spike protein of SARS-Cov-2, such as Beta-20, beta-33, beta-22 or Beta-29; and

(d) Antibodies, such as Beta-44, that interact with leucine and threonine at positions 452 and 478, respectively, of the receptor binding domain of SARS-Cov-2 spike protein.

In one embodiment, the combination may comprise: (a) An antibody according to the invention, for example an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2 and comprising at least three CDRs of any one of the 28 antibodies in table 2; and (b) an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2 and comprising at least three CDRs of the antibody in Table 1. For example, the antibody of (b) may comprise:

(i) At least four, five, or all six CDRs of an antibody in table 1;

(ii) A heavy chain variable domain comprising or consisting of an amino acid sequence having at least 80% (e.g., 80%, > 90%, > 95%, > 96%, > 97%, > 98%, > 99%, or 100%) sequence identity to the heavy chain variable domain of an antibody in table 1;

(iii) A light chain variable domain comprising or consisting of an amino acid sequence having at least 80% (e.g., 80%, > 90%, > 95%, > 96%, > 97%, > 98%, > 99%, or 100%) sequence identity to the light chain variable domain of an antibody in table 1; and/or

(iv) A heavy chain variable domain and a light chain variable domain comprising or consisting of an amino acid sequence having at least 80% (e.g., 80%, > 90%, > 95%, > 96%, > 97%, > 98%, > 99% or 100%) identity to the heavy chain variable domain and the light chain domain, respectively, of an antibody in table 1.

The invention also provides a combination of any one of the antibodies described in table 2 and any one of the antibodies in table 1.

In one embodiment, the combination may comprise: (a) The antibodies of the invention, and (b) one or more antibodies from table 2. The antibodies of table 2 may be:

- (i) antibody 55, and (ii) antibody 58 or 278;

- (i) antibody 58, and (ii) antibody 88, 132, 150, 158, 165, 175, 222, or 282;

- (i) antibody 278, and (ii) antibody 88, 132, 150, 158, 165, 175, 222, or 282;

- (i) antibody 55; (ii) antibody 58 or 278; and (iii) 159;

- (i) antibody 58, (ii) antibody 88, 132, 150, 158, 165, 175, 222 or 282, and (iii) 159;

- (i) antibody 278, (ii) antibody 88, 132, 150, 158, 165, 175, 222 or 282, and (iii) 159;

-any two or more antibodies selected from the group consisting of: 384. 159, 253H55L, 253H165L, 253, 88, 40, and 316;

-any two or more antibodies selected from the group consisting of: 253. 253H55L, 253H165L, 222, 318, 55, and 165;

-any two or more antibodies selected from the group consisting of: 158H222L, 222, 150H222L, 384, 159, 253H55L, 253H165L, 253, 88, 40 and 316; or alternatively

-any two or more antibodies selected from the group consisting of: 158H222L, 222, 150H222L, 253H55L, 253H165L, 222, 318, 55, and 165.

The antibody combinations of the invention may be used as therapeutic mixtures. Accordingly, the present invention also provides a pharmaceutical composition comprising the antibody combination of the invention, as further explained below.

The antibody combinations of the invention are useful for diagnosis. Accordingly, the invention also provides a diagnostic kit comprising the antibody combination of the invention. Also provided herein are methods of diagnosing a disease or complication associated with a coronavirus infection in a subject, as further explained below.

For example, the antibody combinations of the invention can be used to identify the presence of Y501, K484, N/T417 and/or L452+T478 based on reduced binding of antibodies in groups (a) to (d) to spike proteins of a sample of SARS-CoV-2. The fully cross-neutralizing antibodies (e.g., beta-27, beta-32, beta-47, beta-48, beta-49, beta-50, and/or Beta-53) can be used as a reference to confirm the presence and/or amount of SARS-CoV-2 in the sample. For example, if the antibodies in group (a) exhibit reduced binding to a sample of SARS-CoV-2, then the spike protein is unlikely to comprise Y501. This may be determined by any method known to the skilled person, such as via an immunoassay, e.g. an ELISA or immunochromatographic assay. Reduced binding may be determined by comparison to a reference and/or normalized to a reference and/or by comparison to a positive/negative control sample or data.

Pharmaceutical composition

The invention provides a pharmaceutical composition comprising an antibody of the invention. The composition may comprise a combination (such as two, three or four) of the antibodies of the invention. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.

The compositions of the present invention may include one or more pharmaceutically acceptable salts. By "pharmaceutically acceptable salt" is meant a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects. Examples of such salts include acid addition salts and base addition salts.

Suitable pharmaceutically acceptable carriers include aqueous carriers or diluents. Examples of suitable aqueous carriers include water, buffered water, and brine.

Other suitable pharmaceutically acceptable carriers include ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). In many cases, it will be desirable to include isotonic agents (e.g., sugars), polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.

Therapeutic compositions must generally be sterile and stable under the conditions of manufacture and storage. The composition may be formulated as a solution, microemulsion, liposome, or other ordered structure suitable for high drug concentrations.

The pharmaceutical compositions of the invention may comprise additional therapeutic agents, such as antiviral agents. Antiviral agents bind to coronaviruses and inhibit viral activity. Alternatively, the antiviral agent may not bind directly to coronavirus, but still affect viral activity/infectivity. The antiviral agent may be an additional anti-coronavirus antibody that binds somewhere on SARS-CoV-2 other than the spike protein. Examples of antiviral agents useful in the present invention include Remdesivir (Remdesivir), lopinavir (Lopinavir), ritonavir (ritonavir), APN01, and favalavir (Favilavir).

The additional therapeutic agent may be an anti-inflammatory agent, such as a corticosteroid (e.g., dexamethasone) or a non-steroidal anti-inflammatory drug (e.g., tolizumab).

The additional therapeutic agent may be an anti-coronavirus vaccine.

The pharmaceutical composition can be administered subcutaneously, intravenously, intradermally, intramuscularly, intranasally or orally.

Also within the scope of the invention are kits comprising an antibody or other composition of the invention and instructions for use. The kit may also contain one or more additional agents, such as additional therapeutic or prophylactic agents as discussed herein.

The method and use of the invention

The invention also relates to the use of the antibodies, antibody combinations and pharmaceutical compositions described herein, e.g. in a method of treating the human or animal body by therapy or in a diagnostic method. The method of treatment may be therapeutic or prophylactic.

For example, the invention relates to methods of treating coronavirus (e.g., SARS-CoV-2) infection, diseases or complications associated therewith (e.g., COVID-19). The method may comprise administering a therapeutically effective amount of an antibody, a combination of antibodies, or a pharmaceutical composition of the invention. The method can further comprise identifying the presence of a coronavirus or fragment thereof (e.g., SARS-CoV-2) in the sample from the subject. The invention also relates to an antibody, antibody combination or pharmaceutical composition according to the invention for use in a method of treating a coronavirus (e.g., SARS-CoV-2) infection, a disease or complication associated therewith (e.g., covd-19).

The invention also relates to a method of formulating a composition for use in treating a coronavirus (e.g., SARS-CoV-2) infection, a disease or complication associated therewith (e.g., covd-19), wherein the method comprises admixing an antibody, antibody combination or pharmaceutical composition according to the invention with an acceptable carrier to prepare the composition.

The invention also relates to the use of an antibody, antibody combination or pharmaceutical composition according to the invention for the treatment of coronavirus (e.g. SARS-CoV-2) infection or a disease or complication associated therewith (e.g. COVID-19).

The invention also relates to the use of an antibody, antibody combination or pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment or prophylaxis of coronavirus (e.g. SARS-CoV-2) infection or a disease or complication associated therewith (e.g. covd-19).

The invention also relates to the prevention, treatment or diagnosis of coronavirus infection caused by any SARS-CoV-2 strain. Coronavirus infection can be caused by any SARS-CoV-2 strain.

The SARS-CoV-2 strain can be the earliest identified strain (hCoV-19/Wuhan/WIV 04/2019 (WIV); GISAID accession number: EPI_ISL_ 402124) and variants thereof. For example, SARS-CoV-2 strain can be a member of lineage A, A.1, A.2, A.3, A.5, B, B.1, B.1.1, B.2, B.3, B.4, B.1.1.7 (alpha), B.1.351 (beta), P.1 (gamma), delta, kappa, and/or lambda. SARS-CoV-2 strain can be a member of lineages A.23.1, B.1.1.7 (alpha), B.1.351 (beta), B.1.258, B.1.526.2, B.1.616, B.1.617.1 (kappa), B.1.617.2 (delta), C36.3, C.37 (lambda), P.1 (gamma) and/or B.1.1.529 (omicron).

The SARS-CoV-2 strain can, for example, comprise one or more mutations in the spike protein relative to hCoV-19/Wuhan/WIV04/2019 (WIV) (GISAID accession number: EPI_ISL_ 402124). In other words, the SARS-CoV-2 strain can be, for example, a modified hCoV-19/Wuhan/WIV04/2019 (WIV) strain that includes one or more modifications in the spike protein.

The mutation may be a mutation (e.g., a substitution) at position 417 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV) (GISAID accession number: EPI_ISL_ 402124). For example, the mutation may be a substitution from lysine to another amino acid residue, such as asparagine (N) or threonine (T). The SARS-Cov-2 strain can comprise a mutation K417N, such as the beta (B.1.351) strain or a member of the lineage derived therefrom. The SARS-Cov-2 strain can comprise a mutation K417T, such as the P.1 (gamma) strain or a member of the lineage derived therefrom.

Antibodies Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50, beta-53, beta-20, beta-22, beta-29 and/or Beta-44 are particularly effective against spike proteins of hCoV-19/Wuhan/WIV04/2019 (WIV) when they contain a mutant SARS-Cov-2 strain at position 417 in the spike protein. Thus, the invention may relate to these antibodies for use in the treatment, prevention or diagnosis of coronavirus infection caused by a SARS-Cov-2 strain comprising a mutation at position 417 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV). Similarly, the invention relates to methods of using these antibodies and the use of these antibodies in the treatment, prevention or diagnosis of coronavirus infection caused by a SARS-Cov-2 strain comprising a mutation at position 417 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV 04).

The mutation may be a mutation at position 501 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV) (GISAID accession number: EPI_ISL_ 402124). For example, the mutation may be a substitution from asparagine (N) to another amino acid residue such as tyrosine (Y). SARS-Cov-2 strain can comprise a mutation N507Y, such as the B.1.1.7 (alpha) strain or a member of the lineage derived therefrom, the B.1.351 (beta) strain or a member of the lineage derived therefrom, or the P.1 (gamma) strain or a member of the lineage derived therefrom.

Antibodies Beta-06, beta-10, beta-23, beta-24, beta-30, beta-40, beta-54, beta-55, beta-56 and/or Beta-44 are particularly effective in neutralizing SARS-Cov-2 strain comprising a mutation at position 501 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV). Thus, the invention may relate to these antibodies for use in the treatment, prevention or diagnosis of coronavirus infection caused by a SARS-Cov-2 strain comprising a mutation at position 501 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV). Similarly, the invention relates to methods of using these antibodies and the use of these antibodies in the treatment, prevention or diagnosis of coronavirus infection caused by a SARS-Cov-2 strain comprising a mutation at position 501 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV 04).

The mutation may be a mutation at position 484 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV) (GISAID accession number: EPI_ISL_ 402124). For example, the mutation may be a substitution from glutamic acid (E) to another amino acid residue, such as lysine (K). The SARS-Cov-2 strain can comprise a mutation E484K, such as a B.1.351 (beta) strain or a member of the lineage derived therefrom, a P.1 (gamma) strain or a member of the lineage derived therefrom, or a B.1.617.1 (kappa) strain or a member of the lineage derived therefrom.

Antibodies Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50 and Beta-53, beta-26, beta-33, beta-34, beta-38, beta-45, beta-51 and/or Beta-44 are particularly effective against spike proteins of hCoV-19/Wuhan/WIV04/2019 (WIV) when they contain mutated SARS-Cov-2 strains at position 484 in the spike protein. Thus, the invention may relate to these antibodies for use in the treatment, prevention or diagnosis of coronavirus infection caused by a SARS-Cov-2 strain comprising a mutation at position 484 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV). Similarly, the invention relates to methods of using these antibodies and the use of these antibodies in the treatment, prevention or diagnosis of coronavirus infection caused by a SARS-Cov-2 strain comprising a mutation at position 484 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV 04).

The mutation may be a mutation at position 452 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV) (GISAID accession number: EPI_ISL_ 402124). For example, the mutation may be a substitution from leucine (L) to another amino acid residue, such as arginine (R) or glutamine (Q). The SARS-Cov-2 strain can comprise a mutation L452R, such as the B.1.617.2 (delta) strain or a member of the lineage derived therefrom, the B.1.617.1 (kappa) strain or a member of the lineage derived therefrom, or the C.36.3 strain or a member of the lineage derived therefrom. The SARS-Cov-2 strain can comprise a mutation L452Q, such as the C.37 (lambda) strain or a member of the lineage derived therefrom.

Antibodies Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50 and Beta-53 are particularly effective in neutralizing SARS-Cov-2 strains that contain mutations at position 452 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV). Thus, the invention may relate to these antibodies for use in the treatment, prevention or diagnosis of coronavirus infection caused by a SARS-Cov-2 strain comprising a mutation at position 452 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV). Similarly, the invention relates to methods of using these antibodies and the use of these antibodies in the treatment, prevention or diagnosis of coronavirus infection caused by a SARS-Cov-2 strain comprising a mutation at position 452 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV 04).

The mutation may be a mutation at position 478 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV) (GISAID accession number: EPI_ISL_ 402124). For example, the mutation may be a substitution from threonine (T) to another amino acid residue, such as lysine (K). The SARS-Cov-2 strain can comprise a mutation T478K, such as the B.1.617.2 (delta) strain or a member of the lineage derived therefrom.

Antibodies Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50 and Beta-53 are particularly effective in neutralizing SARS-Cov-2 strain that comprises a mutation at position 478 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV). Thus, the invention may relate to these antibodies for use in the treatment, prevention or diagnosis of coronavirus infection caused by a SARS-Cov-2 strain comprising a mutation at position 478 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV). Similarly, the invention relates to methods of using these antibodies and the use of these antibodies in the treatment, prevention or diagnosis of coronavirus infection caused by a SARS-Cov-2 strain comprising a mutation at position 478 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV 04).

The mutation may be a mutation at positions 417, 484 and/or 501 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV) (GISAID accession number: EPI_ISL_ 402124). SARS-Cov-2 strain can comprise mutations K417N/T, E484K and N501Y, e.g., the B.1.351 (beta) strain or members of the lineage derived therefrom or the P.1 (gamma) strain or members of the lineage derived therefrom.

Antibodies Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50 and Beta-53, beta-06, beta-10, beta-23, beta-24, beta-30, beta-40, beta-54, beta-55, beta-56, beta-26, beta-33, beta-34, beta-38, beta-45, beta-51 and/or Beta-44 are particularly effective in neutralizing SARS-Cov-2 strains comprising mutations at positions 417, 484 and 501 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV). Thus, the invention may relate to these antibodies for use in the treatment, prevention or diagnosis of coronavirus infection caused by a SARS-Cov-2 strain comprising mutations at positions 417, 484 and 501 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV). Similarly, the invention relates to methods of using these antibodies and the use of these antibodies in the treatment, prevention or diagnosis of coronavirus infection caused by SARS-Cov-2 strain comprising mutations at positions 417, 484 and 501 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV 04).

The mutation may be a mutation at position 614 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV) (GISAID accession number: EPI_ISL_ 402124). For example, the mutation may be a substitution from aspartic acid (D) to another amino acid residue, such as glycine (G). The SARS-Cov-2 strain can comprise a mutation D614G, such as a beta (B.1.351) strain or a member of the lineage derived therefrom, a B.1.617.1 (kappa) strain or a member of the lineage derived therefrom, a C.37 (lambda) strain or a member of the lineage derived therefrom, a B.1.616 strain or a member of the lineage derived therefrom, a B.1.258 strain or a member of the lineage derived therefrom, a C.36.3 strain or a member of the lineage derived therefrom, or a B.1.526.2 strain or a member of the lineage derived therefrom.

Antibodies Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50 and/or Beta-53 are particularly effective in neutralizing SARS-Cov-2 strain that comprises a mutation at position 614 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV). Thus, the invention may relate to these antibodies for use in the treatment, prevention or diagnosis of coronavirus infection caused by a SARS-Cov-2 strain comprising a mutation at position 614 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV). Similarly, the invention relates to methods of using these antibodies and the use of these antibodies in the treatment, prevention or diagnosis of coronavirus infection caused by a SARS-Cov-2 strain comprising a mutation at position 614 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV 04).

The mutation may be a mutation at position 339, 371, 373, 375, 417, 440, 446, 477, 478, 484, 493, 496, 498, 501 and/or 505 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV) (GISAID accession number: EPI_ISL_ 402124). For example, the mutation may be a substitution from threonine (T) to another amino acid residue, such as lysine (K). The SARS-Cov-2 strain can comprise a member of the B.1.1.529 (omicron) strain or lineage derived therefrom in place of the G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y H.

Antibodies Beta-22, beta-27, beta-29, beta-40, beta-47, beta-53, beta-54, beta-55, and Beta-56 are particularly effective against spike proteins of hCoV-19/Wuhan/WIV04/2019 (WIV) when they contain mutated SARS-Cov-2 strains at positions 339, 371, 373, 375, 417, 440, 446, 477, 478, 484, 493, 496, 498, 501, 505 that neutralize spike proteins. Thus, the invention may relate to these antibodies for use in the treatment, prevention or diagnosis of coronavirus infection caused by a SARS-Cov-2 strain comprising a mutation at positions 339, 371, 373, 375, 417, 440, 446, 477, 478, 484, 493, 496, 498, 501, 505 in the spike protein relative to the position 339, 371, 373, 417, 440, 446, 477, 478, 484, 493, 496, 498 in the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV). Similarly, the invention relates to methods of using these antibodies and the use of these antibodies in the treatment, prevention or diagnosis of coronavirus infection caused by SARS-Cov-2 strains comprising mutations at positions 339, 371, 373, 375, 417, 440, 446, 477, 478, 484, 493, 496, 498, 501, 505 in the spike protein relative to the spike protein of hCoV-19/Wuhan/WIV04/2019 (WIV 04).

The invention also relates to antibodies Beta-06, beta-10, beta-23, beta-24, beta-30, beta-40, beta-54, beta-55, beta-56 and/or Beta-44 for use in the treatment, prevention or diagnosis of coronavirus infection caused by the B.1.1.7 (alpha) SARS-CoV-2 strain or members of the lineage derived therefrom. Similarly, the invention relates to methods of using these antibodies and the use of these antibodies in the treatment, prevention or diagnosis of coronavirus infection caused by the B.1.1.7 (alpha) SARS-CoV-2 strain or members of the lineage derived therefrom.

The invention also relates to antibodies Beta-06, beta-10, beta-23, beta-24, beta-30, beta-40, beta-54, beta-55, beta-56 and Beta-44 for use in the treatment, prevention or diagnosis of coronavirus infection caused by the B.1.351 (Beta) strain or members of the lineage derived therefrom. Similarly, the invention relates to methods of using these antibodies and the use of these antibodies in the treatment, prevention or diagnosis of coronavirus infection caused by the b.1.351 (beta) SARS-CoV-2 strain or members of the lineage derived therefrom.

The invention may also relate to antibodies Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50 and Beta-53; beta-26, beta-33, beta-34, beta-38, beta-45, beta-51; beta-20, beta-22, beta-29 and Beta-44 for use in the treatment, prevention or diagnosis of coronavirus infections caused by the P.1 (gamma) strain or members of the lineage derived therefrom. Similarly, the invention relates to methods of using these antibodies and the use of these antibodies in the treatment, prevention or diagnosis of coronavirus infections caused by the p.1 (gamma) SARS-CoV-2 strain or members of the lineage derived therefrom.

The invention also relates to antibodies Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50 and Beta-53 for use in the treatment, prevention or diagnosis of coronavirus infection caused by the B.1.617.2 (delta) strain or members of the lineages derived therefrom. Similarly, the invention relates to methods of using these antibodies and the use of these antibodies in the treatment, prevention or diagnosis of coronavirus infection caused by the b.1.617.2 (delta) SARS-CoV-2 strain or members of the lineage derived thereof.

The invention also relates to Beta-22, beta-27, beta-29, beta-40, beta-47, beta-53, beta-54, beta-55 and Beta-56 for use in the treatment, prevention or diagnosis of coronavirus infections caused by the B.1.617.2 (delta) strain or members of the lineages derived therefrom. Similarly, the invention relates to methods of using these antibodies and the use of these antibodies in the treatment, prevention or diagnosis of coronavirus infection caused by the b.1.1.529 (omacron) strain SARS-CoV-2 or members of the lineage derived therefrom.

Methods and uses of the invention may include inhibiting a disease state (such as covd-19), e.g., arresting its development; and/or to alleviate a disease state (such as covd-19), for example, causing regression of the disease state until a desired endpoint is reached.

Methods and uses of the invention may include improving or lessening the severity of symptoms of a disease state (such as covd-19), improving or reducing its duration or frequency (e.g., lessening pain or discomfort), and such improvement may or may not directly affect the disease. The symptoms or complications may be fever, headache, fatigue, loss of appetite, myalgia, diarrhea, vomiting, abdominal pain, dehydration, respiratory tract infections, cytokine storms, acute Respiratory Distress Syndrome (ARDS) sepsis and/or organ failure (e.g., heart, kidney, liver, GI, lung).

The methods and uses of the invention can result in a reduction in viral load of coronavirus (e.g., SARS-CoV-2), for example, by ≡10%,. Gtoreq.20%,. Gtoreq.30%,. Gtoreq.40%,. Gtoreq.50%,. Gtoreq.60%,. Gtoreq.70%,. Gtoreq.80%,. Gtoreq.90% or 100% as compared to before treatment. Methods for determining viral load are well known in the art, such as infection assays.

Methods and uses of the invention may include preventing a coronavirus infection from occurring in a subject (e.g., a human), particularly when the subject is susceptible to complications associated with the coronavirus infection.

The invention also relates to identifying subjects infected with a coronavirus, such as SARS-CoV-2. For example, the methods and uses of the invention may involve identifying the presence of a coronavirus (e.g., SARS-CoV-2) or a protein or fragment thereof in a sample. The detection may be performed in vitro or in vivo. In certain embodiments, the invention relates to population screening.

The present invention relates to the identification of any SARS-CoV-2 strain, as described herein.

It has also been identified that many of the antibodies herein cross-react with SARS-CoV-1. Thus, in one embodiment, the invention relates to the use of an antibody, antibody combination or pharmaceutical composition according to the invention to identify the presence of SARS-CoV-1, e.g. for use in diagnosing a SARS-CoV-1 infection or a disease or complication associated therewith.

The invention may also relate to a method of identifying escape mutants of SARS-CoV-2, comprising contacting a sample with a combination of antibodies of the invention and identifying whether each antibody binds to a virus. The term "escape mutant" refers to variants of SARS-CoV-2 that contain non-silent mutations that may affect the efficacy of existing treatments for SARS-CoV-2 infection. Typically, the non-silent mutation is on an epitope recognized by a prior art antibody and/or an antibody described herein that specifically binds to an epitope of SARS-CoV-2, e.g., on the spike protein of SARS-CoV-2. If the antibody does not bind to the target, it may be shown that the target comprises a mutation that may alter the efficacy of the existing SARS-CoV-2 treatment.

Methods and uses of the invention can include contacting a sample with an antibody or antibody combination of the invention, and detecting the presence or absence of an antibody-antigen complex, wherein the presence of the antibody-antigen complex is indicative of a subject being infected with SARS-CoV-2.

For example, when antibodies Beta-6, beta-10, beta-23, beta-24 are used; the presence of the antibody-antigen complex is indicative of the presence of tyrosine 501 in the receptor binding domain of the spike protein of SARS-Cov-2 at Beta-30, beta-40, beta-54, beta-55 and/or Beta-56.

As another example, when antibodies Beta-26, beta-33, beta-34, beta-38 are used; the presence of the antibody-antigen complex at Beta-45 and/or Beta-51 indicates the presence of lysine 484 in the receptor binding domain of the spike protein of SARS-Cov-2.

As another example, when antibodies Beta-20, beta-33, beta-22, and/or Beta-29 are used, the presence of the antibody-antigen complex indicates the presence of asparagine or threonine at position 417 in the receptor binding domain of the spike protein of SARS-Cov-2.

As another example, when antibody Beta-29 is used, the presence of the antibody-antigen complex indicates the presence of leucine or threonine at positions 452 and 478, respectively, in the receptor binding domain of the spike protein of SARS-Cov-2.

Methods for determining the presence of antibody-antigen complexes are known in the art. For example, in vitro detection techniques include enzyme-linked immunosorbent assay (ELISA), western blot, immunoprecipitation, and immunofluorescence. In vivo techniques include introducing a labeled anti-analyte protein antibody into a subject. For example, the antibody may be labeled with a radioactive label, and its presence and location in the subject may be detected by standard imaging techniques. Detection techniques may provide qualitative or quantitative readings, depending on the assay employed.

In general, the present invention relates to methods and uses for a human subject in need thereof. However, non-human animals such as rats, rabbits, sheep, pigs, cows, cats or dogs are also contemplated.

The subject may be at risk of exposure to a coronavirus infection, such as a healthcare worker or a person who has been in contact with an infected individual. The subject may have visited or plan to visit a country where coronaviruses are known or suspected to have exploded. Subjects may also be at greater risk, such as immunocompromised individuals, for example individuals receiving immunosuppressive therapy or individuals suffering from human immunodeficiency syndrome (HIV) or acquired immunodeficiency syndrome (AIDS).

The subject may be asymptomatic or before symptoms appear.

The subject may be in the early, mid or late stages of the disease.

The subject may be in a hospital or community at the time of first onset and/or later in the hospital.

The subject may be male or female. In certain embodiments, the subject is generally male.

The subject may not be infected with a coronavirus, such as SARS-CoV-2.

The subject may be susceptible to more severe symptoms or complications associated with the coronavirus infection. The methods or uses of the invention may include the step of identifying whether the patient is at risk of developing a more severe symptom or complication associated with the coronavirus.

In embodiments of the invention involving prophylaxis or treatment, the subject may or may not have been diagnosed with an infectious coronavirus, such as SARS-CoV-2.

The present invention relates to analyzing a sample from a subject. The sample may be tissue, cells, and biological fluids isolated from the subject, as well as tissues, cells, and fluids present in the subject. The sample may be blood and a portion or component of blood, including serum, plasma, or lymph. Typically, the sample is from a pharyngeal swab, a nasal swab, or saliva.

The antibody-antigen complex detection assay may be performed in situ, in which case the sample is a tissue section (fixed and/or frozen) of tissue obtained from a biopsy or resection of the subject.

In embodiments of the invention where antibody pharmaceutical compositions and combinations are administered, they may be administered subcutaneously, intravenously, intradermally, orally, intranasally, intramuscularly or intracranially. Typically, antibody pharmaceutical compositions and combinations are administered intravenously or subcutaneously.

The dosage of the antibody may vary depending on the age and size of the subject, and the disease, condition, and route of administration. The antibody may be administered at a dose of about 0.1mg/kg body weight to a dose of about 100mg/kg body weight, such as at a dose of about 5mg/kg to about 10 mg/kg. The antibody may also be administered at a dose of about 50mg/kg, 10mg/kg, or about 5mg/kg body weight.

The combination of the invention may be administered, for example, at a dose of about 5mg/kg to about 10mg/kg of each antibody or at a dose of about 10mg/kg or about 5mg/kg of each antibody. Alternatively, the combination may be administered at a dose of about 5mg/kg total (e.g., a dose of 1.67mg/kg for each antibody in the three antibody combinations).

The antibodies or antibody combinations of the invention may be administered in a multi-dose regimen. For example, the initial dose may be followed by a second or more subsequent doses. The second and subsequent doses may be spaced apart at appropriate times.

As discussed above, the antibodies of the invention are typically used in single pharmaceutical compositions/combinations (co-formulated). However, the invention also generally includes the combined use of the antibodies of the invention in separate formulations/compositions. The invention also includes the use of an antibody as described above in combination with an additional therapeutic agent.

The combined administration of two or more agents and/or antibodies can be accomplished in a number of different ways. In one embodiment, all components may be administered together in a single composition. In another embodiment, each component may be administered separately as part of a combination therapy.

For example, an antibody of the invention may be administered before, after, or simultaneously with another antibody of the invention or binding fragment thereof. Particularly useful combinations are described, for example, above.

For example, the antibodies of the invention may be administered before, after, or simultaneously with an antiviral or anti-inflammatory agent.

In embodiments of the invention that relate to detecting the presence of a coronavirus (e.g., SARS-CoV-2) or a protein or fragment thereof in a sample, the antibody contains a detectable label. Methods of attaching a tag to an antibody are known in the art, for example, by directly labeling the antibody by coupling (i.e., physically linking) a detectable substance to the antibody. Alternatively, the antibody may be labeled indirectly, for example by reaction with another reagent that is labeled directly. Examples of indirect labeling include detection of primary antibodies using a fluorescent-labeled secondary antibody and end-labeling of DNA probes with biotin so that they can be detected with fluorescent-labeled streptavidin.

The detecting may further include: (i) Agents are known that can be used to detect coronaviruses (e.g., SARS-CoV-2) or proteins or fragments thereof, such as antibodies to other epitopes of spike proteins or other proteins of coronaviruses, such as anti-nucleocapsid antibodies; and/or (ii) agents known to be unable to detect the presence of coronavirus (e.g., SARS-CoV-2) or fragments thereof, i.e., to provide a negative control.

In certain embodiments, the antibodies are modified to have increased stability. Suitable modifications are explained above.

The invention also includes kits for detecting the presence of coronavirus (e.g., SARS-CoV-2) in a sample. For example, the kit may comprise: a labeled antibody or a combination of labeled antibodies of the invention; means for determining the amount of coronavirus (e.g., SARS-CoV-2) in the sample; and means for comparing the amount of coronavirus (e.g., SARS-CoV-2) in the sample to a standard. The labeled antibody or combination of labeled antibodies may be packaged in a suitable container. The kit may also include instructions for using the kit to detect coronavirus (e.g., SARS-CoV-2) in a sample. The kit may also include other agents known to be useful for detecting the presence of coronavirus, as discussed above.

For example, the antibodies or antibody combinations of the invention are used in lateral flow assays. Typically, a lateral flow test kit is a handheld device with an absorbent pad, which is based on a series of capillary beds, such as porous paper sheets, microstructured polymers, or sintered polymers. The test runs the liquid sample along the pad surface with reactive molecules that show a visually positive or negative result. The test may also include the use of other agents known to be useful in detecting the presence of coronavirus (e.g., SARS-CoV-2) or fragments thereof, as discussed above, such as anti-nucleocapsid antibodies.

Others

It will be appreciated that the different applications of the disclosed antibody combinations or the pharmaceutical compositions of the invention may be adapted to the specific needs of the art. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting.

In addition, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an antibody" includes two or more "antibodies".

Furthermore, when reference is made herein to ". Gtoreq.x", this means equal to or greater than x. When ". Ltoreq.x" is referred to herein, this means less than or equal to x.

References to tables 2 to 9 are intended to be references to tables 2, 3A, 3B, 4, 5, 6, 7, 8 and 9. Similarly, references to tables 1 through 9 mean that tables 1, 2, 3A, 3B, 4, 5, 6, 7, 8, and 9 are being referred to.

For the purposes of the present invention, to determine the percent identity of two sequences (such as two polynucleotides or two polypeptide sequences), these sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in a first sequence for optimal alignment with a second sequence). The nucleotide or amino acid residues at each position are then compared. When a position in a first sequence is occupied by the same nucleotide or amino acid as the corresponding position in a second sequence, then the nucleotide or amino acid at that position is the same. The percent identity between two sequences is a function of the number of identical positions shared by the sequences (i.e.,% identity = number of identical positions/number of total positions in the reference sequence x 100).

Typically, sequence comparisons are made over the length of the reference sequence. For example, if the user wishes to determine if a given ("test") sequence is 395% identical to SEQ ID NO, SEQ ID NO:3 will be the reference sequence. To assess whether a sequence is at least 95% identical to SEQ ID NO. 3 (an example of a reference sequence), the skilled artisan will align the length of SEQ ID NO. 3 and determine how many positions in the test sequence are identical to the positions of SEQ ID NO. 3. If at least 95% of the positions are identical, the test sequence is at least 95% identical to SEQ ID NO. 3. If the sequence is shorter than SEQ ID NO. 3, then the gaps or deletion positions should be regarded as non-identical positions.

The skilled person is aware of different computer programs which can be used to determine homology or identity between two sequences. For example, comparison of sequences and determination of percent identity between two sequences may be accomplished using a mathematical algorithm. In one embodiment, the percent identity between two amino acid or nucleic acid sequences is determined using Needleman and Wunsch (1970) algorithms (which have been incorporated into the GAP program of Accelrys GCG software package (available in http:// www.accelrys.com/products/GCG) and using the Blosum 62 matrix or PAM250 matrix and the GAP weights 16, 14, 12, 10, 8, 6 or 4 and the length weights 1, 2, 3, 4, 5 or 6).

CDRs of the heavy Chain (CDRH) and light chain variable domain (CDRL) are located at residues 27-38 (CDR 1), residues 56-65 (CDR 2) and residues 105-117 (CDR 3) of each chain according to the IMGT numbering system (http:// www.imgt.org; lefranc MP,1997,J,Immunol.Today [ J.Immunol., today ],18,509). This numbering system is used throughout this specification unless otherwise indicated.

All publications, patents, and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

The following examples illustrate the invention.

Examples

EXAMPLE 1 mAb production from Beta SARS-CoV-2 infection cases

Plasma and PBMCs were collected from 18 volunteers who had previously suffered from Beta infection as demonstrated by viral sequencing, or were inferred to suffer from Beta, as they were infected after isolation from confirmed Beta infection cases. Samples were taken 4-8 weeks after Beta infection and ELISA binding assays and lesion reduction neutralization assays (FRNTs) were performed against full length Beta S protein, and the 5 cases with highest titers were selected for further study (fig. 1A). For these selected cases, beta FRNT50 titers were higher than Victoria (an early virus isolate) as expected (fig. 1B).

To isolate memory B cells, PBMC were stained with full-length double Strep-labeled Beta S trimer (Beta-S) and single cell sorting of IgG+B cells binding Beta-S was performed (FIG. 1C, D). IgVH and IgVL sequences were isolated by RT-PCR and the full-length heavy and light chain plasmids were generated using the Gibson (Gibson) assembly reaction. The gibbon assembled product was transfected into HEK-293T cells in 96-well plates and the supernatant was harvested and tested in a neutralization assay against Beta virus at a final concentration of 0.1-1 μg/ml. Only those mabs that reached >90% neutralization in this initial assay were selected for further study. A total of 674 Beta-specific mAb IgG were obtained. Of these, 22% bound RBD and 78% bound non-RBD epitopes, and 18% of RBD-specific mabs reached >90% neutralization and were selected for further study (fig. 1E, F). These antibodies were observed for their ability to block ACE2 binding to S. Most mabs were able to block ACE2 interactions, with the exception that as expected mAb Beta-43, a single non-RBD binding neutralizing antibody (which binds to NTD, fig. 8A) showed no ACE2 blocking, while the very potent RBD binding mAb Beta-53 also showed no ACE2 blocking activity (fig. 1G).

27 of the 674 Beta-specific mAbs were selected for the most potent, with FRNT50 titers <100ng/ml for further study, and antibody Beta-25 sharing the heavy chain V gene with Beta-47. Of the most potent antibodies, only Beta-43 bound to NTD, while the remaining 26 bound to RBD, and of which 25 blocked interactions with ACE2, beta-53 was a clear exception as discussed below (fig. 1G).

The potent but very weak RBD binding antibodies Beta-49 and Beta-50 also showed no ACE2 blocking activity (FIG. 12).

Example 2 cross-reactivity of beta reactive mAb.

Live virus neutralization assays were performed using the following viruses, which contained the indicated changes in RBD: victoria (an early strain), alpha (N501Y), beta (K417N, E484K, N501Y), gamma (K417T, E484K, N501Y), delta (L452R, T478K), alpha+E484K (E484K, N501Y), B.1.525 (E484K) (FIGS. 2A-F and Table 10).

Many mabs showed extremely potent neutralization of Beta, with 50% of foci reduced neutralization titers (focus reduction neutralization titre, FRNT 50) down to 1ng/ml (table 10). Cross-reactivity between different virus variants was mixed, some mabs such as Beta-27, 32, 47, 48, 49, 50 and 53 showed complete cross-reactivity with < 10-fold differences between FRNTs 50 (fig. 2A). A large group of mAbs (Beta-6, 10, 23, 24, 30, 40, 54, 55, 56) showed good neutralization of Alpha, beta, gamma and alpha+ viruses, whereas neutralization of Victoria, B.1.525 (E484K) and Delta viruses was reduced or absent altogether (FIG. 2B). Alpha, beta and Gamma together have a single mutation N501Y, and it is proposed that the presence of the N501Y mutation will generate a new immunodominant epitope.

The E484K mutation disrupts the binding of many potent mabs produced by cases of infection with early pandemic virus, and Lys-484 is expected to play an important role in Beta and mAb. Six mabs showed evidence of Lys-484 interactions (Beta-26, 33, 34, 38, 45, 51), decreased activity on Alpha, but restored activity on alpha+484K (fig. 2C). Three mabs Beta-20, 22 and 29 showed the greatest activity against Beta and Gamma, indicating that they recognized epitopes associated with the K417N/T changes in Beta and Gamma, respectively. Antibodies Beta-22 and 29 showed some neutralization of Alpha and alpha+484K, indicating that they recognized an epitope consisting of Asn/Thr 417+Tyr-501 (FIG. 2D). Four mabs (Beta-26, 34, 44, 51) showed a loss of selectivity for neutralization of Delta (FRNT 50>10 μg/ml). Beta-44 was proposed to be sensitive to the L452R/T478K mutation, while Beta-26, 34 and 51 recognized an epitope consisting of Glu-484+Leu-452/Thr-478 (FIG. 2C, E). Finally, a single potent NTD binding mAb Beta-43 was completely specific for Beta (fig. 2F, 8A).

There is a considerable change in the status of the antibody response after Beta infection compared to the pandemic strain at the early stage of infection. The response to Beta is biased and many potent antibodies pick up the three RBD amino acid changes found in Beta; K417N (3/27 mAb), E484K (6/27 mAb), and especially N501Y (11/27 mAb). This specificity supports antigen differences between Beta, other VoCs and early pandemic strains/vaccines. Of the 27 mabs, titers of Victoria (18, 15, 10), alpha (10, 6, 5), gamma (2, 1), delta (18, 16, 14) were reduced by 1log, 2log, or Knocked Out (KO), respectively, as compared to Beta. These significant decreases in neutralizing potential of Beta-specific mabs underscores the antigen distance between Beta and early pandemic strains (10/27 mAb KO), which is even more extreme in Delta (14/27 mAb KO). Delta differs from Beta by 5 amino acids in RBD (K417, L452, T478, E484, N501), while Beta and Gamma are antigenically close (1/27 mAb KO), finally Alpha containing a single N501Y mutation occupies the middle position (5/27 mAb KO). These data are consistent with neutralization data using Beta and Gamma serum (many serum are completely incapable of neutralizing Delta) with greatly reduced neutralization capacity for Delta (Liu et al 2021).

Example 3 antibody Gene use.

The IgVH and IgVL gene uses of 27 potent Beta-reactive mabs are shown in fig. 3A and table 11. The 7 fully cross-reactive mabs were from different IgVH families, except Beta-49 and 50, which are related to each other via the 1-69 x 01 heavy chain v region. Beta-27 is from the IgVH3-53 gene family, which produces a public response to RBD, and is highly representative in the viral pool isolated from individuals infected with early pandemic strains (5/20 potent mAb FRNT50<100ng/ml in our previous studies (Dejnirattisai, wanwisa et al "antigen dissection of The antigenic anatomy of SARS-CoV-2receptor binding domain[SARS-CoV-2 receptor binding domain ]" Cell [ Cell ]184 (8) (2021): 2183-2200; supasa, piyada et al, "Reduced neutralization ofSARS-CoV-2B.1.1.7variant by convalescent and vaccine sera [ convalescence serum and vaccine serum neutralization decrease of SARS-CoV-2B.1.1.7variant ]" Cell [ Cell ]184 (8) (2021):2201-2211; zhou, daming et al "Evidence of escape of SARS-CoV-2variant B.1.351from natural and vaccine-reduced sera [ evidence of SARS-CoV-2variant B.1.351 escaping from natural serum and vaccine-induced serum ]" Cell [ Cell ]184 (9) (2021):2348-2361; dejniratisai, wanwisa et al "Antibody evasion by the P.1strain of SARS-CoV-2[ antibody avoidance of P.1strain of SARS-CoV-2 ]" Cell ]184 (11) (2021):2939-2954, liu, 617 et al "Reduced neutralization of SARS-CoV-2B.1.617by vaccine and convalescent serum [ vaccine and convalescence serum escape from natural serum and vaccine-induced serum ]" Cell ] but only appears once in the Cell series of "cells" 4232:2361 "and" Cell "4236. Similarly, beta-47 belongs to the common gene family IgVH1-58, found in many mAbs isolated from early pandemic infections (4/20 in our previous study).

There were 11/27 examples of the highest amplification of Tyr-501 reactive antibodies. Of 9, tyr-501 is dominant (FIG. 2B), and of the other 2 (Beta-22, 29), tyr-501 also works in addition to Asn-417 (FIG. 2D). The Tyr-501 reactive mAb of 6/11 uses IgVH 4-39 (Beta-6, 10, 23, 40, 54, 55) to render IgVH 4-39 an immunodominant neutralizing public antibody response to SARS-CoV-2 containing Tyr-501 in spike protein, partially accounting for the bias of the response after Beta infection relative to the early pandemic strain. Six Lys-484 reactive mAbs were from different IgVH backgrounds, whereas 2/3 of the Asn/Thr-417+Tyr-501 reactive mAbs were VH3-30.

27 Beta-reactive mabs showed relatively low levels of somatic mutation, with changes in IgVH and IgVL having a median of 7 (fig. 3B), consistent with the low level of hypermutation seen when mabs were analyzed after infection with early pandemic strains (median igvh=5igvl=3) (Dejnirattisai, wanwisa et al, "The antigenic anatomy of SARS-CoV-2receptorbinding domain[SARS-CoV-2 receptor binding domain antigen dissection ]" Cell [ Cell ]184.8 (2021): 2183-2200).

In summary, potent mabs derived from Beta-infected cases differ greatly in cross-reactivity between variant viruses compared to mabs isolated from early convalescence cases. The Tyr-501 and Glu-484 epitopes predominate in response, resulting in reduced neutralization of some antibodies to Victoria and Delta lacking the epitopes, underscores the antigen distance between these viruses and Beta (Liu et al 2021). Neutralization of Delta is further impaired by a subset of mAbs that are sensitive to RBD mutations in Delta, explaining why Beta and Delta (and Gamma/Delta) occupy the most distant positions on the antigen profile (Liu et al 2021).

Some mabs derived from Beta cases showed specificity for a subgroup of vocs. The 7/27mAb showed potent neutralization (< 100 ng/ml) of all VoCs tested (Beta-27, -47, -48, -49, -50, -53, and-56). In addition, beta-55mAb showed potent neutralization (< 100 ng/ml) of all VoCs tested, except for Victoria strain (108 ng/ml), which is not currently a circulating strain of epidemic. Two of these mAbs belong to a common reaction (mAb 27IgVH3-53 and mAb 45IgVH 1-58) that has been isolated multiple times. The sustained but greatly reduced use of the IgHV3-53 gene family is due to the conversion of light chain CDR1, which normally blocks interaction with the RBD-carrying Tyr-501 (FIG. 7A) and binds rare mutations in CDR1 as previously described (Dejniratisai, wanwisa et al, "Antibody evasion by the P.1strain of SARS-CoV-2[ antibody evasion of P.1strain of SARS-CoV-2 ]," Cell [ Cell ]184.11 (2021): 2939-2954) as an elastic mechanism against such mutations.

Previous studies have used serum collected from Alpha-infected cases to observe neutralization of a panel of related variants (Supasa et al 2021), and found that the resulting response was very cross-reactive between variant viruses after Alpha infection. Alpha serum was found to neutralize Victoria as effectively as Alpha, which is not expected to occur if the response to Tyr501 in Alpha infection is similar to that observed in Beta infection. However, alpha also contains the mutation D614G not found in Victoria/Wuhan, so we returned and used 17 parts of Alpha serum to test neutralization of the early pandemic virus (b.1) version containing the additional D614G mutation. Compared to the neutralization titer of Alpha using Alpha serum (p= 0.0208), the neutralization titer of Alpha serum to b.1 was reduced 1.8-fold (fig. 13), which is consistent with some Tyr501 reactions in Alpha serum.

Example 4. Potent mabs protected mice from Beta infection.

To test in vivo activity against Beta-raised mAbs, a human ACE2 transgenic mouse model was used (McCray et al, 2007; winkler et al, 2020). Four representative mabs from different epitope classes were selected; beta-20, which recognizes the K417N/T mutation and can neutralize Beta strongly and to a lesser extent Gamma; beta-24, which is specific for the N501Y mutation present in Alpha, beta and Gamma; beta-26, which recognizes the E484K mutation found in Beta and Gamma; beta-27, igVH3-53, is a fully cross-reactive mAb that similarly neutralizes all variants.

Mice were vaccinated with Beta of 103FFU and 24 hours post-vaccinated, a single 10mg/kg dose of mAb was administered via intraperitoneal injection. All four Beta-primed mabs, but not the isotype control mAb (hE 16), prevented weight loss and reduced viral load in the lung and brain, but not in the nasal washes, for 6 days post-inoculation (fig. 3C-F). These results indicate that each mAb tested was effective in reducing the severity of infection and preventing systemic disease, but not viral infection of the upper respiratory tract.

Example 5 mapping of mAb binding using biolayer interferometry.

Biological Layer Interferometry (BLI) competition matrices have previously been used to construct high resolution 3D maps of early pandemic mAbs that bind RBD (Dejniratisai, wanwisa et al, "antigen dissection of The antigenic anatomy of SARS-CoV-2receptor binding domain[SARS-CoV-2 receptor binding domain ]" Cell [ Cell ]184.8 (2021): 2183-2200). The results are consistent with subsequent X-ray structural determinations and show that the most potent neutralizing mAb binds on or near the ACE2 footprint (Dejnirattisai, wanwisa et al, "antigen dissection of The antigenic anatomy of SARS-CoV-2receptor binding domain[SARS-CoV-2 receptor binding domain ]," Cell [ Cell ]184.8 (2021): 2183-2200).

A matrix of paired BLI measurements was obtained on the 26 most potent RBDs binding Beta-mabs and some pre-pandemic mabs with known binding sites. Combining BLI data with accurate structural information (mainly from X-ray crystallography) provides reliable mapping information (average error of predictions for 8 mAbs Beta-6, 22, 24, 27, 44, 53 and 54 is). Instead of the antibodies falling into distinct epitopes, cluster analysis (see example 16) showed that almost all of the mapped antibodies fall into an arc (fig. 9). When mapped to the surface of the RBD, the arc can be seen to span Antigen dissection of the neck and shoulder region (Dejnirattisai, wanwisa et al, "The antigenic anatomy of SARS-CoV-2receptor binding domain[SARS-CoV-2 receptor binding Domain)]"Cell [ Cell ]]184.8 (2021) 2183-2200) (FIG. 4).

The detailed correlation with the key residue assignments made above is shown in fig. 4, and there is excellent correlation. For example, beta-44, which is sensitive to the L452R/T478K mutation, is located near residue 478, while the three mAbs Beta-20, 22 and 29, which are shown to recognize an epitope associated with residue 417, are tightly clustered on top of that residue. mabs Beta-49 and 50 showed very low affinity for Beta RBD, although they tightly bound to full-length S (fig. 12), so their positions could not be mapped by BLI competition. Their mode of binding is described later in the examples.

Example 6 Structure of anti-Beta Fab/RBD Complex

To understand the structure-function relationship of potent anti-Beta antibodies, a representative selection of structural analyses was performed based on their serological properties. At 1.7 toResolution therebetween in total, the high resolution crystal structures of eleven RBD/Fab complexes Beta-6, 22, 24, 27, 29, 38, 40, 44, 47, 53 and 54 (FIG. 5A) and Fab Beta-32 (FIG. 5B) were determined (see example 16). In addition, in addition to Beta-S complexed with the Fab of the previously identified cross-reactive mAb 222, generally lower resolution cryo-EM structural information of Beta-S complexed with the Fab of Beta-6, 26, 32, 44 and 53 was obtained (Dejniratisai, wanwisa et al, "Antibody evasion by the P.1strain of SARS-CoV-2[ antibody evasion of P.1strain of SARS-CoV-2 ] ]"Cell [ Cell ]]184.11 (2021) 2939-2954) (FIG. 5C, example 16, FIG. 10).

Structure definition of public antibodies against Tyr-501RBD

Beta-6 and Beta-54 are two examples of the IgVH4-39 gene family. Beta-6 interacts strongly with Tyr-501. Fab is located substantially on the right shoulder top of RBD (FIG. 5A), the major contact is made by the heavy chainContributing, while the light chain generates very little contact +.>And these contacts are limited to CDR L3 (fig. 6A). Overall, the interaction region is still relatively small, with interactions concentrated mainly around residue Tyr-501 (fig. 6A), three CDRs: h1, H2 and H3 encircle the right shoulder. Specifically, the hydroxyl group of Tyr-501 forms a hydrogen bond with the H3 backbone (FIG. 6A).

Beta-54 interacts with the RBD at a significantly different angle of attack than Beta-6 (FIG. 6B), and the Fab swings 32 on the RBD, essentially pivoting about residue 501 on the RBD. The reason for the apparent variation in binding pose between Beta-6 and 54 appears to originate from the apparent difference in heavy chain CDR 3. Beta-6 H3 is 15 residues in length, while Beta-54 is longer, 18 residues. The change in angle of attack allows similar contact to occur with H3 rings of different lengths (fig. 6C), while the H1 and H2 contact areas pivot about the axis. The superposition of the IgVH portion of the heavy chain (fig. 6D) shows that the heavy chain variable domains are very similar except for H3. Examination of the details of the interactions shows that the details are different (fig. 6A and E). Residues Tyr-35 (H1) and Tyr-54 (H2) appear to be central, allowing pivoting, and are characteristic of the IgVH4-39 gene family (they are also present in some other IgVH families and thus insufficient to transmit this binding pattern, fig. 6E, table S3). In general, beta-54 has a slightly smaller interaction area than Beta-6 (heavy and light chains 461 and 461, respectively, of Beta-54) )。

The H3 loop length of IgVH4-39 antibodies falls into two classes, one class of H3 being 15 residues in length, while the smaller subset of H3 is 18 or 19 residues in length. This suggests that there may be some degeneracy in the H1 and H2 interactions, which allows these common antibodies to accommodate two different classes of H3, while still maintaining the relevant interactions in the IgVH4-39 portion (considering all interacting residues of antigen and antibody, of the 28 residues of Beta-6 and 34 residues of Beta-54, 22 residues are common between the two antibodies).

Another low resolution X-ray structure of Beta-40 Fab which binds Beta-RBD was determined as a proposed test for IgHV4-39 antibody CDR3 length modulation binding pose. Beta-40 has the canonical 15 residue heavy chain CDR3 found in four of the IgVH4-39 antibodies (including Beta-6). As predicted, the angle of attack of Beta-40 was substantially the same as Beta-6, and the heavy chain CDR1 and CDR2 positioning was very similar (FIG. 6F). The structure of the Beta-RBD/Beta-24 complex further supports the model. Beta-24 belongs to a closely related IgVH4-30 gene family, the H1 and H2 regions are very similar to IgVH4-39, and canonical H3 is 15 residues in length. Consistently, beta-24 had substantially the same pattern of engagement as Beta-6 (FIG. 5A), although the sequence within the 15 residue heavy chain CDR3 was significantly different. The detailed interactions also partially outline the interaction of Beta-6, however, there is also a difference between Beta-6 and 24, and the light chain interaction area of Beta-24 is more than doubled (to ) While the heavy link contact is slightly reduced +.>

Despite these variations in the details of the interaction between Beta-6 and Beta-24, there are common heavy chain interactions that define a common association pattern. This is summarized in fig. 6H, where the key residues are shown. In detail, the hydroxyl group of Tyr-35 forms a hydrogen bond with the RBD carbonyl oxygen of Val-445, and the carbonyl group of residue Val-102 interacts with the RBD hydroxyl group of Thr-500. However, unlike the interaction of Tyr-501, hydrogen bonds are formed in Beta-6, in Beta-24 this interaction appears to be formed primarily by hydrophobic packing interactions. Interestingly, the light chain interactions were not homologous, and therefore, in both antibodies, hydrogen bonds were formed with the carbonyl group of Gly-446, however, in Beta-6 this was contributed by the guanidino group of Arg-91 (FIG. 6A), while in Beta-24 the hydrogen donor was the hydroxyl group of Tyr-91.

To explore the full scope of spike interactions with such antibodies, the CryoEM structure of Beta-S with Beta-6Fab was assayed, showing that 2 RBDs were attached in a standard manner in the upward configuration, however all three RBDs carried a bound Fab (FIG. 5C). In summary, repeated use of IgVH4-39 appears to flag frequent common binding patterns of targeting residue Tyr-501, although antibodies contain a broad family of different IgVL genes (Table 11).

Example 7 limited use of cross-reactive members of the IgVH3-53/3-66 gene family.

In contrast to the widespread use of the novel public IgVH gene family to target Tyr-501, the well-known class of IgVH3-53/3-66 public antibodies frequently elicited by early pandemic viruses is represented by only a single mAb Beta-27 in the group of most potent Beta neutralizers. Our previous observations explain this that these antibodies are largely sensitive to mutations at residue 501 of RBD, whereas changes in light chain CDR1 can confer elasticity. An example of this is mAb 222 isolated from individuals infected with an early pandemic strain, which contains proline at residue 30 (Dejnirattisai et al, 2021 b) and can effectively neutralize all variants. The cryem structure of Fab 222 complexed with Beta-S was determined to explore the pattern of engagement with full length spikes. Most trimeric spike particles are in the "2RBD up" configuration, with two up RBDs joined with 222Fab in a pattern expected from the early RBD/Fab complex structure (FIG. 5C) (Dejnirattisai, wanwisa et al, "Antibody evasionby the P.1strain of antibody escape for P.1strain of SARS-CoV-2[ SARS-CoV-2 ]," Cell [ Cell ]184.11 (2021): 2939-2954). This is consistent with the RBD "up" engagement pattern observed in other IgVH3-53 spike complexes (Dejnrattisai, wanwisa et al, "antigen dissection of The antigenic anatomy of SARS-CoV-2receptor binding domain[SARS-CoV-2 receptor binding domain ]" Cell [ Cell ]184.8 (2021): 2183-2200).

Beta-27 uses an alternative mechanism to mAb 222 to achieve the same result, i.e., potency against all variants. Extension of the Beta-27 heavy chain CDR3 loop from the usual 9 residues to 11 replaces the light chain CDR1 to create enough space to allow for the large cheese at 501 found in Alpha, beta and Gamma variantsAmino acid side chains, which are very similar to those seen in mAb 222 (fig. 7A, 16H and I), in which Tyr-501 is stabilized by backbone peptide interactions at residues 29-30. This resulted in Beta-27 having strong cross-reactivity for all variants. As with the canonical IgHV3-53 antibody, beta-27 interacts extensively with RBD mainly in the neck region between shoulders (FIG. 5A), with the heavy chainAnd is +.>(antigen dissection of Dejnirattisai, wanwisa et al, "The antigenic anatomy of SARS-CoV-2receptor binding domain[SARS-CoV-2 receptor binding Domain)]"Cell [ Cell ]]184.8 (2021):2183-2200). All three heavy chain CDRs contact the RBD surface in the region between residues 417 and 484, but do not contact both residues. The light chain L1 in the region of residues 28-30 interacts with the RBD backbone around 501, but does not interact specifically with the side chain of Tyr-501 and is therefore insensitive to mutations at this residue.

Example 8 other gene families can attach strongly at the right shoulder around 501 while being cross-reactive.

Beta-32 is highly potent for all variants tested. To identify its interaction pattern, the high resolution crystal structure of Fab and the cryem structure of Fab complexed with Beta-S were determined (fig. 5B and 4C). Fab was observed to attach to both RBDs in the upward configuration. Although there is some ambiguity in the association pattern of Fab, it is clear that there is a strong interaction centered at residue 501. The Beta-32 binding pattern is quite different from that observed in both the variable gene families IgVH4-39 and IgVH3-53 discussed above. Thus, interactions are via heavy chains rather than light chains, as seen for the IgVH3-53 antibody, and angle of attack of Beta-32 is rotated about 90 towards the rear of the RBD compared to Beta-6 (FIG. 7B). Beta-32 thus found a novel cross-reaction pattern for the right shoulder engagement with the RBD.

Example 9A subtle specificity for Lys-484 can be achieved by a combination of salt bridges and hydrophobic cages.

Beta-38 was classified as requiring Lys-484 serologically and by BLI competition mapping (FIG. 4, table 11). The structure of the Beta-38/Beta RBD complex demonstrates this (FIG. 5A), and the antibodies attack the anterior cervical/left shoulder region from the front and show how well to confer specificity. Lys-484 is embedded between the CDR3 loops of the heavy and light chains (FIG. 7C). The hydrophobic stem of the lysine side chain is contained in a hydrophobic cage consisting of Phe-490 (RBD), tyr-108 (heavy chain) and Trp-92 (light chain). At the end of the cage Asp-94 (light chain) forms a salt bridge with the amino group of the lysine side chain of residue 484 (FIG. 7C), while Asn-32 forms a hydrogen bond. There are two Fab-RBD complexes in the crystallographically asymmetric unit and the different crystal packing forces introduce a 13 ° angle of attack difference, indicating some flexibility in attaching such highly concentrated antibodies.

Example 10 indirect effect of mutation at rbd residue 417.

Beta-22 uses IgVH3-30 and is serologically classified as targeting residue 417 (Table 11). The 417 lesion was reinforced by BLI mapping with the antibody almost exactly on top of this residue, and the crystal structure of the complex confirmed this (fig. 4 and 5A). However, binding is quite extensive, although almost entirely limited to the heavy chain, all three CDRs contribute in total In contrast, the light chain only contributes +.>). The heavy chain CDRs are deployed such that H1 approaches residue Tyr-501, H2 wraps Asn-417, and H3 reaches residue Lys-484 upwards (FIG. 7D).

Detailed examination of serological data showed good correlation therewith, H3 failed to reach Lys-484, so this mutation had no significant effect on binding, whereas the N501Y mutation had a positive effect on binding, but K417N/T was also required for effective neutralization. Although Asn-417 is not in direct contact with H2, the additional size of lysine and the concentration of positive electrostatic charge may combine to have a significant effect on antibody affinity. Beta-22 is glycosylated at residue Asn-35 within the light chain CDR1 and the sugar was previously observed to be located near the left shoulder (Dejnirattisai et al 2021 a). Two IgHV3-30 antibodies isolated from different donors were included in this group of potent Beta RBD binders (Table 11), the second being Beta-29. Serology and BLI mapping results showed that Beta-29 was similar to Beta-22 and the crystal structure of the complex with Beta-RBD was determined. The results confirm that the binding patterns of both antibodies are essentially identical (fig. 7E). Interestingly, both antibodies also shared IgVL4-1. Although the structural information of the third potent mAb sharing these serological properties, beta-20, was not obtained, BLI competition mapping places this mAb in the same position and the heavy chain gene family IgHV3-33 is closely related to IgHV3-30, so the pattern of conjugation is likely to be similar (although the NTD binding agent Beta-43 is also IgHV 3-30). In conclusion, the specificity of Asn-417 appears to be achieved indirectly, with residues centered at the antibody binding site between the light chain CDR2 and heavy chain CDR3 loops, but without specific high affinity interactions. Overall, it appears that 417 specificity to Beta-20 and Beta-29 is achieved indirectly, while the placement of the residue in the center of the paratope makes it sensitive to electrostatic charge changes at the 417 character of Alpha, beta and Gamma variants, and also agnostic as to whether the residue is asparagine or threonine. Beta-20 is sensitive to Thr-417 and the antibody may be in direct contact with Asn-417.

Example 11 targeting the left shoulder may introduce sensitivity to Delta through residue 478.

Beta-44 does not neutralize the Delta variant. The mAb was purified via heavy and light chains (408 and light chains, respectively) Relatively minor contacts were made and the antibody was on the left shoulder with the heavy chain over residue 478 (fig. 5A). Residues 484 of CDRs L1 and L3 near RBD, consisting of the hydroxy group of L3 of Tyr-90The group forms a hydrogen bond with the carbonyl oxygen of Lys-484, while H1, H2 and H3 surround residue Thr-478 (FIG. 7F). Since there is no contact at all near the Leu-452 residue of RBD, sensitivity to Delta is created by contact with residue 478, probably due to the loss of hydrophobic interaction between side chain atom CG1 and H3 residue Tyr-90 when residue 478 is mutated to Lys (FIG. 7F). Cryo-EM analysis of Beta-44 Fab complexed with Beta-S showed that the spike had two RBDs in the Fab-attached up configuration (FIG. 5C).

Example 12 cross-reactivity can be achieved by binding to the left shoulder-neck region but avoiding variant mutations.

Beta-47 is cross-reactive to all variants and interacts strongly with the back of the left shoulder-neck interface (contact areas of heavy and light chains 582 and 582, respectively) (FIGS. 5A and 7G). CDRH3 produces the greatest contact, partially against the back of loop bearing 484, while the light chain contacts the distal edge of the left shoulder, near but not contacting residue 478 (fig. 7G). Beta-47 is also glycosylated, this time at residue Asn-102 of the heavy chain CDR3, and as for Beta-22, the sugar is located near the left shoulder but rarely in specific contact with RBD. Beta-47 shares the same variable genes, glycosylation and disulfide bonds in the heavy chain CDR3, much like mAb 253 (Dejnirattisai et al 2021 a) previously identified.

Example 13 targeting to the left shoulder may be sensitive to changes at residues 484 and 478.

MAb Beta-26 requires a strong neutralization of the Beta E484K mutation, but is also very sensitive to the L452R/T478N mutation found in Delta. To explore this, the cryEM structure of Beta-S complexed with Beta-26 Fab was determined. Surprisingly, spikes were found in the 3 RBD up configuration, fab attached to all three RBDs (fig. 5C). Since the resolution of the experimental structure is not sufficient to construct the Fab structure directly in atomic detail, alphafold-2 was used to construct a model (Jumper et al, 2021) that was adjusted to fit the density (see example 16). The main contact is made through the heavy chain, all three CDRs contribute, and CDR2 interacts tightly with residue 484 (fig. 7G). In addition, there is a strong interaction between light chain CDR3 and 478 (fig. 7G). These interactions explain the serological results observed (fig. 2/table 10).

Example 14. Cross-reactive antibody binding sites that do not compete for ACE2 binding but have potent neutralization.

BLI competition analysis placed Beta-53 on the upper right side of RBD and ELISA data showed that binding was independent of ACE2 binding (FIG. 1G). CryoEM analysis of Beta-53 complexed with Beta-S showed attachment to all three RBDs, 2 up and one down (FIG. 5C). Crystallographic analysis of the Beta-53/Beta-RBD complex confirmed that the antibody was attached at an epitope that strongly overlapped with the previously identified antibody S309 (FIGS. 5A and 7H). There was also some overlap with the Beta-49 and Beta-50 "waist" binding antibodies described in example 18 (FIG. 20A). As with S309, there is substantial interaction with the N-linked glycans at residue N343 of RBD (fig. 7H, 16B, F and G). Compared to S309, beta-53 is located approximately on the RBD towards the ACE2 binding site Here, beta-53 thus contacts glycans via H1 and H3 instead of H3 and L2 in S309. It is even further from the Beta-49/Beta-50 "waist" epitope. Fab approaches the ACE2 site and may rub against N53ACE2 glycans (fig. 7I), but ELISA competition data confirm that there is no significant competition with ACE2 (fig. 1G). The heavy and light chains are substantially contacted (466 and +.>)。

The unsolved problem is the mechanism of neutralization, and the above mentioned cryem structure of Beta-53 with Beta-S measured after incubation at 20 ℃ for 30 minutes might elucidate this. Although the incubation temperature is below the physiologically expected temperature, there is evidence that most spike proteins have been degraded to a non-trimeric form, indicating that spike break-through is a potential neutralization mechanism.

Beta-53 remains a puzzle that does not compete with ACE2, binds to an epitope that overlaps with the epitope of S309 (Pinto et al 2020), and as with S309 it interacts with an N-linked glycan at residue N343 of RBD. Although the mechanism of neutralization is not clear, cryo-electron microscopy of complexes of Beta-53 Fab and trimeric S proteins suggests that Fab may disrupt the pre-fusion state of spike at room temperature.

Example 15 further neutralization data of selected antibodies against SARS-CoV-2 antibody

Further neutralization experiments were performed to determine neutralization of SARS-CoV-2variant by the selected antibodies. As discussed in the detailed description above, antibodies derived from the same heavy chain V gene may exchange light chains to produce antibodies comprising the heavy chain variable region of a first antibody and the light chain variable region of a second antibody, and such new antibodies may have improved neutralization and/or other characteristics when compared to the "parent" antibody.

Tables 3-9 provide examples of such antibodies that can be generated by exchanging light chains between antibodies derived from the same heavy chain V gene.

Tables 12 to 13 provide further neutralization data for selected antibodies and antibodies generated by exchanging light chains between antibodies derived from the same heavy chain V gene. Almost all antibodies produced by exchanging light chains between antibodies derived from the same heavy chain V gene exhibit improved neutralization when compared to the "parent" antibody. The data in FIG. 11A depicts mutations in the NTD, RBD and CTD of the spike protein of the SARS-CoV-2variant when compared to the Wuhan SARS-CoV-2 spike protein sequence. The data in fig. 11B corresponds to the data shown in table 13.

Table 14 provides the neutralization and RBD binding of a set of early selected antibodies against SARS-CoV-2 strain Victoria, B.1.1.7, B.1.351 and P.1. This can be used as a reference for comparison of the data in tables 12 and 13 (see also Dejnrattisai et al, "The antigenic anatomy of SARS-CoV-2receptor binding domain[SARS-CoV-2 receptor binding domain antigen anatomy ]" Cell [ Cell ]184.8 (2021): 2183-2200; supasa, piyada et al "Reduced neutralization of SARS-CoV-2B.1.1.7variant by convalescent and vaccine sera [ convalescence serum and vaccine serum neutralization reduction of SARS-CoV-2 B.1.7 variant ]" Cell [ Cell ]184.8 (2021): 2201-2211; zhou, daming et al "Evidence of escape of SARS-CoV-2variant B.1.351from natural and vaccine-reduced sera [ SARS-CoV-2variant B.1.351 ] evidence of escape from natural serum and vaccine-induced serum ]" Cell [ Cell ]184.9 (2021): 2348-2361): dejnratisai, wanwisa et al "20243 p-2 of SARS-52, strain [ Cell ] and" rjwit 2 strain "rj [ Cell ] 2[ gjwit-2021 ] of 2 ] and" Cell [ 52-52 v-52 of the vaccine strain [ 52.52 ] of SARS ].

Example 16. Materials and methods of examples 1 to 15.

Virus stock solution

SARS-CoV-2/human/AUS/VIC01/2020 (Caly et al 2020) and SARS-CoV-2/Beta supplied by UK public health department (Public Health England) were grown in Vero (ATCC CCL-81) cells. Cells were infected with SARS-CoV-2 virus using MOI of 0.0001. The virus-containing supernatant was harvested at 80% CPE and spun at 2000rpm at 4℃and then stored at-80 ℃. Viral titers were determined by performing a lesion formation assay on Vero cells. Both Victoria channel 5 and Beta channel 4 stocks were sequenced to verify that they contained the expected spike protein sequence and that the furin cleavage site was unchanged. The Beta virus used in these studies contained the following mutations: D80A, D G, L-244 deletion, K417N, E484K, N501Y, D614G, A V.

Bacterial strains and cell culture

Vero (ATCC CCL-81) cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) high glucose (Sigma-Aldrich) supplemented with 10% Fetal Bovine Serum (FBS), 2mM GlutaMAX (Ji Bike Co., gibco), 35050061) and 100U/ml penicillin-streptomycin at 37 ℃. Human mAbs were expressed in HEK293T cells cultured in UltraDOMA PF protein-free medium (catalog No. 12-727F, longsha Corp (LONZA)) at 37℃and 5% CO 2. Transformation of plasmid pNEO-RBD K417N, E484K, N Y was performed using E.coli DH 5. Alpha. Bacteria. Single colonies were picked and cultured overnight in LB broth with 50. Mu.g of mL-1 kanamycin at 37℃at 200rpm in a shaker. HEK293T (ATCC CRL-11268) cells were cultured in DMEM high glucose (sigma aldrich) supplemented with 10% fbs, 1%100x Mem Neaa (Ji Bike company) and 1%100x L-glutamine (Ji Bike company) at 37 ℃ and 5% co 2. To express RBD, RBD K417N, E484K, N Y and ACE2 HEK293T cells were cultured at 37 ℃ in DMEM high glucose (Sigma) supplemented with 2% fbs, 1%100x Mem Neaa and 1%100x L-glutamine for transfection.

Serum from Beta infection cases

Beta samples from uk infection cases were oxford gastrointestinal disease according to the discussion above and approved by the central research ethics committee of oxford university: the covd sub-study was collected on the "healthcare home and family member innate and adaptive immunity to SARS-CoV-2" protocol attached. All individuals had sequence-confirmed Beta infection or PCR-confirmed symptomatic disease, which occurred during quarantine and when in direct contact with Beta sequence-confirmed cases. Additional Beta-infected serum was obtained from south Africa (confirmed by sequence). At the time of collection of wipes, the patient signed an informed consent to agree to collect data and a series of blood samples. The study was approved by the university of Witerwald human research ethics Committee (reference number 200313) and was conducted according to the guidelines of the high quality clinical specifications.

Mouse experiment

Animal studies were performed according to recommendations in Guide for the Care and Use of Laboratory Animals of the National Institutes ofHealth [ national institutes of health laboratory animal care and use guidelines ]. The protocol was approved by the laboratory animal management and use committee of the university of washington, medical college (support No. a 3381-01). Virus inoculation was performed under anesthesia induced and maintained by ketamine hydrochloride and xylazine, and all efforts were made to minimize pain in the animals.

Heterozygous K18-hACE C57BL/6J mice (strain: 2B6.Cg-Tg (K18-ACE 2)) 2 Prlmn/J. Animals were group fed and fed a standard food diet. Mice of different ages and sexes were administered 103FFU of SARS-CoV-2 via intranasal administration.

For the mouse experiments, vero-hACE2-TMPRSS2 (A. Creata and B. Graham donations of NIH) and Vero-TMPRSS2 cells were cultured at 37℃in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% Fetal Bovine Serum (FBS), 10mM HEPES pH 7.3, 1mM sodium pyruvate, 1 Xnonessential amino acids and 100U/ml penicillin-streptomycin.

In addition, vero-TMPRSS2 and Vero-hACE2-TMPRSS2 cells were cultured in the presence of blasticidin or puromycin, respectively, at 5. Mu.g/mL. Beta SARS-CoV-2 strain was obtained from nasopharyngeal isolate (M.Suthar donation from Emery university). Infectious stocks were propagated by inoculating Vero-TMPRSS2 cells. The supernatant was collected, aliquoted and stored at-80 ℃. All work on infectious SARS-CoV-2 was performed in the institutional biosafety committee of the university of Washington medical institute approving BSL3 and A-BSL3 facilities using positive pressure air respirators and protective equipment. The viral sequence was confirmed by deep sequencing after RNA extraction to confirm the presence of the expected substitution.

Beta S protein

To construct an expression plasmid for the Beta S protein, a construct of the trimer S of the Wuhan strain was used as a template (Dejniratisai et al, 2021 a), and nine pairs of primers for S (L18F forward primer 5'-GAGCAGCCAGTGCGTGAATTTCACCACCAGAACCCAGCTG-3' (SEQ ID NO: 682), L18F reverse primer 5'-CAGCTGGGTTCTGGTGGTGAAATTCACGCACTGGCTGCTC-3' (SEQ ID NO: 683), D80A forward primer 5'-GCACCAAGAGATTCGCCAATCCTGTGCTGCC-3' (SEQ ID NO: 684) and D80A reverse primer 5'-GGCAGCACAGGATTGGCGAATCTCTTGGTGC-3' (SEQ ID NO: 685), D215G forward primer 5'-ATTAATCTGGTGAGAGGCCTGCCTCAGGGCTTC-3' (SEQ ID NO: 686), D215G reverse primer 5'-GAAGCCCTGAGGCAGGCCTCTCACCAGATTAAT-3' (SEQ ID NO: 687), 242-244 and R246I forward primer 5'-CCAGATTCCAGACCCTGCACATATCATATCTTACACCAG-3' (SEQ ID NO: 688), 242-244 and R246I reverse primer 5'-TGGTGTAAGATATGATATGTGCAGGGTCTGGAATCTGG-3' (SEQ ID NO: 689), K417N forward primer 5'-CAGGGCAGACCGGCAATATCGCCGACTACAATTAC-3' (SEQ ID NO: 690), K417N reverse primer 5'-GTAATTGTAGTCGGCGATATTGCCGGTCTGCCCTG-3' (SEQ ID NO: 691), E484G forward primer 5'-ATTAATCTGGTGAGAGGCCTGCCTCAGGGCTTC-3' (SEQ ID NO: 686), D215G reverse primer 5'-GAAGCCCTGAGGCAGGCCTCTCACCAGATTAAT-3' (SEQ ID NO: 687), 242-244 and R246I forward primer 5'-CCAGATTCCAGACCCTGCACATATCATATCTTACACCAG-3' (SEQ ID NO: 689), K417N forward primer 5'-CAGGGCAGACCGGCAATATCGCCGACTACAATTAC-3' (SEQ ID NO: 6925), K417N forward primer 6967 (SEQ ID NO: 696), K forward primer 6992 (SEQ ID NO: 695) d614G reverse primer 5'-CTCGGTGCAATTCACGCCCTGGTACAGCACGGC-3' (SEQ ID NO: 697); PCR was performed with the two primers of A701V forward primer 5'-CACCATGAGCCTGGGCGTCGAGAATAGCGTGGCC-3' (SEQ ID NO: 698), A701V reverse primer 5'-GGCCACGCTATTCTCGACGCCCAGGCTCATGGTG-3' (SEQ ID NO: 699)) and pHLsec vector (pHLsec forward primer 5'-CCTCAATTTGAGAAATAATGACTCGAGACTAGTATCGCG-3' (SEQ ID NO: 700), pHLsec reverse primer 5'-CGCGATACTAGTCTCGAGTCATTATTTCTCAAATTGAGG-3' (SEQ ID NO: 701)). Amplified PCR fragments were ligated together by gibbon reaction (Gibson, 2011). The new construct was sequenced in its entirety.

Cloning of ACE2 and RBDK417N, E484K, N501Y

ACE2 and RBD K417N, E484K, N501Y (Zhou et al, 2021) were constructed as described previously. Briefly, ACE2 was constructed by amplifying amino acids 19-615 of human ACE2 from an image clone (Source biosciences), clone ID 5297380), using forward primer 5'-GCGTAGCTGAAACCGGCTCCACCATTGAGGAACAGGCC-3' (SEQ ID NO: 702) and reverse primer 5'-GTGATGGTGATGTTTGTCTGCATATGGACTCCAGTC-3' (SEQ ID NO: 703), and inserted into the vector pOPINTTGneo incorporating the C-terminal 6 XHis tag.

To construct RBD K417N, E484K, N501Y, the RBD N501Y construct was used as a template and the DNA fragment was amplified using K417N primers (forward 5'-CAGGGCAGACCGGCAATATCGCCGACTACAATTAC-3' (SEQ ID NO: 690), reverse 5'-GTAATTGTAGTCGGCGATATTGCCGGTCTGCCCTG-3' (SEQ ID NO: 691)), E484K primers (forward 5'-CACCGTGTAATGGCGTGAAGGGCTTCAATTGCTAC-3' (SEQ ID NO: 692), reverse 5'-GTAGCAATTGAAGCCCTTCACGCCATTACACGGTG-3' (SEQ ID NO: 693)) and primers of the pNEO vector (forward 5'-CAGCTCCTGGGCAACGTGCT-3' (SEQ ID NO: 704) and reverse 5'-CGTAAAAGGAGCAACATAG-3' (SEQ ID NO: 705)). Three PCR fragments were used as templates and reamplified using pNEO vector primers. The final PCR fragment was digested with restriction enzymes AgeI and KpnI and ligated into the digested pNEO vector. The construct was confirmed by sequencing.

Protein production

Protein expression and purification were performed as described previously (Dejnirattisai et al, 2021a; zhou et al, 2020). Briefly, a plasmid encoding a protein was transiently expressed in HEK293T (ATCC CRL-11268) cells. The conditioned media was dialyzed and purified using a 5mL HisTrap nickel column (general electric Healthcare) and further purified using a Superdex 75hiload 16/60 gel filtration column (general electric Healthcare).

Isolation of Beta S-specific single B cells by FACS

Beta S-specific single B cell sorting was performed as described previously (Dejnirattisai et al 2021 a). Briefly, PBMC were stained with LIVE/DEAD Fixable Aqua dye (Invitrogen), followed by Beta staining with recombinant trimer S-twin-Strep. Cells were then incubated with CD3-FITC, CD14-FITC, CD16-FITC, CD56-FITC, igM-FITC, igA-FITC, igD-FITC, igG-BV786 and CD19-BUV395 and Strep-MAB-DY549 to stain the twin Strep tag of the S protein. Igg+ memory B cells were gated to cd19+, igg+, CD3-, CD14-, CD56-, CD16-, igM-, igA-, and IgD-, and further s+ were selected and individual cells were sorted into 96-well PCR plates with 10 μl capture buffer (Tris, nuclease-free H2O and ribonuclease inhibitor). Plates were briefly centrifuged at 2000 Xg for 1 min and placed on dry ice and then stored at-80 ℃.

Cloning and expression of Beta S-specific human mAbs

Beta S-specific human mAbs were cloned and expressed as described previously (Dejnirattisai et al 2021 a). Briefly, ig VH, ig V kappa and Ig V lambda genes were recovered from positive wells by RT-PCR. The genes encoding Ig VH, ig vκ, and Ig vλ were then amplified using nested PCR with a mixture of primers specific for human IgG. The PCR products of the heavy and light chains were ligated into expression vectors of human IgG1 or immunoglobulin kappa or lambda chains by gibbon assembly (Gibson, 2011). For mAb expression, plasmids encoding heavy and light chains were co-transfected into HEK293T cell lines by PEI transfection, and supernatants containing mAb were collected and filtered 4-5 days post-transfection and the supernatants were further characterized or purified.

Construction of Fab expression plasmid

The heavy chain expressing the specific mAb was used as a template to amplify the heavy chain vector comprising the variable region and CH1 by Fab primers (forward 5'-CAAGAGAGTTGAGCCCAAATCTTGTCTGGTGCCACGCGGAAGTAGTGCCTGGTCCCAC-3' (SEQ ID NO: 706), reverse 5'-GTGGGACCAGGCACTACTTCCGCGTGGCACCAGACAAGATTTGGGCTCAACTCTCTTG-3' (SEQ ID NO: 707)). Fragments with thrombin cleavage sites and a twin-strep tag overlapping the Fab fragments (forward 5'-CATCCACAGTTCGAGAAATAGGTGCGACGGCCGGCAAG-3' (SEQ ID NO: 708), reverse 5'-CTTGCCGGCCGTCGCACCTATTTCTCGAACTGTGGATG-3' (SEQ ID NO: 709)) were also amplified. Fab fragments and tag fragments were ligated by gibbon assembly (Gibson, 2011) and the complete plasmid was sequenced.

IgGmAb and Fab purification

To purify the full-length IgG mAb, mAb-expressed supernatant was collected and filtered through a vacuum filtration system and loaded onto protein a/G beads overnight at 4 ℃. The beads were washed three times with PBS and IgG was eluted using 0.1M glycine ph 2.7. The eluate was neutralized with Tris-HCl pH8 buffer to a final ph=7. IgG concentrations were determined spectrophotometrically and buffer exchanged into PBS.

For expression and purification of Fab, fab heavy and light chain expression plasmids were co-transfected into HEK293T cells by PEI in Free-style 293 medium. After 5 days of incubation at 37℃and 5% CO2, the culture supernatant was harvested and filtered using a 0.22mm polyethersulfone filter. Fab was purified using Strep-Tactin XT purification system.

Preparation of Fab from IgG

Fab fragments were digested with papain from purified IgG using the Pierce Fab preparation kit (sameifeier (Thermo Fisher)) following the manufacturer's protocol.

Determination of mAb binding to recombinant S or RBD by ELISA

For Beta, MAXISORP immunoplates (442404; enable Kennel (NUNC)) were coated overnight at 4℃with 2.5. Mu.g/ml strep MAB-Classic (2-1597-001; iba) diluted with carbonate-bicarbonate buffer. Plates were blocked with PBS dissolved 2% BSA for 1 hour, then 50. Mu.l of 5. Mu.g/ml double Strep-labeled S was added to each well and incubated for 1 hour at room temperature. Mu.l mAb expression supernatant or serial dilutions of plasma were added followed by ALP conjugated anti-human IgG (A9544; sigma) at a dilution of 1:10,000. Plates were developed by adding PNPP substrate. After 40 minutes, the absorbance was measured at 405 nm.

To confirm binding to recombinant Beta RBD, MAXISORP immunoplates were coated overnight at 4℃with 5. Mu.g/ml purified recombinant RBD-K417N, E484K, N Y. Plates were blocked with PBS dissolved 2% bsa for 1 hour. After addition of 50 μl mAb expression supernatant or serial dilutions of plasma, the rest of the procedure was the same as the S binding assay.

Focal Reduction Neutralization (FRNT)

The reduced focus neutralization test (Liu et al, 2021) was performed as previously described. Briefly, serial dilutions of Ab were mixed with SARS-CoV-2 strain Victoria, alpha, beta, gamma, alpha +E484K, delta or B.1.525 and incubated for 1 hour at 37 ℃. The mixture was then transferred in duplicate to 96-well, cell culture microplates containing confluent Vero cell monolayers and incubated for 2 hours before 1.5% semi-solid carboxymethylcellulose (CMC) cover medium was added. Foci formation assays were then performed by staining Vero cells with human anti-NP mAb (mAb 206) as primary antibody and peroxidase conjugated goat anti-human IgG (a 0170; sigma company) as secondary antibody. Finally, truebue peroxidase substrate was added to each well to visualize the foci (infected cells). Virus infected cell foci were counted using AID ELISpot software on a classical AID ELISpot reader.

Quantification and statistical analysis

Statistical analysis is reported in the results and legend. Neutralization was measured by FRNT. The percent lesion reduction was calculated and IC50 (FRNT 50) was determined using the probit program from the SPSS software package. Analysis was performed using the Wilcoxon paired symbol rank test and two-tailed P values were calculated from geometric mean. BLI Data were analyzed using a 1:1 fitting model using Data Analysis HT 11.1 (Fortebio).

ACE2 binding inhibition assay by ELISA

MAXISORP immunoplates were coated with 5. Mu.g/ml purified ACE2-His protein overnight at 4℃and then blocked with 2% BSA in PBS. Simultaneously, mAbs were serially diluted and mixed with 2.5. Mu.g/ml recombinant Beta trimer S-twin-Strep. The antibody-S protein mixture was incubated at 37℃for 1 hour. After incubation, the mixture was transferred to ACE2 coated plates and incubated for 1 hour at 37 ℃. After washing, strepMAB-Classic (2-1507-001, iba) was diluted with 2% BSA at 0.2. Mu.g/ml and used as primary antibody, and goat anti-mouse IgG-AP (#A 16093, england Corp.) was added at 1:2000 dilution. The reaction was developed by adding PNPP substrate and quenched with NaOH. Absorbance was measured at 405 nm. ACE2/S binding inhibition was calculated by comparison to control wells without antibody. The IC50 was determined using the Probit program from the SPSS software package.

Measurement of viral load.

Tissues were weighed and homogenized with zirconia beads in 1,000 μl DMEM medium supplemented with 2% heat inactivated FBS in a MagNA Lyser instrument (rogowski life sciences (Roche Life Science)). The tissue homogenate was clarified by centrifugation at 10,000rpm for 5 minutes and stored at-80 ℃. RNA was extracted on a KingfisherFlex extraction robot (Semerle Firex technology (Thermo Scientific)) using MagMax mirVana Total RNA isolation kit (Semerle Firex technology). RNA was reverse transcribed and amplified using TaqMan RNA-to-CT 1-step kit (Sieimerfeier). Reverse transcription was performed at 48℃for 15 minutes and then at 95℃for 2 minutes. Amplification was completed in 50 cycles as follows: 95℃for 15 seconds and 60℃for 1 minute. The copy of SARS-CoV-2N gene RNA in the sample was determined using the previously disclosed assay (Case et al 2020; hassan et al 2020). Briefly, taqMan assays were designed to target highly conserved regions of the N gene (forward primer: ATGCTGCAATCGTGCTACAA (SEQ ID NO: 710), reverse primer: GACTGCCGCCTCTGCTC (SEQ ID NO: 711), probe:/56-FAM/TCAAGGAAC/ZEN/AACATTGCCAA/3 IABkFQ/(SEQ ID NO: 712)). This region was included in the RNA standard to allow copy number determinations as low as 10 copies per reaction. The reaction mixture contained primers and probes at final concentrations of 500 and 100nM, respectively.

There was statistical significance when P-value <0.05 using Prism Version 8 (GraphPad). Test, number of animals, median and statistical comparison groups are indicated in each legend. Analysis of weight change was determined by ANOVA https:// www.socscistatistics.com/tests/ANOVA/default2. Aspx. Changes in viral load were compared to control antibody treated animals and analyzed by one-way ANOVA using multiple comparison assays.

Biological Layer Interferometry (BLI)

The BLI experiments were run on an Octet Red 96e machine (Fortebio). Competition assays for anti-Beta RBD antibodies were performed with the Fortebio Ni-NTA biosensor. His-tagged Beta RBD dissolved in running buffer (10mM HEPES pH 7.4 and 150mM NaCl) was used as ligand and first immobilized on the biosensor. The biosensor was then washed with running buffer to remove unbound RBD. Each biosensor was immersed in a different saturated antibody (Ab 1) to saturate the bound RBD, but one biosensor was immersed in the running buffer to serve as a reference during this step. All biosensors were then washed again with running buffer and immersed in wells containing the same competing antibody (Ab 2). The y-axis value of the signal of the different saturated antibodies in this step is divided by the value of the reference channel to obtain the ratio result of the different Ab1-Ab2 pairs. A ratio result approaching 0 indicates complete contention, while a 1 indicates no contention.

To measure the binding affinity of the mAb to the Beta RBD, the RBD was immobilized on an AR2G biosensor (Fortebio) and mAb was used as the analyte. All experiments were run at 30 ℃. Data were recorded using the software Data Acquisition 11.1 (Fortebio) and Data Analysis HT 11.1 (Fortebio) using a 1:1 fitting model for Analysis.

Antibody mapping based on biological layer interferometry competition data

This procedure uses the previously described program Mabscape (Dejnirattisai et al 2021 a). Briefly: the contention values are prepared by limiting all contention values between 0 and 1. The competition value between antibodies i and j is averaged with the competition value of j and i (when both are available). The surface of the receptor binding domain is found on PyMOL (PyMOL Molecular Graphics System [ PyMOL molecular graphics System)]1.2r3pre version, (-) Schrodinger companyLLC)) is generated from chain E of PDB code 6 YLA. The mesh is generated and iteratively shrunk and constrained to the surface of the RBD to provide a smoother surface in the Mabscape. The fixed positions of those antibodies of known structure were objectively calculated from atomic coordinates and locked to the nearest vertices on the grid (FD 5D (not published), EY6A (Zhou et al 2020), S309 (Pinto et al 2020) and mabs 45, 75, 150 and 253) as previously described (dejniratisai et al 2021 a). In addition, mabs 55, 58 and 61 (which gave predicted positions in previous studies) were fixed at these predicted positions to help map the beta antibodies.

Beta antibodies of known structure are also locked according to atomic coordinates (SA 06, SA22, SA24, SA27, SA44, SA47, SA53, SA 54). The objective function is the sum of the squared differences between the competition estimates and the competition values from the SPR data. LBFGS refinement is used for the most simplicity over 1000 macrocycles. The starting position of the antibody is generated by randomly assigning a starting vertex on the RBD grid and taking into account the data points of the pair with at least one immobilized antibody, the objective function is minimized for 20 cycles, and then all data points are subjected to 40 cycles. Between each cycle, the antibody positions are locked on the nearest mesh vertices. The average position of each antibody was chosen as the sampling position with the smallest average squared distance from all other sampling positions, and the RMSD was calculated from all contributing antibody positions (Dejnirattisai et al, 2021a; ginn, 2020).

Crystallization

Endoglycosidase H1 was added to the purified Beta RBD to remove glycans. Beta RBD was mixed with Beta-22, 24, 27, 38, 40 and 47Fab in a 1:1 molar ratio, respectively, to a final concentration of 13.0mg ml ^-1 . Beta RBD was combined with Beta-6 and COVOX-45Fab, beta-53 and Beta-29 Fab, beta-54 and Beta-37 Fab and Beta-54 and Beta-44Fab in a molar ratio of 1:1:1, with final concentrations of 7mg ml-1, respectively. These complexes were incubated for 30 min at room temperature, respectively. Beta-32 Fab at a concentration of 35mg ml-was also used for crystallization. Preliminary screening of crystals was set up in a crystal quick96 well X plate (GreinerBio-One) using a nanoliter sitting-drop vapor diffusion method with a Cartesian robot with 100nL protein plus 100nL stock per drop as described previously (Walter et al, 2003). Crystals of the Beta-RBD/Beta-22 Fab complex were formed under Molecular Dimensions Proplex conditions 1-28 containing 0.2M lithium sulfate, 0.1M MES pH 6.0 and 20% (w/v) PEG 4000. Crystals of Beta-RBD/Beta-24 Fab complex were formed under Proplex conditions 1-40 containing 0.2M ammonium sulfate, 0.1M Tris pH 7.5 and 20% (w/v) PEG 5000 MME. Crystals of the Beta-RBD/Beta-27 Fab complex were formed under Proplex conditions 1-36 containing 0.2M potassium iodide, 0.1M MES pH 6.5 and 25% (w/v) PEG 4000. Crystals of the Beta-RBD/Beta-38 Fab complex were formed under Proplex conditions 2-32 with 0.8M sodium/potassium phosphate pH 7.5. Crystals of the Beta-RBD/Beta-40 Fab complex were formed under Molecular Dimensions Morpheus conditions 2-28 containing 12.5% (w/v) PEG 1000, 12.5% (w/v) PEG 3350, 12.5% (v/v) MPD, 0.02M each carboxylic acid, and 0.1M MES/imidazole pH 6.5. Crystals of Beta-RBD/Beta-47 Fab complex were formed under Proplex conditions 1-10 containing 0.1M potassium chloride, 0.1M Tris pH 8.0 and 15% (w/v) PEG 2000 MME. Crystals of the Beta-RBD/Beta-6/COVOX-45 complex were formed under Hampton Research PEGRx conditions 1-46 containing 0.1M trisodium citrate dihydrate pH 5.0 and 18% (w/v) PEG 20000. In the presence of 0.1M sodium chloride and 0.1M BIS-TRIS p Crystals of Beta-RBD/Beta-53/Beta-29 complex were formed under conditions of Hampton Research Index of H6.5 and 1.5M ammonium sulfate 30. Crystals of the Beta-RBD/Beta-54/Beta-37 complex were formed under PEGRx conditions 2-35 containing 0.15M lithium sulfate monohydrate, 0.1M citric acid pH 3.5, and 18% (w/v) PEG 6000. Crystals of the Beta-RBD/Beta-54/Beta-44 complex were formed under PEGRx conditions 1-28 containing 0.1M citric acid pH 3.5 and 25% (w/v) PEG 3350. Crystals of Beta-32 Fab were formed under Index condition 23 containing 2.1M DL-malic acid pH 7.0.

X-ray data collection, structure determination and refinement

The crystals were mounted in a ring and immersed for one second in a solution containing 25% glycerol and 75% mother liquor, then frozen in liquid nitrogen. Diffraction data were collected at 100K at beam line I03 of UK diamond light source company (Diamond Light Source, UK). All Data is collected as part of an automated queuing system that allows for unattended automated Data collection (https:// www.diamond.ac.uk/Instruments/Mx/I03-Manual/unattended-Data-collection. Diffraction images (each image having an exposure time of 0.004 to 0.01 seconds, a beam size of 80×20 μm, a beam transmission rate of 30%, and a wavelength of 0.1 ° rotation were recorded on an Eiger2 XE 16M detector ). The data is indexed, integrated, and scaled. 360 ° data was collected from each crystal. The datasets for Beta-32Fab were pooled from 4 crystals, the datasets for Beta-RBD each with the complex of Beta-22 and Beta-24 were pooled from 3 crystals, the datasets for Beta-27 and Beta-29-Beta-53 each were pooled from 2 crystals, and the remaining respective datasets were pooled from a single crystal. The structure is determined by molecular replacement. Beta-RBD (PDB ID 7 NXA) (Dejnrattisai et al, 2021b; zhou et al, 2020) (Vhl and ChCl domains with maximum sequence similarity to the previously determined SARS-CoV-2RBD/Fab structure) (Dejnrattisai et al, 2021a; dejnrattisai et al, 2021b; huo et al, 2020; liu et al, 2021; supasa et al, 2021; zhou et al, 2020) of the SARS-CoV-2Beta-RBD-EY6A-222 complex was used as each currentAnd (5) a search model with a determined structure. All structures were reconstructed and refined using models.

Cryo-EM grid preparation

mu.L of S-1.2 μm aliquots with fab (1:6 molar ratio) were prepared, and fresh glow discharge was aspirated and almost immediately applied to either an Auflat 2/2-200 mesh porous grid (Protochips, supplied by molecular size company (Molecular Dimensions) in the case of mAb 222) or a C-flat 200 mesh 2/1 grid (high intensity, 20S, plasma Cleaner PDC-002-CE, harrick Plasma in the case of the remaining fab-S complexes). Excess liquid was removed by blotting with-1 force for 5s at 4.5 ℃ at 100% reported humidity using a vitro filter paper (grade 595, tedpe la inc.) and then flash frozen into liquid ethane using a vitro Mark IV (semer feier). The Fab/Spike complex was incubated for 10-30 minutes, then applied to the grid and flash frozen.

Cryo-EM data collection

Beta-S/Beta-44 Fab and Beta-S/mAb 222

Fab data were collected in EER format using EPU on a 300kV Titan Krios microscope equipped with a Falcon-IV detector and a select energy filter. For Beta-44, a 50 μm aperture, 100 μm objective lens was used. A total of 20K films were recorded with a total dose ofThe pixel size is +.>The fringe-free illumination is in EER format.

Beta-S/Beta-6、26、32、53

Compressed tif format films were acquired on Titan Krios (Sieimers), operating at 300kV, with a K2 detector with a 20eV slit (Gatan), nominal magnification of 165kX (vs.Corresponds to the calibrated pixel size) and the defocus range is0.8-2.6 μm.48 for SA026, SA032 and SA053, films were also acquired on Titan Krios (Sieimer's), as with SA006, but with a 10eV slit and 70 μm C aperture.

Cryo-EM data analysis

For all data sets except b.1.135apo, the collected movies were binned 4 times and the sports and ctf corrected. Particles are initially picked with a blob-picker module, and then the 2D classified spike-like particles from this initial set are used as templates for template-based picking.

Beta S with mAb 222Fab

Motion correction was performed on twice-binned movies and aligned using a 5x5 film based alignment. The aligned movies are then processed. For CoVOx-222, a strong agreement between the fab/RBD positions and the higher resolution crystal structure was observed. Most particles are in a "2-up" configuration, with two upward RBDs engaged with 222 fab. In view of the superior resolution of the crystallographic structure of the RBD/222 complex, this structure was used to evaluate atomic level details.

To generate the initial model, a deposited cryo-EM Beta 2-RBD upward spike model (PDB: 7 lyk) was rigid fitted to the partially filtered atlas, then the crystal structure of N501Y-mAb222 (PDB: 7nx 9) was initially superimposed on the upward RBD, and then the rigid fitted to the atlas. The Beta-only RBD model from the crystal structure with SA022 (residues 334-515) was then aligned with the N501Y-mAb-222 RBD structure and combined with mAb222 fab. The RBD/fab model rigid body is then fitted to the atlas and then merged with the spike model.

Beta S with Beta-6

Using the Nu refinement module of cross-pa, a total of 79905 particles from 6910 micrographs were used in the final 3D reconstruction to achieveIs estimated to have a b factor of-175.5 (fsc=0.143, cross pa). To further resolve the interface between spike/Fab and between adjacent Fab, additional local variability was runAnd local refinement processing. In addition, the derived particles were 3D classified without alignment and with a mask around the Fab/RBD region. Consistent with the 3D variability analysis, the resulting five categories showed little movement between Fab/RBD.

For the full spike map, a model was created by combining our crystal structure with that of Beta 2-upward spikes (PDB: 7 lyk), each rigid body fitting into the locally filtered cryEM map. These models are then combined in the coot before further rigid body fitting.

Good agreement was found between the crystal structure of Beta-S and Beta-6 Fab alone and the locally refined pattern concentrated in the Fab decorated RBD down and adjacent (also decorated) RBD up regions, except for the region between 472-492 for which slight repackaging of the loop was observed in both fabs. However, the quality of the map is too poor in this region to reliably reconstruct a significant slight distortion in the loops in this region processing of the map (especially since the fab CDR loops are not modeled well).

In addition to the contacts described between RBD plus Beta-6 deduced from the crystallographic structural analysis, the fab decorates residues S202/203 of the RBD-down constant heavy chain domain, as if it were "kissing" residues S66/G67 of the adjacent heavy chain variable domain. Of course, this interaction is an artificial product of a relatively small size of fab relative to the whole antibody, but may be a potential site for cross-linking the fab, whereby an S- > C mutation may be inserted at both sites.

Beta S with Beta-26 particles was first picked using the blob picker module within the cross-patch framework, followed by template picking, where a total of 224,609 particles were picked. The exposure was then further planned and the selected particles were classified twice, resulting in a set of particles with clear "deer horn" like extensions consistent with Fab decorated spikes. Beginning from scratch, heterogeneous micronization into three classes resulted in one class containing 50,878 particles with intact Fab decorated spikes.

Micronizing the final classified group of particles intoReport resolution (-101.1 b factor) (C1 symmetry) andfactor 110.3b (C3 symmetry). A clear 3-upward spike configuration can be seen in which the RBDs are arranged in a "straight-up" position similar to the anti-Victoria mAb 88 (Dejnirattisai et al 2021 a), at a density commensurate with the fab variable domain at the neck-left shoulder RBD region. For the C1 and C3 symmetry patterns, fab densities were clear at low profile levels, but when no symmetry was applied, two Fab were more clear than the third and appeared to be in contact with the N-terminal region of the heavy chain. The "individual" RBD-fab is twisted farther back from its neighbors and away from the nearest N-terminal domain. This is consistent with a cluster analysis, where the clusters show two Fab's closer together than the third one.

To better resolve the RBD/Fab interface, two kissing Fab's, intersecting NTDs and the relevant RBD and a single Fab/RBD/NTD are locally refined (mask generation process for this is described in the Beta-32 subsection below). Although the quality of the fab/RBD interface is improved to some extent (see supplementary materials), this is still insufficient to model and evaluate the critical interactions between RBD and CDR loops.

Beta S with Beta-32

As previously described, a total of 856192 particles were picked from a total of 8177 aligned movies using templates from spot selection. Particles were then filtered through 2d, and then 3d classified into 4 categories (using the ab initio model), yielding 54,932 spike-like particles supporting a subset of clear fab decorations. Difficulties are encountered in aligning the particle sets, probably due to the strong fab signal and running an initial non-uniform refinement (toResolution) and then used to run the concentration refinement +.>Which is then used as the basis for subsequent local variability analysis and local refinement. Further global classification with and without the ab initio model failed to distinguish individual spike populations.

For Beta-32, blast searches are performed on the H and L chains and an initial model is selected based on sequence coverage (especially loop region). For the H chain, 5U15 was found to be most suitable, with a single tyrosine substitution at residue 114. For initial masking, this was reduced to residues 1-130H and 1-113L for the two Fab's that were conjugated to RBD in the upward position (large variability was observed in the final Fab). In order to generate a mask for local refinement, a Chimera color region module is used to extract a region of interest for the mask from the map and set it as To cover the two Fab variable domains and the associated RBD, i.e. the NTD at the intersection between the two fabs and the tip of the central helical bundle. The extracted regions are then gaussian filtered and normalized to a mask within the cross parc. By->And 5o displacement and angular search to mask the region from the subtracted density, yielding a better but still lower resolution profile at the Fab/RBD interface (report resolution +.> Aussc=0.143, as determined). Local variability analysis is then run on the map to determine potentially flexible regions that may compromise the resolution obtained. Then fitting the crystal structure rigid body of Beta-32 into the local map, fitting into the coot, and then carrying out single-round rigid body refinement. One RBD appears to interact with the edge of the variable domain of the Fab decorating the adjacent RBD.

Beta S with Beta-44

The same procedure as before was used to select particles (initially 418400) and then two rounds of 2D classification were performed. These 149272 particles were then used to generate three ab initio models, which were then used for 3d classification. Particles from a single class with sharp decorative spikes are then non-uniformly refined and then further model generated and classified from scratch into three classes. Likewise, only one category showed clear spikes, then the last group 61603 particles from 15710 movies were extracted into the original box. Subsequent non-uniform refinement results Reconstruction of resolution. However, despite the broad classification, the density corresponding to Fab decorated RBDs is poor. To better resolve the RBD/Fab interface, all spikes except one RBD and Fab were subtracted and the focus refinement was tested with the fulcrum set to the RBD/Fab interface. However, fab signals remain very weak, probably due to the unmodified spike population. To isolate Fab-decorated spike populations, local variability analysis in "cluster mode" was used. Two of the five clusters (corresponding to 21886 particles) were found to be significantly decorated with Fab, with the Fab signal of the last three being significantly weaker. The last group of 21886 particles was locally refined, yielding +.>Final low resolution reconstruction of resolution.

After extensive classification, a spike was observed with a resolution ofThere are two RBDs in the upward condition, each decorated with weak Fab densities. After further classification and local refinement focused on one Fab/RBD region, the Fab/RBD interface improves slightly and because it is consistent with a much higher resolution crystal structure, it is not further refined.

Beta S with Beta-53

After the initial treatment, a significant population decorated with three Fab spikes was observed. Each of the three RBDs of the three Fab-decorated spike proteins was found and their density was very high.

Evidence of destructive Beta-53 was observed in the 2D class mean, where a single RBD plus Fab was observed after incubation for about 20 minutes. Comparison of spike distribution with incubation in the absence of antibody confirmed some Fab-mediated disruption.

Blast searches were performed on PDB to obtain 3nab_h as the closest match to the heavy chain variable region with a sequence ID of 83%, while 7dk0_b was found to be the closest match to the light chain with a sequence identity of 94%. Then, its rigid body is fitted into the fab portion of the atlas as previously described, and then a round of rigid body refinement is performed in Phenix.

Alphafold

To generate the fab model of beta-26, two strategies were tested. First, heavy and light chain amino acid sequences were submitted separately and the resulting models were independently rigid fitted into a local refinement map. However, the atlas density is too poor for reliable modeling and there is a clear conflict at the H/L interface. Alignment of the H and L chains with the closest PDB sequence match resulted in unsatisfactory fitting of the fab densities. A second strategy, more successful, involves submitting H and L variable domain sequences together with a Ser/Gly linker of 19 residues [ SSSGGGGSGGGGSGGGGSS (SEQ ID NO: 713) ]. The linker length and content were determined based on BLAST searches using H and L sequences together. The best fit rigid body in the five alphafold2 model was then fitted into the density and the joint region removed. Some conflicts still exist in the model and the spectrogram density is too poor to reliably resolve these conflicts.

Cryo-EM model refinement

Since the resolution of the fab-RBD regions of all cryem maps is poor, model rigid-bodies of RBD, fab without RBD, and S are fitted into the final map. For structures where locally refined maps are available, the RBD-fab model is considered a rigid body. In each case, the interface between the RBD and the remaining S model is checked in the coot, and then the final round of rigid body refinement is performed in Phenix, whereby the entire S-fab composite model (or RBD-fab model in the case of local refinement) is considered as a rigid body.

For SA006 chain B, it is necessary to fit the NTD (residues 38-305) and regions 320-591 of chain B separately, omitting the RBD regions (333-524) because the regions are significantly distorted relative to the S model used.

Example 17 quantitative resolution of similarity and differences in mab reactions.

The 27 potent RBDs bound to the Beta mAb and exhibited a considerable difference compared to the 20 potent mabs produced after infection with the early pandemic strain. To objectively determine how they differ, a neutralization-related approach was devised in which the neutralization results of antibodies against seven virus strains were compared between all possible pairs of 47 potent mabs. The measure of comparison is the correlation coefficient between the neutralization results of the two antibodies (see example 16). The results are shown in figure 14A as a thermal matrix revealing significant differences between Beta antibodies and early antibodies. Cluster analysis revealed the separation of the two groups (with few exceptions, fig. 14B), i.e. strain neutralization patterns inclined to be similar in the early pandemic mAb and Beta-mAb, but different between the two groups. This separation was very significant (P <0.00001 for Mann-Whitney U test), indicating that the antibody population had a consistent but different pattern of neutralization of strains specific for the priming virus. Using the same method to further analyze Beta antibodies, fig. 14C shows a cluster analysis of 27 Beta mabs, where it can be seen that antibodies are generally grouped into different groups based on their specificity for the individual RBD mutations depicted in fig. 2A-F.

EXAMPLE 18 IgVH1-69 antibody targets neutralization Table conserved between SARS-CoV-1 and 2 that was not previously observed Bits.

Beta-49 and Beta-50 strongly neutralized all SARS-CoV-2 strains tested, bound tightly to intact S-trimer, but bound very weakly to RBD and did not block ACE2 binding (figures 1G and 12). Both belong to the IgVH1-69 gene family. Fab/RBD complexes and Cryo-ball complexes of both antibodies were assayedThe crystal structure of the EM Fab/S complex (FIG. 15), including the structure of Beta-49 Fab/S trimer (FIG. 15), is relatively high in resolutionIndicating that the composite is relatively rigid. Both antibodies were attached in essentially the same configuration, although there were 19 amino acid differences in the individual VH domains (fig. 16A and table S3). Their epitopes were predominantly on RBD, but included the "waist" regions with the RBD linked to the N and C termini of the rest of S1 (torso analogy, fig. 5, 20A), and included the N and C terminal residues of the RBD construct (fig. 20B). The N-linked glycans attached to residue 343 of RBD also form part of an epitope from which the saccharide is displaced from its usual position, during which the side chain of N343 is distorted into an unfavorable conformation (fig. 16B). Despite sequence variation between the two antibodies, RBD interactions are very similar and involve conserved residues. The majority of the heavy chain interaction area is formed by the H3 loop (Beta-49 375 of them). Fab-bound S-trimers show all three RBDs in the down configuration (fig. 15), with the heavy chain interacting with both RBDs (fig. 16C), resulting in RBDs translating/rotating slightly toward the periphery of the trimer (fig. 16D). To the authors' knowledge, this "downward and outward" orientation was not seen before. Close packing (formation of secondary or quaternary epitopes) for the second RBD involves about +.>Is shown (fig. 16C and E and fig. 20B). The low affinity of Beta-49 and 50 for soluble monomeric RBDs and the fact that the lumbar residues, except for the expression tag, were in contact with the extreme ends of the soluble RBD construct can be explained by the generation of this quaternary epitope with 1Fab:2RBD (FIG. 20B). Residues containing primary (rather than secondary) epitopes (FIGS. 16F and G) were conserved between SARS-CoV-1 and-2 (FIG. 20B), so we tested their ability to bind SARS-CoV-1S (FIG. 18). Both antibodies bind SARS-CoV-1S to a similar extent as SARS-CoV-2S.

The mechanism of neutralization may be to lock the RBD in an unusual "down and out" conformation.

Example 19 beta-specific NTD binding antibodies.

Beta-43 is the only non-RBD mAb in the set of potent anti-Beta antibodies described herein and is highly specific for Beta-S (FIG. 8). The crystal structure and cryo-EM analysis confirm the direct interaction with NTD in the so-called "super-site" region (fig. 15, 17, 21). In the point mutations in NTD (L18F, D80A, D G and R246I), only L18F is part of the epitope.

Although the epitope was slightly removed from the site of Beta-characterized three-residue (242-244) NTD deletion, comparison of Beta-NTD structure with early pandemic NTD showed that the deletion introduced a knock change in the downstream polypeptide chain, significantly transferring part of the Beta-43 epitope, thus conferring Beta specificity (fig. 21). In addition to this variant-specific conformational change, there are many other differences between Beta-NTD and other reported NTD structures (fig. 21). These and the variability seen between other NTD structures demonstrate the inherent flexibility of this highly variable domain.

Example 20 cross-reactivity of mab.

Live virus neutralization assays were performed using the following viruses, which contained the indicated changes in RBD: victoria (an early strain), alpha (N501Y), beta (K417N, E484K, N501Y), gamma (K417T, E484K, N Y), delta (L452R, T478K) and Omicron (G339D, S371L, S373 3834 375 417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y H) (FIG. 22 and Table 15).

Mab Beta-22, 27, 29, 40, 47, 53, 54, 55 and 56 from Beta infection cases showed neutralization of Omicron. Specifically, beta-22, beta-29, beta-40, beta-47, beta-53, beta-54, beta-55, and Beta-56 maintain potent neutralization of omicron. Beta-40, beta-47, beta-54 and Beta-55 were potent in neutralizing all strains tested.

The interaction of Beta antibodies Beta-55, beta-24 and Beta-40 with the RBD of Omicron is shown in FIG. 23.

Watch (watch)

TABLE 1 SEQ ID NO of antibodies

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TABLE 2 SEQ ID NO of antibodies

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TABLE 12 IC50 titres of selected antibodies against SARS-CoV-2 variants

The following table shows 50% focal reduced neutralization titers (FRNT 50) of the indicated monoclonal antibodies against the indicated viruses. Supp stands for tissue culture supernatant, but not other antibodies that use purified antibodies in the assay. The Beta prefix represents antibodies made from B cells isolated from cases of Beta SARS-CoV-2 infection, whereas those without Beta prefix were isolated from cases of early-stage pandemic strains of infection. Chimeric antibodies from the combination of the Heavy Chain (HC) of one antibody with the Light Chain (LC) of another antibody are represented as follows: beta 47HC/55LC represents the combination of the heavy chain from antibody Beta-47 with the light chain of antibody 55.

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* Blank boxes have no available data

TABLE 13 containing an indicator mutation in the spike protein when compared to the Wuhan SARS-CoV-2 spike protein sequence The IC50% value of neutralization of a set of pseudoviral constructs.

IC50 values for the indicator antibodies are shown. The Beta prefix represents antibodies made from B cells isolated from cases of Beta SARS-CoV-2 infection, whereas those without Beta prefix were isolated from cases of early-stage pandemic strains of infection. Mixed chain antibodies from the combination of Heavy Chains (HC) of one antibody with Light Chains (LC) of another antibody are represented as follows: beta 47HC/55LC represents the combination of the heavy chain from antibody Beta-47 with the light chain of antibody 55.

TABLE 14 neutralization of selected antibodies against SARS-CoV-2 strains Victoria, B.1.1.7, B.1.351 and P.1 And RBD combination.

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Watch 14 (Xuezhi)

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Watch 14 (Xuezhi)

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In the case where the table is blank, the data of these points have not been obtained yet.

TABLE 15 IC50 titres of 27 Beta SARS-CoV-2 specific human mAbs against SARS-CoV-2 variants

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Sequence listing

Amino acid sequences of heavy and light chain variable regions of selected antibodies

/>

Nucleotide sequences of heavy and light chain variable regions of selected antibodies

/>

Amino acid sequence of CDR

/>

Amino acid sequence of CDR

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The amino acid sequence of the spike glycoprotein of the isolate Genbank Ref.QHR63260.2 of SEQ ID NO 681-WIV 04

MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDKVFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDNPVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNATNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSSANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFKIYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALHRSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTITDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESIVRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKSTNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDIADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVLYQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLIGAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSIIAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTSVDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQDKNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRSFIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNGLTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPFAMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLNDILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRASANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGVVFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGTHWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPLQPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGKYEQYIKWPWYIWLGFIAGLIAIVMVTIMLCCMTSCCSCLKGCCSCGSCCKFDEDDSEPVLKGVKLHYT

Sequence listing

<110> oxford university innovation Co., ltd (Oxford University Innovation Limited)

<120> antibody

<130> N422566WO

<150> GB2101578.9

<151> 2021-02-04

<150> GB2101580.5

<151> 2021-02-04

<150> GB2102401.3

<151> 2021-02-19

<150> GB2103388.1

<151> 2021-03-11

<150> GB2118423.9

<151> 2021-12-17

<150> GB2112297.3

<151> 2021-08-27

<150> GB2115824.1

<151> 2021-11-03

<150> GB2118426.2

<151> 2021-12-17

<160> 715

<170> patent In version 3.5

<210> 1

<211> 379

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 1

gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg caccttcagc aactatgcta tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatcccta tctttggtac agcaaactac 180

gcacagaact tccagggcag agtcacgatt accgcggacg aatccatgag cacagcctac 240

atggagctga gcagcctgag atctgaggac acggccgtat attactgtgc gggaggtggg 300

aggtattgta gtggtggtag gtgccactct gcctactctg cctactgggg ccagggaacc 360

ctggtcaccg tctcctcag 379

<210> 2

<211> 126

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 2

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

1 5 10 15

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

20 25 30

Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Asn Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Met Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Gly Gly Gly Arg Tyr Cys Ser Gly Gly Arg Cys His Ser Ala Tyr

100 105 110

Ser Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 3

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 3

gccatccagt tgacccagtc tccaggcacc ctgtctttgc ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120

cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggac 240

cctgaagatt ttgcagtgta ttactgtcag caatatggta gctcactcac tttcggcgga 300

gggaccaaag tggatatcaa ac 322

<210> 4

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 4

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

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

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

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys

100 105

<210> 5

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 5

Gly Gly Thr Phe Ser Asn Tyr Ala

1 5

<210> 6

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 6

Ile Ile Pro Ile Phe Gly Thr Ala

1 5

<210> 7

<211> 19

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 7

Ala Gly Gly Gly Arg Tyr Cys Ser Gly Gly Arg Cys His Ser Ala Tyr

1 5 10 15

Ser Ala Tyr

<210> 8

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 8

Gln Ser Val Ser Ser Ser Tyr

1 5

<210> 9

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 9

Gly Ala Ser

1

<210> 10

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 10

Gln Gln Tyr Gly Ser Ser Leu Thr

1 5

<210> 11

<211> 364

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 11

caggtgcagc tggtggagtc tgggggaggc ttggtccacc ctggggggtc cctgagactc 60

tcctgttcag cctctggatt caccttcagt aactatgcta tgcactgggt ccgccaggct 120

ccagggaagg gactggaata tgtttcagct attagtagta gtggggatat cacatactac 180

gcggactccg taaagggcag attcaccatc tccagagaca attccaagaa ctcactgtat 240

cttcaaatga acagtctgag agctgaggac acggctgttt attactgtgt gaaagatgta 300

acgaggacct actacgtagt ctttgactac tggggccagg gaaccctggt caccgtctcc 360

tcag 364

<210> 12

<211> 121

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 12

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val His Pro Gly Gly

1 5 10 15

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

20 25 30

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

35 40 45

Ser Ala Ile Ser Ser Ser Gly Asp Ile Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Val Lys Asp Val Thr Arg Thr Tyr Tyr Val Val Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 13

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 13

gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtgggaga cagagtcacc 60

atcacttgcc gggcaagtca gagcattagc agttatttaa attggtatca gcaggaacca 120

gggaaagccc ctaaactcct gatctatgct gcatccagtt tgcaaggtgg ggtcccatca 180

aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240

gaagattttg caacttacta ctgtcaacag agttacacta ccccgtacac ttttggccag 300

gggaccaaag tggatatcaa ac 322

<210> 14

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 14

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys

100 105

<210> 15

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 15

Gly Phe Thr Phe Ser Asn Tyr Ala

1 5

<210> 16

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 16

Ile Ser Ser Ser Gly Asp Ile Thr

1 5

<210> 17

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 17

Val Lys Asp Val Thr Arg Thr Tyr Tyr Val Val Phe Asp Tyr

1 5 10

<210> 18

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 18

Gln Ser Ile Ser Ser Tyr

1 5

<210> 19

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 19

Ala Ala Ser

1

<210> 20

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 20

Gln Gln Ser Tyr Thr Thr Pro Tyr Thr

1 5

<210> 21

<211> 358

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 21

caggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60

tcctgtgcag tctctggatt caccgtcagt aggaactaca tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcactt atttatagcg gtggtagcac attctacgca 180

gactccgtga agggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240

caaatgaaca gcctgagagc cgaggacacg gctgtgtatt actgtgcgag agatctgttt 300

cataggagtg gttatcacga ctactggggc cagggaaccc tggtcaccgt ctcctcag 358

<210> 22

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 22

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

1 5 10 15

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

20 25 30

Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asp Leu Phe His Arg Ser Gly Tyr His Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 23

<211> 319

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 23

gtcatctgga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc aggcgagtca ggacattaac aactatttaa attggtatca gcagaaacca 120

gggaaagccc ctaagctcct gatcttcgat gcctccaatt tggaaacagg ggtcccatca 180

aggttcagtg gcagtggatc tgggacagat tttactttca ccatcagcag cctacagcct 240

gaagatattg caacatatta ctgtcaacag tatgataatc tccctgcctt cggcggaggg 300

accaaagtgg atatcaaac 319

<210> 24

<211> 106

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 24

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Phe Gly Gly Gly Thr Lys Val Asp Ile Lys

100 105

<210> 25

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 25

Gly Phe Thr Val Ser Arg Asn Tyr

1 5

<210> 26

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 26

Ile Tyr Ser Gly Gly Ser Thr

1 5

<210> 27

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 27

Ala Arg Asp Leu Phe His Arg Ser Gly Tyr His Asp Tyr

1 5 10

<210> 28

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 28

Gln Asp Ile Asn Asn Tyr

1 5

<210> 29

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 29

Asp Ala Ser

1

<210> 30

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 30

Gln Gln Tyr Asp Asn Leu Pro Ala

1 5

<210> 31

<211> 361

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 31

gaagtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60

tcctgtgcag cgtctggatt caccttcagt aactatggca tgcactgggt ccgccaggct 120

ccaggcaagg ggctggagtg ggtggcggtt gtatggtatg atggaagcaa gaaatactat 180

gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa caccctgtat 240

ctgcaaatga acagcctgag agtcgaggac acggctgtgt attactgcgc gagagatttt 300

gcggtggggg aggagatcgc tgactcctgg ggccagggaa ccctggtcac cgtctcctca 360

g 361

<210> 32

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 32

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

1 5 10 15

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

20 25 30

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

35 40 45

Ala Val Val Trp Tyr Asp Gly Ser Lys Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

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

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 33

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 33

tcctatgagc tgactcagcc accctcggtg tcagtgtccc caggacaaac ggccaggatc 60

acctgctctg gagatgcatt gccaaaaaaa tatgcttatt ggtaccagca gaagtcaggc 120

caggcccctg tactggtcat ctatgaggac agcaaacgac cctccgggat ccctgagaga 180

ttctctgggt ccagctcagg gacaatggcc accttgacta tcagtggggc ccaggtggag 240

gatgaaggtg actactactg ttactcaaga gacagcagtg gtgatcattg ggtgttcggc 300

gcagggacca agctgaccgt cctag 325

<210> 34

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 34

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

1 5 10 15

Thr Ala Arg Ile Thr Cys Ser Gly Asp Ala Leu Pro Lys Lys Tyr Ala

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Asp Glu Gly Asp Tyr Tyr Cys Tyr Ser Arg Asp Ser Ser Gly Asp His

85 90 95

Trp Val Phe Gly Ala Gly Thr Lys Leu Thr Val Leu

100 105

<210> 35

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 35

Gly Phe Thr Phe Ser Asn Tyr Gly

1 5

<210> 36

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 36

Val Trp Tyr Asp Gly Ser Lys Lys

1 5

<210> 37

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 37

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

1 5 10

<210> 38

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 38

Ala Leu Pro Lys Lys Tyr

1 5

<210> 39

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 39

Glu Asp Ser

1

<210> 40

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 40

Tyr Ser Arg Asp Ser Ser Gly Asp His Trp Val

1 5 10

<210> 41

<211> 363

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 41

caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60

tcctgtgcag cctctggatt caccttcagt acctatgcta tgcactgggt ccgccaggct 120

ccaggcaagg ggctggagtg ggtggctgtt ctttcatatg atggaagcaa taaatactac 180

gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgc gaaagggggc 300

tcgtacgcgt actactacta catggacgtc tggggcaaag ggaccacggt caccgtctcc 360

tca 363

<210> 42

<211> 121

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 42

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Gly Gly Ser Tyr Ala Tyr Tyr Tyr Tyr Met Asp Val Trp Gly

100 105 110

Lys Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 43

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 43

gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc aggcgagtca ggacattagc aactatttaa attggtatca gcagaaacca 120

gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180

aggttcagtg gaggtggatc tgggacagat tttactttca ccatcaccag cctgcagcct 240

gaagatattg caacatatta ctgtcaacag tatgataatc tcccgctcac tttcggcgga 300

gggaccaaag tggatatcaa ac 322

<210> 44

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 44

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys

100 105

<210> 45

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 45

Gly Phe Thr Phe Ser Thr Tyr Ala

1 5

<210> 46

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 46

Leu Ser Tyr Asp Gly Ser Asn Lys

1 5

<210> 47

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 47

Ala Lys Gly Gly Ser Tyr Ala Tyr Tyr Tyr Tyr Met Asp Val

1 5 10

<210> 48

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 48

Gln Asp Ile Ser Asn Tyr

1 5

<210> 49

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 49

Asp Ala Ser

1

<210> 50

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 50

Gln Gln Tyr Asp Asn Leu Pro Leu Thr

1 5

<210> 51

<211> 376

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 51

gttcagctgg tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60

acctgcactg tctctggtgg ctccgtcagt agtggtagtt actactggag ctggatccgg 120

cagcccccag ggaagggact ggagtggatt gggtatatgt atttcagtgg gagcaccaac 180

tataatccct ccctcaagag tcgagtcacc atatcattag ccacgtccaa gaaccagttc 240

tccctgaagc tgagctctgt gaccgctgcg gacacggccg tctattactg tgcgagaggg 300

gattacgatt tttggagtgg tccccccggt cgggtggacg tctggggcaa agggaccacg 360

gtcaccgtct cctcag 376

<210> 52

<211> 125

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 52

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly

20 25 30

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

35 40 45

Trp Ile Gly Tyr Met Tyr Phe Ser Gly Ser Thr Asn Tyr Asn Pro Ser

50 55 60

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

65 70 75 80

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

85 90 95

Cys Ala Arg Gly Asp Tyr Asp Phe Trp Ser Gly Pro Pro Gly Arg Val

100 105 110

Asp Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 53

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 53

gaaatagtga tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120

cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttgcagtgta ttactgtcag cactatggta gttcacccgt aacttttggc 300

caggggacca aagtggatat caaac 325

<210> 54

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 54

Glu Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

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

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Gly Ser Ser Pro

85 90 95

Val Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys

100 105

<210> 55

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 55

Gly Gly Ser Val Ser Ser Gly Ser Tyr Tyr

1 5 10

<210> 56

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 56

Met Tyr Phe Ser Gly Ser Thr

1 5

<210> 57

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 57

Ala Arg Gly Asp Tyr Asp Phe Trp Ser Gly Pro Pro Gly Arg Val Asp

1 5 10 15

Val

<210> 58

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 58

Gln Ser Val Ser Ser Ser Tyr

1 5

<210> 59

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 59

Gly Ala Ser

1

<210> 60

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 60

Gln His Tyr Gly Ser Ser Pro Val Thr

1 5

<210> 61

<211> 367

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 61

caggtgcagc tggtgcagtc tgggcctgag gtgaagaagc ctgggacctc agtgaaggtc 60

tcctgcaagg cttctggatt cacctttact agctctgctg tgcagtgggt gcgacaggct 120

cgtggacaac gccttgagtg gataggatgg atcgtcgttg gcagtggtaa cacaaactac 180

gcacagaagt tccaggaaag agtcaccatt accagggaca tgtccacaag cacagcctac 240

atggagatga gcagcctgag atccgaggac acggccgtgt attactgtgc ggcaccggcc 300

tgtggtacca gctgctctga tgcctttgat atctggggcc aagggacaat ggtcaccgtc 360

tcttcag 367

<210> 62

<211> 122

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 62

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Ser Ser

20 25 30

Ala Val Gln Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Trp Ile Val Val Gly Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Glu Arg Val Thr Ile Thr Arg Asp Met Ser Thr Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Ala Pro Ala Cys Gly Thr Ser Cys Ser Asp Ala Phe Asp Ile Trp

100 105 110

Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 63

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 63

gacatccaga tgacccagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120

cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttggagtgta ttactgtcag cagtatggta gctcaccgtg gacgttcggc 300

caagggacca aggtggaaat caaac 325

<210> 64

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 64

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

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

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

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Gly Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 65

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 65

Gly Phe Thr Phe Thr Ser Ser Ala

1 5

<210> 66

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 66

Ile Val Val Gly Ser Gly Asn Thr

1 5

<210> 67

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 67

Ala Ala Pro Ala Cys Gly Thr Ser Cys Ser Asp Ala Phe Asp Ile

1 5 10 15

<210> 68

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 68

Gln Ser Val Ser Ser Ser Tyr

1 5

<210> 69

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 69

Gly Ala Ser

1

<210> 70

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 70

Gln Gln Tyr Gly Ser Ser Pro Trp Thr

1 5

<210> 71

<211> 382

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 71

caggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60

tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaacct 120

ccagggaagg gcctggagtg ggtctcaggt gtcagttgga acagtggtac cataggctat 180

gcggactctg tgaagggccg attcatcatc tccagagaca acgccaagaa ctccctgtat 240

ctgcaaatga acagtctgaa agctgaggac acggccttgt attactgtgc aagagaagtg 300

ggggggactt ttggagtcct tatttcacgc gaggggggac ttgattactg gggccaggga 360

accctggtca ccgtctcctc ag 382

<210> 72

<211> 127

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 72

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Lys Gly Arg Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Ala Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Glu Val Gly Gly Thr Phe Gly Val Leu Ile Ser Arg Glu Gly

100 105 110

Gly Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 73

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 73

tcctatgagc tgacacagcc accctcggtg tcagtggccc caggacagac ggccagaatt 60

acctgtgggg gaaacaccat tggaagtaaa agtgtgcact ggtaccagca gagaccaggc 120

caggcccctg tgctggtcgt ctatgatgat agcgaccggc cctcagggat ccctgagcga 180

ttctctggct ccaactctgg gaacacggcc accctgacca tcagcagggt cgaagccggg 240

gatgaggccg actattactg tcaggtgtgg gatagtagta gtgatcgggt ggtattcggc 300

ggagggacca agctgaccgt cctag 325

<210> 74

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 74

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

1 5 10 15

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

20 25 30

His Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Val Leu Val Val Tyr

35 40 45

Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

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

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp Arg

85 90 95

Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 75

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 75

Gly Phe Thr Phe Asp Asp Tyr Ala

1 5

<210> 76

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 76

Val Ser Trp Asn Ser Gly Thr Ile

1 5

<210> 77

<211> 20

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 77

Ala Arg Glu Val Gly Gly Thr Phe Gly Val Leu Ile Ser Arg Glu Gly

1 5 10 15

Gly Leu Asp Tyr

20

<210> 78

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 78

Thr Ile Gly Ser Lys Ser

1 5

<210> 79

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 79

Asp Asp Ser

1

<210> 80

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 80

Gln Val Trp Asp Ser Ser Ser Asp Arg Val Val

1 5 10

<210> 81

<211> 385

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 81

caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60

atctgcactg tctctggtgg ctccgtcagc agtggtaatt tctactggag ctggatccgg 120

cagcccccag ggaagggact ggagtggatt ggatctatct attacactgg gagccccaac 180

tacaacccct ccctcaagag tcgagtcacc atatccctag acacgtccaa gaaccagttc 240

tccctgaagc tgagctctgt gaccgctgcg gacacggccg tgtattactg tgcgagagag 300

atctattatt atgatagaag tggttcttac aactctgatg cttttgatat ctggggccaa 360

gggacaatgg tcaccgtctc ttcag 385

<210> 82

<211> 128

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 82

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

1 5 10 15

Thr Leu Ser Leu Ile Cys Thr Val Ser Gly Gly Ser Val Ser Ser Gly

20 25 30

Asn Phe Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Thr Gly Ser Pro Asn Tyr Asn Pro Ser

50 55 60

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

65 70 75 80

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

85 90 95

Cys Ala Arg Glu Ile Tyr Tyr Tyr Asp Arg Ser Gly Ser Tyr Asn Ser

100 105 110

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

115 120 125

<210> 83

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 83

gatatcgtga tgactcagtc tccagccacc ctgtctgtgt ctccagggga aagaggcacc 60

ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaaccg 120

ggccaggctc ccaggctcct catctatggt gcatccacga gggccactgg tatcccagcc 180

aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240

gaagattttg cagtttatta ctgccagcag tataataact ggcctccgct cactttcggc 300

ggagggacca aagtggatat caaac 325

<210> 84

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 84

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Pro

85 90 95

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

100 105

<210> 85

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 85

Gly Gly Ser Val Ser Ser Gly Asn Phe Tyr

1 5 10

<210> 86

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 86

Ile Tyr Tyr Thr Gly Ser Pro

1 5

<210> 87

<211> 20

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 87

Ala Arg Glu Ile Tyr Tyr Tyr Asp Arg Ser Gly Ser Tyr Asn Ser Asp

1 5 10 15

Ala Phe Asp Ile

20

<210> 88

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 88

Gln Ser Val Ser Ser Asn

1 5

<210> 89

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 89

Gly Ala Ser

1

<210> 90

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 90

Gln Gln Tyr Asn Asn Trp Pro Pro Leu Thr

1 5 10

<210> 91

<211> 381

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 91

caggtgcagc tggtggagtc tgggggaggc gtggttcagc ctgggaggtc cctgagactc 60

tcctgtgcag cctctggatt caccttcaat aactatcctt tgcactgggt ccgccaggct 120

ccaggcaagg ggccggagtg ggtggcagtt atttcacagg atggaggcaa taaatactac 180

gtagactccg tgaagggccg attcaccatc tccagagaca attccaagaa caccctgtat 240

ctgcaaatga acaacctgag agctgaggac acggctctgt attactgtgc gagagatgtt 300

gtagtggtgg tagctgctag gaaccactac tacaacggta tggacgtctg gggccaaggg 360

accacggtca ccgtctcctc a 381

<210> 92

<211> 127

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 92

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

1 5 10 15

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

20 25 30

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

35 40 45

Ala Val Ile Ser Gln Asp Gly Gly Asn Lys Tyr Tyr Val Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

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

85 90 95

Ala Arg Asp Val Val Val Val Val Ala Ala Arg Asn His Tyr Tyr Asn

100 105 110

Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 93

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 93

gacatccagt tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60

atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120

gggaaagccc ctaagctcct gatctatgct gtatccagtt tgcaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240

gaagattttg caacttacta ttgtcaacag gctaagagtt tccctttcac tttcggccct 300

gggaccaagg tggagattaa ac 322

<210> 94

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 94

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Lys Ser Phe Pro Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Glu Ile Lys

100 105

<210> 95

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 95

Gly Phe Thr Phe Asn Asn Tyr Pro

1 5

<210> 96

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 96

Ile Ser Gln Asp Gly Gly Asn Lys

1 5

<210> 97

<211> 20

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 97

Ala Arg Asp Val Val Val Val Val Ala Ala Arg Asn His Tyr Tyr Asn

1 5 10 15

Gly Met Asp Val

20

<210> 98

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 98

Gln Gly Ile Ser Ser Trp

1 5

<210> 99

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 99

Ala Val Ser

1

<210> 100

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 100

Gln Gln Ala Lys Ser Phe Pro Phe Thr

1 5

<210> 101

<211> 381

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 101

cagctgcagc tgcaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60

acctgcactg tctctggtgg ctccatcagt agtggtagtt ataattggac ctggatccgg 120

cagcccgccg ggaagggact ggagtggatt gggcgtatat ataatagtgg gagcaccaac 180

tacaacccct ccctcaagag tcgagtcacc atatcagtag acacgtccaa gaaccagttg 240

tccctgaagg tgaggtctgt gaccgccgca gacacggccg tgtattactg tgcgagacat 300

tgcagtggtg gtacctgcta cccgaagtac tactacggta tggacgtctg gggccaaggg 360

accacggtca ccgtctcctc a 381

<210> 102

<211> 127

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 102

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly

20 25 30

Ser Tyr Asn Trp Thr Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Arg Ile Tyr Asn Ser Gly Ser Thr Asn Tyr Asn Pro Ser

50 55 60

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

65 70 75 80

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

85 90 95

Cys Ala Arg His Cys Ser Gly Gly Thr Cys Tyr Pro Lys Tyr Tyr Tyr

100 105 110

Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 103

<211> 331

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 103

caatctgccc tgactcagcc accctcggtg tctgaagccc ccaggcagag ggtcaccatc 60

tcctgttctg gaagcagctc caacatcgga aataatgctg taaactggta ccagcagttc 120

ccaggaaagg ctcccaaact cctcatctat tatgatgatc tgctgccctc aggggtctct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tggggtccag 240

tctgaggatg aggctgatta ttactgtgca gcatgggatg acagcctgaa tgtcgtggta 300

ttcggcggag ggaccaagct gaccgtccta g 331

<210> 104

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 104

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

1 5 10 15

Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn

20 25 30

Ala Val Asn Trp Tyr Gln Gln Phe Pro Gly Lys Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Ser Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu

85 90 95

Asn Val Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 105

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 105

Gly Gly Ser Ile Ser Ser Gly Ser Tyr Asn

1 5 10

<210> 106

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 106

Ile Tyr Asn Ser Gly Ser Thr

1 5

<210> 107

<211> 19

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 107

Ala Arg His Cys Ser Gly Gly Thr Cys Tyr Pro Lys Tyr Tyr Tyr Gly

1 5 10 15

Met Asp Val

<210> 108

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 108

Ser Ser Asn Ile Gly Asn Asn Ala

1 5

<210> 109

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 109

Tyr Asp Asp

1

<210> 110

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 110

Ala Ala Trp Asp Asp Ser Leu Asn Val Val Val

1 5 10

<210> 111

<211> 370

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 111

caggtgcagc tggtggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60

acctgcactg tctctggtgg ctccatcagc agtaatagtt acttctgggg ctggatccgc 120

cagcccccag ggacggggct ggagtggatt gggaatatct attatactgg gagcacctac 180

tacaacccgt cgttcgagag tcgagtcacc atgtccgtag acacgtcgaa gaaccagttc 240

tccctgaggc tgagctctgt gaccgccgca gacacggctg tgtattactg tgcgagacat 300

gtcagggcct acgactatga tgcccctttt gatatctggg gccaagggac aatggtcacc 360

gtctcttcag 370

<210> 112

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 112

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Asn

20 25 30

Ser Tyr Phe Trp Gly Trp Ile Arg Gln Pro Pro Gly Thr Gly Leu Glu

35 40 45

Trp Ile Gly Asn Ile Tyr Tyr Thr Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

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

65 70 75 80

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

85 90 95

Cys Ala Arg His Val Arg Ala Tyr Asp Tyr Asp Ala Pro Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 113

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 113

gtcatctgga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120

gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacacaa ttcactctca caatcagcag cctgcagcct 240

gaagattttg caacttatta ctgtctacag attaatagtt atccgctcac tttcggcgga 300

gggaccaagg tggaaatcaa ac 322

<210> 114

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 114

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Ile Asn Ser Tyr Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 115

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 115

Gly Gly Ser Ile Ser Ser Asn Ser Tyr Phe

1 5 10

<210> 116

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 116

Ile Tyr Tyr Thr Gly Ser Thr

1 5

<210> 117

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 117

Ala Arg His Val Arg Ala Tyr Asp Tyr Asp Ala Pro Phe Asp Ile

1 5 10 15

<210> 118

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 118

Gln Gly Ile Arg Asn Asp

1 5

<210> 119

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 119

Ala Ala Ser

1

<210> 120

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 120

Leu Gln Ile Asn Ser Tyr Pro Leu Thr

1 5

<210> 121

<211> 349

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 121

caggtacagc tgcagcagtg gggcgcagga ctgttgaagc cttcggagac cctgtccctc 60

acctgcgctg tctatggtgg gtccttcagt ggttactact ggagctggat ccgccagccc 120

ccagggaagg ggctggagtg gattggggaa atcaatcata gtggaagcac caactacaac 180

ccgtccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240

aagctgagtt ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgag aactgattac 300

tatgatagta tagactgggg ccagggaacc ctggtcaccg tctcctcag 349

<210> 122

<211> 116

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 122

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Thr Val Ser Ser

115

<210> 123

<211> 328

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 123

cagtctgtgc tgactcagga gccctcactg actgtgtccc caggagggac agtcactctc 60

acctgtggct ccagcactgg agctgtcacc agtggtcatt atccctactg gttccagcag 120

aagcctggcc aagtccccag gacactgatt tatgatacaa ggaacaaaca ctcctggacc 180

cctgcccggt tctcaggctc cctccttggg ggcaaagctg ccctgaccct ttcgggtgcg 240

cagcctgagg atgaggctga atattactgc ttgctctcct ctagtggtgc tcgggtgttc 300

ggcggaggga ccaagctgac cgtcctag 328

<210> 124

<211> 109

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 124

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

1 5 10 15

Thr Val Thr Leu Thr Cys Gly Ser Ser Thr Gly Ala Val Thr Ser Gly

20 25 30

His Tyr Pro Tyr Trp Phe Gln Gln Lys Pro Gly Gln Val Pro Arg Thr

35 40 45

Leu Ile Tyr Asp Thr Arg Asn Lys His Ser Trp Thr Pro Ala Arg Phe

50 55 60

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

65 70 75 80

Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Leu Leu Ser Ser Ser Gly

85 90 95

Ala Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 125

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 125

Gly Gly Ser Phe Ser Gly Tyr Tyr

1 5

<210> 126

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 126

Ile Asn His Ser Gly Ser Thr

1 5

<210> 127

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 127

Ala Arg Thr Asp Tyr Tyr Asp Ser Ile Asp

1 5 10

<210> 128

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 128

Thr Gly Ala Val Thr Ser Gly His Tyr

1 5

<210> 129

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 129

Asp Thr Arg

1

<210> 130

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 130

Leu Leu Ser Ser Ser Gly Ala Arg Val

1 5

<210> 131

<211> 358

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 131

gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt caccttcagt acctacgaca tccactgggt ccgccaagct 120

acaggaaaag gtctggagtg ggtctcagct attggtactg ctggtgacac atactattca 180

ggctccgtga agggccgatt caccatctcc agagaaaatg ccaagaactc cttgtatctt 240

caaatgaaca gcctgagagc cggggacacg gctgtgtatt actgtgcaag gggtagtggg 300

acctacttct actactttga ctactggggc cagggaaccc tggtcaccgt ctcctcag 358

<210> 132

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 132

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

1 5 10 15

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

20 25 30

Asp Ile His Trp Val Arg Gln Ala Thr Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Gly Ser Gly Thr Tyr Phe Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 133

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 133

gacatcgtga tgactcagtc tccatcctcc ctgtctgcat ctgtaggaga cagaatcacc 60

atcacttgcc gggcaagtca gagcattaac aactatttaa attggtatca gcagaaacca 120

gggaaagccc ctaagctcct gatctatgct gcatcccgtt tgcaaactgg ggtcccatca 180

aggttcagtg gcagtggatc tgggacagat tccactctca ccatcaacac tctgcaacct 240

gaagattttg caacttacta ctgtcaacag agttacagtg cccctccgtg gacgttcggc 300

caagggacca aagtggatat caaac 325

<210> 134

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 134

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Ala Ala Ser Arg Leu Gln Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

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

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys

100 105

<210> 135

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 135

Gly Phe Thr Phe Ser Thr Tyr Asp

1 5

<210> 136

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 136

Ile Gly Thr Ala Gly Asp Thr

1 5

<210> 137

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 137

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

1 5 10

<210> 138

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 138

Gln Ser Ile Asn Asn Tyr

1 5

<210> 139

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 139

Ala Ala Ser

1

<210> 140

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 140

Gln Gln Ser Tyr Ser Ala Pro Pro Trp Thr

1 5 10

<210> 141

<211> 366

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 141

caggtgcagc tggtggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60

acctgcactg tctctggtgg ctcgatcagc agttcttact actggggctg gatccgccag 120

cccccaggga aggggctgga gtggattggg agtgtctatt atagtgggag cacctactac 180

aacccgtccc tcaagagtcg agtcaccata tccgtggaca cgtccaagaa ccagttctcc 240

ctgaggctga gctctgtgac cgccgcagac acggctgtgt attattgtgc gaggctgatg 300

accacggaag actactactc cggtatggac gtctggggcc aagggaccac ggtcaccgtc 360

tcctca 366

<210> 142

<211> 122

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 142

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp

35 40 45

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

50 55 60

Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser

65 70 75 80

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

85 90 95

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

100 105 110

Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 143

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 143

gccatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgtc gggcgagtca gggcattagc gattatttag cctggtttca gcagaaacca 120

gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180

aagttcagcg gcggtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240

gaagattttg caacttatta ctgccaacag tatcatagtt acccgatcac cttcggccaa 300

gggacacgac tggagattaa ac 322

<210> 144

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 144

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

1 5 10 15

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

20 25 30

Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr His Ser Tyr Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 145

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 145

Gly Gly Ser Ile Ser Ser Ser Tyr Tyr

1 5

<210> 146

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 146

Val Tyr Tyr Ser Gly Ser Thr

1 5

<210> 147

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 147

Ala Arg Leu Met Thr Thr Glu Asp Tyr Tyr Ser Gly Met Asp Val

1 5 10 15

<210> 148

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 148

Gln Gly Ile Ser Asp Tyr

1 5

<210> 149

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 149

Ala Ala Ser

1

<210> 150

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 150

Gln Gln Tyr His Ser Tyr Pro Ile Thr

1 5

<210> 151

<211> 351

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 151

caggtgcagc tggtggagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggggt caccgtcagt agcaactaca tgagttgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcaatt atttatagtg gtggtaccac atactacgca 180

gactccgtga agggccgatt caccatctcc agagactctt ccatgaacac gctgtatctt 240

caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctgatg 300

gtgtacggta tagacgtctg gggccaaggg accacggtca ccgtctcctc a 351

<210> 152

<211> 117

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 152

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly

1 5 10 15

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

20 25 30

Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Ser Ser Met Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asp Leu Met Val Tyr Gly Ile Asp Val Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 153

<211> 328

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 153

gaaatagtga tgacgcagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120

gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240

gaagattttg caacttatta ctgtcaacag cttgatagtt acccccccgg gtacactttt 300

ggccagggga ccaaagtgga tatcaaac 328

<210> 154

<211> 109

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 154

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asp Ser Tyr Pro Pro

85 90 95

Gly Tyr Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys

100 105

<210> 155

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 155

Gly Val Thr Val Ser Ser Asn Tyr

1 5

<210> 156

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 156

Ile Tyr Ser Gly Gly Thr Thr

1 5

<210> 157

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 157

Ala Arg Asp Leu Met Val Tyr Gly Ile Asp Val

1 5 10

<210> 158

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 158

Gln Gly Ile Ser Ser Tyr

1 5

<210> 159

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 159

Ala Ala Ser

1

<210> 160

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 160

Gln Gln Leu Asp Ser Tyr Pro Pro Gly Tyr Thr

1 5 10

<210> 161

<211> 351

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 161

gaggtgcagc tgttggagtc tggaggagac ttgatccagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggggt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcaatt atttatcccg gtgggagcac attctacgca 180

gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240

caaatgcaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatcttggc 300

tcaggggaca tggacgtctg gggcaaaggg accacggtca ccgtctcctc a 351

<210> 162

<211> 117

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 162

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

1 5 10 15

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

20 25 30

Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met His Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asp Leu Gly Ser Gly Asp Met Asp Val Trp Gly Lys Gly Thr Thr

100 105 110

Val Thr Val Ser Ser

115

<210> 163

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 163

gacatcgtga tgactcagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaaccg 120

gggaaagccc ctaagctcct gatccaagct gcatccactt tgcaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240

gaagattttg caacttatta ctgtcaacag cttaatagtt accggtacac ttttggccag 300

gggaccaagg tggagatcaa ac 322

<210> 164

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 164

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Leu Asn Ser Tyr Arg Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 165

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 165

Gly Val Thr Val Ser Ser Asn Tyr

1 5

<210> 166

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 166

Ile Tyr Pro Gly Gly Ser Thr

1 5

<210> 167

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 167

Ala Arg Asp Leu Gly Ser Gly Asp Met Asp Val

1 5 10

<210> 168

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 168

Gln Gly Ile Ser Ser Tyr

1 5

<210> 169

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 169

Ala Ala Ser

1

<210> 170

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 170

Gln Gln Leu Asn Ser Tyr Arg Tyr Thr

1 5

<210> 171

<211> 369

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 171

gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60

tcctgtgcag cctctggatt caccttcagt agctatggca tgcactgggt ccgccaggct 120

ccaggcaagg ggctggagtg ggtggcactt atatcatatg atggaggtaa tagatactat 180

gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagactgag agctgaagac acggctatgt attactgtgc gaaagatcgt 300

gatgatgggt gggattggta ctacttcatg gacgtctggg gcaaagggac cacggtcacc 360

gtctcctca 369

<210> 172

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 172

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

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

85 90 95

Ala Lys Asp Arg Asp Asp Gly Trp Asp Trp Tyr Tyr Phe Met Asp Val

100 105 110

Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 173

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 173

gacatccagt tgacccagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtattagc ggcaactact tagcctggta ccagcataaa 120

cctggccagg ctcccagact cctcatctat ggtgcatcca ccagggccac tggcatccca 180

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcgtacac ttttggccag 300

gggaccaagg tggagatcaa ac 322

<210> 174

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 174

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

1 5 10 15

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

20 25 30

Tyr Leu Ala Trp Tyr Gln His Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 175

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 175

Gly Phe Thr Phe Ser Ser Tyr Gly

1 5

<210> 176

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 176

Ile Ser Tyr Asp Gly Gly Asn Arg

1 5

<210> 177

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 177

Ala Lys Asp Arg Asp Asp Gly Trp Asp Trp Tyr Tyr Phe Met Asp Val

1 5 10 15

<210> 178

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 178

Gln Ser Ile Ser Gly Asn Tyr

1 5

<210> 179

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 179

Gly Ala Ser

1

<210> 180

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 180

Gln Gln Tyr Gly Ser Ser Tyr Thr

1 5

<210> 181

<211> 370

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 181

caggttcagc tggtgcagtc tgggcctgag gtgaagaagc ctgggacctc agtgaaggtc 60

tcctgcaagg cttctggatt cacctttact agctctgctg tgcagtgggt gcgacaggct 120

cgtggacagc gccttgagtg gataggatgg atcgtcgttg gcagtggtaa cacaaactac 180

gcacagaagt tccaggaaag cgtcaccatt accagggaca tgtccacaag cacagcctac 240

atggagctga gcagcctgag atccgaggac acggccgtgt attactgtgc ggccccacat 300

tgtattggtg gtagctgcca tgatgctttt gatatctggg gccaagggac aatggtcacc 360

gtctcttcag 370

<210> 182

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 182

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Ser Ser

20 25 30

Ala Val Gln Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Trp Ile Val Val Gly Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Glu Ser Val Thr Ile Thr Arg Asp Met Ser Thr Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Ala Pro His Cys Ile Gly Gly Ser Cys His Asp Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 183

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 183

gatatcgtga tgacccagtc tccaggcacc ctatctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttaga agcagctact tagcctggta ccagcagaaa 120

cctggccagg ctcccaggct cctcatctat ggtgcatcca ggaggggcac tggcatccca 180

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccctg gacgttcggc 300

caagggacca aggtggaaat caaac 325

<210> 184

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 184

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

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Arg Ser Ser

20 25 30

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

35 40 45

Ile Tyr Gly Ala Ser Arg Arg Gly Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 185

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 185

Gly Phe Thr Phe Thr Ser Ser Ala

1 5

<210> 186

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 186

Ile Val Val Gly Ser Gly Asn Thr

1 5

<210> 187

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 187

Ala Ala Pro His Cys Ile Gly Gly Ser Cys His Asp Ala Phe Asp Ile

1 5 10 15

<210> 188

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 188

Gln Ser Val Arg Ser Ser Tyr

1 5

<210> 189

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 189

Gly Ala Ser

1

<210> 190

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 190

Gln Gln Tyr Gly Ser Ser Pro Trp Thr

1 5

<210> 191

<211> 352

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 191

caggtgcagc tggtggagtc aggagcagag gtgaaaaagc ccggggagtc tctgaagatc 60

tcctgtaagg gttctggata cagctttacc agctactgga tcgtctgggt gcgccagatg 120

cccgggaaag gcctggagtg gatggggatc atctatcctg gtgactctga taccaaatac 180

agtccgtcct tccaaggcca ggtcagcatc tcagccgaca agcccatcag caccgcctac 240

ctgcagtgga gcaggctgaa ggcctcggac accgccatgt attactgtgc gagactaggg 300

aattggctgg tggactactg gggccaggga accctggtca ccgtctcctc ag 352

<210> 192

<211> 117

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 192

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

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Ser Tyr

20 25 30

Trp Ile Val Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Asp Thr Lys Tyr Ser Pro Ser Phe

50 55 60

Gln Gly Gln Val Ser Ile Ser Ala Asp Lys Pro Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Arg Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Leu Gly Asn Trp Leu Val Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 193

<211> 343

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 193

gatattgtga tgactcagtc tcctctctct ctgtccgtca cccctggaca gccggcctcc 60

atctcctgca agtctagtca gagcctcctg catagtgatg gaaagaccta tttgtattgg 120

tacctgcaga agccaggcca gcctccacag ctcctgatgt atgaagtttc caaccggttc 180

tctggagtgc cagataggtt cagtggcagc gggtcaggga cagacttcac acttaaaatc 240

agccgggtgg agtctgagga tgttggggtt tattactgca tgcaaagtat acagcttcct 300

cgcgggatca ccttcggcca agggacacga ctggagatta aac 343

<210> 194

<211> 114

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 194

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu His Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Pro

35 40 45

Pro Gln Leu Leu Met Tyr Glu Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ser Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ser

85 90 95

Ile Gln Leu Pro Arg Gly Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu

100 105 110

Ile Lys

<210> 195

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 195

Gly Tyr Ser Phe Thr Ser Tyr Trp

1 5

<210> 196

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 196

Ile Tyr Pro Gly Asp Ser Asp Thr

1 5

<210> 197

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 197

Ala Arg Leu Gly Asn Trp Leu Val Asp Tyr

1 5 10

<210> 198

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 198

Gln Ser Leu Leu His Ser Asp Gly Lys Thr Tyr

1 5 10

<210> 199

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 199

Glu Val Ser

1

<210> 200

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 200

Met Gln Ser Ile Gln Leu Pro Arg Gly Ile Thr

1 5 10

<210> 201

<211> 343

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 201

gaggtgcagc tggtggagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60

tcctgtgcag cctctgggct caccgtcagt cgcaattaca tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcactt atttatagcg gtggtagcac atactacgca 180

gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240

caaatgaaca gcctgagagc cgaggacacg gccgtgtatt actgtgcgag agatctacgc 300

ggagaagtct ggggccaagg gacaatggtc accgtctctt cag 343

<210> 202

<211> 114

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 202

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly

1 5 10 15

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

20 25 30

Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Leu Ile Tyr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asp Leu Arg Gly Glu Val Trp Gly Gln Gly Thr Met Val Thr Val

100 105 110

Ser Ser

<210> 203

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 203

gccatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc aggcgagtca ggacattagc aactttttaa attggtatca gcagaaacca 120

gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180

aggttcagtg gaagtggatc tgggacagat tttactttca ccatcagtag cctgcagcct 240

gaagatattg caacatatta ctgtcaccag tatgataatc tccctcgaac gttcggccaa 300

gggaccaaag tggatatcaa ac 322

<210> 204

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 204

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

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Phe

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys His Gln Tyr Asp Asn Leu Pro Arg

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys

100 105

<210> 205

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 205

Gly Leu Thr Val Ser Arg Asn Tyr

1 5

<210> 206

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 206

Ile Tyr Ser Gly Gly Ser Thr

1 5

<210> 207

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 207

Ala Arg Asp Leu Arg Gly Glu Val

1 5

<210> 208

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 208

Gln Asp Ile Ser Asn Phe

1 5

<210> 209

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 209

Asp Ala Ser

1

<210> 210

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 210

His Gln Tyr Asp Asn Leu Pro Arg Thr

1 5

<210> 211

<211> 372

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 211

gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt caccttcagt aactacgaca tgcactgggt ccgccaagct 120

acaggaaaag gtctggagtg ggtctcactt attggtactg ctggtgacac atactatcca 180

gactccgtga agggccgatt caccatctcc agagaaaatg ccaagaactc cttgtatctt 240

caaatgaaca gcctgagagc cggggacacg gctgtgtatt actgtgcaag agggcaacac 300

actcaaatcg gtcactacta ctactactac atggacgtct ggggcaaagg gaccacggtc 360

accgtctcct ca 372

<210> 212

<211> 124

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 212

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

1 5 10 15

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

20 25 30

Asp Met His Trp Val Arg Gln Ala Thr Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Gly Gln His Thr Gln Ile Gly His Tyr Tyr Tyr Tyr Tyr Met Asp

100 105 110

Val Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 213

<211> 328

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 213

gccatccgga tgacccagtc tccatcgtcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120

gggaaagccc ctaagctcct gatctttgct gcatccagtt tgcaaagtgg ggtcccatca 180

aggttcagtg gcagtggatc tgggacagat tccactctaa ccatcagcag tctgcaacct 240

gaagattttg caacttacta ctgtcaacag agttacagta accctccgga gggcagtttt 300

ggccagggga ccaaagtgga gattaaac 328

<210> 214

<211> 109

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 214

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

1 5 10 15

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

20 25 30

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

35 40 45

Phe Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 215

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 215

Gly Phe Thr Phe Ser Asn Tyr Asp

1 5

<210> 216

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 216

Ile Gly Thr Ala Gly Asp Thr

1 5

<210> 217

<211> 18

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 217

Ala Arg Gly Gln His Thr Gln Ile Gly His Tyr Tyr Tyr Tyr Tyr Met

1 5 10 15

Asp Val

<210> 218

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 218

Gln Ser Ile Ser Ser Tyr

1 5

<210> 219

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 219

Ala Ala Ser

1

<210> 220

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 220

Gln Gln Ser Tyr Ser Asn Pro Pro Glu Gly Ser

1 5 10

<210> 221

<211> 361

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 221

gaagtgcagc tggtggagac tggaggaggc ttgatccagc ctggggggtc cctgagactc 60

tcctgtgcag cctctgggtt caccgtcagt agcaactaca tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtt gtttatggcg gtggtaccac atactacgca 180

gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240

caaatgaaca gcctgagagc cgaggacacg gccgtatatt actgtgcgac tgacaatgga 300

tacagctatg gtttttcatt tgactactgg ggccagggaa ccctggtcat cgtctcctca 360

g 361

<210> 222

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 222

Glu Val Gln Leu Val Glu Thr Gly Gly Gly Leu Ile Gln Pro Gly Gly

1 5 10 15

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

20 25 30

Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Val Tyr Gly Gly Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Thr Asp Asn Gly Tyr Ser Tyr Gly Phe Ser Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Ile Val Ser Ser

115 120

<210> 223

<211> 331

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 223

cagtctgtgc tgactcagcc tgcctccatg tctgggtctc ctggacagtc gatcaccatc 60

tcctgcactg gaaccagcag tgatgttggg ggttataacc ttgtctcctg gtaccaacag 120

cacccaggca aagcccccaa actcatgatt tatgagggca gtaagcggcc ctcaggggtt 180

tctaatcgct tctctggctc caagtctggc aacacggcct ccctgacaat ctctgggctc 240

caggctgagg acgaggctga ttattactgc tgctcatatg caggtagtag taattgggtg 300

ttcggcggag ggaccaagct gaccgtccta g 331

<210> 224

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 224

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

1 5 10 15

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

20 25 30

Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Glu Gly Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser

85 90 95

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

100 105 110

<210> 225

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 225

Gly Phe Thr Val Ser Ser Asn Tyr

1 5

<210> 226

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 226

Val Tyr Gly Gly Gly Thr Thr

1 5

<210> 227

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 227

Ala Thr Asp Asn Gly Tyr Ser Tyr Gly Phe Ser Phe Asp Tyr

1 5 10

<210> 228

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 228

Ser Ser Asp Val Gly Gly Tyr Asn Leu

1 5

<210> 229

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 229

Glu Gly Ser

1

<210> 230

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 230

Cys Ser Tyr Ala Gly Ser Ser Asn Trp Val

1 5 10

<210> 231

<211> 373

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 231

caggtgcagc tggtggagtc tggggctgag gtggagaagc ctggggcctc agtgaaggtc 60

tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggatgg atcaacccta tcagtggtgg cacaaactat 180

gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240

atggacctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagaggaacg 300

tattactatg atagtagtgg ttacatccca tttgactact ggggccaggg aaccctggtc 360

accgtctcct cag 373

<210> 232

<211> 124

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 232

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Trp Ile Asn Pro Ile Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Arg Gly Thr Tyr Tyr Tyr Asp Ser Ser Gly Tyr Ile Pro Phe Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 233

<211> 331

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 233

cagtctgtgc tgactcagcc tgcctccgta tctgggtctc ctggacagtc gatcaccatc 60

tcctgcactg gaaccagcag tgatgttggg agttataacc ttgtctcctg gtaccaacag 120

cacccaggca aagcccccaa actcatgatt tatgagggca gtaagcggcc ctcaggggtt 180

tctaatcgct tctctggctc caagtctggc aacacggcct ccctgacaat ctctgggctc 240

caggctgagg acgaggctga ttattactgc tgctcatatg caggtagtag cactttggta 300

ttcggcggag ggaccaagct gaccgtccta g 331

<210> 234

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 234

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

1 5 10 15

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

20 25 30

Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Glu Gly Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser

85 90 95

Ser Thr Leu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 235

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 235

Gly Tyr Thr Phe Thr Gly Tyr Tyr

1 5

<210> 236

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 236

Ile Asn Pro Ile Ser Gly Gly Thr

1 5

<210> 237

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 237

Ala Arg Gly Thr Tyr Tyr Tyr Asp Ser Ser Gly Tyr Ile Pro Phe Asp

1 5 10 15

Tyr

<210> 238

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 238

Ser Ser Asp Val Gly Ser Tyr Asn Leu

1 5

<210> 239

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 239

Glu Gly Ser

1

<210> 240

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 240

Cys Ser Tyr Ala Gly Ser Ser Thr Leu Val

1 5 10

<210> 241

<211> 385

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 241

caggttcagc tggtgcagtc tgggtctgag ttgaagaagc ctggggcctc agtgaaggtt 60

tcctgcaagg cttctggata caccttcagt agctatgcta tgacttgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggatgg atcaacacca acactgggaa cccaacgtat 180

gcccagggct tcacaggacg gtttgtcttc tccttggaca cctctgtcag cacggcatat 240

ctgcagatca gcagcctaaa ggctgaggac actgccgtgt attactgtgc gagagctctg 300

ggatattgta gtagtaccag ctgctatccc gcttgggctg cttttgatat ctggggccaa 360

gggacaatgg tcaccgtctc ttcag 385

<210> 242

<211> 128

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 242

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

1 5 10 15

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

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Thr Asn Thr Gly Asn Pro Thr Tyr Ala Gln Gly Phe

50 55 60

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

65 70 75 80

Leu Gln Ile Ser Ser Leu Lys Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Leu Gly Tyr Cys Ser Ser Thr Ser Cys Tyr Pro Ala Trp

100 105 110

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

115 120 125

<210> 243

<211> 316

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 243

tcctatgagc tgactcagcc actctcagtg tcagtggccc tgggacagac ggccagtatt 60

acctgtgggg gaaacaacat tggaagtaaa aatgtgcact ggtaccagca gaagccaggc 120

caggcccctg tgctggtcat ctatagggat agcaaccggc cctctgggat ccctgagcga 180

ttctctggct ccaactcggg gaacacggcc accctgacca tcagcagagc ccaagccggg 240

gatgaggctg actataactg tcaggtgtgg gacagcagcg tggtattcgg cggagggacc 300

aagctgaccg tcctag 316

<210> 244

<211> 105

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 244

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

1 5 10 15

Thr Ala Ser Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Asn Val

20 25 30

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

35 40 45

Arg Asp Ser Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Ala Gln Ala Gly

65 70 75 80

Asp Glu Ala Asp Tyr Asn Cys Gln Val Trp Asp Ser Ser Val Val Phe

85 90 95

Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 245

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 245

Gly Tyr Thr Phe Ser Ser Tyr Ala

1 5

<210> 246

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 246

Ile Asn Thr Asn Thr Gly Asn Pro

1 5

<210> 247

<211> 21

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 247

Ala Arg Ala Leu Gly Tyr Cys Ser Ser Thr Ser Cys Tyr Pro Ala Trp

1 5 10 15

Ala Ala Phe Asp Ile

20

<210> 248

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 248

Asn Ile Gly Ser Lys Asn

1 5

<210> 249

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 249

Arg Asp Ser

1

<210> 250

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 250

Gln Val Trp Asp Ser Ser Val Val

1 5

<210> 251

<211> 358

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 251

gaggtgcagc tggtggagtc tggaggaggc ttgatccagc cgggggggtc cctgagactc 60

tcctgtgcag cctctgggct caccgtcagt agcaactaca tgagttgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtt atttatagtg gtggtagcac gttctacgca 180

gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240

caaatgaaca gcctgggagc cgaggacacg gccgtgtatt actgtgcgag aggagaaggt 300

agtcctggaa actggttcga cccctggggc cagggaaccc tggtcaccgt ctcctcag 358

<210> 252

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 252

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly

1 5 10 15

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

20 25 30

Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Tyr Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Gly Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Gly Glu Gly Ser Pro Gly Asn Trp Phe Asp Pro Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 253

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 253

gatgttgtga tgactcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttccc agcagctact tagcctggta ccagcagaaa 120

cctggccagg ctcccaggct cctcatctat ggtgcatcca ccagggccac tggcatccca 180

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaggatt ttgcagtgta ttactgtcag cactatgata cctcaccccg tttcggcgga 300

gggaccaaag tggatatcaa ac 322

<210> 254

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 254

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

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Pro Ser Ser

20 25 30

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

35 40 45

Ile Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln His Tyr Asp Thr Ser Pro

85 90 95

Arg Phe Gly Gly Gly Thr Lys Val Asp Ile Lys

100 105

<210> 255

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 255

Gly Leu Thr Val Ser Ser Asn Tyr

1 5

<210> 256

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 256

Ile Tyr Ser Gly Gly Ser Thr

1 5

<210> 257

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 257

Ala Arg Gly Glu Gly Ser Pro Gly Asn Trp Phe Asp Pro

1 5 10

<210> 258

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 258

Gln Ser Val Pro Ser Ser Tyr

1 5

<210> 259

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 259

Gly Ala Ser

1

<210> 260

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 260

Gln His Tyr Asp Thr Ser Pro Arg

1 5

<210> 261

<211> 370

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 261

caggtccagc tggtacagtc tgggcctgag gtgaagaagc ctgggacctc agtgaaggtc 60

tcctgcaagg cttctggatt cacctttact acctctgctg tgcagtgggt gcgacaggct 120

cgtggacaac gccttgagtg gataggatgg atcgtcgttg gcagtggtaa cacaaactac 180

gcacagaagt tccaggaaag agtcaccatt accagggaca tgtccacaac cacagcctac 240

atggagctga gcagcctgag atccgaggac acggccgtgt atttctgtgc ggcgcctcat 300

tgtaatagta ccagctgcta tgacgctttt gatatctggg gccaagggac aatggtcacc 360

gtctcttcag 370

<210> 262

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 262

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Thr Ser

20 25 30

Ala Val Gln Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Trp Ile Val Val Gly Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Glu Arg Val Thr Ile Thr Arg Asp Met Ser Thr Thr Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Ala Pro His Cys Asn Ser Thr Ser Cys Tyr Asp Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 263

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 263

gacatccaga tgacccagtc tccaggcacc ctgtctttgt ctccagggga aggagccacc 60

ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120

cctggccagg ctcccaggct cctcatctat ggtgcatcta gtggggccac tggcatccca 180

gacagattca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacctta cacttttggc 300

caggggacca aggtggaaat caaac 325

<210> 264

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 264

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

1 5 10 15

Glu Gly Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

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

35 40 45

Ile Tyr Gly Ala Ser Ser Gly Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

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

100 105

<210> 265

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 265

Gly Phe Thr Phe Thr Thr Ser Ala

1 5

<210> 266

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 266

Ile Val Val Gly Ser Gly Asn Thr

1 5

<210> 267

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 267

Ala Ala Pro His Cys Asn Ser Thr Ser Cys Tyr Asp Ala Phe Asp Ile

1 5 10 15

<210> 268

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 268

Gln Ser Val Ser Ser Ser Tyr

1 5

<210> 269

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 269

Gly Ala Ser

1

<210> 270

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 270

Gln Gln Tyr Gly Ser Ser Pro Tyr Thr

1 5

<210> 271

<211> 352

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 271

caggtgcagc tggtggagtc tggaggaggc ttgatccagc ctggggggtc cctgagactc 60

tcctgtgcag cctctgggct caccgtcaat aggaactaca tgagctggat ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagtac attttacgca 180

gactccgtga agggccgatt caccatctcc agagacaatt ccaagaacac actgtctctt 240

caaatgaaca gcctgagagc cgaggacacg gccatttatt actgtgcgag agacttctac 300

gagggttctt ttgatatctg gggccaaggg acaatggtca ccgtctcttc ag 352

<210> 272

<211> 117

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 272

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly

1 5 10 15

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

20 25 30

Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Tyr Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val Lys

50 55 60

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

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys Ala

85 90 95

Arg Asp Phe Tyr Glu Gly Ser Phe Asp Ile Trp Gly Gln Gly Thr Met

100 105 110

Val Thr Val Ser Ser

115

<210> 273

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 273

gccatccagt tgacccagtc tccttccttc ctgtctgcat ctataggaga cagagtcacc 60

atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120

gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240

gaagattttg catcttatta ctgtcaacag cttaatagtt accccgctcc ggttttcggc 300

cctgggacca aagtggatat caaac 325

<210> 274

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 274

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 275

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 275

Gly Leu Thr Val Asn Arg Asn Tyr

1 5

<210> 276

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 276

Ile Tyr Ser Gly Gly Ser Thr

1 5

<210> 277

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 277

Ala Arg Asp Phe Tyr Glu Gly Ser Phe Asp Ile

1 5 10

<210> 278

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 278

Gln Gly Ile Ser Ser Tyr

1 5

<210> 279

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 279

Ala Ala Ser

1

<210> 280

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 280

Gln Gln Leu Asn Ser Tyr Pro Ala Pro Val

1 5 10

<210> 281

<211> 370

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 281

caggtacagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60

tcctgcaagg cttctggtta catctttatc agatatggta ttagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggatgg atcagcgcta acaatggtta cacaaactat 180

gcacagaagc tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240

atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagagatggg 300

ggtattttga ctggttatct cgactacttt gaccactggg gccagggaac cctggtcacc 360

gtctcctcag 370

<210> 282

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 282

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Ile Arg Tyr

20 25 30

Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Ser Ala Asn Asn Gly Tyr Thr Asn Tyr Ala Gln Lys Leu

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asp Gly Gly Ile Leu Thr Gly Tyr Leu Asp Tyr Phe Asp His

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 283

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 283

gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagactcacc 60

atcacttgcc gggcaagtca gagcattgcc agctatttaa attggtatca gcagaaacca 120

gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180

aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag tctgcaacct 240

gaagattttg caacttacca ctgtcaacag agttacagta ccctcggaat cactttcggc 300

cctgggacca aagtggatat caaac 325

<210> 284

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 284

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr His Cys Gln Gln Ser Tyr Ser Thr Leu Gly

85 90 95

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

100 105

<210> 285

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 285

Gly Tyr Ile Phe Ile Arg Tyr Gly

1 5

<210> 286

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 286

Ile Ser Ala Asn Asn Gly Tyr Thr

1 5

<210> 287

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 287

Ala Arg Asp Gly Gly Ile Leu Thr Gly Tyr Leu Asp Tyr Phe Asp His

1 5 10 15

<210> 288

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 288

Gln Ser Ile Ala Ser Tyr

1 5

<210> 289

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 289

Ala Ala Ser

1

<210> 290

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 290

Gln Gln Ser Tyr Ser Thr Leu Gly Ile Thr

1 5 10

<210> 291

<211> 367

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 291

caggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt cccctttagt atctattgga tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtggccaac ataaagcaag atggaagtga gaaatactat 180

gtggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctcactgtat 240

ctgcacatga acagcctgag aggcgaggac acggctgtgt attactgtgc gagccgatat 300

tacgattttc gaccggaggc ttggtttgac tactggggcc agggaaccct ggtcaccgtc 360

tcctcag 367

<210> 292

<211> 122

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 292

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

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Ser Ile Tyr

20 25 30

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

35 40 45

Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val

50 55 60

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

65 70 75 80

Leu His Met Asn Ser Leu Arg Gly Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Arg Tyr Tyr Asp Phe Arg Pro Glu Ala Trp Phe Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 293

<211> 343

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 293

gatattgtga tgacccagac tccactctcc tcacctgtca cccttggaca gccggcctcc 60

atctcctgca ggtctagtca aagcctcgta cacagggatg gaaacaccta cttgagctgg 120

cttcagcaga ggccaggcca gcctccaaga ctcctaattt ataagatttc taaccggttc 180

tctggggtcc cagacagatt cagtggcagt ggggcaggga cagatttcac actgaaaatc 240

agcagggtgg aagctgagga tgtcggggtt tattactgca tgcaagctac acaatttcct 300

catgggtaca cttttggcca ggggaccaag gtggagatca aac 343

<210> 294

<211> 114

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 294

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

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Arg

20 25 30

Asp Gly Asn Thr Tyr Leu Ser Trp Leu Gln Gln Arg Pro Gly Gln Pro

35 40 45

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

50 55 60

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

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala

85 90 95

Thr Gln Phe Pro His Gly Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu

100 105 110

Ile Lys

<210> 295

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 295

Gly Phe Pro Phe Ser Ile Tyr Trp

1 5

<210> 296

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 296

Ile Lys Gln Asp Gly Ser Glu Lys

1 5

<210> 297

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 297

Ala Ser Arg Tyr Tyr Asp Phe Arg Pro Glu Ala Trp Phe Asp Tyr

1 5 10 15

<210> 298

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 298

Gln Ser Leu Val His Arg Asp Gly Asn Thr Tyr

1 5 10

<210> 299

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 299

Lys Ile Ser

1

<210> 300

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 300

Met Gln Ala Thr Gln Phe Pro His Gly Tyr Thr

1 5 10

<210> 301

<211> 355

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 301

caggtgcagc tgcaggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60

tcctgttcag cctctggatt caccgtcagt agcaactaca tgacctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac attctacgca 180

gactccgtga agggcagatt caccatctcc agagacaatt ccaagaacac gctgtatctt 240

caaatgaaca gcctgagagc cgaggacacc gctgtgtatt actgtgcgag agatctggaa 300

gaggccgggg gatttgacta ctggggccag ggaaccctgg tcaccgtctc ctcag 355

<210> 302

<211> 118

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 302

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

1 5 10 15

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

20 25 30

Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Tyr Ser Gly Gly Ser Thr Phe Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

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

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 303

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 303

gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aaaagtcacc 60

ctctcctgca gggccagtca gagtgttagc agcacctact tagcctggta ccagcagaaa 120

cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcgtccca 180

gacaggttcc gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcgctgta cacttttggc 300

caggggacca aagtggatat caaac 325

<210> 304

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 304

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

1 5 10 15

Glu Lys Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr

20 25 30

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

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Val Pro Asp Arg Phe Arg

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Leu

85 90 95

Tyr Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys

100 105

<210> 305

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 305

Gly Phe Thr Val Ser Ser Asn Tyr

1 5

<210> 306

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 306

Ile Tyr Ser Gly Gly Ser Thr

1 5

<210> 307

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 307

Ala Arg Asp Leu Glu Glu Ala Gly Gly Phe Asp Tyr

1 5 10

<210> 308

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 308

Gln Ser Val Ser Ser Thr Tyr

1 5

<210> 309

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 309

Gly Ala Ser

1

<210> 310

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 310

Gln Gln Tyr Gly Ser Ser Leu Tyr Thr

1 5

<210> 311

<211> 385

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 311

cagctgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60

acctgcactg tctccggtga ctccgtcagt aattactact ggagctggat ccggcagccc 120

gccgggaagg gactggagtg gattgggcgt atctatacca gtgggagcac caactacaac 180

ccctccctca agagtcgagt caccatgtca gtagacacgt ccaagaacca gttctccctg 240

aagctgagct ctgtgaccgc cgcggacacg gccgtgtatt actgtgcgag agatcaccgg 300

gcttcccggt atagcagtgg ctggtacgaa tggtggaact gcttcgaccc ctggggccag 360

ggaaccctgg tcaccgtctc ctcag 385

<210> 312

<211> 128

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 312

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

1 5 10 15

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

20 25 30

Tyr Trp Ser Trp Ile Arg Gln Pro Ala Gly Lys Gly Leu Glu Trp Ile

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Asp His Arg Ala Ser Arg Tyr Ser Ser Gly Trp Tyr Glu Trp Trp

100 105 110

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

115 120 125

<210> 313

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 313

gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggcaagtca gagcattagc agctatttaa attggtatca gcagaaacca 120

gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccgtca 180

aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcaacag tctgcaacct 240

gaagattttg caacttacta ctgtcaacag agttacagta cccccgcgct cactttcggc 300

ggagggacca aagtggatat caaac 325

<210> 314

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 314

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 315

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 315

Gly Asp Ser Val Ser Asn Tyr Tyr

1 5

<210> 316

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 316

Ile Tyr Thr Ser Gly Ser Thr

1 5

<210> 317

<211> 22

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 317

Ala Arg Asp His Arg Ala Ser Arg Tyr Ser Ser Gly Trp Tyr Glu Trp

1 5 10 15

Trp Asn Cys Phe Asp Pro

20

<210> 318

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 318

Gln Ser Ile Ser Ser Tyr

1 5

<210> 319

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 319

Ala Ala Ser

1

<210> 320

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 320

Gln Gln Ser Tyr Ser Thr Pro Ala Leu Thr

1 5 10

<210> 321

<211> 367

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 321

caggttcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60

tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180

acacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240

atggagctga gcaggctgag atctgacgac acggccgtgt attcctgtgc gagagatatg 300

gcgtttagta tggttcgggg ttcctttgac tactggggcc agggaaccct ggtcaccgtc 360

tcctcag 367

<210> 322

<211> 122

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 322

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Thr Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Arg Asp Met Ala Phe Ser Met Val Arg Gly Ser Phe Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 323

<211> 331

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 323

caggctgtgc tgactcagcc tccctccgcg tccgggtctc ctggacagtc agtcaccatc 60

tcctgcactg gaaccagcag tgacgttggt ggttataact atgtctcctg gtaccaacag 120

cacccaggca aagcccccaa actcatgatt tatgaggtca gtaagcggcc ctcaggggtc 180

cctgatcgct tctctggctc caagtctggc aacacggcct ccctgaccgt ctctgggctc 240

caggctgagg atgaggctga ttattactgc agctcatatg caggcagcaa ccattgggtg 300

ttcggcggag ggaccaagct gaccgtccta g 331

<210> 324

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 324

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

1 5 10 15

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

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

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

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Ala Gly Ser

85 90 95

Asn His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 325

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 325

Gly Tyr Thr Phe Thr Gly Tyr Tyr

1 5

<210> 326

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 326

Ile Asn Pro Asn Ser Gly Gly Thr

1 5

<210> 327

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 327

Ala Arg Asp Met Ala Phe Ser Met Val Arg Gly Ser Phe Asp Tyr

1 5 10 15

<210> 328

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 328

Ser Ser Asp Val Gly Gly Tyr Asn Tyr

1 5

<210> 329

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 329

Glu Val Ser

1

<210> 330

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 330

Ser Ser Tyr Ala Gly Ser Asn His Trp Val

1 5 10

<210> 331

<211> 358

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 331

caggtgcagc tggtgcagtc tgggcctgag gtgaagaagc ctgggacctc agtgaaggtc 60

tcctgcaagg cgtctggatt cacccttact agctctgcta tgcagtgggt gcgacaggct 120

cgtggacaac gccttgagtg gataggatgg atcgtcgttg gcagtggcaa cacaaactac 180

gcacagaagt tccaggaaag agtcaccatt accagggaca tgtccacaag cacagcctac 240

atggagctga gcagcctgag atccgaggac acggccgtgt attattgtgc ggccggccgt 300

ggctacaatt cggactttga ctactggggc cagggaaccc tggtcaccgt ctcctcag 358

<210> 332

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 332

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

1 5 10 15

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

20 25 30

Ala Met Gln Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Trp Ile Val Val Gly Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Glu Arg Val Thr Ile Thr Arg Asp Met Ser Thr Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Ala Gly Arg Gly Tyr Asn Ser Asp Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 333

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 333

gccatccgga tgacccagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaga 120

cctggccagg ctcccaggct cctcatctat ggtacatcca gcagggccac tggcatccca 180

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttgcagtgta ttactgtcag cagtatggtt actcagtgta cacttttggc 300

caggggacca aagtggatat caaac 325

<210> 334

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 334

Ala Ile Arg Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Arg Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Thr Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Tyr Ser Val

85 90 95

Tyr Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys

100 105

<210> 335

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 335

Gly Phe Thr Leu Thr Ser Ser Ala

1 5

<210> 336

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 336

Ile Val Val Gly Ser Gly Asn Thr

1 5

<210> 337

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 337

Ala Ala Gly Arg Gly Tyr Asn Ser Asp Phe Asp Tyr

1 5 10

<210> 338

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 338

Gln Ser Val Ser Ser Ser Tyr

1 5

<210> 339

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 339

Gly Thr Ser

1

<210> 340

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 340

Gln Gln Tyr Gly Tyr Ser Val Tyr Thr

1 5

<210> 341

<211> 367

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 341

caggtgcagc tggtggagtc tgaggctgag gtgaagaagc ctggggcctc agtgaaggtt 60

tcctgcaagg catctggata caccttcacc agctactata tgcactgggt gcgacaggcc 120

cctggacaag ggcttcagtg gatgggaata atcaacccta gtgctggtag cacaagctac 180

gcacagaagt tccagggcag agtcaccatg accacggaca cgtccacgac cacagtctac 240

atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagattct 300

gtactagtac cagctgctaa tgcttttgat atctggggcc aagggacaat ggtcaccgtc 360

tcttcag 367

<210> 342

<211> 122

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 342

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

1 5 10 15

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

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Gln Trp Met

35 40 45

Gly Ile Ile Asn Pro Ser Ala Gly Ser Thr Ser Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Thr Thr Val Tyr

65 70 75 80

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

85 90 95

Ala Arg Asp Ser Val Leu Val Pro Ala Ala Asn Ala Phe Asp Ile Trp

100 105 110

Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 343

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 343

gaaatagtga tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagt agctacttag cctggtacca acagaaacct 120

ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180

aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240

gaagattttg cagtttatta ctgtcagcag cgtcgcaact ggctattcac tttcggccct 300

gggaccaaag tggatatcaa ac 322

<210> 344

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 344

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Arg Asn Trp Leu Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 345

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 345

Gly Tyr Thr Phe Thr Ser Tyr Tyr

1 5

<210> 346

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 346

Ile Asn Pro Ser Ala Gly Ser Thr

1 5

<210> 347

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 347

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

1 5 10 15

<210> 348

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 348

Gln Ser Val Ser Ser Tyr

1 5

<210> 349

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 349

Asp Ala Ser

1

<210> 350

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 350

Gln Gln Arg Arg Asn Trp Leu Phe Thr

1 5

<210> 351

<211> 358

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 351

caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtt 60

tcctgcaagg cttctggaga caccttcact agctatactc tgcattgggt gcgccaggcc 120

cccggacaaa ggcttgagtg gatgggatgg atcaacgctg gcaatggtta cacaaaatat 180

tcacagaagt tccagggcag agtcaccatt accagggaca catccgcgag cacagcctac 240

atggagctga gcagcctgag atctgaagac acggctgtgt attactgtgc gaaatgtact 300

atgatagtag actactttga ctactggggc cagggaaccc tggtcaccgt ctcctcag 358

<210> 352

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 352

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Asp Thr Phe Thr Ser Tyr

20 25 30

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

35 40 45

Gly Trp Ile Asn Ala Gly Asn Gly Tyr Thr Lys Tyr Ser Gln Lys Phe

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Cys Thr Met Ile Val Asp Tyr Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 353

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 353

gccatccgga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggccagtca gagtattagt ggctggttgg cctggtatca gcagaaacca 120

gagaaagccc ctaagctcct gatctatgat gcctccaatt tggaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcaacag cctgcagcct 240

gatgattttg caacttatta ctgccaacag tataatagtt acccgtggac gttcggccaa 300

gggaccaaag tggatatcaa ac 322

<210> 354

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 354

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys

100 105

<210> 355

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 355

Gly Asp Thr Phe Thr Ser Tyr Thr

1 5

<210> 356

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 356

Ile Asn Ala Gly Asn Gly Tyr Thr

1 5

<210> 357

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 357

Ala Lys Cys Thr Met Ile Val Asp Tyr Phe Asp Tyr

1 5 10

<210> 358

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 358

Gln Ser Ile Ser Gly Trp

1 5

<210> 359

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 359

Asp Ala Ser

1

<210> 360

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 360

Gln Gln Tyr Asn Ser Tyr Pro Trp Thr

1 5

<210> 361

<211> 357

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 361

gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60

tcctgcaagg cttctgggta caccttcacc agttatgata tcaactgggt gcgacaggcc 120

actggacaag ggcttgagtg gatgggatgg atgaaccctc acagtgatac cacaggctat 180

gcacagaagt tccagggcag agtcaccatg accaggaaca cctccataac cacagcctac 240

atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc tcagggaccc 300

atagcagtga actacatgga cgtctggggc aaagggacca cggtcaccgt ctcctca 357

<210> 362

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 362

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

1 5 10 15

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

20 25 30

Asp Ile Asn Trp Val Arg Gln Ala Thr Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Met Asn Pro His Ser Asp Thr Thr Gly Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asn Thr Ser Ile Thr Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Gln Gly Pro Ile Ala Val Asn Tyr Met Asp Val Trp Gly Lys Gly

100 105 110

Thr Thr Val Thr Val Ser Ser

115

<210> 363

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 363

cagcctgtgc tgactcagcc accctcagtg tcagtggccc caggaaagac ggccaggatt 60

acctgtgggg gaagcaacat tggaagtaaa agtgtgcact ggtaccagca gaagccaggc 120

caggcccctg tgctgatcat ctattatgat agcgaccggc cctcagggat ccctgagcga 180

ttctctggct ccaactctgg gaacacggcc accctgacca tcagcagggt cgaagccggg 240

gatgaggccg acttttactg tcaggtgtgg gatagtagta ctgatcatgt ggtattcggc 300

ggggggacca agctgaccgt cctag 325

<210> 364

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 364

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

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

65 70 75 80

Asp Glu Ala Asp Phe Tyr Cys Gln Val Trp Asp Ser Ser Thr Asp His

85 90 95

Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 365

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 365

Gly Tyr Thr Phe Thr Ser Tyr Asp

1 5

<210> 366

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 366

Met Asn Pro His Ser Asp Thr Thr

1 5

<210> 367

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 367

Ala Gln Gly Pro Ile Ala Val Asn Tyr Met Asp Val

1 5 10

<210> 368

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 368

Asn Ile Gly Ser Lys Ser

1 5

<210> 369

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 369

Tyr Asp Ser

1

<210> 370

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 370

Gln Val Trp Asp Ser Ser Thr Asp His Val Val

1 5 10

<210> 371

<211> 376

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 371

gaggtgcagc tggtggagtc tgggggaggc ttggtcaagc ctggagagtc cctgagactc 60

tcctgtgcag cctctggatt caccttcagt gactactaca tgacctggat ccgccaggct 120

ccagggaagg ggctggagtg ggtttcatac attaggagta gtggtcatac tatatactac 180

gcagactctg tgaagggccg attcaccatc tccagggaca acgccaagaa ctcactgtat 240

ctacaaatga acagcctgag agtcgaggac acggccgtgt attactgtgc gagaggaggg 300

gttttacgat ttttggagtg gcctctcaat gcttttgata tctggggcca agggacaatg 360

gtcaccgtct cttcag 376

<210> 372

<211> 125

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 372

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

1 5 10 15

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

20 25 30

Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Tyr Ile Arg Ser Ser Gly His Thr Ile Tyr Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Gly Val Leu Arg Phe Leu Glu Trp Pro Leu Asn Ala Phe

100 105 110

Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120 125

<210> 373

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 373

gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggcgagtca gggcattagc aattatttag cctggtatca gcagaaacca 120

gggaaagttc ctaagctcct gatctatgct gcatccactt tgcaatcagg ggtcccatct 180

cggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240

gaagatgttg caacttatta ctgtcaaaag tataacaatg ccctcgggac gttcggccaa 300

gggaccaagg tggagatcaa ac 322

<210> 374

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 374

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Asn Ala Leu Gly

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 375

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 375

Gly Phe Thr Phe Ser Asp Tyr Tyr

1 5

<210> 376

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 376

Ile Arg Ser Ser Gly His Thr Ile

1 5

<210> 377

<211> 18

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 377

Ala Arg Gly Gly Val Leu Arg Phe Leu Glu Trp Pro Leu Asn Ala Phe

1 5 10 15

Asp Ile

<210> 378

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 378

Gln Gly Ile Ser Asn Tyr

1 5

<210> 379

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 379

Ala Ala Ser

1

<210> 380

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 380

Gln Lys Tyr Asn Asn Ala Leu Gly Thr

1 5

<210> 381

<211> 364

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 381

gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60

tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggatgg atcagcccta acagtggtgg cacaaactat 180

gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcac cacagcctac 240

atggacctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagaggttat 300

tactatgaag ccctcgatgc ttttgatatc tggggccaag ggacaatggt caccgtctct 360

tcag 364

<210> 382

<211> 121

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 382

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Trp Ile Ser Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Thr Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Arg Gly Tyr Tyr Tyr Glu Ala Leu Asp Ala Phe Asp Ile Trp Gly

100 105 110

Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 383

<211> 331

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 383

cagtctgtcg tgacgcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60

tcctgcactg gaaccagcag tgacgttggt ggttataact ttgtctcctg gtaccaacag 120

cacccaggca aagcccccaa actcatgatt tatgaggtca gtaatcggcc ctcaggggtt 180

tctaatcgct tctctggctc caagtctggc atcacggcct ccctgaccat ctctgggctc 240

caggctgagg acgaggctga ttattactgc aactcatata caagcaacag tactcgggta 300

ttcggcggag ggaccaagct gaccgtccta g 331

<210> 384

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 384

Gln Ser Val Val Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

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

20 25 30

Asn Phe Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Glu Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Ile Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn Ser Tyr Thr Ser Asn

85 90 95

Ser Thr Arg Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 385

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 385

Gly Tyr Thr Phe Thr Gly Tyr Tyr

1 5

<210> 386

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 386

Ile Ser Pro Asn Ser Gly Gly Thr

1 5

<210> 387

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 387

Ala Arg Gly Tyr Tyr Tyr Glu Ala Leu Asp Ala Phe Asp Ile

1 5 10

<210> 388

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 388

Ser Ser Asp Val Gly Gly Tyr Asn Phe

1 5

<210> 389

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 389

Glu Val Ser

1

<210> 390

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 390

Asn Ser Tyr Thr Ser Asn Ser Thr Arg Val

1 5 10

<210> 391

<211> 382

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 391

caggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt caccgtcagt agcaactaca tgacctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtt atttatagcg gtggtagcac atactacgca 180

gactccgtga agggcagatt caccatctcc agagacaatt ccaagaacac gctatatctt 240

caaatgaaca gcctgagagc cgacgacacg gctgtatatt actgtgcgag agactctaca 300

gccgattacg atttttggag tggttattat gtaggtgctt ttcatatctg gggccaaggg 360

acaatggtca ccgtctcttc ag 382

<210> 392

<211> 127

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 392

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

1 5 10 15

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

20 25 30

Tyr Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

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

100 105 110

Ala Phe His Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120 125

<210> 393

<211> 331

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 393

cagactgtgc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60

tcctgcactg gaaccagcag tgacgttggt ggttacaact atgtctcctg gtaccaacag 120

cacccaggca aagcccccaa actcatgatt tatgaggtca ctaagcggcc ctcaggggtc 180

cctgatcgct tctctggctc caagtctggc aacacggcct ccctgaccgt ctctgggctc 240

caggctgagg atgaggctga ttattactgc agctcatatg caggcagcaa caattgggtg 300

ttcggcggag ggaccaagct gaccgtccta g 331

<210> 394

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 394

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

1 5 10 15

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

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

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

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Ala Gly Ser

85 90 95

Asn Asn Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 395

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 395

Gly Phe Thr Val Ser Ser Asn Tyr

1 5

<210> 396

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 396

Ile Tyr Ser Gly Gly Ser Thr

1 5

<210> 397

<211> 21

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 397

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

1 5 10 15

Gly Ala Phe His Ile

20

<210> 398

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 398

Ser Ser Asp Val Gly Gly Tyr Asn Tyr

1 5

<210> 399

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 399

Glu Val Thr

1

<210> 400

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 400

Ser Ser Tyr Ala Gly Ser Asn Asn Trp Val

1 5 10

<210> 401

<211> 370

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 401

gaggtgcagc tggtggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60

acctgcactg tctctggtgg gtccatcagc agtagtagtc actactgggg ctggatccgc 120

cagcccccag ggaaggggct ggagtggatt gggagtattt attatagtga gagtgcctac 180

tacaacccgt ccctcaagag tcgagtcacc atgtcaatag acacgtccaa gaaccagttc 240

tccctgaagc tgaactctgt gaccgccgcg gacacggccg tgtattactg tgcgagagtc 300

actgagcctc ggtggacttc ttgttacttt gactactggg gccagggaac cctggtcacc 360

gtctcctcag 370

<210> 402

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 402

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Ser His Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Glu Ser Ala Tyr Tyr Asn Pro Ser

50 55 60

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

65 70 75 80

Ser Leu Lys Leu Asn Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Val Thr Glu Pro Arg Trp Thr Ser Cys Tyr Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 403

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 403

gaaatagtga tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca ggaccagtca gagtgttacc agctacttag cctggtacca acagagacct 120

ggccaggctc ccaggctcct catctatgat gcatccgaca gggccactgg catcccagcc 180

aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcaa cctagagcct 240

gaagattttg cagtttatta ctgtcagctg cgtagcaact ggcctccgat caccttcggc 300

caagggacac gactggagac taaac 325

<210> 404

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 404

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Asp Ala Ser Asp Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Leu Arg Ser Asn Trp Pro Pro

85 90 95

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

100 105

<210> 405

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 405

Gly Gly Ser Ile Ser Ser Ser Ser His Tyr

1 5 10

<210> 406

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 406

Ile Tyr Tyr Ser Glu Ser Ala

1 5

<210> 407

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 407

Ala Arg Val Thr Glu Pro Arg Trp Thr Ser Cys Tyr Phe Asp Tyr

1 5 10 15

<210> 408

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 408

Gln Ser Val Thr Ser Tyr

1 5

<210> 409

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 409

Asp Ala Ser

1

<210> 410

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 410

Gln Leu Arg Ser Asn Trp Pro Pro Ile Thr

1 5 10

<210> 411

<211> 370

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 411

gaagtgcagc tggtggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60

acctgcactg tctctggggg ctccatcagc agtagtagtt actactgggg ctggatccgc 120

cagcccccag ggaaggggct ggagtggatt gggagtatct attatagtgg gagcacctac 180

tacaacccgt ccctcaagag tcgagtcacc atatcagtag acacgtccaa gaaccagttc 240

tccctgaagc tgagctctgt gaccgccgcg gacacggccg tgtttttctg tgcgagagag 300

aggagcgctc ctctcgcggg caactggttc gacccctggg gccagggaac cctggtcacc 360

gtctcttcag 370

<210> 412

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 412

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

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

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

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

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Phe Phe

85 90 95

Cys Ala Arg Glu Arg Ser Ala Pro Leu Ala Gly Asn Trp Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 413

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 413

gacatccaga tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120

gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240

gaagattttg caacttatta ctgtcaacag cttaatactt acccttcgat caccttcggc 300

caagggacac gactggagat taaac 325

<210> 414

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 414

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105

<210> 415

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 415

Gly Gly Ser Ile Ser Ser Ser Ser Tyr Tyr

1 5 10

<210> 416

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 416

Ile Tyr Tyr Ser Gly Ser Thr

1 5

<210> 417

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 417

Ala Arg Glu Arg Ser Ala Pro Leu Ala Gly Asn Trp Phe Asp Pro

1 5 10 15

<210> 418

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 418

Gln Gly Ile Ser Ser Tyr

1 5

<210> 419

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 419

Ala Ala Ser

1

<210> 420

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 420

Gln Gln Leu Asn Thr Tyr Pro Ser Ile Thr

1 5 10

<210> 421

<211> 369

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 421

gaagtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggcc cctgagactc 60

tcctgtgcag cctctggatt ccccttcagt aactatggca tgcactgggt ccgccaggct 120

ccaggcaagg ggctggaatg ggtggcagtt atatggtatg atggaagtaa taaatactat 180

gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acaacctgag agctgaggac acggctatat attactgtgc gaaagatggg 300

tacacggccc actactacta ctactacatg gacgtctggg gcaaagggac cacggtcacc 360

gtctcctca 369

<210> 422

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 422

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

1 5 10 15

Pro Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Phe Ser Asn Tyr

20 25 30

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

35 40 45

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

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

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

85 90 95

Ala Lys Asp Gly Tyr Thr Ala His Tyr Tyr Tyr Tyr Tyr Met Asp Val

100 105 110

Trp Gly Lys Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 423

<211> 328

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 423

gccatccagt tgacccagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120

cctggccagg ctcccaggct cctaatctat ggtgcatcca gcagggccac tggcatccca 180

ggcaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacctgg gatcactttc 300

ggcggaggga ccaaagtgga tatcaaac 328

<210> 424

<211> 109

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 424

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

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

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

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Gly Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Gly Ile Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys

100 105

<210> 425

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 425

Gly Phe Pro Phe Ser Asn Tyr Gly

1 5

<210> 426

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 426

Ile Trp Tyr Asp Gly Ser Asn Lys

1 5

<210> 427

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 427

Ala Lys Asp Gly Tyr Thr Ala His Tyr Tyr Tyr Tyr Tyr Met Asp Val

1 5 10 15

<210> 428

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 428

Gln Ser Val Ser Ser Ser Tyr

1 5

<210> 429

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 429

Gly Ala Ser

1

<210> 430

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 430

Gln Gln Tyr Gly Ser Ser Pro Gly Ile Thr

1 5 10

<210> 431

<211> 372

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 431

gaagtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60

tcctgtgcag cctctggatt caccttcagt aactatggca tacactgggt ccgccaggct 120

ccaggcaagg ggctggagtg ggtggcagtt atttcatatg atggaagtca taaatattat 180

gcagactctg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctatat 240

ctgcaaatga acagcctgaa aactgaggac acggctgtgt attactgtgc gaaagatagt 300

tcagctgcta ttccctacta ctactacggt atggacgtct ggggccaagg gaccacggtc 360

accgtctctt ca 372

<210> 432

<211> 124

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 432

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

1 5 10 15

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

20 25 30

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

35 40 45

Ala Val Ile Ser Tyr Asp Gly Ser His Lys Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Asp Ser Ser Ala Ala Ile Pro Tyr Tyr Tyr Tyr Gly Met Asp

100 105 110

Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 433

<211> 340

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 433

gccatccaga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60

atcaactgca agtccagcca gagtatttta tacaactcca acaataagac ctacttagct 120

tggtaccagc agaaaccagg acagcctcct aagctgctca ttttctgggc atctacccgg 180

gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240

atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtatt 300

ccccttattt tcggccctgg gaccaaagtg gatatcaaac 340

<210> 434

<211> 113

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 434

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

1 5 10 15

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

20 25 30

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

35 40 45

Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

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

100 105 110

Lys

<210> 435

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 435

Gly Phe Thr Phe Ser Asn Tyr Gly

1 5

<210> 436

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 436

Ile Ser Tyr Asp Gly Ser His Lys

1 5

<210> 437

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 437

Ala Lys Asp Ser Ser Ala Ala Ile Pro Tyr Tyr Tyr Tyr Gly Met Asp

1 5 10 15

Val

<210> 438

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 438

Gln Ser Ile Leu Tyr Asn Ser Asn Asn Lys Thr Tyr

1 5 10

<210> 439

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 439

Trp Ala Ser

1

<210> 440

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 440

Gln Gln Tyr Tyr Ser Ile Pro Leu Ile

1 5

<210> 441

<211> 370

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 441

cagctgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60

acctgcactg tctctggtgg ctccatcagc agtagtagtt actactgggg ctggatccgc 120

cagcccccag ggaaggggct ggagtggatt gggaatgtct actatagtgg gggcacctac 180

tgcaacccgt ccctcaagag tcgagtcacc atatcagtag acacgtccaa gaatcagttc 240

tccctgaacc tgagctccgt gaccgccgcg gacacggccg tgtattactg tgcgagaata 300

tggttcgggg agcctgcggg tgggtacttt gactactggg gccagggaac cctggtcacc 360

gtctcctcag 370

<210> 442

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 442

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

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

35 40 45

Trp Ile Gly Asn Val Tyr Tyr Ser Gly Gly Thr Tyr Cys Asn Pro Ser

50 55 60

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

65 70 75 80

Ser Leu Asn Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Ile Trp Phe Gly Glu Pro Ala Gly Gly Tyr Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 443

<211> 319

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 443

tcctatgagc tgactcagcc accctcagtg tccgtgtccc caggacagac agccagcatc 60

acctgctctg gacataagtt gggggataaa aatgcttgct ggtatcagca gaagccaggc 120

cagtcccctg tgctggtcat ctatgaatat aacaagcggc cctcagggat ccctgagcga 180

ttctctggct ccaactctgg gaacacagcc actctgacca tcagcgggac ccaggctatg 240

gatgaggctg actattactg tcaggcgtgg gacaccggca ctcatgtctt cggaactggg 300

accaaggtca ccgtcctag 319

<210> 444

<211> 106

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 444

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

1 5 10 15

Thr Ala Ser Ile Thr Cys Ser Gly His Lys Leu Gly Asp Lys Asn Ala

20 25 30

Cys Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Val Leu Val Ile Tyr

35 40 45

Glu Tyr Asn Lys Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Ala Trp Asp Thr Gly Thr His Val

85 90 95

Phe Gly Thr Gly Thr Lys Val Thr Val Leu

100 105

<210> 445

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 445

Gly Gly Ser Ile Ser Ser Ser Ser Tyr Tyr

1 5 10

<210> 446

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 446

Val Tyr Tyr Ser Gly Gly Thr

1 5

<210> 447

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 447

Ala Arg Ile Trp Phe Gly Glu Pro Ala Gly Gly Tyr Phe Asp Tyr

1 5 10 15

<210> 448

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 448

Lys Leu Gly Asp Lys Asn

1 5

<210> 449

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 449

Glu Tyr Asn

1

<210> 450

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 450

Gln Ala Trp Asp Thr Gly Thr His Val

1 5

<210> 451

<211> 370

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 451

caggtccagc tggtacagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60

acctgctctg tctctgatgg ctccatcagc agtagtgatt actactggag ctggatccgc 120

cagccccccg ggaagggcct ggagtggatt gggtacatct attacactgg gagcacctac 180

tacaacccgt ccctcaagag tcgagtttcc atatcagtag acaggtccaa gaaccaattc 240

tccctgaagc tgagttctgt gactgccgca gacacggccg tttactattg tgccagactc 300

gtagtaccat ctccgaaggg ctcctggttc gacccctggg gccagggaac cctggtcacc 360

gtctcctcaa 370

<210> 452

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 452

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

1 5 10 15

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

20 25 30

Asp Tyr Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Ile Tyr Tyr Thr Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Ser Ile Ser Val Asp Arg Ser Lys Asn Gln Phe

65 70 75 80

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

85 90 95

Cys Ala Arg Leu Val Val Pro Ser Pro Lys Gly Ser Trp Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 453

<211> 331

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 453

tcctatgagc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60

tcctgcactg ggaccagcat tgatgttggg aattataacc ttgcctcctg gtaccaacag 120

cacccaggca aagcccccaa actcatcatt tatgagggca gtaggcggcc ctcaggggtt 180

tctaatcgct tctctggcgc caagtctggc aacacggcct ccctgacaat ctctgggctc 240

caggctgagg acgaggctga ttattactgc tgctcatatg taggtagtag cacttatgtc 300

ttcggatctg ggaccaaggt caccgtccta g 331

<210> 454

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 454

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

1 5 10 15

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

20 25 30

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

35 40 45

Ile Ile Tyr Glu Gly Ser Arg Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ala Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Val Gly Ser

85 90 95

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

100 105 110

<210> 455

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 455

Asp Gly Ser Ile Ser Ser Ser Asp Tyr Tyr

1 5 10

<210> 456

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 456

Ile Tyr Tyr Thr Gly Ser Thr

1 5

<210> 457

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 457

Ala Arg Leu Val Val Pro Ser Pro Lys Gly Ser Trp Phe Asp Pro

1 5 10 15

<210> 458

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 458

Ser Ile Asp Val Gly Asn Tyr Asn Leu

1 5

<210> 459

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 459

Glu Gly Ser

1

<210> 460

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 460

Cys Ser Tyr Val Gly Ser Ser Thr Tyr Val

1 5 10

<210> 461

<211> 370

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 461

caggtccagc tggtacagtc tgggcctgag gtgaagaagc ctgggacctc agtgaaggtc 60

tcctgcaagg cttctggatt cacctttact agctctgcta tgcagtgggt gcgacaggct 120

cgtggacaac gccttgagtg gataggatgg atcgtcgttg gcagtggtaa cacaaactac 180

gcacagaagt tccaggaaag agtcaccatt accagggaca tgtccacaag cacagcctac 240

atggagctga gcagcctgag atccgaggac acggccgtgt attactgtgc ggcagtttat 300

tgtagtggtg gtagctgtaa tgatgctttt gatatctggg gccaagggac aatggtcacc 360

gtctcttcag 370

<210> 462

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 462

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Ser Ser

20 25 30

Ala Met Gln Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Trp Ile Val Val Gly Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Glu Arg Val Thr Ile Thr Arg Asp Met Ser Thr Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Ala Val Tyr Cys Ser Gly Gly Ser Cys Asn Asp Ala Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 463

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 463

gaaatagtga tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120

cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcaccctt cactttcggc 300

ggagggacca aggtggaaat caaac 325

<210> 464

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 464

Glu Ile Val Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

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

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Phe Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 465

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 465

Gly Phe Thr Phe Thr Ser Ser Ala

1 5

<210> 466

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 466

Ile Val Val Gly Ser Gly Asn Thr

1 5

<210> 467

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 467

Ala Ala Val Tyr Cys Ser Gly Gly Ser Cys Asn Asp Ala Phe Asp Ile

1 5 10 15

<210> 468

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 468

Gln Ser Val Ser Ser Ser Tyr

1 5

<210> 469

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 469

Gly Ala Ser

1

<210> 470

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 470

Gln Gln Tyr Gly Ser Ser Pro Phe Thr

1 5

<210> 471

<211> 367

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 471

caggtacagc tgcagcagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60

acctgcactg tctctggtgc ctccattagt aattattact ggagttggat ccggcagccc 120

ccagggaagg gactggagtg ggttggatat atctattaca ctgggagcac caaccacaac 180

ccctccctca agagtcgagt caccatatca ctagacacgt ccaagaatca gttctccctg 240

aggctgagct ctgtgaccgc tgcggacacg gccgtctatt actgtgcgcg agcctattgt 300

agtggtggta gctgcttcga tacttttgat atctggggcc aagggacaat ggtcaccgtc 360

tcttcag 367

<210> 472

<211> 122

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 472

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Ala Ser Ile Ser Asn Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Ala Tyr Cys Ser Gly Gly Ser Cys Phe Asp Thr Phe Asp Ile Trp

100 105 110

Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 473

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 473

tcctatgagc tgacacagcc accctcggtg tcagtggccc caggacagac ggccagaatt 60

acctgtgggg gaaacaacat tggaagtaaa agtgtgcact ggttccagca gaagccaggc 120

caggcccctg tgctggtcgt ctatgatgat agcgaccggc cctcagggat ccctgagcga 180

ttctctggct ccaactctgg gaacacggcc tccctgacca tcagcagggt cgaagccggg 240

gatgaggccg actattactg tcaggtgtgg gatagtgcta gtgattcagg tgtcttcgga 300

actgggacca agctcaccgt cccag 325

<210> 474

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 474

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

1 5 10 15

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

20 25 30

His Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Tyr

35 40 45

Asp Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

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

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ala Ser Asp Ser

85 90 95

Gly Val Phe Gly Thr Gly Thr Lys Leu Thr Val Pro

100 105

<210> 475

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 475

Gly Ala Ser Ile Ser Asn Tyr Tyr

1 5

<210> 476

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 476

Ile Tyr Tyr Thr Gly Ser Thr

1 5

<210> 477

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 477

Ala Arg Ala Tyr Cys Ser Gly Gly Ser Cys Phe Asp Thr Phe Asp Ile

1 5 10 15

<210> 478

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 478

Asn Ile Gly Ser Lys Ser

1 5

<210> 479

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 479

Asp Asp Ser

1

<210> 480

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 480

Gln Val Trp Asp Ser Ala Ser Asp Ser Gly Val

1 5 10

<210> 481

<211> 351

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 481

gaagtgcagc tgttggagtc tggaggaggc ttggtccagc ctggggggtc cctgagactc 60

tcctgtgcag cctctgggtt aaccgtcaga agcaactaca tgaactgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcactt atttatagcg gtggtagtac attctacgca 180

gactccgtga agggccgatt caccatctcc agacacgatt ccaagaacac actgtatctt 240

caaatgaaca gcctgagagc tgaggacacg gccgtgtatt actgtgcgcg agatttggta 300

gtctacggaa tggacgtctg gggccaaggg accacggtca ccgtctcctc a 351

<210> 482

<211> 117

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 482

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

1 5 10 15

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

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

Gly Arg Phe Thr Ile Ser Arg His Asp Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

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

100 105 110

Val Thr Val Ser Ser

115

<210> 483

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 483

gacatccaga tgacccagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agcagctcct tagcctggta ccagcagaaa 120

catggccagg ctcccaggct cctcatctat ggtacatcca gcagggccac tggcatccca 180

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag tggactggag 240

cctgaagatt ttgcagtgta ttactgtcag cagtatggta gctcacccct tttcggcggg 300

gggaccaagg tggaaatcaa ac 322

<210> 484

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 484

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

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

Ser Leu Ala Trp Tyr Gln Gln Lys His Gly Gln Ala Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Thr Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro

85 90 95

Leu Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 485

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 485

Gly Leu Thr Val Arg Ser Asn Tyr

1 5

<210> 486

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 486

Ile Tyr Ser Gly Gly Ser Thr

1 5

<210> 487

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 487

Ala Arg Asp Leu Val Val Tyr Gly Met Asp Val

1 5 10

<210> 488

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 488

Gln Ser Val Ser Ser Ser Ser

1 5

<210> 489

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 489

Gly Thr Ser

1

<210> 490

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 490

Gln Gln Tyr Gly Ser Ser Pro Leu

1 5

<210> 491

<211> 382

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 491

gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60

tcctgtgcag cctctggatt caccttcagt aattatggca tgcaccgggt ccgccaggct 120

ccaggcaagg ggctggagtg ggtggcactt atttcatatg aagaaagtaa tagatattat 180

ggagactccg tgaggggccg attcaccatc tccagagaca attccaagaa cactctgtat 240

ctgcaaatga acagcctgag acctgaggac acggctgtgt attactgtgc gaaagatcaa 300

ggcccggcta ctgtgatggt gactgctatt cggggcgcta tggacgtctg gggccaaggg 360

accacggtca ccgtctcctc ag 382

<210> 492

<211> 127

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 492

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

1 5 10 15

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

20 25 30

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

35 40 45

Ala Leu Ile Ser Tyr Glu Glu Ser Asn Arg Tyr Tyr Gly Asp Ser Val

50 55 60

Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Asp Gln Gly Pro Ala Thr Val Met Val Thr Ala Ile Arg Gly

100 105 110

Ala Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 493

<211> 343

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 493

gacatccagt tgacccagtc tccagattcc ctggctgtgt ctctgggcga gagggccacc 60

atcaactgca agtccagcca gagtgtttta tacagctcca acaataagaa ctacttagct 120

tggtaccagc agaaaccagg ccagcctcct aaactcctca tttactgggc gtctacccgg 180

gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240

atcagcagcc tgcaggctga agatgtggca gtatattact gtcagcaata ttttggttct 300

ccttcgatca ccttcggcca agggacacga ctggagatta aac 343

<210> 494

<211> 114

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 494

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

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser

20 25 30

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

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Tyr Phe Gly Ser Pro Ser Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu

100 105 110

Ile Lys

<210> 495

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 495

Gly Phe Thr Phe Ser Asn Tyr Gly

1 5

<210> 496

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 496

Ile Ser Tyr Glu Glu Ser Asn Arg

1 5

<210> 497

<211> 20

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 497

Ala Lys Asp Gln Gly Pro Ala Thr Val Met Val Thr Ala Ile Arg Gly

1 5 10 15

Ala Met Asp Val

20

<210> 498

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 498

Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr

1 5 10

<210> 499

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 499

Trp Ala Ser

1

<210> 500

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 500

Gln Gln Tyr Phe Gly Ser Pro Ser Ile Thr

1 5 10

<210> 501

<211> 373

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 501

caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60

tcctgcaagg cttctggata caccttcacc gactactata tgcactgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggatgg atcaactcta aagatggtgg cgcgaactat 180

gcacagaagt ttcagggcag ggtcaccctg accagggaca cgtcaatcga cacagcctac 240

atagaactga gcaggctcag atctgacgac acggccgtgt attactgtgc gagatccgcc 300

tctacagtaa ccgaaccacc gacaaactgg ttcgacccct ggggccaggg aaccctggtc 360

accgtctcct cag 373

<210> 502

<211> 124

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 502

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

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

35 40 45

Gly Trp Ile Asn Ser Lys Asp Gly Gly Ala Asn Tyr Ala Gln Lys Phe

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Ser Ala Ser Thr Val Thr Glu Pro Pro Thr Asn Trp Phe Asp

100 105 110

Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 503

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 503

gatgttgtga tgactcagtc tccatcctcc ctgtctgcat ctgtaggcga cagagtcacc 60

gtcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120

gggaaagctc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg tgtcccatca 180

aggttcagcg gcagtggatc tgggacagac ttcactctca caatcagcag cctgcagcct 240

gaagattttg caacttatta ctgtctacag cataatagtt acctccgttt cactttcggc 300

cctgggacca aagtggatat caaac 325

<210> 504

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 504

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Leu Arg

85 90 95

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

100 105

<210> 505

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 505

Gly Tyr Thr Phe Thr Asp Tyr Tyr

1 5

<210> 506

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 506

Ile Asn Ser Lys Asp Gly Gly Ala

1 5

<210> 507

<211> 17

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 507

Ala Arg Ser Ala Ser Thr Val Thr Glu Pro Pro Thr Asn Trp Phe Asp

1 5 10 15

Pro

<210> 508

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 508

Gln Gly Ile Arg Asn Asp

1 5

<210> 509

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 509

Ala Ala Ser

1

<210> 510

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 510

Leu Gln His Asn Ser Tyr Leu Arg Phe Thr

1 5 10

<210> 511

<211> 376

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 511

gaagtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60

tcctgcaagg cttctggata caccttcacc ggctactata tgcactgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180

gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcac cacaggctac 240

atggagctga gcagcctgag atctgacgac acggccctgt attactgtgc gagagttggg 300

gctcacgatt actatgatag tagtgacaac tggttcgacc cctggggcca gggaaccctg 360

gtcaccgtct tctcag 376

<210> 512

<211> 125

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 512

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Thr Thr Gly Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Asp Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Val Gly Ala His Asp Tyr Tyr Asp Ser Ser Asp Asn Trp Phe

100 105 110

Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Phe Ser

115 120 125

<210> 513

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 513

gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagactcacc 60

atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120

gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240

gaagattttg caacttacta ttgtcaacag gctaacagtt tcccgtggac gttcggccaa 300

gggaccaagg tggagatcaa ac 322

<210> 514

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 514

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 515

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 515

Gly Tyr Thr Phe Thr Gly Tyr Tyr

1 5

<210> 516

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 516

Ile Asn Pro Asn Ser Gly Gly Thr

1 5

<210> 517

<211> 18

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 517

Ala Arg Val Gly Ala His Asp Tyr Tyr Asp Ser Ser Asp Asn Trp Phe

1 5 10 15

Asp Pro

<210> 518

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 518

Gln Gly Ile Ser Ser Trp

1 5

<210> 519

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 519

Ala Ala Ser

1

<210> 520

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 520

Gln Gln Ala Asn Ser Phe Pro Trp Thr

1 5

<210> 521

<211> 375

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 521

caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60

tcctgcaagg cttctggata ccccctcacc ggctactata tacactgggt gcgacaggcc 120

cctggacaag gacttgagtg gatgggatgg ctcaacccta acagtggtgg cacaaagtat 180

gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacaggctac 240

atggagctga gcaggctgag atctgacgac acggccgtgt actactgtgc gagagatggg 300

gggggaatag atgattacgt tcaggaggac ggtatggacg tctggggcca agggcccatg 360

gtcaccgtct cttca 375

<210> 522

<211> 125

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 522

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

1 5 10 15

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

20 25 30

Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Leu Asn Pro Asn Ser Gly Gly Thr Lys Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Gly Tyr

65 70 75 80

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

85 90 95

Ala Arg Asp Gly Gly Gly Ile Asp Asp Tyr Val Gln Glu Asp Gly Met

100 105 110

Asp Val Trp Gly Gln Gly Pro Met Val Thr Val Ser Ser

115 120 125

<210> 523

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 523

caatctgccc tgactcagcc accctcggtg tcagtgtccc caggacagac ggccaggatc 60

acctgctctg gagatgcatt gtcaaagcaa catgcttatt ggtaccagca gaagccaggc 120

caggcccctg tattggtgat atataaagac agtgagaggc cctcagggat ccctgagcga 180

ttctctggct ccagctcagg gacaatagtc acgttgacca tcagtggagt ccaggcagaa 240

gacgaggctg actattactg tcaatcagca gacaacagtg gtagtagata tgtcttcgga 300

actgggacca aggtcaccgt cctag 325

<210> 524

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 524

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

1 5 10 15

Thr Ala Arg Ile Thr Cys Ser Gly Asp Ala Leu Ser Lys Gln His Ala

20 25 30

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

35 40 45

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

50 55 60

Ser Ser Gly Thr Ile Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Ala Asp Asn Ser Gly Ser Arg

85 90 95

Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu

100 105

<210> 525

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 525

Gly Tyr Pro Leu Thr Gly Tyr Tyr

1 5

<210> 526

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 526

Leu Asn Pro Asn Ser Gly Gly Thr

1 5

<210> 527

<211> 18

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 527

Ala Arg Asp Gly Gly Gly Ile Asp Asp Tyr Val Gln Glu Asp Gly Met

1 5 10 15

Asp Val

<210> 528

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 528

Ala Leu Ser Lys Gln His

1 5

<210> 529

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 529

Lys Asp Ser

1

<210> 530

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 530

Gln Ser Ala Asp Asn Ser Gly Ser Arg Tyr Val

1 5 10

<210> 531

<211> 355

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 531

gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt caccttcagt agctatagca tgaactgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcatac attagtggca ttaatagtgc catatattac 180

gcagactctg tgaagggccg cttcaccatc tccagagaca acgccaagaa ctcactgtat 240

ctgcaaatga acagcctgag agtcgaggac acggctgtgt attactgtgc gagagataaa 300

tacttaggta taaaagatat gtggggccaa gggacaatgg tcaccgtctc ttcag 355

<210> 532

<211> 118

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 532

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

1 5 10 15

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

20 25 30

Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

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

50 55 60

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

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Lys Tyr Leu Gly Ile Lys Asp Met Trp Gly Gln Gly Thr

100 105 110

Met Val Thr Val Ser Ser

115

<210> 533

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 533

gacatccaga tgacccagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc acctacttag cctggtacca acagaaacct 120

ggccaggctc ccaggctcgt catctatgat gcatccaaca gggccactgg catcccagcc 180

aggttcagtg gcggtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240

gaagattttg cagtttatta ctgtcaacag cgtctcaact ggcctctcac tttcggcgga 300

gggaccaaag tggatatcaa ac 322

<210> 534

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 534

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

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

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Leu Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Asp Ile Lys

100 105

<210> 535

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 535

Gly Phe Thr Phe Ser Ser Tyr Ser

1 5

<210> 536

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 536

Ile Ser Gly Ile Asn Ser Ala Ile

1 5

<210> 537

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 537

Ala Arg Asp Lys Tyr Leu Gly Ile Lys Asp Met

1 5 10

<210> 538

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 538

Gln Ser Val Ser Thr Tyr

1 5

<210> 539

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 539

Asp Ala Ser

1

<210> 540

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 540

Gln Gln Arg Leu Asn Trp Pro Leu Thr

1 5

<210> 541

<211> 375

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 541

gaggtgcagc tggtacagtc tggagcagag gtgaaaaagc cgggggagtc tctgaagatc 60

tcctgtaagg gctctggata cagctttacc aactactgga tcggctgggt gcgccagatg 120

cccgggaaag gcctggagtg gatggggatc atctatcctg gtgactctgg taccagatac 180

agcccgtcct tccaaggcca ggtcaccatc tcagccgaca agtccatcag aaccgcctac 240

ctgcagtgga gcagcctgaa ggcctcggac agcgccatgt attactgtgc gaggtctaga 300

gtgggagcta ctgggggcta ttatgactac tatatggacg tctggggcca agggaccacg 360

gtcaccgtct cctca 375

<210> 542

<211> 125

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 542

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

1 5 10 15

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

20 25 30

Trp Ile Gly Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Ile Ile Tyr Pro Gly Asp Ser Gly Thr Arg Tyr Ser Pro Ser Phe

50 55 60

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

65 70 75 80

Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Ser Ala Met Tyr Tyr Cys

85 90 95

Ala Arg Ser Arg Val Gly Ala Thr Gly Gly Tyr Tyr Asp Tyr Tyr Met

100 105 110

Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 543

<211> 331

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 543

cagtctgtgt tgacgcagcc accctcagcg tctgggaccc ccgggcagag ggtcaccatc 60

tcttgttctg gaagcagctc caacctcgga ggtaatactg taaactggta ccagcagctc 120

ccaggaacgg cccccaaact cctcatctat agtaataatc agcggccctc aggggtccct 180

gaccgattct ctggctccaa gtctggcacc tcagcctccc tggccatcag tgggctccag 240

tctgaggatg aggctgatta ttactgtgca gcatgggatg acagcctgaa tggtcccgtc 300

ttcggaactg ggaccaaggt caccgtccta g 331

<210> 544

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 544

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

1 5 10 15

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

20 25 30

Thr Val Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser

50 55 60

Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln

65 70 75 80

Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu

85 90 95

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

100 105 110

<210> 545

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 545

Gly Tyr Ser Phe Thr Asn Tyr Trp

1 5

<210> 546

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 546

Ile Tyr Pro Gly Asp Ser Gly Thr

1 5

<210> 547

<211> 18

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 547

Ala Arg Ser Arg Val Gly Ala Thr Gly Gly Tyr Tyr Asp Tyr Tyr Met

1 5 10 15

Asp Val

<210> 548

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 548

Ser Ser Asn Leu Gly Gly Asn Thr

1 5

<210> 549

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 549

Ser Asn Asn

1

<210> 550

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 550

Ala Ala Trp Asp Asp Ser Leu Asn Gly Pro Val

1 5 10

<210> 551

<211> 370

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 551

caggtgcagc tggtggagtc gggcccagga caggtgaagc cttcggagac cctgtccctc 60

acctgcactg tctctggtgg ctccatcagc agtagtagtt actactgggg ctggatccgc 120

cagcccccag ggaagggact ggagtggatt gggagtatct attatagtgg gagcgcctac 180

tataacccgt ccctcaagag tcgagtcacc atatccgtag acacgtccaa gaaccagttc 240

tccctgaagc tgaactctgt gaccgccgca gacacggctg tcttttactg tgcgagacac 300

gcagctccca gtccggggga caactggttc gacccctggg gccagggaac cctggtcacc 360

gtctcctcag 370

<210> 552

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 552

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

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

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Ser Ala Tyr Tyr Asn Pro Ser

50 55 60

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

65 70 75 80

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

85 90 95

Cys Ala Arg His Ala Ala Pro Ser Pro Gly Asp Asn Trp Phe Asp Pro

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 553

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 553

cagtctgtgt tgactcagcc accctcggtg tcagtgtccc caggacagac ggcccggatc 60

acctgctctg gagatgcatt gtcaacgcaa aatggtaatt ggtaccagca gaagccaggc 120

caggcccctg tgatggtgat atgtaaagac agtgagaggc cctcagggat ccctgagcga 180

ttctctggct ccaggtcagg gacaacagtc acgttgacca tcagtggagt ccaggcagaa 240

gacgaagctg actatcactg tcaatcagca gacaacaggg cacatgtagt attcggcgga 300

gggaccaagc tgaccgtcct ag 322

<210> 554

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 554

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

1 5 10 15

Thr Ala Arg Ile Thr Cys Ser Gly Asp Ala Leu Ser Thr Gln Asn Gly

20 25 30

Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Met Val Ile Cys

35 40 45

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

50 55 60

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

65 70 75 80

Asp Glu Ala Asp Tyr His Cys Gln Ser Ala Asp Asn Arg Ala His Val

85 90 95

Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 555

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 555

Gly Gly Ser Ile Ser Ser Ser Ser Tyr Tyr

1 5 10

<210> 556

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 556

Ile Tyr Tyr Ser Gly Ser Ala

1 5

<210> 557

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 557

Ala Arg His Ala Ala Pro Ser Pro Gly Asp Asn Trp Phe Asp Pro

1 5 10 15

<210> 558

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 558

Ala Leu Ser Thr Gln Asn

1 5

<210> 559

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 559

Lys Asp Ser

1

<210> 560

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 560

Gln Ser Ala Asp Asn Arg Ala His Val Val

1 5 10

<210> 561

<211> 378

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 561

gaggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60

tcctgtgcag cgtctggatt cacctttagt agttatggca tgcactgggt ccgccaggct 120

ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagtaa taacttctat 180

gcagactccg tgaagggccg attcaccatc tccagagaca atttcaagaa cacgctgtat 240

ttgcaaatga acagcctgag agccgaggac acggctgtgt attactgtgc gagatcatat 300

tgtagtggtg gtttctgctt cggctactac tatggtttgg acgtgtgggg ccaagggacc 360

acggtcaccg tctcctca 378

<210> 562

<211> 126

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 562

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Phe Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Tyr Cys Ser Gly Gly Phe Cys Phe Gly Tyr Tyr Tyr Gly

100 105 110

Leu Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 563

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 563

tcctatgagc tgactcagcc accctcagtg tcagtggccc caggaaagac ggccacgatt 60

acctgtgggg gaaacaacat tggaactaaa agtgtgcact ggtaccagca gaagccaggc 120

caggcccctg tgttggtcat ctattataat agcgaccggc cctccgggat ccctgagcga 180

ttctctggct ccaactctgg gaacacggtc accctgacca tcagcagggt cgaagccggg 240

gatgaggccg actattactg tcaggtgtgg gatagtggta gtgatcatta tgtcttcgga 300

actgggacca aggtcaccgt cgtag 325

<210> 564

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 564

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

1 5 10 15

Thr Ala Thr Ile Thr Cys Gly Gly Asn Asn Ile Gly Thr Lys Ser Val

20 25 30

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

35 40 45

Tyr Asn Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

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

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Gly Ser Asp His

85 90 95

Tyr Val Phe Gly Thr Gly Thr Lys Val Thr Val Val

100 105

<210> 565

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 565

Gly Phe Thr Phe Ser Ser Tyr Gly

1 5

<210> 566

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 566

Ile Trp Tyr Asp Gly Ser Asn Asn

1 5

<210> 567

<211> 19

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 567

Ala Arg Ser Tyr Cys Ser Gly Gly Phe Cys Phe Gly Tyr Tyr Tyr Gly

1 5 10 15

Leu Asp Val

<210> 568

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 568

Asn Ile Gly Thr Lys Ser

1 5

<210> 569

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 569

Tyr Asn Ser

1

<210> 570

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 570

Gln Val Trp Asp Ser Gly Ser Asp His Tyr Val

1 5 10

<210> 571

<211> 358

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 571

caggtgcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60

tcctgcaagg cttctggtta cacctttacc agctatggta tcagctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggatgg atcagccctt acaatggtaa cacacactat 180

gcacagaagc tccagggcag agtcaccatg accacagaca catccacgag cacagcctac 240

atggagctga ggagcctgag atctgacgac acggccgtat attactgtgc gagagatggg 300

gagttattgg gctggttcga cccctggggc cagggaaccc tggtcaccgt ctcctcag 358

<210> 572

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 572

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

1 5 10 15

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

20 25 30

Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ala Arg Asp Gly Glu Leu Leu Gly Trp Phe Asp Pro Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 573

<211> 331

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 573

cagtctgtcg tgacgcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60

tcctgcactg gaaccagcag tgatgttggg agttataacc ttgtctcctg gtaccaacag 120

cacccaggca aagcccccaa actcatgatt tatgcgggca gtaagcggcc ctcaggggtt 180

tctaatcgct tctctggctc caagtctggc aacacggcct ccctgacaat ctctgggctc 240

caggctgagg acgaggctga ttattactgc tgctcatatg caggtagtag cacttgggtg 300

ttcggcggag ggaccaagct gaccgtccta g 331

<210> 574

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 574

Gln Ser Val Val Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

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

20 25 30

Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Ala Gly Ser Lys Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Cys Ser Tyr Ala Gly Ser

85 90 95

Ser Thr Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 575

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 575

Gly Tyr Thr Phe Thr Ser Tyr Gly

1 5

<210> 576

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 576

Ile Ser Pro Tyr Asn Gly Asn Thr

1 5

<210> 577

<211> 12

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 577

Ala Arg Asp Gly Glu Leu Leu Gly Trp Phe Asp Pro

1 5 10

<210> 578

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 578

Ser Ser Asp Val Gly Ser Tyr Asn Leu

1 5

<210> 579

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 579

Ala Gly Ser

1

<210> 580

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 580

Cys Ser Tyr Ala Gly Ser Ser Thr Trp Val

1 5 10

<210> 581

<211> 378

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 581

ccaggtcagc tggtggaatc tgggggaagc ttggtacagc ctgggggggc cctgagactc 60

tcctgtgaag cctctggatt cacctttagc gactatgcca tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagtt attaatagta gtggtggtat cacaaactac 180

gcagactccg tgaagggccg gttcaccatc tccagaaaca attccaagaa cacgctctat 240

ctgcaaatga acagcctgag aggcgacgac acggccatat attactgtgc gaagggaccc 300

ccgagaatta acaccttcta caggcactac tacggtatgg acgtctgggg ccaagggatc 360

acggtcaccg tctcctca 378

<210> 582

<211> 126

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 582

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

1 5 10 15

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

20 25 30

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

35 40 45

Ser Val Ile Asn Ser Ser Gly Gly Ile Thr Asn Tyr Ala Asp Ser Val

50 55 60

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

65 70 75 80

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

85 90 95

Ala Lys Gly Pro Pro Arg Ile Asn Thr Phe Tyr Arg His Tyr Tyr Gly

100 105 110

Met Asp Val Trp Gly Gln Gly Ile Thr Val Thr Val Ser Ser

115 120 125

<210> 583

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 583

gccatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc aggcgagtca ggacattagg aactatttaa attggtatca gcagaaacca 120

gggaaagccc ctaagctcct gatctacgat gcatccaatt tggaaacagg ggtcccatca 180

aggttcagtg gaagtggatc tgggacagat tttactttca ccatcggcag cctgcagcct 240

gaagatattg caacatatta ctgtcaacaa tatgataatc tccgggccac tttcggcgga 300

gggaccaagg tggagatcaa ac 322

<210> 584

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 584

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Asn Leu Arg Ala

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 585

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 585

Gly Phe Thr Phe Ser Asp Tyr Ala

1 5

<210> 586

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 586

Ile Asn Ser Ser Gly Gly Ile Thr

1 5

<210> 587

<211> 19

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 587

Ala Lys Gly Pro Pro Arg Ile Asn Thr Phe Tyr Arg His Tyr Tyr Gly

1 5 10 15

Met Asp Val

<210> 588

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 588

Gln Asp Ile Arg Asn Tyr

1 5

<210> 589

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 589

Asp Ala Ser

1

<210> 590

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 590

Gln Gln Tyr Asp Asn Leu Arg Ala Thr

1 5

<210> 591

<211> 370

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 591

caggtgcagc tggtggagtc tgggcctgaa atgaagaagc ctgggacctc agtgaaggtc 60

tcctgcaagg cttctggatt cacctttatt acgtctgctg ttcagtgggt gcgacaggct 120

cgtggacaac gccttgagtg gatgggatgg atcgccgttg gcagtggtaa cacaaactac 180

gcacagaaat tccaggacag agtcaccatt aacagggaca tgtccacaag cacagcctac 240

atggagctga gcagcctgag atccgaggac acggccgtgt attactgtgc ggccccgcat 300

tgtaatcgta ccagctgcca tgatggtttt gatatctggg gccaagggac aatggtcacc 360

gtctcttcag 370

<210> 592

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 592

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Ile Thr Ser

20 25 30

Ala Val Gln Trp Val Arg Gln Ala Arg Gly Gln Arg Leu Glu Trp Met

35 40 45

Gly Trp Ile Ala Val Gly Ser Gly Asn Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Asp Arg Val Thr Ile Asn Arg Asp Met Ser Thr Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Ala Pro His Cys Asn Arg Thr Ser Cys His Asp Gly Phe Asp Ile

100 105 110

Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 593

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 593

gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agaaactact tagcctggta ccagcagaaa 120

cctggccagg ttcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180

gacaggttca gaggtagtgg gtctgggaca gacttcactc tcaccatcaa cagactggag 240

tctgaagatt ttgcagtgta ttactgtcag cagtatggta gctccctatt cactttcggc 300

cctgggacca aagtggatat caaac 325

<210> 594

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 594

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

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Asn

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Val Pro Arg Leu Leu

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Arg

50 55 60

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

65 70 75 80

Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Leu

85 90 95

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

100 105

<210> 595

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 595

Gly Phe Thr Phe Ile Thr Ser Ala

1 5

<210> 596

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 596

Ile Ala Val Gly Ser Gly Asn Thr

1 5

<210> 597

<211> 16

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 597

Ala Ala Pro His Cys Asn Arg Thr Ser Cys His Asp Gly Phe Asp Ile

1 5 10 15

<210> 598

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 598

Gln Ser Val Ser Arg Asn Tyr

1 5

<210> 599

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 599

Gly Ala Ser

1

<210> 600

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 600

Gln Gln Tyr Gly Ser Ser Leu Phe Thr

1 5

<210> 601

<211> 361

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 601

gaagtgcagc tggtggagtc ggggggaggc ctggtcaagc ctggggagtc cctgagactc 60

tcctgtgcag cctctggatt caccttcagt agctatgcca tgaactgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcatcc attagtactg gtagttattt catatactac 180

tcagactcag tgaagggccg attcaccatt tccagagaca acgccaagaa ctcactgtat 240

ctgcaaatga acagcctgag agccgcggac acggctatct attactgtgc gagaggaaag 300

gaagatacaa gcgctgcttt tgatatctgg ggccaaggga caatggtcac cgtctcttca 360

g 361

<210> 602

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 602

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

1 5 10 15

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

20 25 30

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

35 40 45

Ser Ser Ile Ser Thr Gly Ser Tyr Phe Ile Tyr Tyr Ser Asp Ser Val

50 55 60

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

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Ala Asp Thr Ala Ile Tyr Tyr Cys

85 90 95

Ala Arg Gly Lys Glu Asp Thr Ser Ala Ala Phe Asp Ile Trp Gly Gln

100 105 110

Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 603

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 603

gccatccaga tgacccagtc tcttcctcct gcgactctgg ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc aacaacttag cctggtacca gcagaaacct 120

ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180

aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240

gaagattttg cagtttatta ctgtcagcag tataataact ggcctccgtg gacgttcggc 300

caagggacca aagtggatat caaac 325

<210> 604

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 604

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

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Asn Asn

20 25 30

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

35 40 45

Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Pro

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys

100 105

<210> 605

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 605

Gly Phe Thr Phe Ser Ser Tyr Ala

1 5

<210> 606

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 606

Ile Ser Thr Gly Ser Tyr Phe Ile

1 5

<210> 607

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 607

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

1 5 10

<210> 608

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 608

Gln Ser Val Ser Asn Asn

1 5

<210> 609

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 609

Gly Ala Ser

1

<210> 610

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 610

Gln Gln Tyr Asn Asn Trp Pro Pro Trp Thr

1 5 10

<210> 611

<211> 355

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 611

gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cttctggagg caccttcagc agctctgtta tcagctgggt gcgacaggcc 120

cctggacaag gccttgagtg gatgggaggg atcatccctc tctttggttc agcaaactac 180

gcacagaagt tccagggcag agtcacgatt accgcggacg aatccacgag cacagcctac 240

atggagatga ctagcctgag atctgaagac acggccgtgt attactgtgc gaaagtttcc 300

cagtgggcgt taatactctt ctggggccag ggaaccctgg tcaccgtctc ctcag 355

<210> 612

<211> 118

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 612

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Ser

20 25 30

Val Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Ile Pro Leu Phe Gly Ser Ala Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

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

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 613

<211> 328

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 613

gccatccgga tgacccagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agcagctact tagcctggta ccagcagaaa 120

cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180

gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttgcagtgta ttactgtcag cagtatggta cctcaccttc gtggacgttc 300

ggccaaggga ccaaggtgga gatcaaac 328

<210> 614

<211> 109

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 614

Ala Ile Arg Met Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser

20 25 30

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

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

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

85 90 95

Ser Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 615

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 615

Gly Gly Thr Phe Ser Ser Ser Val

1 5

<210> 616

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 616

Ile Ile Pro Leu Phe Gly Ser Ala

1 5

<210> 617

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 617

Ala Lys Val Ser Gln Trp Ala Leu Ile Leu Phe

1 5 10

<210> 618

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 618

Gln Ser Val Ser Ser Ser Tyr

1 5

<210> 619

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 619

Gly Ala Ser

1

<210> 620

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 620

Gln Gln Tyr Gly Thr Ser Pro Ser Trp Thr

1 5 10

<210> 621

<211> 355

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 621

gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60

tcctgcaagg cgtctagagg caccttcaac acctatgttt tcacctgggt gcgacaggcc 120

cctggacaag ggcttgagtg gatgggaggg atcatccctt tctttggtac agcagactac 180

gcacagaagt tccagggcag agtcacgatt accgcggacg actccacgag cacagcctac 240

atggagctga gcagcctgag atctgaggac acggccgtgt attactgttc gaggctcagc 300

cagtgggacc tactacccat gtggggccag ggaaccctgg tcaccgtctc ctcag 355

<210> 622

<211> 118

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 622

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

1 5 10 15

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

20 25 30

Val Phe Thr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Ser Arg Leu Ser Gln Trp Asp Leu Leu Pro Met Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 623

<211> 331

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 623

gatattgtga tgactcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagttttacc agcagctact tagcctggta ccagcagaaa 120

cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca 180

gacaggttca gtggcactgg gtctgggaca gacttcactc tcaccatcag cagactggag 240

cctgaagatt ttgcagtata ttactgtcag cagtatggta cgtcacctcg catgtacact 300

tttggccagg ggaccaaagt ggatatcaaa c 331

<210> 624

<211> 110

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 624

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

1 5 10 15

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

20 25 30

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

35 40 45

Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

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

65 70 75 80

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

85 90 95

Arg Met Tyr Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys

100 105 110

<210> 625

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 625

Arg Gly Thr Phe Asn Thr Tyr Val

1 5

<210> 626

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 626

Ile Ile Pro Phe Phe Gly Thr Ala

1 5

<210> 627

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 627

Ser Arg Leu Ser Gln Trp Asp Leu Leu Pro Met

1 5 10

<210> 628

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 628

Gln Ser Phe Thr Ser Ser Tyr

1 5

<210> 629

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 629

Gly Ala Ser

1

<210> 630

<211> 11

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 630

Gln Gln Tyr Gly Thr Ser Pro Arg Met Tyr Thr

1 5 10

<210> 631

<211> 361

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 631

cagctgcagc tggtggagtc tggggctgag gtgaagaagc ctggggcttc agtgaaggtc 60

tcctgcaagg tttccggata caccctcact gaattatcca tgcactgggt gcgacaggct 120

cctggaaaag ggcttgagtg gatggggggt tttgatcctg aagatggtga gacaatctac 180

gcacagaagt tccagggcag agtcaccatg accgaggaca catctataga cacagtgtac 240

atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc aatagatcgc 300

aagcactggc tggtaggtct tgactactgg ggccagggaa ccctggtcac cgtctcctca 360

g 361

<210> 632

<211> 120

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 632

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

1 5 10 15

Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Thr Leu Thr Glu Leu

20 25 30

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

35 40 45

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

50 55 60

Gln Gly Arg Val Thr Met Thr Glu Asp Thr Ser Ile Asp Thr Val Tyr

65 70 75 80

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

85 90 95

Ala Ile Asp Arg Lys His Trp Leu Val Gly Leu Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 633

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 633

gccatccgga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgtc gggcgagtca gggcattagg aattatttag cctggtttca gcagaaacca 120

gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180

aagttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240

gaagattttg caacttatta ctgccaacag tataatagtt accccctcac cttcggccaa 300

gggacacgac tggagattaa ac 322

<210> 634

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 634

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

1 5 10 15

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

20 25 30

Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 635

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 635

Gly Tyr Thr Leu Thr Glu Leu Ser

1 5

<210> 636

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 636

Phe Asp Pro Glu Asp Gly Glu Thr

1 5

<210> 637

<211> 13

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 637

Ala Ile Asp Arg Lys His Trp Leu Val Gly Leu Asp Tyr

1 5 10

<210> 638

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 638

Gln Gly Ile Arg Asn Tyr

1 5

<210> 639

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 639

Ala Ala Ser

1

<210> 640

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 640

Gln Gln Tyr Asn Ser Tyr Pro Leu Thr

1 5

<210> 641

<211> 364

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 641

caggtgcagc tggtgcagtc cggagcagag gtgaaaaagc ccggggagtc tctgaggatc 60

tcctgtaagg gttctggaca caactctccc agctactgga ttagctgggt gcgccagatg 120

cccgggaaag gcctggagtg gatggggaga attgatccta gtgactctta taccaactac 180

agcccgtcct tccaaggcca tgtcaccatc tcagctgaca agtccatcag tactgcctac 240

ctacagtgga gcagcctgca ggcctcggac accgccattt attactgtgc gagacacgtg 300

gttgcattga ctcatttgta ccctgactac tggggccagg gaaccctggt caccgtctcc 360

tcag 364

<210> 642

<211> 121

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 642

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

1 5 10 15

Ser Leu Arg Ile Ser Cys Lys Gly Ser Gly His Asn Ser Pro Ser Tyr

20 25 30

Trp Ile Ser Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Asp Pro Ser Asp Ser Tyr Thr Asn Tyr Ser Pro Ser Phe

50 55 60

Gln Gly His Val Thr Ile Ser Ala Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Leu Gln Trp Ser Ser Leu Gln Ala Ser Asp Thr Ala Ile Tyr Tyr Cys

85 90 95

Ala Arg His Val Val Ala Leu Thr His Leu Tyr Pro Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 643

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 643

gacatccaga tgacccagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca aagtgttagc agcaccttag cctggtacca gcagaaacct 120

ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180

aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240

gaagattttg cagtttatta ctgtcagcaa tataataact ggtccacgtg gacgttcggc 300

caagggacca aagtggatat caaac 325

<210> 644

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 644

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

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Thr

20 25 30

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

35 40 45

Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Ser Thr

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Asp Ile Lys

100 105

<210> 645

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 645

Gly His Asn Ser Pro Ser Tyr Trp

1 5

<210> 646

<211> 8

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 646

Ile Asp Pro Ser Asp Ser Tyr Thr

1 5

<210> 647

<211> 14

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 647

Ala Arg His Val Val Ala Leu Thr His Leu Tyr Pro Asp Tyr

1 5 10

<210> 648

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 648

Gln Ser Val Ser Ser Thr

1 5

<210> 649

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 649

Gly Ala Ser

1

<210> 650

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 650

Gln Gln Tyr Asn Asn Trp Ser Thr Trp Thr

1 5 10

<210> 651

<211> 379

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 651

caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60

acctgcactg tctttggtgg ctccatcacc agtagtaatc actactgggt ctggatccgc 120

cagcccccag ggaaggggct ggagtggatt gggagtatgt attatagtgg gagcaccgcc 180

tacaacccgt ccctcacgaa tcgagtcacc atatccgtag acacgtccaa gaaccagttc 240

tccctgaagc tgagctccgt gaccgccgca gacacggctg tgtattactg tgcgagacaa 300

atcgggccca agaggccctc gcaagtggct gactggttcg acccctgggg ccagggaacc 360

ctggtcaccg tctcctcag 379

<210> 652

<211> 126

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 652

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

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Phe Gly Gly Ser Ile Thr Ser Ser

20 25 30

Asn His Tyr Trp Val Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Met Tyr Tyr Ser Gly Ser Thr Ala Tyr Asn Pro Ser

50 55 60

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

65 70 75 80

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

85 90 95

Cys Ala Arg Gln Ile Gly Pro Lys Arg Pro Ser Gln Val Ala Asp Trp

100 105 110

Phe Asp Pro Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 653

<211> 322

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 653

gacatccagt tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacct 120

gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240

gaagattttg caacttatta ctgtcaacag cttaatagtt acccgctcac tttcggcgga 300

gggaccaagg tggaaatcaa ac 322

<210> 654

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 654

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

1 5 10 15

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

20 25 30

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

35 40 45

Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 655

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 655

Gly Gly Ser Ile Thr Ser Ser Asn His Tyr

1 5 10

<210> 656

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 656

Met Tyr Tyr Ser Gly Ser Thr

1 5

<210> 657

<211> 18

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 657

Ala Arg Gln Ile Gly Pro Lys Arg Pro Ser Gln Val Ala Asp Trp Phe

1 5 10 15

Asp Pro

<210> 658

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 658

Gln Gly Ile Ser Ser Tyr

1 5

<210> 659

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 659

Ala Ala Ser

1

<210> 660

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 660

Gln Gln Leu Asn Ser Tyr Pro Leu Thr

1 5

<210> 661

<211> 382

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 661

caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60

acttgcactg tctctggtga ctccatcagc agtagtcgtt actactgggg ctggatccgc 120

cagcccccag ggaaggggct ggagtggatt gggactttct attatagtgg gatcacgtac 180

tacaacccgt ccctcaagag tcgagtcacc atattcgtag acacgtccaa gaaccagttc 240

tccctgaagc tgagctctgt gaccgccgca gacacggctg tttattactg tgcgagaccc 300

cgaccccccg attactatga taatagtggt gcgctccttt ttgatatctg gggccaaggg 360

acaatggtca ccgtctcttc ag 382

<210> 662

<211> 127

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 662

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

1 5 10 15

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

20 25 30

Arg Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Cys Ala Arg Pro Arg Pro Pro Asp Tyr Tyr Asp Asn Ser Gly Ala Leu

100 105 110

Leu Phe Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120 125

<210> 663

<211> 325

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 663

gccatccgga tgacccagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60

atcgcttgcc gggccagtca gagtattagt gcctggttgg cctggtatca gcagaaacca 120

gggaaagccc ctaagctcct gatctataag gcatctagtt tagaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcaacag cctgcagcct 240

gatgattttg ccacttatta ctgccaacag tatattagtt cttctccgtg gacgttcggc 300

caagggacca aggtggaaat caaac 325

<210> 664

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 664

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ile Ser Ser Ser Pro

85 90 95

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

100 105

<210> 665

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 665

Gly Asp Ser Ile Ser Ser Ser Arg Tyr Tyr

1 5 10

<210> 666

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 666

Phe Tyr Tyr Ser Gly Ile Thr

1 5

<210> 667

<211> 19

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 667

Ala Arg Pro Arg Pro Pro Asp Tyr Tyr Asp Asn Ser Gly Ala Leu Leu

1 5 10 15

Phe Asp Ile

<210> 668

<211> 6

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 668

Gln Ser Ile Ser Ala Trp

1 5

<210> 669

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 669

Lys Ala Ser

1

<210> 670

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 670

Gln Gln Tyr Ile Ser Ser Ser Pro Trp Thr

1 5 10

<210> 671

<211> 370

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 671

cagctgcagc tgcaggagtc gggcccagga ctggtgaggc cttcacagac cctgtccctc 60

tcctgcactg tctctggtgg ctccatcagc agtgccactc actactggag ctggatccgc 120

cagcacccag ggagaggcct ggagtggatt gggtacatct attacactgg gggcaccttt 180

tacaatccgt ccctcaagag tcgacttacc atatcagtgg acacgtctaa gaaccagttc 240

tccctgaagc tgagcgctgt gactgccgcg gacacggccg tgtattactg tgcgagagtt 300

atagcagctc gtccgggatc tacctacttt gacttctggg gccggggaac cctggtcacc 360

gtctcctcag 370

<210> 672

<211> 123

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 672

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

1 5 10 15

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

20 25 30

Thr His Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Arg Gly Leu Glu

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Cys Ala Arg Val Ile Ala Ala Arg Pro Gly Ser Thr Tyr Phe Asp Phe

100 105 110

Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 673

<211> 337

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 673

caatctgccc tgactcagcc tgcctccgtg tctgggtctc ctggacagtc gatcaccatc 60

tcctgcactg gaaccagcag tgacgttagt ggctataact atgtctcctg gtaccaacaa 120

cacccagaca aagcccccaa actcttgatt tatgatgtca ctaatcggcc cacaggggtt 180

tctaatcgct tctctgcctc caagtctggc aacacggcct ccctgaccat ctctgggctc 240

caggctgagg acgaggctga ttattactgc agctcagata caaatagtat tcctcggtat 300

gtggtgttcg gcggagggac caagctgacc gtcctag 337

<210> 674

<211> 112

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 674

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

1 5 10 15

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

20 25 30

Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Asp Lys Ala Pro Lys Leu

35 40 45

Leu Ile Tyr Asp Val Thr Asn Arg Pro Thr Gly Val Ser Asn Arg Phe

50 55 60

Ser Ala Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Asp Thr Asn Ser

85 90 95

Ile Pro Arg Tyr Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105 110

<210> 675

<211> 10

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 675

Gly Gly Ser Ile Ser Ser Ala Thr His Tyr

1 5 10

<210> 676

<211> 7

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 676

Ile Tyr Tyr Thr Gly Gly Thr

1 5

<210> 677

<211> 15

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 677

Ala Arg Val Ile Ala Ala Arg Pro Gly Ser Thr Tyr Phe Asp Phe

1 5 10 15

<210> 678

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 678

Ser Ser Asp Val Ser Gly Tyr Asn Tyr

1 5

<210> 679

<211> 3

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 679

Asp Val Thr

1

<210> 680

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 680

Ser Ser Asp Thr Asn Ser Ile Pro Arg

1 5

<210> 681

<211> 1273

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 681

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> 682

<211> 40

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 682

gagcagccag tgcgtgaatt tcaccaccag aacccagctg 40

<210> 683

<211> 40

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 683

cagctgggtt ctggtggtga aattcacgca ctggctgctc 40

<210> 684

<211> 31

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 684

gcaccaagag attcgccaat cctgtgctgc c 31

<210> 685

<211> 31

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 685

ggcagcacag gattggcgaa tctcttggtg c 31

<210> 686

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 686

attaatctgg tgagaggcct gcctcagggc ttc 33

<210> 687

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 687

gaagccctga ggcaggcctc tcaccagatt aat 33

<210> 688

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 688

ccagattcca gaccctgcac atatcatatc ttacaccag 39

<210> 689

<211> 38

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 689

tggtgtaaga tatgatatgt gcagggtctg gaatctgg 38

<210> 690

<211> 35

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 690

cagggcagac cggcaatatc gccgactaca attac 35

<210> 691

<211> 35

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 691

gtaattgtag tcggcgatat tgccggtctg ccctg 35

<210> 692

<211> 35

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 692

caccgtgtaa tggcgtgaag ggcttcaatt gctac 35

<210> 693

<211> 35

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 693

gtagcaattg aagcccttca cgccattaca cggtg 35

<210> 694

<211> 29

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 694

gcttccagcc tacctatggc gtgggctac 29

<210> 695

<211> 29

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 695

gtagcccacg ccataggtag gctggaagc 29

<210> 696

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 696

gccgtgctgt accagggcgt gaattgcacc gag 33

<210> 697

<211> 33

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 697

ctcggtgcaa ttcacgccct ggtacagcac ggc 33

<210> 698

<211> 34

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 698

caccatgagc ctgggcgtcg agaatagcgt ggcc 34

<210> 699

<211> 34

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 699

ggccacgcta ttctcgacgc ccaggctcat ggtg 34

<210> 700

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 700

cctcaatttg agaaataatg actcgagact agtatcgcg 39

<210> 701

<211> 39

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 701

cgcgatacta gtctcgagtc attatttctc aaattgagg 39

<210> 702

<211> 38

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 702

gcgtagctga aaccggctcc accattgagg aacaggcc 38

<210> 703

<211> 36

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 703

gtgatggtga tgtttgtctg catatggact ccagtc 36

<210> 704

<211> 20

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 704

cagctcctgg gcaacgtgct 20

<210> 705

<211> 19

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 705

cgtaaaagga gcaacatag 19

<210> 706

<211> 58

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 706

caagagagtt gagcccaaat cttgtctggt gccacgcgga agtagtgcct ggtcccac 58

<210> 707

<211> 58

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 707

gtgggaccag gcactacttc cgcgtggcac cagacaagat ttgggctcaa ctctcttg 58

<210> 708

<211> 38

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 708

catccacagt tcgagaaata ggtgcgacgg ccggcaag 38

<210> 709

<211> 38

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 709

cttgccggcc gtcgcaccta tttctcgaac tgtggatg 38

<210> 710

<211> 20

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 710

atgctgcaat cgtgctacaa 20

<210> 711

<211> 17

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<400> 711

gactgccgcc tctgctc 17

<210> 712

<211> 20

<212> DNA

<213> artificial sequence

<220>

<223> Synthesis of Polynucleotide

<220>

<221> feature not yet classified

<222> (1)..(1)

<223> 56-FAM

<220>

<221> feature not yet classified

<222> (9)..(10)

<223> ZEN

<220>

<221> feature not yet classified

<222> (20)..(20)

<223> 3IABkFQ

<400> 712

tcaaggaaca acattgccaa 20

<210> 713

<211> 19

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 713

Ser Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

1 5 10 15

Gly Ser Ser

<210> 714

<211> 204

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 714

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

1 5 10 15

Ala Thr Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser

20 25 30

Asn Cys Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser

35 40 45

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

50 55 60

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

65 70 75 80

Arg Gln Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr

85 90 95

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

100 105 110

Asn Leu Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu

115 120 125

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

130 135 140

Ile Tyr Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn

145 150 155 160

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

165 170 175

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

180 185 190

Ala Pro Ala Thr Val Cys Gly Pro Lys Lys Ser Thr

195 200

<210> 715

<211> 203

<212> PRT

<213> artificial sequence

<220>

<223> synthetic polypeptide

<400> 715

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

1 5 10 15

Ala Thr Lys Phe Pro Ser Val Tyr Ala Trp Glu Arg Lys Lys Ile Ser

20 25 30

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

35 40 45

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

50 55 60

Phe Ser Asn Val Tyr Ala Asp Ser Phe Val Val Lys Gly Asp Asp Val

65 70 75 80

Arg Gln Ile Ala Pro Gly Gln Thr Gly Val Ile Ala Asp Tyr Asn Tyr

85 90 95

Lys Leu Pro Asp Asp Phe Met Gly Cys Val Leu Ala Trp Asn Thr Arg

100 105 110

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

115 120 125

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

130 135 140

Pro Phe Ser Pro Asp Gly Lys Pro Cys Thr Pro Pro Ala Leu Asn Cys

145 150 155 160

Tyr Trp Pro Leu Asn Asp Tyr Gly Phe Tyr Thr Thr Ile Gly Ile Gly

165 170 175

Tyr Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu Asn Ala

180 185 190

Pro Ala Thr Val Cys Gly Pro Lys Leu Ser Thr

195 200

Claims

1. An antibody capable of binding to spike protein of coronavirus SARS-CoV-2, wherein:

(a) The antibody comprises at least three CDRs of antibody Beta-47 or any one of the 27 antibodies in table 2;

(b) The antibody is capable of binding to the same epitope on the spike protein as the antibody Beta-49 or Beta-50, or competing with the antibody Beta-49 or Beta-50; or alternatively

(c) The antibody is capable of locking the spike protein in a downward and outward conformation, wherein the downward and outward conformation is characterized by spike trimers comprising three spike proteins, without direct contact between the Receptor Binding Domains (RBDs) of the spike proteins, except via contact with the N-glycosylation site at amino acid position 343 of the spike protein relative to the hCoV-19/Wuhan/WIV04/2019 strain.

2. The antibody of claim 1, comprising:

(a) At least four, five, or all six CDRs of an antibody in table 2;

(b) A heavy chain variable domain comprising or consisting of an amino acid sequence having at least 80% sequence identity to a heavy chain variable domain of an antibody in table 2;

(c) A light chain variable domain comprising or consisting of an amino acid sequence having at least 80% sequence identity to a light chain variable domain of an antibody in table 2; and/or

(d) A heavy chain variable domain and a light chain variable domain comprising or consisting of an amino acid sequence having at least 80% identity to the heavy chain variable domain and the light chain variable domain, respectively, of an antibody in table 2.

3. The antibody of claim 1 or claim 2, wherein the antibody in table 2 is selected from the group consisting of:

(a) Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50, beta-53, beta-55, and Beta-56;

(b) Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50, and Beta-53;

(c) Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50, beta-53, beta-06, beta-10, beta-23, beta-24, beta-30, beta-40, beta-54, beta-55, beta-56, and Beta-44;

(d) Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50, beta-53, beta-26, beta-33, beta-34, beta-38, beta-45, beta-51, and Beta-44;

(e) Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50, beta-53, beta-20, beta-22, beta-29, and Beta-44;

(f)Beta-44；

(g)Beta-43；

(h) Beta-06, beta-10, beta-23, beta-24, beta-30, beta-40, beta-54, beta-55, beta-56, and Beta-44;

(i) Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50, and Beta-53; beta-26, beta-33, beta-34, beta-38, beta-45, beta-51, beta-20, beta-22, beta-29, and Beta-44;

(j) Beta-20, beta-24, beta-26 and Beta-27;

(k) Beta-27, beta-47, beta-48, beta-49, beta-50, beta-56, beta-55, beta-25, and Beta-53;

(l) Beta-27, beta-47, beta-48, beta-49, beta-50, beta-56, beta-47H/55L, beta-47H/Beta-25L and Beta-53;

(m) Beta-49 and Beta-50;

(n) Beta-22, beta-27, beta-29, beta-40, beta-47, beta-53, beta-54, beta-55, and Beta-56;

(o) Beta-22, beta-29, beta-40, beta-47, beta-53, beta-54, beta-55, and Beta-56; or alternatively

(p) Beta-40, beta-47, beta-54 and Beta-55.

4. The antibody of claim 1, comprising CDRH1, CDRH2 and CDRH3 from a first antibody in table 1 or 2, and CDRL1, CDRL2 and CDRL3 from a second antibody in table 1 or 2, provided that the first antibody and the second antibody are different.

5. The antibody of claim 4, comprising a heavy chain variable domain amino acid sequence having at least 80% sequence identity to a heavy chain variable domain from a first antibody in table 1 or table 2 and a light chain variable domain amino acid sequence having at least 80% sequence identity to a light chain variable domain from a second antibody in table 1 or table 2.

6. The antibody according to claim 4 or claim 5, wherein the first antibody and the second antibody are derived from the same germline heavy chain v-region, optionally wherein the heavy chain v-region is IGHV3-53, IGHV1-58, IGHV3-66, IGHV4-39, IGHV3-30, IGHV5-51, IGHVl-02 or IGHV1-69.

7. The antibody according to any one of claims 4 to 6, wherein the first antibody and the second antibody are both selected from the group consisting of:

(a) Beta-27, antibody 150, antibody 158, antibody 175, antibody 222, and antibody 269; optionally wherein the antibody comprises a heavy chain variable domain and a light chain variable domain of one of the antibodies as listed in table 3A;

(b) Beta-47, beta-25, antibody 55, antibody 165, antibody 253, and antibody 318; optionally wherein the antibody comprises a heavy chain variable domain and a light chain variable domain of one of the antibodies as listed in table 4;

(c) Beta-06, beta-10, beta-23, beta-40, beta-54, and Beta-55; optionally wherein the antibody comprises a heavy chain variable domain and a light chain variable domain of one of the antibodies as listed in table 5;

(d) Beta-22, beta-29, and antibody 159; optionally wherein the antibody comprises a heavy chain variable domain and a light chain variable domain of one of the antibodies as listed in table 6;

(e) Beta-38 and antibody 170; optionally wherein the antibody comprises a heavy chain variable domain and a light chain variable domain of one of the antibodies as listed in table 7;

(f) Beta-30, beta-32, beta-33, and antibody 316; optionally wherein the antibody comprises a heavy chain variable domain and a light chain variable domain of one of the antibodies as listed in table 8;

(g) Beta-20 and Beta-43; optionally wherein the antibody comprises a heavy chain variable domain and a light chain variable domain of one of the antibodies as listed in table 9;

(h) Beta-27, antibody 150, antibody 158, antibody 175, antibody 222, antibody 269, antibody 40 and antibody 298; optionally wherein the antibody comprises a heavy chain variable domain and a light chain variable domain of one of the antibodies as listed in table 3B;

(i) Beta-49 and Beta-50;

(j) Beta-27 and antibody 222;

(k) Beta-22 and Beta-29;

(l) Beta-40, beta-54 and Beta-55; or alternatively

(m) Beta-47 and antibody 253.

8. The antibody of any one of the preceding claims, wherein the antibody in tables 2-9 is Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50, beta-53, beta-55, beta-56, beta-47H/Beta-25L, or Beta-47H/55L.

9. The antibody according to claim 1 (b), wherein the epitope comprises:

(a) N343 and/or D364 of the spike protein of coronavirus SARS-CoV-2, wherein N343 is glycosylated; and/or

(b) (i) a hydrophobic pocket formed by residues 335-336, 338-342, 363, 365 and 367-368 of the first spike protein;

(ii) Residues 477 and 486-487 of the second spike protein; and/or

(iii) Residues 333-334 and 527-529 of the first spike protein.

10. The antibody of claim 1 (b), wherein the epitope comprises residues 332-340, 342-345, 362-365, 367-368, 527, and 529 of the first spike protein and residues 476-478, 486-487, and 489 of the second spike protein.

11. The antibody according to any one of the preceding claims, which is, for example, a full length antibody comprising an IgG1 constant region.

12. The antibody according to one of the preceding claims, comprising an Fc region comprising at least one modification such that serum half-life is prolonged.

13. An antibody combination comprising two or more antibodies according to any one of the preceding claims.

14. An antibody combination comprising:

(a) The antibody of any one of claims 1 to 12; and

(b) An antibody comprising at least three CDRs of an antibody in table 1, e.g., the antibody comprises:

(i) At least four, five, or all six CDRs of an antibody in table 1;

(ii) A heavy chain variable domain comprising or consisting of an amino acid sequence having at least 80% sequence identity to a heavy chain variable domain of an antibody in table 1;

(iii) A light chain variable domain comprising or consisting of an amino acid sequence having at least 80% sequence identity to a light chain variable domain of an antibody in table 1; and/or

(iv) A heavy chain variable domain and a light chain variable domain comprising or consisting of an amino acid sequence having at least 80% identity to the heavy chain variable domain and the light chain variable domain, respectively, of an antibody in table 1.

15. An antibody combination according to claim 13 or claim 14 comprising two, three or four antibodies according to any one of claims 1 to 12.

16. The antibody combination according to any one of claims 13 to 15, wherein the combination comprises at least two of the following:

17. One or more polynucleotides encoding the antibody of any one of claims 1 to 12, one or more vectors comprising said polynucleotides, or a host cell comprising said vectors.

18. A method for producing an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, the method comprising culturing the host cell of claim 17 and isolating the antibody from said culturing.

19. A pharmaceutical composition comprising: (a) The antibody of any one of claims 1 to 12 or the antibody combination of any one of claims 13 to 16, and (b) at least one pharmaceutically acceptable diluent or carrier.

20. The antibody according to any one of claims 1 to 12, the combination according to any one of claims 13 to 16 or the pharmaceutical composition according to claim 19 for use in a method of treatment of the human or animal body by therapy.

21. The antibody according to any one of claims 1 to 12, the combination according to any one of claims 13 to 16 or the pharmaceutical composition according to claim 19 for use in a method of treating or preventing a coronavirus infection or a disease or complication associated with a coronavirus infection.

22. A method of treating or preventing a coronavirus infection or a disease or complication associated with a coronavirus infection in a subject, the method comprising administering to the subject a therapeutically effective amount of an antibody according to any one of claims 1 to 12, a combination according to any one of claims 13 to 16, or a pharmaceutical composition according to claim 19.

23. The method according to claim 21 or 22, wherein the method is for the treatment of SARS-CoV-2 infection or a disease or complication associated therewith, such as covd-19.

24. A method of identifying the presence of a coronavirus or a protein fragment thereof in a sample, the method comprising:

(i) Contacting the sample with an antibody according to any one of claims 1 to 12 or a combination according to any one of claims 13 to 16, and

(ii) Detecting the presence or absence of an antibody-antigen complex,

Wherein the presence of the antibody-antigen complex is indicative of the presence of coronavirus or a fragment thereof in the sample.

25. The method according to claim 24, wherein:

(a) The antibody is Beta-6, beta-10, beta-23, beta-24; beta-30, beta-40, beta-54, beta-55, and/or Beta-56; and the presence of an antibody-antigen complex indicates the presence of tyrosine 501 in the receptor binding domain of the spike protein of SARS-Cov-2;

(b) The antibody is Beta-26, beta-33, beta-34, beta-38; beta-45 and/or Beta-51; and the presence of an antibody-antigen complex indicates the presence of lysine 484 in the receptor binding domain of the spike protein of SARS-Cov-2;

(c) The antibody is Beta-20, beta-33, beta-22 and/or Beta-29; and the presence of the antibody-antigen complex is indicative of the presence of asparagine or threonine at position 417 in the receptor binding domain of the spike protein of SARS-Cov-2; and

(d) The antibody is Beta-29; and the presence of the antibody-antigen complex indicates the presence of leucine or threonine at positions 452 and 478, respectively, in the receptor binding domain of the spike protein of SARS-Cov-2.

26. A method of treating or preventing a coronavirus infection or a disease or complication associated therewith in a subject, the method comprising identifying the presence of coronavirus in a sample according to the method of claim 24 or claim 25 and treating the subject with an antibody or combination, antiviral drug or anti-inflammatory agent according to any one of claims 1 to 16.

27. Use of an antibody according to any one of claims 1 to 12, a combination according to any one of claims 13 to 16 or a pharmaceutical composition according to claim 19 for the prevention, treatment and/or diagnosis of a coronavirus infection or a disease or complication associated therewith.

28. Use of an antibody according to any one of claims 1 to 12, a combination according to any one of claims 13 to 16 or a pharmaceutical composition according to claim 19 for the manufacture of a medicament for the treatment or prevention of a coronavirus infection or a disease or complication associated therewith.

29. Antibody for use according to claims 20 to 21, method according to any one of claims 22, 23 and 26 and use according to claim 27 or claim 28, wherein the coronavirus infection is caused by a SARS-CoV-2 strain comprising a substitution at position 417, 484, 501, 452 and/or 478 in the spike protein relative to the spike protein of the hCoV-19/Wuhan/WIV04/2019 strain, e.g. it is a member of lineage alpha, beta, gamma, delta or omicron.

30. Antibody, method or use according to claim 29, wherein the coronavirus infection is caused by a SARS-CoV-2 strain comprising a substitution at position 501 in the spike protein relative to the spike protein of the hCoV-19/Wuhan/WIV04/2019 strain, e.g. it is a b.1.1.7 (alpha) strain or a member of the lineage derived thereof, a b.1.351 (beta) strain or a member of the lineage derived thereof or a p.1 (gamma) strain or a member of the lineage derived thereof; optionally, wherein the antibody is Beta-06, beta-10, beta-23, beta-24, beta-30, beta-40, beta-54, beta-55, beta-56, and/or Beta-44.

31. Antibody, method or use according to claim 29, wherein the coronavirus infection is caused by a SARS-CoV-2 strain comprising substitutions at positions 417, 484 and 501 in the spike protein relative to the spike protein of the hCoV-19/Wuhan/WIV04/2019 strain, e.g. it is a b.1.351 (beta) strain or a member of the lineage derived thereof or a p.1 (gamma) strain or a member of the lineage derived thereof; optionally, wherein the antibody is Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50, and Beta-53, beta-06, beta-10, beta-23, beta-24, beta-30, beta-40, beta-54, beta-55, beta-56, beta-26, beta-33, beta-34, beta-38, beta-45, beta-51, and/or Beta-44.

32. Antibody, method or use according to claim 29, wherein the coronavirus infection is caused by a strain of SARS-CoV-2, which strain comprises substitutions in the spike protein at positions 452 and 478, for example which is a member of lineage delta, relative to the spike protein of the strain hCoV-19/Wuhan/WIV 04/2019; optionally, wherein the antibody is Beta-47, beta-27, beta-32, beta-48, beta-49, beta-50 and/or Beta-53.

33. A method of producing an antibody capable of binding to a spike protein of SARS-CoV-2, the method comprising producing an antibody directed against a modified spike protein locked in a downward and outward conformation, wherein the downward and outward conformation is characterized by spike trimers comprising three spike proteins, the Receptor Binding Domains (RBDs) of which are not in direct contact with each other, except via contact with an N-glycosylation site at amino acid position 343 of the spike protein relative to the hCoV-19/Wuhan/WIV04/2019 strain.

34. The method according to claim 33, wherein the modified spike protein comprises cysteine residues as positions 198 and 463 of the spike protein.

35. The method according to claim 33 or 34, wherein the production of the antibody is performed by hybridoma technology, phage display technology, or by immunizing an animal with the modified spike protein.