Treatment and inhibition of inflammatory lung diseases in patients with risk alleles in genes encoding il33 and il1rl1

Abstract

IL33 antagonists, alone or in combination with IL-4R antagonists, can be used to treat or inhibit eosinophilic asthma, eosinophilic COPD, eosinophilic ACOS, and nasal polyps in subjects having one or more risk alleles in intronic IL1RL1 variant rs1420101, in IL33 variant rs1342326, in both, or in variants in linkage disequilibrium therewith.

Description

TECHNICAL FIELD

[0001] The present disclosure relates generally to the field of precision medicine. More specifically, the present disclosure relates to detecting risk alleles in genes encoding IL33 and IL1RL1 that can be used to stratify patients with inflammatory lung diseases as having a high risk of developing one or more of these conditions and their eosinophilic subtypes. BACKGROUND

[0002] Throughout this specification, various publications, including patents, published applications, accession numbers, technical articles and scholarly articles are cited. Each of these cited publications is incorporated by reference herein, in its entirety and for all purposes, into this document.

[0003] Asthma and chronic obstructive pulmonary disease (COPD) are very common obstructive lung diseases with a large unmet clinical need and significant diagnostic overlap, and there is growing interest in the intersection of these conditions, referred to as asthma-COPD overlap syndrome (ACOS). There is a long-standing debate as to whether the two diseases have a common etiology (the so-called "Dutch hypothesis") or independent mechanistic causes (the so-called "British hypothesis"). Despite recent advances in elucidating the genetic contribution to risk of common complex diseases, including obstructive lung diseases, there are no established genetic findings that link asthma and COPD.

[0004] Genome-wide association studies (GWAS) have identified common genetic variants associated with asthma at interleukin-33 (IL33) and / or IL1RL1. IL33, a proinflammatory cytokine and member of the interleukin-1 (IL-1) family of cytokines, is expressed in a subset of cells in barrier tissues, including lung epithelial cells. IL33 signals through a heterodimeric receptor complex composed of IL33-specific receptor IL1RL1 (also known as ST2 or IL33R) and the IL-1RAcP co-receptor (common to several receptors of the IL-1 family).

[0005] In damaged tissues, previously sequestered IL33 is passively released by necrotic cells into the extracellular compartment and acts as an endogenous "danger signal" (alarm) that activates inflammatory and repair pathways. Cigarette smoke induces IL33 expression in mouse lung epithelial cells, and IL33 expression is elevated in bronchial epithelial cells of asthma and COPD patients. In disease states where inflammatory infiltrates and inflammatory cytokines are already present, the IL33-responsive cell pool is increased and IL33 signaling further amplifies the immune response, leading to pathological inflammation and excessive immune responses that can drive chronic inflammatory diseases such as COPD.

[0006] There also exists asthma-COPD overlap syndrome (ACOS), which is characterized by symptoms common to both asthma and COPD. However, given the difficulty in separating asthma from COPD due to the common overlapping features, there remains a clinical challenge in the ability to diagnose ACOS.

[0007] There also remains a therapeutic challenge for asthma, COPD, and ACOS, with resistance to corticosteroids (standard of care) being quite common. Likewise, other treatments such as IL-5 therapies do not work well for the eosinophilic subgroups of asthma and COPD.

[0008] Accordingly, there remains a need in the art to distinguish between asthma, COPD, and ACOS, and to more accurately identify patients with the eosinophilic subgroups of these conditions. Proper diagnosis can better guide treatment regimens and improve patient outcomes. SUMMARY

[0009] In a first aspect of the disclosure, a method of treating or inhibiting eosinophilic asthma comprises administering to a subject having one or more risk alleles associated with eosinophilic asthma in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith, in the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith, or in both the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith and the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith, an IL33 antagonist or administering an IL33 antagonist and an IL-4R antagonist. Administering the IL33 antagonist and / or the IL-4R antagonist results in the treatment or inhibition of eosinophilic asthma in the subject.

[0010] In a second aspect of the disclosure, a method of treating or inhibiting eosinophilic chronic obstructive pulmonary disease (COPD) comprises administering to a subject having one or more risk alleles associated with eosinophilic COPD in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith, in the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith, or both the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith and the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith, an IL33 antagonist or an IL33 antagonist and an IL-4R antagonist. Administering the IL33 antagonist and / or IL-4R antagonist results in the treatment or inhibition of eosinophilic COPD in the subject.

[0011] In a third aspect of the disclosure, a method of treating or inhibiting eosinophilic asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) comprises administering to a subject having one or more risk alleles associated with eosinophilic asthma in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith, in the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith, or both the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith and the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith, an IL33 antagonist or an IL33 antagonist and an IL-4R antagonist. Administering the IL33 antagonist and / or IL-4R antagonist results in the treatment or inhibition of eosinophilic COPD in the subject.

[0012] In a fourth aspect of the disclosure, a method of treating or inhibiting nasal polyps comprises administering to a subject having one or more risk alleles associated with nasal polyps in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith, in the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith, or in both the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith and the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith, an IL33 antagonist or administering an IL33 antagonist and an IL-4R antagonist. Administering the IL33 antagonist and / or the IL-4R antagonist results in the treatment or inhibition of nasal polyps in the subject.

[0013] In a fifth aspect of the disclosure, a method of assessing the risk of developing eosinophilic asthma, eosinophilic chronic obstructive pulmonary disease (COPD), or eosinophilic asthma COPD overlap syndrome (ACOS) comprises the steps of:

[0014] (A) detecting in a sample obtained from a subject, one or more risk alleles associated with eosinophilic asthma, eosinophilic COPD, or eosinophilic ACOS in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith, in the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith, or in both the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith and the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith;

[0015] (B) (i) assigning a risk score of 1 to the subject when the subject has a risk allele in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith in one of the chromosome 2 homologs or has a risk allele in the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith in one of the chromosome 9 homologs,

[0016] (B)(ii) when the subject has a risk allele in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a linkage disequilibrium variant thereof in both of the chromosome 2 homologs, when the subject has a risk allele in the IL33 variant rs1342326 (SEQ ID NO: 358) or a linkage disequilibrium variant thereof in both of the chromosome 9 homologs, or when the subject has a risk allele in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a linkage disequilibrium variant thereof in one of the chromosome 2 homologs and a risk allele in the IL33 variant rs1342326 (SEQ ID NO: 358) or a linkage disequilibrium variant thereof in one of the chromosome 9 homologs, the subject is assigned a risk score of 2,

[0017] (B)(iii) when the subject has a risk allele in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a linkage disequilibrium variant thereof in both of the chromosome 2 homologs and a risk allele in the IL33 variant rs1342326 (SEQ ID NO: 358) or a linkage disequilibrium variant thereof in one of the chromosome 9 homologs, or when the subject has a risk allele in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a linkage disequilibrium variant thereof in one of the chromosome 2 homologs and a risk allele in the IL33 variant rs1342326 (SEQ ID NO: 358) or a linkage disequilibrium variant thereof in both of the chromosome 9 homologs, the subject is assigned a risk score of 3, or

[0018] (B)(iv) when the subject has a risk allele in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a linkage disequilibrium variant thereof in both of the chromosome 2 homologs and a risk allele in the IL33 variant rs1342326 (SEQ ID NO: 358) or a linkage disequilibrium variant thereof in both of the chromosome 9 homologs, the subject is assigned a risk score of 4; and

[0019] (C) classifying the subject's risk of developing eosinophilic asthma, eosinophilic COPD, or eosinophilic ACOS, where a risk score of 1 indicates that the subject is at risk of developing a high-eosinophilic subtype of the eosinophilic asthma, a high-eosinophilic subtype of the eosinophilic COPD, or a high-eosinophilic subtype of the eosinophilic ACOS, a risk score of 2 indicates that the subject is at increased risk of developing the high-eosinophilic subtype of the eosinophilic asthma, the high-eosinophilic subtype of the eosinophilic COPD, or the high-eosinophilic subtype of the eosinophilic ACOS, a risk score of 3 indicates that the subject is at high risk of developing the high-eosinophilic subtype of the eosinophilic asthma, the high-eosinophilic subtype of the eosinophilic COPD, or the high-eosinophilic subtype of the eosinophilic ACOS, and a risk score of 4 indicates that the subject is at very high risk of developing the high-eosinophilic subtype of the eosinophilic asthma, the high-eosinophilic subtype of the eosinophilic COPD, or the high-eosinophilic subtype of the eosinophilic ACOS. The method can further comprise treating or inhibiting one or more of eosinophilic asthma, eosinophilic COPD, or eosinophilic ACOS (including high-eosinophilic subtypes thereof) in the subject by administering to the subject an IL33 antagonist or an IL33 antagonist and an IL-4R antagonist.

[0020] In a sixth aspect of the application, an IL33 antagonist or a combination of an IL33 antagonist and an IL-4R antagonist is for use in the treatment or inhibition of any one of eosinophilic asthma, eosinophilic chronic obstructive pulmonary disease (COPD), eosinophilic asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS), high-eosinophilic eosinophilic asthma, high-eosinophilic eosinophilic COPD, high-eosinophilic eosinophilic ACOS, or nasal polyps, or for the manufacture of a medicament for the treatment or inhibition of any one of eosinophilic asthma, eosinophilic chronic obstructive pulmonary disease (COPD), eosinophilic asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS), high-eosinophilic eosinophilic asthma, high-eosinophilic eosinophilic COPD, high-eosinophilic eosinophilic ACOS, or nasal polyps, in a patient having one or more risk alleles associated with eosinophilic asthma, eosinophilic COPD, or eosinophilic ACOS in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith, in the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith, or in both the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith and the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith.

[0021] According to any of these aspects, the subject can have at least one risk allele associated with eosinophilic asthma in intron IL1RL1 variant rs1420101 (SEQ ID NO: 357), or a variant in linkage disequilibrium therewith, can have two risk alleles associated with eosinophilic asthma in intron IL1RL1 variant rs1420101 (SEQ ID NO: 357), or a variant in linkage disequilibrium therewith, can have at least one risk allele associated with eosinophilic asthma in IL33 variant rs1342326 (SEQ ID NO: 358), or a variant in linkage disequilibrium therewith, or can have two risk alleles associated with eosinophilic asthma in IL33 variant rs1342326 (SEQ ID NO: 358), or a variant in linkage disequilibrium therewith, and can further have at least one risk allele associated with eosinophilic asthma in IL33 variant rs1342326 (SEQ ID NO: 358), or a variant in linkage disequilibrium therewith, and / or can further have two risk alleles associated with eosinophilic asthma in IL33 variant rs1342326 (SEQ ID NO: 358), or a variant in linkage disequilibrium therewith.

[0022] According to any of these aspects, the method can further comprise or the use can be for administering to the subject an IL33 antagonist, or the method can comprise or the use can be for administering to the subject an IL33 antagonist and an IL-4R antagonist. The IL33 antagonist can comprise an IL33 trap or an antibody that specifically binds to IL33. The IL-4R antagonist can comprise an antibody that specifically binds to IL-4R.

[0023] According to any of these aspects, the IL33 trap comprises a first IL33 binding domain comprising an IL33 binding portion of IL1RL1 and a second IL33 binding domain comprising an extracellular portion of IL-1RAcP. According to any of these aspects, the antibody or antigen-binding fragment thereof that specifically binds to IL33 can comprise the H1, H2, and H3 domains of SEQ ID NO: 274 and the L1, L2, and L3 domains of SEQ ID NO: 282. According to any of these aspects, the antibody or antigen-binding fragment thereof that specifically binds to IL-4R can comprise the H1, H2, and H3 domains of SEQ ID NO: 337 and the L1, L2, and L3 domains of SEQ ID NO: 338. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1(Fig. A, Fig. B, Fig. C, and Fig. D) show four exemplary arrangements of the individual components of an IL33 antagonist relative to one another. Fig. A shows an arrangement in which a first IL33 binding domain (D1) is attached to the N-terminus of a first multimerization domain (M1), and a second IL33 binding domain (D2) is attached to the N-terminus of a second multimerization domain (M2). D1 is shown as a white box and D2 is shown as a black box to indicate that D1 and D2 are derived from different IL33 binding proteins. Fig. B shows an arrangement in which a first IL33 binding domain (D1) is attached to the N-terminus of a first multimerization domain (M1), and a second IL33 binding domain (D2) is attached to the C-terminus of a second multimerization domain (M2). D1 is shown as a white box and D2 is shown as a black box to indicate that D1 and D2 are derived from different IL33 binding proteins. Fig. C and Fig. D show arrangements that include four IL33 binding domains, D1, D2, D3, and D4. In these arrangements, D3-D1-M1 and D4-D2-M2 are attached in series, with D3 attached to the N-terminus of D1, D1 attached to the N-terminus of M1; and D4 attached to the N-terminus of D2, D2 attached to the N-terminus of M2. In Fig. C, D3 and D4 are the same or substantially the same as one another, and D1 and D2 are the same or substantially the same as one another. In Fig. D, D1 and D4 are the same or substantially the same as one another, and D3 and D2 are the same or substantially the same as one another.

[0025] Figure 2 (Fig. A, Fig. B, Fig. C, and Fig. D) show the association of rs1420101 (IL1RL1, also known as ST2), s1342326 (IL33), and rs146597587 (IL33-pLoF) with (Fig. A) eosinophil count (Fig. B) log 10 transformed eosinophil count. Also shown is the total load of rs1420101 and rs1342326 risk alleles with (Fig. C) eosinophil count (Fig. D) log 10 transformed eosinophil count. Also shown is the total load of rs1420101 and rs1342326 risk alleles with (Fig. C) eosinophil count (Fig. D) log 10 transformed eosinophil count. Also shown is the total load of rs1420101 and rs1342326 risk alleles with (Fig. C) eosinophil count (Fig. D) log 2 transformed eosinophil count. Also shown is the total load of rs1420101 and rs1342326 risk alleles with (Fig. C) eosinophil count (Fig. D) log

[0026] Figure 3Figures A, B, and C show the associations of rs1420101 (IL1RL1, also known as ST2), s1342326 (IL33), and rs146597587 (IL33-pLoF) with (Figure A) asthma, (Figure B) the hypereosinophilic asthma subclass, and (Figure C) the hypoeosinophilic asthma subclass. Odds ratios for the diseases were calculated using logistic regression, and age-related data were analyzed. 2 Adjustments were made based on factors such as gender, smoking status, and major ancestral components.

[0027] Figure 4 Figures A, B, and C show the associations of rs1420101 (IL1RL1, also known as ST2), s1342326 (IL33), and rs146597587 (IL33-pLoF) with COPD in Figure A, the hypereosinophilic COPD subclass in Figure B, and the hypoeosinophilic COPD subclass in Figure C. Odds ratios for the diseases were calculated using logistic regression, and age-related data were analyzed. 2 Adjustments were made based on factors such as gender, smoking status, and major ancestral components.

[0028] Figure 5 (Figures A, B, and C) show rs1420101 ( IL1RL1 The associations of s1342326 (IL33) and rs146597587 (IL33-pLoF) with (Figure A) ACOS, (Figure B) the high eosinophilic ACOS subclass, and (Figure C) the low eosinophilic ACOS subclass were analyzed. Odds ratios for the diseases were calculated using logistic regression, and age-related data were analyzed. 2 Adjustments were made based on factors such as gender, smoking status, and major ancestral components.

[0029] Figure 6 Figures A, B, and C show the associations between genetic scores (total load of risk alleles rs1420101 and rs1342326) and (Figure A) asthma, (Figure B) COPD, and (Figure C) ACOS. P-values ​​were estimated for individual scores; in each case, comparisons were made between individuals with zero-risk alleles. Additionally, p-values ​​for the overall trend test are shown.

[0030] Figure 7 Figures A, B, and C show the associations between genetic scores (total load of risk alleles rs1420101 and rs1342326) and (Figure A) high and low eosinophilic asthma, (Figure B) high and low eosinophilic COPD, and (Figure C) high and low eosinophilic ACOS. P-values ​​were estimated for individual scores; in each case, comparisons were made with individuals having zero-risk alleles. Additionally, p-values ​​for the overall trend test are shown.

[0031] Figure 8 (Figures A, B, C, and D) show stratification of clinical characteristics of study participants by capture reagent (Figure A) VCRome and (Figure B) xGEN and chip platform (Figure C) OMNI and (Figure D) GSA.

[0032] Figure 9 (Figures A and B) show association of rs1420101 (IL1RL1, also known as ST2), s1342326 (IL33), rs146597587 (IL33-pLoF), and genetic score (total load of risk alleles for rs1420101 and rs1342326) with (Figure A) allergic rhinitis and (Figure B) nasal polyps. Odds ratios for disease were calculated using logistic regression and adjusted for age, age 2 , sex, smoking status, and major components of ancestry. To examine the load of common risk variants, p values and odds ratios were estimated for each individual score; in each case, comparisons were made to individuals with zero risk alleles. In addition, overall trend test p values are shown. DETAILED DESCRIPTION

[0033] Various terms related to aspects of the present disclosure are used throughout the specification and claims. Such terms are given their ordinary meaning in the art unless otherwise specified. Other specifically defined terms are to be construed in a manner consistent with the definition provided herein.

[0034] As used herein, the singular forms "a", "an" and "the" include plural referents unless expressly stated otherwise.

[0035] The terms "subject" and "patient" are used interchangeably and include any animal. Mammals are preferred, including companion mammals (e.g., cats, dogs) and farm mammals (e.g., pigs, horses, cows), as well as rodents, including mice, rabbits, and rats, guinea pigs, and other rodents. Non-human primates are more preferred, and humans are most preferred.

[0036] The term "isolated" means removed and / or altered by human labor from the natural environment.

[0037] A "risk allele" includes an alternative polymorphism at a particular location that is associated with a risk of developing a disease, disorder, or condition.

[0038] "Linkage disequilibrium" refers to non-random association of alleles at two or more loci.

[0039] Single nucleotide polymorphisms in IL1R1 rs1420101 (SEQ ID NO: 357) and IL33 rs1342326 (SEQ ID NO: 358) have been observed to be associated with an increased risk of asthma and the high-eosinophilic sub-classes of asthma, COPD, and ACOS according to the present disclosure. Additionally, it was observed that individuals carrying a greater burden of these risk alleles at both loci have a concomitant greater disease risk, and heterozygous carriers with rare pLOF variants in IL33 have lower median life-time eosinophil counts and a trend towards a reduced risk of asthma, and a trend towards a reduced risk of the high-eosinophilic sub-classes of asthma, COPD, and ACOS. It is believed that IL33 pathway genetic variants have not been previously associated with COPD, and further that there is no reported genetic link between asthma and COPD or between the IL33 pathway and the risk of the high-eosinophilic sub-classes of asthma, COPD, and ACOS. Moreover, it was observed that single nucleotide polymorphisms in IL1R1 rs1420101 and IL33 rs1342326, alone and in combination, are associated with an increased risk of nasal polyps and allergic rhinitis. These data suggest a role for interleukin-33 blockade in the treatment of high-eosinophil forms of obstructive lung diseases such as asthma, COPD, and ACOS, and other upper respiratory diseases such as nasal polyps and their high-eosinophilic sub-classes. Accordingly, the present disclosure features methods of identifying the risk of asthma, COPD, and ACOS, in particular the high-eosinophilic sub-classes thereof, diagnosing, treating, and inhibiting asthma, COPD, and ACOS, in particular the high-eosinophilic sub-classes thereof.

[0040] In a first aspect, the present disclosure features a method of assessing the risk of developing an inflammatory lung disease. The inflammatory lung disease can be one or more of asthma, COPD, ACOS, or nasal polyps. The asthma can be eosinophilic asthma or high-eosinophilic type eosinophilic asthma. The COPD can be eosinophilic COPD or high-eosinophilic type eosinophilic COPD. The ACOS can be eosinophilic ACOS or high-eosinophilic type eosinophilic ACOS. In general, the method includes detecting one or more risk alleles associated with the risk of developing such an inflammatory lung disease.

[0041] In some embodiments, the method comprises detecting in a sample obtained from a subject, one or more risk alleles in intron IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant thereof that is in linkage disequilibrium therewith, in IL33 variant rs1342326 (SEQ ID NO: 358) or a variant thereof that is in linkage disequilibrium therewith, or in both the intron IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant thereof that is in linkage disequilibrium therewith and the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant thereof that is in linkage disequilibrium therewith, that are associated with eosinophilic asthma, eosinophilic COPD, eosinophilic ACOS, or nasal polyps; then assigning the subject a risk score of 1 when the subject has a risk allele in the intron IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant thereof that is in linkage disequilibrium therewith in one of the chromosome 2 homologs or a risk allele in the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant thereof that is in linkage disequilibrium therewith in one of the chromosome 9 homologs; assigning the subject a risk score of 2 when the subject has a risk allele in the intron IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant thereof that is in linkage disequilibrium therewith in both of the chromosome 2 homologs, when the subject has a risk allele in the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant thereof that is in linkage disequilibrium therewith in both of the chromosome 9 homologs, or when the subject has a risk allele in the intron IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant thereof that is in linkage disequilibrium therewith in one of the chromosome 2 homologs and a risk allele in the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant thereof that is in linkage disequilibrium therewith in one of the chromosome 9 homologs;when the subject has a risk allele in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith in both of the chromosome 2 homologs and a risk allele in the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith in one of the chromosome 9 homologs, or when the subject has a risk allele in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith in one of the chromosome 2 homologs and a risk allele in the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith in both of the chromosome 9 homologs, the subject is assigned a risk score of 3; or when the subject has a risk allele in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith in both of the chromosome 2 homologs and a risk allele in the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith in both of the chromosome 9 homologs, the subject is assigned a risk score of 4.

[0042] In some embodiments, the risk allele in IL33 variant rs1342326 comprises a single nucleotide polymorphism (SNP). In some detailed embodiments, the IL33 variant comprises SNP 9:6190076:A:C (human genome GRCh38). Variant rs1342326 comprises the following nucleic acid sequence: CCAATCTTTTCTCATGAAGACACCA[G / T]CATGACCTCTTATTCTTATTTATAT (SEQ ID NO: 358).

[0043] In some embodiments, the risk allele in IL1RL1 variant rs1420101 comprises a SNP. In some detailed embodiments, the IL1RL1 variant comprises SNP 2: 102341256:C:T (human genome GRCh38). Variant rs1342326 comprises the following nucleic acid sequence: TATACCATCACAAAGCCTCTCATTA[A / G]ACTTTGAATCCAATGAGTATTACTA (SEQ ID NO: 357).

[0044] Detection can be according to any suitable method. Risk alleles can be detected, for example, by sequencing, genotyping, imputation, probing with complementary nucleic acid probes.

[0045] The method can further comprise classifying the subject's risk of developing eosinophilic asthma, eosinophilic COPD, or eosinophilic ACOS, wherein a risk score of 1 indicates that the subject is at risk of developing a high-eosinophilic subtype of the eosinophilic asthma, a high-eosinophilic subtype of the eosinophilic COPD, or a high-eosinophilic subtype of the eosinophilic ACOS, a risk score of 2 indicates that the subject is at an elevated risk of developing a high-eosinophilic subtype of the eosinophilic asthma, a high-eosinophilic subtype of the eosinophilic COPD, or a high-eosinophilic subtype of the eosinophilic ACOS, a risk score of 3 indicates that the subject is at a high risk of developing a high-eosinophilic subtype of the eosinophilic asthma, a high-eosinophilic subtype of the eosinophilic COPD, or a high-eosinophilic subtype of the eosinophilic ACOS, and a risk score of 4 indicates that the subject is at an extremely high risk of developing a high-eosinophilic subtype of the eosinophilic asthma, a high-eosinophilic subtype of the eosinophilic COPD, or a high-eosinophilic subtype of the eosinophilic ACOS. In this scale, elevated risk is higher than risk but lower than high risk, and extremely high risk is higher than high risk. Thus, in terms of the risk of the patient developing the disease, risk < elevated risk < high risk < extremely high risk, or risk score of 1 < risk score of 2 < risk score of 3 < risk score of 4.

[0046] The method can further comprise obtaining a sample from the subject. In general, the sample can comprise any sample from which a risk allele can be detected. The sample can comprise a tissue sample or sputum. The tissue sample can comprise peripheral blood, airway or lung tissue.

[0047] The method can further comprise identifying the subject as a candidate for treatment with an IL33 antagonist or a combination of an IL33 antagonist and an IL-4R antagonist. Depending on the subject's risk classification as a risk score of 1, a risk score of 2, a risk score of 3, or a risk score of 4, the subject can benefit from a treatment regimen that suppresses eosinophilic asthma, eosinophilic COPD, eosinophilic ACOS, or a high-eosinophilic subtype thereof, or nasal polyps. The suppressive treatment regimen can include, for example, adjustments to the IL33 antagonist in terms of type, dose, frequency of administration, etc., and whether combined with an IL-4R antagonist, and if combined, including adjustments to the IL-4R antagonist in terms of type, dose, and frequency of administration, etc., depending on the level of risk.

[0048] The method can further comprise detecting an increased level of eosinophil count in blood or sputum isolated from the subject. Increased levels are those considered above normal levels or above levels typically observed in subjects with non-eosinophilic sub-classes of asthma, COPD, or ACOS. The method can further comprise isolating blood or sputum from the subject for this purpose.

[0049] The method can further comprise administering to the subject an IL33 antagonist or administering an IL33 antagonist and an IL-4R antagonist. Such administration can be in an amount effective to inhibit eosinophilic asthma, eosinophilic COPD, or eosinophilic ACOS, or a hyper-eosinophilic sub-class thereof. In some embodiments, the IL33 antagonist can comprise an IL33 trap. In some embodiments, the IL33 antagonist can comprise an antibody or antigen-binding fragment thereof that specifically binds to IL33. Suitable IL33 antagonists are described herein. In some embodiments, the IL-4R antagonist can comprise an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. Suitable IL-4R antagonists are described herein.

[0050] In a second aspect, the disclosure features a method of treating or inhibiting eosinophilic asthma in a subject in need thereof. The eosinophilic asthma can be a hypo-eosinophilic sub-class of eosinophilic asthma, or can be a hyper-eosinophilic sub-class of eosinophilic asthma.

[0051] In some embodiments, the method comprises administering to a subject having one or more risk alleles associated with eosinophilic asthma in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith, in the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith, or in both the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357) or a variant in linkage disequilibrium therewith and the IL33 variant rs1342326 (SEQ ID NO: 358) or a variant in linkage disequilibrium therewith, an IL33 antagonist or administering an IL33 antagonist and an IL-4R antagonist, such that eosinophilic asthma is treated or inhibited in the subject.

[0052] In some embodiments, the IL33 antagonist can comprise an IL33 trap. In some embodiments, the IL33 antagonist can comprise an antibody or antigen-binding fragment thereof that specifically binds IL33. Suitable IL33 antagonists are described herein. In some embodiments, the IL-4R antagonist can comprise an antibody or antigen-binding fragment thereof that specifically binds IL-4R. Suitable IL-4R antagonists are described herein.

[0053] In a third aspect, the disclosure features a method of treating or inhibiting eosinophilic COPD in a subject in need thereof. The eosinophilic COPD can be a low-eosinophilic subcategory of eosinophilic COPD, or can be a high-eosinophilic subcategory of eosinophilic COPD.

[0054] In some embodiments, the method comprises administering to a subject having one or more risk alleles associated with eosinophilic COPD in the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357), or a variant in linkage disequilibrium therewith, in the IL33 variant rs1342326 (SEQ ID NO: 358), or a variant in linkage disequilibrium therewith, or both the intronic IL1RL1 variant rs1420101 (SEQ ID NO: 357), or a variant in linkage disequilibrium therewith, and the IL33 variant rs1342326 (SEQ ID NO: 358), or a variant in linkage disequilibrium therewith, an IL33 antagonist or an IL33 antagonist and an IL-4R antagonist, such that eosinophilic COPD is treated or inhibited in the subject.

[0055] In some embodiments, the IL33 antagonist can comprise an IL33 trap. In some embodiments, the IL33 antagonist can comprise an antibody or antigen-binding fragment thereof that specifically binds IL33. Suitable IL33 antagonists are described herein. In some embodiments, the IL-4R antagonist can comprise an antibody or antigen-binding fragment thereof that specifically binds IL-4R. Suitable IL-4R antagonists are described herein.

[0056] In a fourth aspect, the disclosure features a method of treating or inhibiting eosinophilic ACOS in a subject in need thereof. The eosinophilic ACOS can be a low-eosinophilic subcategory of eosinophilic ACOS, or can be a high-eosinophilic subcategory of eosinophilic ACOS.

[0057] In some embodiments, the method includes administering an IL33 antagonist or an IL33 antagonist and an IL-4R antagonist to a subject who has one or more risk alleles associated with eosinophilic ACOS in either the intronic IL1RL1 variant rs1420101 (SEQ ID NO:357) or its linkage disequilibrium variant, the IL33 variant rs1342326 (SEQ ID NO:358) or its linkage disequilibrium variant, or both the intronic IL1RL1 variant rs1420101 (SEQ ID NO:357) or its linkage disequilibrium variant and the IL33 variant rs1342326 (SEQ ID NO:358) or its linkage disequilibrium variant, such that eosinophilic ACOS is treated or suppressed in the subject.

[0058] In some embodiments, the IL33 antagonist may comprise an IL33 trapping agent. In some embodiments, the IL33 antagonist may comprise an antibody that specifically binds to IL33 or an antigen-binding fragment thereof. Suitable IL33 antagonists are described herein. In some embodiments, the IL-4R antagonist may comprise an antibody that specifically binds to IL-4R or an antigen-binding fragment thereof. Suitable IL-4R antagonists are described herein.

[0059] In any of the methods described or illustrated herein, an IL33 antagonist may be administered as part of a treatment regimen. An IL33 antagonist may comprise any agent that inhibits the interaction of IL33 with one or more binding partners, and in the process inhibits IL33-mediated signaling. For example, an IL33 antagonist may bind to and / or interact with IL33, or with the IL33 receptor (called the “oncogenic suppressor gene” (aka ST2)), or with the IL33 co-receptor interleukin-1 receptor accessory protein (IL-1RAcP), or with a complex of any of the following: IL33 / ST2 or ST2 / IL-1RAcP.

[0060] Non-limiting examples of the IL33 antagonist class include small molecule IL33 inhibitors, or receptor antagonists, or nucleic acids that hybridize under stringent conditions to nucleic acid sequences encoding IL33 or IL33 receptors or co-receptors (e.g., short interfering RNA (siRNA) or clusters of regularly spaced short palindromic repeats of RNA (CRISPR-RNA or crRNA), including single-guide RNA (sgRNA) having both crRNA and tracrRNA sequences). Other IL33 antagonists include proteins containing a ligand-binding moiety of an IL33 receptor (e.g., ST2), IL33-binding scaffold molecules (e.g., DARPins, HEAT repeats, ARM repeats, tetrapeptide repeats, fibronectin-based scaffold constructs and other scaffolds based on naturally occurring repeats), and anti-IL33 aptamers or portions thereof.

[0061] In a preferred embodiment, the IL33 antagonist comprises an antibody that specifically binds to human IL33 (IL33 antibody) or an antigen-binding fragment thereof. Exemplary anti-IL33 antibodies used in the methods described herein are shown in Table 1. Anti-IL33 antibodies may comprise any antibody described in U.S. Patent No. 9,453,072, which is incorporated herein by reference in its entirety.

[0062] Table 1. Amino acid sequence identifiers of IL33 antibodies

[0063]

[0064] In some embodiments, the IL33 antagonist comprises an anti-IL33 antibody or an antigen-binding fragment thereof, which includes a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR) of the amino acid sequence of the anti-IL33 antibody as set forth in U.S. Patent No. 9,453,072 and Table 1 herein. In some embodiments, the IL33 antagonist comprises a heavy chain complementarity-determining region (CDR; e.g., H1, H2, H3) of the heavy chain variable region containing the amino acid sequence of SEQ ID NO:274 and a light chain CDR (e.g., L1, L2, L3) of the light chain variable region containing the amino acid sequence of SEQ ID NO:282. In some embodiments, H1 contains the amino acid sequence of SEQ ID NO:276, H2 contains the amino acid sequence of SEQ ID NO:278, and H3 contains the amino acid sequence of SEQ ID NO:280. In some embodiments, L1 comprises the amino acid sequence of SEQ ID NO:284, L2 comprises the amino acid sequence of SEQ ID NO:286, and L3 comprises the amino acid sequence of SEQ ID NO:288. In other embodiments, the anti-IL33 antibody or its antigen-binding fragment comprises HCVR containing SEQ ID NO:274 and LCVR containing SEQ ID NO:282.

[0065] In some embodiments, the IL33 antibody or its antigen-binding fragment comprises three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained in the amino acid sequence of the heavy chain variable region (HCVR) selected from the group consisting of: SEQ ID NO: 2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, and 308; and comprises three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained in the amino acid sequence of the light chain variable region (LCVR) selected from the group consisting of: SEQ ID NO: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, and 316.

[0066] In some embodiments, the anti-IL33 antibody or its antigen-binding fragment comprises an HCVR and LCVR (HCVR / LCVR) sequence pair of SEQ ID NO: 2 / 10, 18 / 26, 34 / 42, 50 / 58, 66 / 74, 82 / 90, 98 / 106, 114 / 122, 130 / 138, 146 / 154, 162 / 170, 178 / 186, 194 / 202, 210 / 218, 226 / 234, 242 / 250, 258 / 266, 274 / 282, 290 / 298 or 308 / 316.

[0067] In some embodiments, the anti-IL33 antibody or its antigen-binding fragment comprises: a heavy chain CDR1 (HCDR1) domain having an amino acid sequence selected from SEQ ID NO:4, 20, 36, 52, 68, 84, 100, 116, 132, 148, 164, 180, 196, 212, 228, 244, 260, 276, 292, and 310, or substantially similar sequences having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity; and a heavy chain CDR2 (HCDR2) domain having an amino acid sequence selected from SEQ ID NO:4, 20, 36, 52, 68, 84, 100, 116, 132, 148, 164, 180, 196, 212, 228, 244, 260, 276, 292, and 310. NO: 6, 22, 38, 54, 70, 86, 102, 118, 134, 150, 166, 182, 198, 214, 230, 246, 262, 278, 294, and 312, or substantially similar sequences having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity; a light chain CDR1 (LCDR1) domain having a sequence selected from SEQ ID SEQ ID NO: 12, 28, 44, 60, 76, 92, 108, 124, 140, 156, 172, 188, 204, 220, 236, 252, 268, 284, 300, and 318, or substantially similar sequences having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity; and a light chain CDR2 (LCDR2) domain having an amino acid sequence selected from SEQ ID NO: 14, 30, 46, 62, 78, 94, 110, 126, 142, 158, 174, 190, 206, 222, 238, 254, 270, 286, 302, and 320, or substantially similar sequences having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity.

[0068] In some preferred embodiments, the anti-IL33 antibody or its antigen-binding fragment respectively comprises an HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domain having an amino acid sequence selected from the group consisting of: SEQ ID NO: 4-6-8-12-14-16 (e.g., H1M9559N); 20-22-24-28-30-32 (e.g., H1M9566N); 36-38-40-44-46-48 (e.g., H1M9568N); 52-54-56-60-62-64 (e.g., H4H9629P); 68-70-72-76-78-80 (e.g., H4H9633P); 84-86-88-92-94-96 (e.g., ... H4H9640P); 100-102-104-108-110-112 (e.g., H4H9659P); 116-118-120-124-126-128 (e.g., H4H9660P); 132-134-136-140-142-144 (e.g., H4H9662P); 148-150-152-156-158-160 (e.g., H4H9663P); 164-166-168-172-1 74-176 (e.g., H4H9664P); 180-182-184-188-190-192 (e.g., H4H9665P); 196-198-200-204-206-208 (e.g., H4H9666P); 212-214-216-220-222-224 (e.g., H4H9667P); 228-230-232-236-238-240 (e.g., H4H9670P); 244-246 -248-252-254-256 (e.g., H4H9671P); 260-262-264-268-270-272 (e.g., H4H9672P); 276-278-280-284-286-288 (e.g., H4H9675P); 292-294-296-300-302-304 (e.g., H4H9676P); and 310-312-314-318-320-322 (H1M9565N).

[0069] In some embodiments, the anti-IL33 antibody or its antigen-binding fragment comprises heavy and light chain CDR domains contained within the heavy and light chain variable regions (HCVR / LCVR) sequences of SEQ ID NO:2 / 10, 18 / 26, 34 / 42, 50 / 58, 66 / 74, 82 / 90, 98 / 106, 114 / 122, 130 / 138, 146 / 154, 162 / 170, 178 / 186, 194 / 202, 210 / 218, 226 / 234, 242 / 250, 258 / 266, 274 / 282, 290 / 298, or 308 / 316. The boundaries of the CDRs can be defined according to the Kabat definition, the Chothia definition, or the AbM definition.

[0070] Other anti-IL33 antibodies and their antigen-binding fragments that can be used in the methods described herein are disclosed in European Publication Publication No. EP 1725261, PCT Publication Nos. WO 2011 / 031600, WO 2015 / 099175, WO 2015 / 106080(ANB020), WO2016 / 077381, WO 2016 / 077366 or WO2016 / 156440, U.S. Patent No. 8,187,596 and U.S. Publication No. 2016 / 0168242, each of which is incorporated herein by reference in its entirety.

[0071] In an alternative preferred embodiment, the IL33 antagonist comprises an IL33 scavenger. The IL33 scavenger comprises at least one IL33-binding domain, which includes the IL33-binding portion of an IL33 receptor protein named ST2. In some embodiments, the IL33 scavenger further comprises the extracellular portion of an IL33 co-receptor named IL-1 receptor accessory protein or IL-1RAcP. The IL33 scavenger may also comprise at least one polymerizing component that serves to link the various components of the scavenger together. The various components of the IL33 scavenger are described below, such as... Figure 1 As shown. IL33 capture agents may include any capture agents described in U.S. Publication No. 2014 / 0271642 and PCT Publication No. WO 2014 / 152195, each of which is incorporated herein by reference in its entirety.

[0072] The IL33 scavenger may comprise a first IL33-binding domain (D1) attached to a polymerizing domain (M). In some embodiments, the IL33 scavenger comprises a second IL33-binding domain (D2) attached to D1 and / or M. In some preferred embodiments, D1 comprises the IL33-binding portion of the ST2 protein. In some preferred embodiments, D2 comprises the extracellular portion of the IL-1RAcP protein.

[0073] The components of an IL33 trap can be arranged relative to each other in a variety of ways to produce a functional antagonist molecule capable of binding IL33. For example, D1 and / or D2 can be attached to the N-terminus of M. In some embodiments, D1 and / or D2 are attached to the C-terminus of M. In other embodiments, D1 is attached to the N-terminus of D2, and D2 is attached to the N-terminus of M, resulting in a linear fusion of the antagonist molecule from the N-terminus to the C-terminus, represented by the formula D1-D2-M. Other orientations of the components are discussed herein. Figure 1 Other places in the document are open to the public.

[0074] The IL33 trapping agent comprises at least one IL33-binding domain (sometimes referred to herein as "D" or "D1", "D2", etc.). In some embodiments, the IL33-binding domain comprises the IL33-binding portion of the ST2 protein. The IL33-binding portion of the ST2 protein may comprise or consist of the entire or partial extracellular domain of the ST2 protein. In a preferred embodiment, the ST2 protein is the human ST2 protein, comprising amino acids 1-556 of accession number NP_057316.3 (SEQ ID NO:352). In some alternative embodiments, the ST2 protein comprises an ST2 protein derived from a non-human species (e.g., mouse ST2, non-human primate ST2, etc.). A preferred IL33-binding portion of the ST2 protein is shown herein as the amino acid sequence of SEQ ID NO:328 (corresponding to the extracellular domain of human ST2 [K19-S328 of NCBI accession number NP_057316.3]). Other examples of the IL33-binding portion of the ST2 protein are shown in this paper as the amino acid sequence of SEQ ID NO:329 (corresponding to the extracellular domain of mouse ST2 [NCBI accession number P14719 S27-R332]).

[0075] In some embodiments, the IL33-binding domain of the trapping agent comprises the extracellular portion of the IL-1RAcP protein. In some embodiments, the IL-1RAcP protein comprises the human IL-1RAcP protein, including the IL-1RAcP protein having the amino acid sequence SEQ ID NO:353. In some alternative embodiments, the IL-1RAcP protein comprises the IL-1RAcP protein from a non-human species (e.g., mouse IL-1RAcP, non-human primate IL-1RAcP, etc.). An exemplary extracellular portion of the IL-1RAcP protein is shown herein as the amino acid sequence SEQ ID NO:330 (corresponding to the extracellular domain of human IL-1RAcP [NCBI accession number Q9NPH3, S21-E359]). Another example of the extracellular portion of the IL-1RAcP protein is shown herein as the amino acid sequence SEQ ID NO:331 (corresponding to the extracellular domain of mouse IL-1RAcP [NCBI accession number Q61730, S21-E359]).

[0076] Non-limiting examples of IL33 scavengers for use in this method are shown in Table 2, and include IL33 scavengers named “hST2-hFc”, “hST2-mFc”, “hST2-hIL1RAcP-mFc”, “hST2-hIL1RAcP-hFc”, and “mST2-mIL1RAcP-mFc”. These correspond to SEQ ID NO:323, 324, 325, 326, and 327, respectively. IL33 receptor-based scavengers may contain at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the same amino acid sequence as the exemplary IL33 receptor-based scavengers described herein (e.g., SEQ ID NO:323, 324, 325, 326, and 327). The IL33 trapping agent may comprise D1 and / or D2 components having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the amino acid sequence of any one of the exemplary IL33 binding domain components described herein (e.g., SEQ ID NO: 328, 329, 330, and 331).

[0077] Five different exemplary IL33 traps were constructed. The first IL33 antagonist (hST2-hFc, SEQ ID NO:323) comprises a soluble extracellular region of human ST2 (SEQ ID NO:328) fused at its C-terminus to the N-terminus of the human IgG1 Fc region (SEQ ID NO:332). The second IL33 antagonist (hST2-mFc, SEQ ID NO:324) consists of a soluble extracellular region of human ST2 (SEQ ID NO:328) fused at its C-terminus to the N-terminus of the mouse IgG2a Fc region (SEQ ID NO:333). The third IL33 antagonist (hST2-hIL1RAcP-mFc, SEQ ID NO:325) consists of a linear fusion having human ST2 (SEQ ID NO:328) at its N-terminus, followed by the extracellular region of human IL-1RAcP (SEQ ID NO:330), and then mouse IgG2a Fc (SEQ ID NO:333) at its C-terminus. The fourth IL33 antagonist (mST2-mIL1RAcP-mFc, SEQ ID NO:326) consists of a linear fusion having mouse ST2 (SEQ ID NO:329) at its N-terminus, followed by the extracellular region of mouse IL-1RAcP (SEQ ID NO:331), and then mouse IgG2a Fc (SEQ ID NO:333) at its C-terminus. The fifth IL33 antagonist (hST2-hIL1RAcP-hFc, SEQ ID NO:327) consists of a linear fusion of human ST2 (SEQ ID NO:328) at its N-terminus, followed by the extracellular region of human IL-1RAcP (SEQ ID NO:330), and then human IgG1 Fc (SEQ ID NO:332) at its C-terminus. See Table 2.

[0078] Table 2. Overview of IL33 antagonists and their components

[0079]

[0080] IL33 scavengers may contain at least one polymerizing domain (sometimes referred to herein by the abbreviations “M,” “M1,” “M2,” etc.). Generally, the polymerizing domain serves to link the various components of the IL33 antagonist (e.g., the IL33-binding domain) together. The polymerizing domain may contain any macromolecule capable of associating (covalently or non-covalently) with a second macromolecule of the same or similar structure or composition. For example, the polymerizing domain may contain a polypeptide containing the CH3 domain of an immunoglobulin. Non-limiting examples of polymerizing domains are the Fc portions of immunoglobulins, such as the Fc domains of isotypes IgG1, IgG2, IgG3, and IgG4, and any allotype of IgG within each isotype group.

[0081] Non-limiting exemplary polymerizable domains that can be used in IL33 scavengers include human IgG1 Fc (SEQ ID NO: 332) or mouse IgG2a Fc (SEQ ID NO: 333). The IL33 scavenger may comprise an M component having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the amino acid sequence of any one of the exemplary M components described herein (e.g., SEQ ID NO: 332 or 333).

[0082] In some embodiments, the IL33 scavenger comprises two polymerized domains, M1 and M2, wherein M1 and M2 are identical to each other. For example, M1 may be an Fc domain having a specific amino acid sequence, and M2 may be an Fc domain having the same amino acid sequence as M1. The various components of the IL33 antagonist (e.g., D1, D2, M, etc.) may be arranged in various ways. Non-limiting examples of all the above arrangements include examples of IL33 scavengers comprising two polymerized domains (M1 and M2) and four IL33-binding domains (D1, D2, D3, and D4). Figure 1 The illustration is provided in the text.

[0083] The components of the IL33 trap (e.g., D1, D2, M1, M2, etc.) can be directly attached to each other (e.g., D1 and / or D2 can be directly attached to M, etc.); alternatively, the components can be attached to each other through connector components (e.g., D1 and / or D2 can be attached to M through connectors oriented between the components; D1 can be attached to D2 through a connector; etc.).

[0084] Peptides that bind to IL33 and / or its receptors (ST2 and / or IL-1RAcP) and block ligand-receptor interactions are considered IL33 antagonists and are disclosed in PCT Publication No. WO2014 / 152195, which is incorporated herein by reference in its entirety. The biological characteristics of IL33 scavengers are described in U.S. Publication No. 2014 / 0271642, which is incorporated herein by reference in its entirety.

[0085] Other agents that can act as IL33 antagonists and can be used in the methods include immunoadhesins, peptides, and soluble ST2, or derivatives thereof; anti-IL33 receptor antibodies (e.g., anti-ST2 antibodies, such as AMG-282 (Amgen) or STLM15 (Janssen) or any anti-ST2 antibody described in PCT Publications WO 2012 / 113813, WO 2013 / 173761 and WO 2013 / 165894 and U.S. Patents 8,444,987 and 7,452,980, each of which is incorporated herein by reference in its entirety. Other IL33 antagonists include ST2-Fc proteins, such as those described in PCT Publications WO 2013 / 173761 and WO 2013 / 165894, each of which is incorporated herein by reference in its entirety.

[0086] In any of the methods described or illustrated herein, an IL-4R antagonist may be administered as part of a treatment regimen. The IL-4R antagonist is preferably administered in combination with an IL-33 antagonist, but simultaneous administration of the IL-4R antagonist with an IL-33 antagonist is not required. The IL-4R antagonist may comprise any agent that binds to or interacts with IL-4Rα or IL-4R ligands and inhibits or attenuates the normal biological signal transduction function of type 1 and / or type 2 IL-4 receptors. IL-4R may comprise the amino acid sequence of SEQ ID NO:347, or a biologically active fragment thereof. Type 1 IL-4 receptors are dimeric receptors comprising an IL-4Rα chain and a γc chain. Type 2 IL-4 receptors are dimeric receptors comprising an IL-4Rα chain and an IL-13Rα1 chain. Type 1 IL-4 receptors interact with and are stimulated by IL-4, while type 2 IL-4 receptors interact with and are stimulated by both IL-4 and IL-13. Therefore, the IL-4R antagonists used in the method can work by blocking IL-4-mediated signal transduction, IL-13-mediated signal transduction, or both IL-4 and IL-13-mediated signal transduction. Thus, IL-4R antagonists can inhibit or prevent the interaction of IL-4 and / or IL-13 with type 1 or type 2 receptors.

[0087] Non-limiting examples of the IL-4R antagonist class include small molecule IL-4R antagonists, nucleic acid-based inhibitors of IL-4R expression or activity (e.g., siRNA or antisense), peptide-based molecules that specifically interact with IL-4R (e.g., peptibody), "receptor-body" (e.g., engineered molecules containing ligand-binding domains of IL-4R components), IL-4R binding scaffold molecules (e.g., DARPins, HEAT repeats, ARM repeats, tetrapeptide repeats, fibronectin-based scaffold constructs and other scaffolds based on naturally occurring repeats, and anti-IL-4R aptamers or portions thereof).

[0088] In a preferred embodiment, the IL-4R antagonist comprises an antibody that specifically binds to human IL-4R. Antibodies are typically referred to herein according to the following nomenclature: an Fc prefix (e.g., “H1M” or “H4H”), followed by a numerical identifier (e.g., “9559”, “9566”, or “9629” as shown in Table 1), followed by a “P” or “N” suffix. According to this nomenclature, antibodies may be referred to herein as, for example, “H1M9559N”, “H1M9566N”, “H4H9629P”, etc. The H1M and H4H prefixes in antibody names used herein indicate a specific Fc region isotype of the antibody. For example, an “H1M” antibody has mouse IgG1 Fc, while an “H4H” antibody has human IgG4 Fc. Antibodies with a specific Fc isotype can be converted into antibodies with different Fc isotypes (e.g., an antibody with mouse IgG1 Fc can be converted into an antibody with human IgG4, etc.), but in any case, the variable domains (including CDRs) represented by the numerical identifiers shown in Table 1 will remain the same, and the binding properties are expected to be the same or substantially similar, regardless of the nature of the Fc.

[0089] In a preferred embodiment, the anti-IL-4R antibody is dupilumab. See U.S. Patent Nos. 7,605,237, 7,608,693, and 9,290,574, which are incorporated herein by reference.

[0090] Human anti-IL-4R antibodies can be produced as described in U.S. Patent No. 7,608,693. An exemplary IL-4R antibody is a mouse antibody specific to mouse IL-4R and has the following amino acid sequence: a heavy chain variable region (HCVR) comprising SEQ ID NO:335 and a light chain variable domain (LCVR) comprising SEQ ID NO:336. A human anti-IL-4R antibody called dupilumab specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising SEQ ID NO:337 and a light chain variable region (LCVR) comprising SEQ ID NO:338, a heavy chain complementarity-determining region 1 (HCDR1) comprising SEQ ID NO:339, HCDR2 comprising SEQ ID NO:340, HCDR3 comprising SEQ ID NO:341, a light chain complementarity-determining region 1 (LCDR1) comprising SEQ ID NO:342, LCDR2 comprising SEQ ID NO:343, and LCDR3 comprising SEQ ID NO:344. The full-length heavy chain of dupilumab is shown in SEQ ID NO:345, and the full-length light chain is shown in SEQ ID NO:346.

[0091] In some embodiments, the IL-4R antagonist comprises an anti-IL-4Rα antibody or an antigen-binding fragment thereof, which includes a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR) containing any amino acid sequence of an anti-IL-4R antibody as set forth in U.S. Patent Nos. 7,605,237 and 7,608,693. In some embodiments, the IL-4R antagonist comprises an anti-IL-4R antibody (U.S. Patent Nos. 7,605,237 and 7,608,693) having the binding characteristics of a reference antibody referred to herein as dupilumab. In some embodiments, the anti-IL-4Rα antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (HCDR) containing the heavy chain variable region (HCVR) of the amino acid sequence SEQ ID NO:337 and a light chain complementarity-determining region (LCDR) containing the light chain variable region (LCVR) of the amino acid sequence SEQ ID NO:338. In some embodiments, the anti-IL-4Rα antibody or its antigen-binding fragment comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:339; HCDR2 comprises the amino acid sequence of SEQ ID NO:340; HCDR3 comprises the amino acid sequence of SEQ ID NO:341; LCDR1 comprises the amino acid sequence of SEQ ID NO:342; LCDR2 comprises the amino acid sequence of SEQ ID NO:343; and LCDR3 comprises the amino acid sequence of SEQ ID NO:344. In other embodiments, the anti-IL-4R antibody or its antigen-binding fragment comprises an HCVR containing SEQ ID NO:337 and an LCVR containing SEQ ID NO:338. In other embodiments, the anti-IL-4R antibody or its antigen-binding fragment comprises an HCVR containing SEQ ID NO:335 and an LCVR containing SEQ ID NO:336. In some embodiments, the anti-IL-4R antibody or its antigen-binding fragment comprises a heavy chain (HC) amino acid sequence as shown in SEQ ID NO:345 and a light chain (LC) amino acid sequence as shown in SEQ ID NO:346.

[0092] In some embodiments, the IL-4R antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (HCDR) of a heavy chain variable region (HCVR) containing the amino acid sequence of SEQ ID NO:335 or SEQ ID NO:337 and a light chain complementarity-determining region (LCDR) of a light chain variable region (LCVR) containing the amino acid sequence of SEQ ID NO:336 or SEQ ID NO:338.

[0093] In some embodiments, the IL-4R antibody or its antigen-binding fragment comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO:339; HCDR2 comprises the amino acid sequence of SEQ ID NO:340; HCDR3 comprises the amino acid sequence of SEQ ID NO:341; LCDR1 comprises the amino acid sequence of SEQ ID NO:342; LCDR2 comprises the amino acid sequence of SEQ ID NO:343; and LCDR3 comprises the amino acid sequence of SEQ ID NO:344.

[0094] In some embodiments, the IL-4R antibody or its antigen-binding fragment used in the methods of this disclosure comprises an HCVR containing the amino acid sequence of SEQ ID NO:335 or SEQ ID NO:337 and an LCVR containing the amino acid sequence of SEQ ID NO:336 or SEQ ID NO:338.

[0095] In some embodiments, the IL-4R antibody or its antigen-binding fragment used in the methods of this disclosure comprises the HCVR / LCVR amino acid sequence pair of SEQ ID NO:335 / 336 or SEQ ID NOs:337 / 338.

[0096] Other anti-IL-4Rα antibodies include, for example, antibodies mentioned in the art and known as AMG317 (Corren et al., 2010, AmJ Respir Crit Care Med., 181(8):788-796) or MEDI 9314, or any of the anti-IL-4Rα antibodies described in any of the following U.S. patents: U.S. Patent Nos. 7,186,809, 7,605,237, 7,638,606, 8,092,804, 8,679,487, or 8,877,189.

[0097] Anti-IL-4Rα and anti-IL33 antibodies may exhibit pH-dependent binding characteristics. For example, compared to neutral pH, anti-IL-4Rα antibodies or anti-IL33 antibodies may show reduced binding to IL-4Rα or IL33, respectively, at acidic pH. Alternatively, compared to neutral pH, anti-IL-4Rα antibodies or anti-IL33 antibodies may show enhanced binding to their antigens at acidic pH. “Acidic pH” includes pH values ​​below about 6.2, such as about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0, or lower. "Neutral pH" includes pH from about 7.0 to about 7.4, as well as pH values ​​of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35 and 7.4.

[0098] On the other hand, IL33 antagonists, used alone or in combination with IL-4R antagonists, are used to treat or suppress lung inflammation. IL33 antagonists or combinations can be used to treat or suppress one or more of asthma, COPD, or ACOS. IL33 antagonists or combinations can be used to treat or suppress nasal polyps. This combination can be used to treat or suppress one or more of eosinophilic asthma, eosinophilic COPD, or eosinophilic ACOS. IL33 antagonists or combinations can be used to treat or suppress one or more of the hypereosinophilic subclass of eosinophilic asthma, eosinophilic COPD, or eosinophilic ACOS. The combination demonstrates enhanced efficacy compared to the therapeutic or inhibitory effects obtained when each antibody is used as a monotherapy.

[0099] In some implementations, an IL33 antagonist or a combination of an IL33 antagonist and an IL-4R antagonist is used to produce an agent for treating or inhibiting any of the following: eosinophilic asthma, eosinophilic chronic obstructive pulmonary disease (COPD), eosinophilic asthma-COPD overlap syndrome (ACOS), hypereosinophilic eosinophilic asthma, hypereosinophilic eosinophilic COPD, hypereosinophilic eosinophilic ACOS, or nasal polyps. In a preferred embodiment, the IL33 antagonist or combination is used to produce an agent in patients with the intronic IL1RL1 variant rs1420101 (SEQ ID NO:357) or its linkage-disequilibrium variant, the IL33 variant rs1342326 (SEQ ID NO:358) or its linkage-disequilibrium variant, or the intronic IL1RL1 variant rs1420101 (SEQ ID NO:357) or its linkage-disequilibrium variant and the IL33 variant rs1342326 (SEQ ID NO:358)... When either IDNO:358 or a linkage disequilibrium variant thereof has one or more risk alleles associated with eosinophilic asthma, eosinophilic COPD, or eosinophilic ACOS, the agent is used for such treatment or inhibition of any of the following: eosinophilic asthma, eosinophilic COPD, eosinophilic ACOS, hypereosinophilic eosinophilic asthma, hypereosinophilic eosinophilic COPD, hypereosinophilic eosinophilic ACOS, or nasal polyps.

[0100] According to such uses, IL33 antagonists may comprise an IL33 trapping agent. The IL33 trapping agent comprises a first IL33-binding domain and a second IL33-binding domain, the first IL33-binding domain comprising the IL33-binding portion of IL1RL1, and the second IL33-binding domain comprising the extracellular portion of IL-1RAcP. Alternatively, IL33 antagonists may comprise an antibody or antigen-binding fragment thereof that specifically binds to IL33. The antibody or antigen-binding fragment thereof that specifically binds to IL33 may comprise the H1, H2, and H3 domains of SEQ ID NO:274 and the L1, L2, and L3 domains of SEQ ID NO:282. IL-4R antagonists may comprise an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. The antibody or antigen-binding fragment thereof that specifically binds to IL-4R may comprise the H1, H2, and H3 domains of SEQ ID NO:337 and the L1, L2, and L3 domains of SEQ ID NO:338.

[0101] The following embodiments are provided to describe the invention in more detail. These embodiments are intended to illustrate, not limit, this disclosure.

[0102] Example 1

[0103] Anti-IL33 antibodies, anti-IL-4R antibodies, and combinations thereof in a chronic house dust mite-induced fibrosis and severe lung inflammation model.

[0104] Chronic inflammatory airway disease is the result of recurrent episodes of airway inflammation primarily caused by repeated exposure to allergens or other pathogens. In humans, this type of chronic damage induces a host of pathologies, including immune cell infiltration of the lungs, increased cytokine production, mucus production, and collagen deposition. This increase in inflammatory cytokines and immune cell infiltration is accompanied by intense airway remodeling, leading to airway narrowing, hyperresponsiveness to inhaled triggers such as allergens or pathogens, airway obstruction, and loss of lung function.

[0105] To determine the efficacy of anti-IL33 inhibition in relevant in vivo models, chronic house dust mite extract (HDM)-induced fibrosis, severe lung inflammation, and remodeling were studied in mice homozygous for human IL33 expression but not mouse IL33 (IL33 HumIn mice). See US Publications 2015 / 0320021 and 2015 / 0320022. Chronic exposure to HDM extract induces severe lung inflammation, leading to significant cellular infiltration, cytokine expression, and remodeling. The efficacy of anti-IL33 antibodies, anti-mouse IL-4R antibody α, or a combination of both was compared in this model. The anti-mouse IL-4R α antibody used in this study was named M1M1875N and contains the HCVR / LCVR amino acid sequence pair of SEQ ID NO:335 / 336. The anti-IL33 antibody used in this study was named H4H9675P and contains the HCVR / LCVR amino acid sequence pair of SEQ ID NO:274 / 282.

[0106] IL33 HumIn mice were intranasally administered 50 μg of house dust mite extract (HDM; Greer, #XPB70D3A2.5) diluted in 20 μL of 1X phosphate-buffered saline (PBS) or 20 μL of PBS, 3 days a week for 15 weeks. A second control group of IL33 HumIn mice was administered 50 μg of HDM extract diluted in 20 μL of 1X PBS, 3 days a week for 11 weeks to assess disease severity at the start of antibody treatment. Four groups of HDM-challenged mice began subcutaneous injections of 25 mg / kg of anti-IL33 antibody H4H9675P, anti-mouse IL-4Rα antibody M1M1875N, a combination of both antibodies, or an isotype control antibody 11 weeks after HDM challenge, followed by twice-weekly injections until the end of HDM challenge (4 weeks of antibody treatment). On day 108 of the study, all mice were sacrificed and their lungs harvested. Table 3 shows the experimental doses and treatment regimens for each group of mice.

[0107] Table 3. Experimental dosage and treatment regimen for mice in each group

[0108]

[0109]

[0110] Lung harvested for cytokine analysis. Elevated lung levels of key mediators such as the original type 2 cytokines IL-4, IL-5, and IL-13, as well as more type 1 immune response-specific cytokines such as IL-1β or TNFα, have been involved in the development of human lung diseases. Lung levels of these inflammatory cytokines were measured in this study.

[0111] After bleeding, the lateral and median lobes of the right lung from each mouse were removed and placed in tubes containing a solution of tissue protein extraction reagent (1X T-PER reagent; Pierce, #78510) supplemented with a 1X stop protease inhibitor mixture (Thermo Scientific, #87786). All other steps were performed on ice. The volume of T-PER reagent (containing the protease inhibitor mixture) was adjusted for each sample to match a 1:7 (w / v) tissue:T-PER ratio. Lung samples were mechanically lysed using a TissueLyser II (Qiagen #85300). The resulting lysates were centrifuged to precipitate debris. The supernatant containing soluble protein extracts was transferred to new tubes and stored at 4°C until further analysis.

[0112] Total protein content in lung protein extracts was measured using the Bradford assay. For this assay, 10 μL of diluted extract sample was plated twice into 96-well plates and mixed with 200 μL of 1X dye reagent (Biorad, #500-0006). Protein concentration of the extract was determined using a serially diluted buffer of bovine serum albumin (BSA; Sigma, #A7979) starting at 700 μg / mL in 1X T-Per reagent as a standard. After incubation at room temperature for 5 minutes, the extract was analyzed using Molecular Devices. Absorbance at 595 nm was measured using an M5 plate reader. A GraphPad Prism was used. TM The software performs data analysis based on the BSA standard to determine the total protein content of lung extracts.

[0113] Using the Proinflammatory Panel 1 (mouse) multiplex immunoassay kit (MesoScaleDiscovery, #K15048G-2) and custom-made 6plex MULTI mice... An immunoassay kit (MesoScaleDiscovery, #K152A41-4) was used to measure cytokine concentrations in lung protein extracts according to the manufacturer's instructions. Simply put, 50 μL / well of calibrator and sample (diluted in diluent 41) was added to a plate pre-coated with capture antibody and incubated at room temperature for 2 hours with shaking at 700 rpm. The plate was then treated with 0.05% (w / v) cytokine. Wash three times with 1X PBS containing -20 surfactant, then add 25 μL of the detection antibody solution diluted in diluent 45. Incubate at room temperature with shaking for 2 hours, then wash three times and add 150 μL of 2X Read buffer to each well. Immediately read the electrochemiluminescence on an MSD Spector instrument. Perform data analysis using GraphPad Prism software.

[0114] The concentrations of each cytokine in the total lung protein extract of all mice in each group were normalized to the total protein content of the extract as measured by the Bradford assay, and for each group, as shown in Table 4, they are expressed as the mean pg of cytokines per mg of total lung protein (pg / mg lung protein, ±SD).

[0115] Lung cytokine analysis. As shown in Table 4, the levels of cytokines and chemokines IL-4, IL-5, IL-6, IL-1β, and MCP-1 released in the lungs of IL33 HumIn mice treated with or without an allotype control antibody for 15 weeks after HDM treatment were significantly higher than those in IL33 HumIn mice challenged with 1X PBS alone. Similarly, there was a trend of increased release of cytokines IL-13 and TNFα in the lungs of IL33 HumIn mice treated with a combination of anti-IL33 antibody and anti-mouse IL-4Rα antibody during the long-term HDM challenge of the past four weeks were significantly lower in the lungs compared with IL33 HumIn mice treated with HDM and an allotype control antibody during the same period. IL33 HumIn mice treated with a combination of anti-IL33 antibody and anti-mouse IL-4Rα antibody during a prolonged HDM challenge of the past four weeks showed a trend toward decreased lung levels of IL-4, IL-5, IL-1β, and TNFα compared to IL33 HumIn mice treated with HDM and isotype control antibodies during the same period. The effects on lung cytokines observed with the combination of anti-IL33 antibody and anti-mouse IL-4Rα antibody were greater than those observed with treatment using a single antibody alone.

[0116] Table 4. Cytokine concentrations in lung protein extracts

[0117]

[0118]

[0119] Note: The statistical significance was indicated by Kruskal-Wallis one-way ANOVA and Dunn's multiple comparison post-hoc test (* = p < 0.05, ** = p < 0.01, compared to Group 1: IL33 HumIn mice, saline challenge; Compared to Group 4: IL33 Humin mice, challenged with HDM for 15 weeks + isotype control antibody). ND: Not determined.

[0120] Lung harvest for gene expression analysis. After bleeding, the accessory lobe of the right lung of each mouse was removed and placed in a tube containing 400 μL of RNA Later (Ambion, #AM7020) and stored at -20°C until processing. The tissue was homogenized in TRIzol and phased using chloroform. The total RNA isolation kit (Ambion, Life Technologies, #AM1839) was used according to the manufacturer's instructions using MagMAX microarray RNA isolation kit. TM -96°C purification of the aqueous phase containing total RNA. Use MagMAX kits from the MagMAX kits listed above. TM Turbo TM DNAse buffer and TURBO DNAse are used to remove genomic DNA. VILO TM The master mixture (Invitrogen, Life Technologies, #11755500) reverse transcribed mRNA (up to 2.5 μg) into cDNA. The cDNA was diluted to 2 ng / μL, and 10 ng of cDNA was then used... Gene expression master mixture (Applied Biosystems, Life Technologies, #4369542) and related probes (Life Technologies; mouse B2m: Mm00437762_m1; mouse Il4: Mm00445259_m1; mouse Il5: Mm00439646_m1; mouse Il13: Mm00434204_m1; mouse Il9: Mm00434305_m1; mouse Il6: Mm00446190_m1; mouse Ccl2: Mm00441242_m1; mouse Ccl11: Mm 00441238_m1; Mouse Ccl24: Mm00444701_m1; Mouse Tnf: Mm00443258_m1; Mouse Tgfb1: Mm01178820_m1; Mouse Il1rl1: Mm00516117_m1; Mouse Il13ra2: Mm00515166_m1; Mouse Col15a1: Mm00456584_m1; Mouse Col24a1: Mm01323744_m1;) Amplification was performed using an ABI 7900HT sequence detection system (Applied Biosystems). B2m was used as an internal control gene to normalize any differences in cDNA input. The reference group used to normalize all samples was the mean of the first group of samples ('1X PBS challenge'). The expression of each gene was normalized to the B2m expression in the same sample and expressed relative to its normalized expression in the reference group (mean ± SD), as shown in Table 5.

[0121] Lung gene expression analysis. As shown in Table 5, after 15 weeks of HDM treatment, the expression levels of cytokines, chemokines, and collagen genes Il4, Il13, Il6, Ccl2, Tgfb1, Il13ra2, and Col24a1 in the lungs of IL33 HumIn mice treated with or without isotype control antibodies were significantly increased compared to IL33 HumIn mice challenged with 1X PBS alone. Similarly, there was a trend of increased expression of genes Il5, Il9, Ccl11, Ccl24, Tnf, Il1rl1, and Col15a1 in the lungs of IL33 HumIn mice treated with HDM for 15 weeks.

[0122] Conversely, in IL33 HumIn mice treated with a combination of anti-IL33 antibody and anti-mouse IL-4Rα antibody during the past four weeks of prolonged HDM challenge, the expression levels of Il6, Ccl2, Ccl11, and Ccl24 in the lungs were significantly reduced compared to IL33 HumIn mice treated with HDM and isotype control antibody during the same period. In mice treated with the combination of anti-IL33 antibody and anti-mouse IL-4Rα antibody during the past four weeks of prolonged HDM challenge, there was a trend towards reduced expression levels of Il4, Il5, Il13, Il9, Tnf, Tgfb1, Il1rl1, Il13ra2, Col15a1, and Col24a1 compared to IL33 HumIn mice treated with HDM and isotype control antibody during the same period. The effect on gene expression observed with the combination of anti-IL33 antibody and anti-mouse IL-4Rα antibody was greater than that with treatment using a single antibody alone.

[0123] Table 5. Gene expression in mouse lungs (TaqMan).

[0124]

[0125]

[0126] Table 5 (continued): Gene expression in mouse lungs (TaqMan).

[0127]

[0128]

[0129] Note: The statistical significance was determined by Kruskal-Wallis one-way ANOVA and Dunn's multiple comparison post-hoc test (*=p<0.05, **=p<0.01, ***=p<0.01, compared to Group 1: IL33 HumIn mice, saline challenge; §p<0.05, §§ p<0.01, compared to group 3: IL33 Humin mice, HDM challenged for 15 weeks; Compared to Group 4: IL33 Humin mice, challenged with HDM for 15 weeks + isotype control antibody.

[0130] Lung harvested for analysis of pulmonary cell infiltration. Immune cell infiltration of the lungs has been observed in a variety of airway inflammatory diseases, including asthma and COPD. Neutrophilic lung inflammation has been associated with reduced lung function and severe tissue remodeling in asthmatic patients. Eosinophilic lung inflammation is a hallmark of type 2 inflammation commonly found in atopic diseases. In humans, a high CD4 / CD8 ratio has been observed in patients with granulomatous lung disease and other chronic inflammatory conditions. In this study, flow cytometry was used to determine the level of cellular infiltration in the lungs of mice exposed to HDM.

[0131] After bloodletting, the caudate lobe of the right lung of each mouse was removed, cut into cubes approximately 2 to 3 mm in size, and placed into tubes containing 20 μg / mL DNase (Roche, #10104159001) and 0.7 U / mL Liberase TH (Roche, #05401151001) diluted in Hanke Balanced Salt Solution (HBSS) (Gibco, #14025). The tubes were incubated in a 37°C water bath for 20 minutes, vortexed every 5 minutes. The reaction was terminated by adding EDTA (Gibco, #15575) to a final concentration of 10 mM. Each lung was then dissociated using a mild MACS dissociator (Miltenyi Biotec, #130-095-937), filtered through a 70 μm filter, and centrifuged. The resulting lung clumps were resuspended in 1 mL of 1X erythrocyte lysis buffer (Sigma, #R7757) to remove erythrocytes. After incubation at room temperature for 3 minutes, 3 mL of 1X DMEM was added to inactivate the erythrocyte lysis buffer. The cell suspension was then centrifuged, and the resulting cell clumps were resuspended in 5 mL of MACS buffer (autoMACS electrophoresis buffer; Miltenyi Biotec, #130-091-221). The resuspended sample was filtered through a 70 μm filter and plated at 1 x 10⁶ cells per well in a 96-well V-bottom plate. 6Cells were then centrifuged, and the clumps were washed in 1X PBS. After a second centrifugation, the cell clumps were resuspended in 100 μL of LIVE / DEAD fixed blue dead cell stain (Life Technologies, #L23105) diluted 1:500 in 1X PBS to determine cell viability and incubated at room temperature in the dark for 20 min. After washing once in 1X PBS, the cells were incubated at 4°C for 10 min in MACS buffer containing 10 μg / mL of purified rat anti-mouse CD16 / CD32 Fc Block (clone: ​​2.4G2; BD Biosciences, #553142). The cells were then incubated at 4°C in the dark for 30 min in an appropriate 2x antibody mixture diluted in MACS buffer (as described in Table 6). After antibody incubation, cells were washed twice in MACS buffer, resuspended in BDCytoFix (BD Biosciences, #554655), and then incubated at 4°C in the dark for 15 minutes. Cells were then washed again, resuspended in MACS buffer, and transferred to BD FACS tubes (BD Biosciences, #352235) for flow cytometry analysis of cell infiltrates.

[0132] CD4 and CD8 T cells are defined as live and CD45 T cells, respectively. + SSC Lo FSC Lo CD3 + CD19 - CD4 + CD8 - And live, CD45 + SSC Lo FSC Lo CD3 + CD19 - CD4 - CD8 + Cells. Activated CD4 T cells are defined as live, CD45-positive cells. + SSC Lo FSC Lo CD3 + CD19 - CD4 + CD8 - and CD69 + Cells. Activated CD8 T cells are defined as live, CD45+ cells. + SSC Lo FSC Lo CD3 + CD19 - CD4- CD8 + and CD69 + Cells. Activated B cells are defined as living, CD45-positive cells. + SSC Lo FSC Lo CD3-, CD19 + and CD69 + ST2+CD4+ T cells are defined as live, CD45+ cells. + SSC Lo FSC Lo CD3+, CD19-, ST2+ and CD4 + Cells. Eosinophils are defined as living, CD45-rich cells. + GR1 - CD11c lo SiglecF hi Alveolar macrophages are defined as living, CD45-positive cells. + GR1 - CD11c Hi SiglecF hi Data on activated cells are expressed as (CD4, ±SD) activated cells (CD69) within the parental population. + The frequency of ST2+CD4+ T cells. Data for ST2+CD4+ T cells are expressed as T cells (defined as live, CD45+). + SSC Lo FSC Lo The frequencies of CD3+ and CD19- cells are shown. Eosinophil and alveolar macrophage data are expressed as live cell frequencies. The CD4 / CD8 T cell ratio is calculated as the ratio of CD4 T cell frequency to CD8 T cell frequency in the live population. All data are shown in Table 7.

[0133] Table 6. Antibodies used for flow cytometry analysis

[0134]

[0135] Lung cellular infiltrate analysis. As shown in Table 7, the frequencies of eosinophils, activated B cells, activated CD8 cells, ST2+Cd4+ T cells, and the CD4 / CD8 T cell ratio in the lungs of IL33 HumIn mice treated with or without allotype control antibody for 15 weeks were significantly higher than those in IL33 HumIn mice challenged with 1X PBS alone. Similarly, there was a trend of increased frequency of activated CD4 T cells in the lungs of IL33 HumIn mice treated with HDM for 15 weeks. In the absence or presence of allotype control antibody treatment, there was a trend of decreased frequency of alveolar macrophages detected by flow cytometry in the lungs of IL33 HumIn mice treated with HDM for 15 weeks. In the lungs of IL33 HumIn mice treated with a combination of anti-IL33 antibody and anti-mouse IL-4Rα antibody during a prolonged HDM challenge of the past four weeks, the frequency of alveolar macrophages was significantly increased compared to IL33 HumIn mice treated with HDM and an isotype control antibody during the same period. Similarly, in the lungs of mice treated with a combination of anti-IL33 antibody and anti-mouse IL-4Rα antibody during a prolonged HDM challenge of the past four weeks, there was a trend towards decreased frequencies of eosinophils, activated CD4 and CD8 T cells, activated B cells, ST2+CD4+ T cells, and the CD4 / CD8 T cell ratio compared to IL33 HumIn mice treated with HDM and an isotype control antibody during the same period. The effects of the combination of anti-IL33 antibody and anti-mouse IL-4Rα antibody on the frequency of eosinophils, alveolar macrophages, activated CD8 T cells, ST2+CD4+ T cells, and the CD4 / CD8 ratio in the lungs showed a trend towards greater efficacy than treatment with a single antibody alone.

[0136] Table 7. Frequency of lung cell infiltrates as determined by flow cytometry

[0137]

[0138]

[0139] Note: The statistical significance was determined by Kruskal-Wallis one-way ANOVA and Dunn's multiple comparison post-hoc test (* = p < 0.05, ** = p < 0.01, compared to Group 1: IL33 HumIn mice, saline challenge; Compared to Group 4: IL33 Humin mice, challenged with HDM for 15 weeks + isotype control antibody.

[0140] Lung harvested for histopathological quantification. The inflammatory pattern observed in this model is accompanied by extensive and severe structural changes in the lungs exposed to HDM, with evidence of goblet cell metaplasia, increased subepithelial collagen deposition, and significant pulmonary consolidation. These pathologies are known features of human inflammatory respiratory diseases leading to decreased lung function and airway hyperresponsiveness.

[0141] After phlebotomy, the left lung was removed and placed in a plate containing 3 mL of 4% (w / v) paraformaldehyde (Boston Bioproducts, #BM-155) in 1X phosphate-buffered saline solution, and stored at room temperature for 3 days. The lung sample was then aspirated and transferred to a tube containing 70% ethanol for histological analysis. The sample was sent to Histoserv, Inc. (Germantown, MD) for paraffin embedding, sectioning, and staining with periodic acid Schiff (PAS) or hematoxylin and eosin (H&E).

[0142] Quantification of goblet cell metaplasia. Goblet cell metaplasia and excessive mucus secretion are hallmarks of many lung diseases, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Excessive mucus production leads to airway obstruction and affects several important outcomes in humans, such as lung function, health-related quality of life, deterioration, hospitalization, and mortality. Counts of PAS-positive goblet cells and total epithelial cells in millimeters of main bronchial epithelium. Goblet cell metaplasia is expressed as the frequency (%, ± SD) of PAS-positive cells per millimeter of bronchial epithelium, as shown in Table 8.

[0143] Quantification of pulmonary consolidation. Pulmonary consolidation includes the accumulation of solid or liquid material in the alveolar spaces. Pulmonary consolidation is a complex endpoint that may reflect a combination of cellular infiltration, proliferation, and mucus production, and is used here as a gross pathological measurement. The fraction of lung area occupied by the crystalline body was quantified using ImageJ software (NIH, Bethesda, MD) on paraffin-embedded lung sections stained with Movat pentachrome. The total lung area and the combined area in the sections were measured using particle analysis. The fraction of the combined lung area was given by the ratio of the two measurements, as shown in Table 8.

[0144] Quantification of subepithelial fibrosis. Subepithelial fibrosis involves excessive interstitial collagen deposition in the subepithelial space of the lungs. Increased subepithelial fibrosis has been reported to be clearly associated with asthma in humans. In this model, subepithelial fibrosis was measured using HaLo software (Indica Labs, NM) on paraffin-embedded lung sections stained with Masson's trichrome. The thickness of the collagen layer under the bronchial epithelium was recorded multiple times at approximately 30 μm intervals along the main bronchus, using the Layer thickness tool. Subepithelial fibrosis is expressed as the mean thickness (μm, ±SD) of the collagen layer under the epithelium, as shown in Table 8.

[0145] Lung histopathological analysis. As shown in Table 9, compared with IL33 HumIn mice challenged with 1X PBS alone, there was a trend of increased goblet cell metaplasia in the lungs of IL33 HumIn mice treated with or without isotype control antibodies after 15 weeks of HDM treatment. Similarly, lung consolidation and subepithelial collagen thickness were significantly increased in IL33 HumIn mice treated with HDM for 15 weeks.

[0146] Conversely, IL33 HumIn mice treated with a combination of anti-IL33 and anti-mouse IL-4Rα antibodies during a prolonged four-week HDM challenge showed a trend toward reduced goblet cell metaplasia, subepithelial collagen thickness, and significantly reduced pulmonary consolidation compared to IL33 HumIn mice treated with HDM and isotype control antibodies during the same period. The effects of the anti-IL33 and anti-mouse IL-4Rα antibody combination on goblet cell metaplasia, pulmonary consolidation, and subepithelial collagen thickness showed a trend toward greater efficacy than single-antibody treatment alone.

[0147] Table 8. Quantification of histopathology in mouse lungs

[0148]

[0149] Note: Statistical significance was determined by Kruskal-Wallis one-way ANOVA and Dunn's multiple comparison post-hoc test (** = p < 0.01, compared to Group 1: IL33 HumIn mice, saline challenge).

[0150] Serum collection for IgE and HDM-specific IgG1 level measurement. To determine the total IgE concentration in serum samples from each mouse, a sandwich ELISA OPTEIA kit (BD Biosciences, #555248) was used according to the manufacturer's instructions. Serum samples were diluted and incubated with anti-IgE capture antibody coated on 96-well plates. Total IgE was detected using biotinylated anti-mouse IgE secondary antibody. Purified horseradish peroxidase (HRP)-labeled mouse IgE was used as a standard. HRP activity was detected using the chromophore 3,3',5,5'-tetramethylbenzidine (TMB) (BD OPTEIA substrate kit, BD, #555214). A stop solution of 1M sulfuric acid was then added, and absorbance was measured at 450 nm on a Molecular Devices SpectraMax M5 reader. Prism was used. TM The software was used for data analysis. The mean level of circulating IgE in serum of each experimental group was expressed as ng / mL (±SD), as shown in Table 9.

[0151] To determine HDM-specific IgG1 levels in serum samples from each mouse, an ELISA was used. HDM (Greer, #XPB70D3A2.5) coated plates were incubated with serially diluted mouse serum samples, followed by incubation with rat anti-mouse IgG1-HRP conjugate antibody (BD Biosciences, #559626). All samples were developed with TMB solution and analyzed as described above. Relative levels of circulating IgG1 in serum are expressed in titer units (titer units are calculated by multiplying the measured OD by the dilution factor required to reach OD450 twice the background). The mean circulating HDM-specific IgG1 level in serum from each experimental group is expressed as titer x 10⁻¹⁰. 6 (±SD), as shown in Table 9.

[0152] Analysis of circulating levels of IgE and HDM-specific IgG1. As shown in Table 9, compared with IL33 HumIn mice challenged with 1X PBS alone, the circulating IgE level in the serum of IL33 HumIn mice treated with or without allotype control antibodies was significantly increased after 15 weeks of HDM treatment. Similarly, there was a trend of increased circulating HDM-specific IgG1 levels in the serum of IL33 HumIn mice treated with a combination of anti-IL33 antibody and anti-mouse IL-4Rα antibody during the long-term HDM challenge period of the past four weeks, compared with IL33 HumIn mice treated with HDM and allotype control antibodies, showed a significant decrease in circulating IgE levels and a trend of decreased circulating HDM-specific IgG1 levels.

[0153] Table 9. Circulating levels of IgE and HDM-specific IgG1 in mouse serum.

[0154]

[0155]

[0156] Note: The statistical significance determined by Kruskal-Wallis one-way ANOVA and Dunn's multiple comparison post-hoc test is indicated (*=p<0.05, **=p<0.01, ***=p<0.001, compared to Group 1: IL33 HumIn mice, saline challenge; Compared to Group 4: IL33 Humin mice, challenged with HDM for 15 weeks + isotype control antibody). ND: Not determined.

[0157] In cases of severe mixed inflammation, the combination of H4H9675P and anti-mIL-4Rα therapy improved all measured inflammatory parameters, reducing most to baseline levels. Furthermore, an additive effect was observed on some of the most detrimental endpoints, including complex lung gross pathology, goblet cell metaplasia, pulmonary cell infiltration, and cytokine levels. Therefore, simultaneous blockade of both pathways has the potential to affect multiple inflammatory mediators and normalize multiple parameters to baseline in cases of severe mixed inflammation and histopathology.

[0158] Example 2

[0159] Genetic variants of IL33 and its receptor are associated with eosinophilic asthma and COPD.

[0160] In this embodiment, the relationship between previously identified asthma risk variants at IL33 and IL1RL1 and the risk of asthma, COPD, and ACOS was examined within the largest combined set of such cases that had been aggregated, with genetic data linked to electronic health records. The importance of these variants for eosinophilic subtypes of asthma, COPD, and ACOS, as well as for related upper respiratory tract diseases such as nasal polyps, was examined. Additionally, the association between predicted loss-of-function variants (pLOFs) at IL1RL1 and IL33 and these diseases was evaluated.

[0161] Supervision of human genetics research. The human genetics research is part of the DiscovEHR study at the Regeneron Genetics Center (RGC) and Geisinger Health System (GHS).

[0162] DiscovEHR participants and disease definition. At the time of this study, the DiscovEHR study included GHS. Community Health Initiative ( A total of 92,323 adults were recruited by the Community Health Initiative of the GHS. For this study, 86,004 and 83,339 individuals of European descent had phenotypic and exome sequencing and genotypic data, respectively, for analysis. Participants were recruited from outpatient primary care and specialist clinics. Eosinophil counts and disease diagnostic codes (International Classification of Diseases, Ninth Revision [ICD-9]) were extracted from the EHR, which included medians from 14 years of clinical care. Median eosinophil count measurements recorded by the EHR were whole blood counts after removing possible spurious values ​​that differed from the intra-individual median by >3 standard deviations. Case status was assigned based on ICD-9 codes if at least one of the following criteria was met: (1) a question list entry for the diagnostic code; or (2) a separate diagnostic code entered for two separate clinical visits on separate calendar days. Individuals were assigned one or more of the three case categories (asthma, COPD, and ACOS) based on the ICD-9 diagnostic code.

[0163] Control patients in all binary trait analyses were defined as individuals without a single ICD-9 diagnostic code for asthma or COPD.

[0164] Sequencing and genotyping. Sample preparation and whole-exome sequencing are performed. In short, exome capture is performed using NimbleGen probes (Roche, SeqCap VCRome) or Integrated DNA Technologies probes (IDT, xGEN Exome Research Group), along with other features recommended by the respective manufacturers. The captured DNA is amplified by PCR and quantified by qRT-PCR (Kapa Biosystems). Multiplexed samples are sequenced using 75bp paired-end sequencing on an Illumina v4 HiSeq 2500 or HiSeq X sequencer, achieving coverage depth sufficient to provide over 85% target base haplotype read depths greater than 20x in 96% of the samples (approximately 80x the average target base haplotype read depth). Raw sequence data from each Illumina HiSeq 2500 run are uploaded to the DNAnexus platform for read alignment and variant identification. Raw sequence data were converted from BCL files to sample-specific FASTQ files, which were then aligned with the human reference construct GRCh38 using BWA-mem. Single nucleotide variants (SNVs) and indel sequence variants were identified using the Genome Analysis Toolkit. Samples with a genotypic rate below 10% were excluded. For the final analysis, exome data were available for 59,082 and 29,504 individuals of European descent, respectively, captured using the VCRome xGEN probe set.

[0165] Genotyping of DNA aliquots was performed using either the Human OmniExpress exome microbead array or the Global Screening Array (Illumina Corp.). For the final analysis, chip data were available for 56,239 and 28,500 individuals of European descent, respectively, determined on the Omni and GSA microbead arrays.

[0166] Study Design and Statistical Analysis. The associations of two previously identified asthma risk variants (IL33 (rs1342326) and IL1RL1 (rs1420101)) with obstructive pulmonary disease, other airway disorders, and circulating eosinophil count were evaluated using OMNI and GSA microarray data. In an additive model, the associations of PLINK or R (including age as a covariate) were analyzed. 2The association between these variants and the disease was tested using logistic regression (the first four main components: sex, smoking status, and ancestry). Eosinophil counts recorded at median EHR were log-transformed and their association with genotype was tested using a linear (PLINK, R) model controlling for the same covariates as described above under an additive genetic model. All p-values ​​correspond to the additive genetic model. Summary statistics from analyses on both platforms were combined via meta-analysis.

[0167] Within the same statistical framework, exome data were used to identify associations between pLOF variants clustered within IL1RL1 or IL33 and outcomes of obstructive pulmonary disease and eosinophil counts. At each gene, individuals were coded as 0 if they did not carry any pLOF, and as 1 if they were heterozygous carriers of at least one pLOF; homozygous pLOF carriers of IL1RL1 or IL33 were not observed in this study. Summary statistics from analyses on both platforms were combined via meta-analysis.

[0168] Genetic risk scores, reflecting the sum of risk alleles for two independent variants (IL33 (rs1342326) and IL1RL1 (rs1420101)), were also modeled using logistic and linear regression, with the same covariates described above used as predictors of obstructive pulmonary disease outcomes and eosinophil counts. Individuals lacking genotypic data for either or both variants were excluded. The effects of carrying one, two, three, or four risk alleles were assessed individually relative to individuals not carrying any of the risk alleles in either variant. The trend between increased scores and increased eosinophil count or disease risk was tested using linear regression and the Cochran-Armitage test, respectively.

[0169] All statistical analyses were performed using PLINK software (v1.90p) or R version 3.2.1.

[0170] The previously identified asthma risk variants in IL33 and IL1RL1 were confirmed using DiscovEHR eosinophil counts and the EHR-defined asthma. Figure 8 The DiscovEHR study is described in Clinical characteristics of participants. Of the 86,004 patients of European descent who underwent exome sequencing in this study, 13,267 (15.4%) were diagnosed with asthma, 9,783 (11.4%) with COPD, and 2,993 (3.4%) with both asthma and COPD (referred here as asthma-COPD overlap syndrome, or ACOS). Of the 83,339 patients of European descent for whom microarray data was available in this study, 12,832 (15.4%) were diagnosed with asthma, 9,536 (11.4%) with COPD, and 2,909 (3.5%) with ACOS.

[0171] The first major GWAS study on asthma identified an intronic IL1RL1 variant (rs1420101) associated with asthma and circulating eosinophil count, and a subsequent GWAS identified an upstream IL33 variant (rs1342326) associated with asthma. In this study, rs1420101 (IL1RL1) and rs1342326 (IL33) were associated with asthma (meta-allelic ratio (OR)). 等位基因 The results were confirmed (95% confidence interval) at 1.07 (1.04-1.11), P = 8.2 x 10⁻⁶. -7 and Meta-OR 等位基因 1.09(1.05-1.16), P = 6.0 x 10 -6 ()( Figure 3 ).

[0172] In addition, both variants were associated with lifetime median circulating eosinophil counts (n = 66,776 individuals) (Meta-β = 0.0066 (0.0054–0.0079) eos / ml, respectively, P = 2.0 x 10⁻⁶). -23 Meta-β = 0.0061 (0.0045–0.0078) eos / ml, P = 2.0 x 10⁻⁶ -13 .

[0173] The association between IL33 and IL1RL1 and asthma is specific to the eosinophilic subclass. Eosinophilic asthma is considered an important subclass of asthma and appears to be associated with increased asthma severity and steroid resistance, as well as differential responsiveness to biologics. Having already confirmed the association between previously described IL33 and IL1RL1 variants and eosinophil counts and asthma independently assessed as different phenotypes, this study next assessed whether these risks are linked through a specific association with the eosinophilic subclass of asthma, and thus evaluated the association in asthma patient subgroups stratified by high (>200 eos / μL) and low (≤200 eos / μL) median lifetime eosinophil counts. Figure 3 The IL33 (rs1342326) and IL1RL1 (rs1420101) variants were significantly associated only with the eosinophilic asthma subclass (for IL33, the allele ratio was 1.12 (1.06–1.18) in the high eosinophil group and 1.04 (0.98–1.09) in the low eosinophil group; for IL1RL1, the allele ratio was 1.07 (1.04–1.1) in the high eosinophil group and 1.02 (0.98–1.06) in the low eosinophil group). Figure 3 ).

[0174] Novel associations have been found between asthma risk variants in IL33 and IL1RL1 and increased risk of COPD and ACOS, particularly in the eosinophilic subclass. In addition to the aforementioned associations with eosinophilic asthma, further studies have been found between IL33 (rs1342326) and IL1RL1 (rs1420101) variants and COPD ( Figure 4 For IL33, Meta OR 等位基因 =1.04(0.99–1.09), P=8.9x10 -2 And for IL1RL1, Meta-OR 等位基因 =1.04(1–1.07), P=3.9x10 -2 ) and ACOS Figure 5 For IL33, Meta OR 等位基因 1.08 (1.0–1.16), P = 3.8 x 10 -2 And for IL1RL1, 1.06 (1.0–1.12), P = 4.8 x 10⁻⁶. -2 It has a suggestive or slightly significant association.

[0175] Similar to asthma, eosinophilic subclasses of COPD and ACOS are associated with more severe disease. To determine whether the associations of IL33 and IL1RL1 with COPD and ACOS are also eosinophilic subclass specific, as we have seen in asthma, the association between IL33 (rs1342326) and IL1RL1 (rs1420101) in COPD and ACOS subgroups stratified by high (>200 eos / μL) and low (≤200 eos / μL) median lifetime eosinophil counts was assessed. Figure 4 and Figure 5 Both variants were suggestively associated with COPD and ACOS only in disease subgroups characterized by high circulating eosinophil counts.

[0176] Higher risk allele loads in the IL33 signaling pathway were associated with a greater risk of asthma, COPD, and ACOS. Because IL33 and IL1RL1 are part of the same signaling complex, and because these variants exhibit a clear allele-dose dependence in their risk associations when analyzed individually, a dual-variant genetic risk score (ranging from 0 to 4 per individual) was constructed by summing the number of risk alleles at IL33 (rs1342326) and IL1RL1 (rs1420101), and the association between this score and eosinophil count and the risk of asthma, COPD, and ACOS was examined. Individual groups carrying each genetic risk score were compared to groups with zero-risk alleles. In a trend test, increasingly higher genetic risk scores were associated with increasingly higher eosinophil counts ( Figure 2 P = 1 x 10 -39 ) and increasingly high rates of asthma ( Figure 6 P = 3.27 x 10 -12 COPD Figure 6 P = 6.65 x 10 -3 ) and ACOS(P=4.3x10 -3 The risk was significantly associated. The largest effect (exceeding nominal significance) was observed in patients carrying all three risk alleles. Figure 2 For eosinophil count, Metaβ = 0.0071 (0.0057-0.0085) eos / ml, P = 8.8 x 10⁻⁶. -24 For asthma ( Figure 6 ), Meta OR=1.28(1.17–1.41), P=6.99x10 -8 For COPD ( Figure 6 ), OR=1.17(1.04–1.31), P=9.35x10 -3 ); and for ACOS ( Figure 6), OR=1.23(1.03–1.48), P=2.49x10 -2 ( Figure 2 Almost no individuals carry all four risk alleles, therefore the effect size estimate has a wide confidence interval.

[0177] The association between the dual variant score and subgroups of patients with high and low eosinophil counts was also assessed. Figure 7 In the trend test, the score was correlated with asthma (P = 1.37 x 10⁻⁶). -15 COPD (P = 3.9 x 10⁻⁶) -8 ) and ACOS(P=1.8x10 -5 The high eosinophilic subclass was significantly associated with asthma, COPD, or ACOS, but not with the low eosinophilic subclass (P>0.05 for each disease). The largest score-specific effect was observed in patients carrying all three risk alleles (Meta-OR = 1.61 (1.42–1.84) for high eosinophilic asthma, P = 6.33 x 10⁻⁶). -13 For hypereosinophilic COPD, the meta-OR was 1.53 (1.31–1.79), with a p-value of 4.76 x 10⁻⁶. -8 For eosinophilic ACOS, OR = 1.7 (1.34–2.14), P = 1 x 10⁻⁶. -5 As mentioned earlier, there are relatively few individuals carrying four risk alleles, and the corresponding effect size estimates have wide confidence intervals.

[0178] Predicted loss-of-function (pLOF) variants of IL33 are associated with reduced circulating eosinophil counts and the risk of obstructive pulmonary disease. In the analysis of the IL33 pLOF variant rs146597587, IL33 inactivation was associated with decreased eosinophil counts (Meta-β = -0.02 (-0.03 -0.0092, P = 7.3 x 10⁻⁶)). -5 However, it was not significantly associated with a reduced risk of eosinophilic asthma, COPD, and ACOS (OR = 0.82 (0.63–1.07), P = 0.15; OR = 0.99 (0.74–1.33), P = 0.94; and OR = 0.93 (0.56–1.53), P = 0.76, respectively). Figure 7 The IL1RL1 pLOF variant is not associated with the risk of obstructive lung disease.

[0179] Analysis of IL1RL1 variants rs1420101 and IL33 variant rs1342326 with other airway diseases. The unified airway theory posits that asthma may co-occur with other airway diseases due to shared mechanisms. Therefore, the association between rs1420101 and rs1342326 and airway diseases recorded in other EHRs was tested. Figure 9 IL33 variant rs1342326 and IL1RL1 variant rs1420101 were associated with an increased risk of allergic rhinitis (Meta-OR 1.04 (1.01–1.08), P = 0.02; Meta-OR 1.04 (1.01–1.06), P = 2.4 x 10⁻⁶). -3 And an increased risk of nasal polyps (Meta-OR 1.48 (1.28-1.72), P = 1.2 x 10⁻⁶). -7 , Meta-OR 1.17(1.04-1.33), P=1.2x10 -2 Related to this. Furthermore, the burden of these common risk variants also significantly increased the risk of allergic rhinitis and nasal polyps (P = 1.45 x 10⁻⁶). -4 P = 2.48 x 10 -7 These results are consistent with previous reports, suggesting a common genetic variant of IL33 in the risk of nasal polyps.

[0180] In summary, IL33 is believed to be involved in barrier defense in epithelial tissues, including the lung epithelium, and has been implicated in the pathogenesis of asthma. The two variants of IL33 (rs1342326) and IL1RL1 (rs1420101) described in this example have been previously associated with asthma in several studies. These reproducible independent associations with the ligand (IL33) and its specific receptor (IL1R1) (IL33 is located on chromosome 9; IL1RL1 is located on chromosome 2) suggest a role in IL33 signaling in asthma risk.

[0181] The current study significantly expands upon previous findings. Through whole-exome sequencing and genotyping of over 83,000 adult participants in the DiscovEHR study, associations between IL33 and IL1RL1 and eosinophil counts, as well as asthma assessed independently as distinct phenotypes, were confirmed. Furthermore, suggestive associations between IL33 and IL1RL1 variants and increased risk of COPD and ACOS were demonstrated—providing a genetic link supporting the possibility of a common mechanistic etiology among all three very common lung diseases. Associations of these variants with nasal polyps and allergic rhinitis were also demonstrated. Additionally, a greater impact on disease risk was observed in individuals carrying a larger load of these risk alleles at both loci. Moreover, heterozygous carriers of rare pLOF variants in IL33 showed a trend toward lower median lifetime eosinophil counts and a reduction in asthma risk of approximately 20%. These data are believed to provide genetic evidence linking the IL33 pathway to asthma and possibly COPD through allele series, which include common alleles that increase risk and rare pLOF alleles that decrease risk.

[0182] Prior to this study, it is believed that no genetic variants in the IL33 pathway had previously been associated with COPD. Similarly, it is believed that no previous genetic data linked any pathway to the risk of eosinophilic subtypes of asthma, COPD, and ACOS. The results of this example demonstrate an association between enhanced IL33 signaling and an increased risk of eosinophilic subtypes of asthma and COPD, and the numerically higher risk association observed in ACOS patients suggests that this entity at the crossroads of these conditions may indeed be distinctive. In addition to providing a unified genetic and mechanistic link between previously labeled eosinophilic subtypes of obstructive pulmonary disease, this data also supports the principle of the “unified airway theory,” which presupposes that eosinophilic lung disease may represent a continuum with associated upper respiratory tract diseases. In this regard, a significantly increased risk for IL33 variants was observed in allergic rhinitis and nasal polyps.

[0183] Although not statistically significant, the protective association with the IL33 pLOF variants described in this embodiment is consistent with recent studies demonstrating the protective effect of rare loss-of-function variants of IL33 in asthma, supporting the possibility that inhibiting IL33 signaling may be an important therapeutic strategy for obstructive pulmonary diseases. These data particularly demonstrate the role of interleukin-33 blockade in eosinophilic forms of obstructive pulmonary diseases such as asthma and COPD, and in eosinophilic upper respiratory tract diseases such as allergic rhinitis and nasal polyps.

[0184] Relatedly, recent advances in biologics for the treatment of severe and steroid-resistant asthma appear to differentiate eosinophilic disorders. Various therapies targeting interleukin-5 and interleukin-13 appear to benefit only the eosinophilic subclass in asthma patients, while antibodies blocking the interleukin-4 and interleukin-13 pathways (dupixumab) show numerically greater benefit in eosinophilic patients, but also appear to have potent activity in the low eosinophilic subclass. These therapies also appear to benefit nasal polyps and allergic rhinitis. Consistent with these previously described differences in response to biologic therapies in eosinophilic asthma patients, data from this example suggest that interleukin-33 blockade may best target the eosinophilic subclass in asthma, ACOS, and COPD.

[0185] While this study has certain limitations, it still represents a real-world clinical care setting, and in this population, genetic variants of IL33 and IL1RL1 are associated with an increased risk of diagnosis for both asthma and COPD. For personalized treatment of patients, obtaining a diagnostic label for asthma, COPD, or ACOS may be less important than identifying the mechanistic pathology occurring in a particular patient or patient group, and these data suggest that subclasses of patients with asthma, COPD, and ACOS may be partially driven by excessive IL33 activity. Mitigating the various limitations of these data is the remarkable consistency of findings using genetic variants within two different genes in the same pathway—parallel results were observed for variants in the IL33 gene and its receptor. Consistent risk associations were observed for variants in both genes across multiple relevant EHR-defined disease settings, and consistent results specific to the eosinophilic subclass of these diseases were repeatedly noted within these settings. Another compelling aspect of the data involves the consistent and significant allelic dependence of most risk associations, and the additional power derived from dual-variant risk score analysis. Finally, the corresponding findings with the IL33 pLOF variant also provide support.

[0186] These data suggest that genetic variants that enhance IL33 signaling contribute to an increased risk of eosinophilic forms of asthma, COPD, and ACOS, while pLOF genetic variants in IL33 may help reduce the risk of these diseases; the risk of upper respiratory tract diseases such as nasal polyps also appears to be associated with IL33 signaling. Individuals carrying genetic variants that enhance IL33 signaling represent an opportunity for precision medicine, as those with specific asthma and COPD conditions may benefit most from therapeutic blockade of IL33. This data also increases the likelihood that patients with eosinophilic airway diseases (regardless of subtype and variant status) may benefit from IL33 inhibition.

[0187] This disclosure is not limited to the embodiments described and illustrated above, but is open to changes and modifications within the scope of the appended claims. U.S. Application No. 15 / 827,357, filed November 30, 2017, is incorporated herein by reference in its entirety for all purposes. sequence list <110> Regeneron Pharmaceuticals, Inc. <120> Treatment and suppression of inflammatory lung disease in patients with risk alleles in genes encoding IL33 and IL1RL1 <130> 189238.01102 (3022) <150> US 62 / 485,077 <151> 2017-04-13 <160> 358 <170> FastSEQ for Windows version 4.0 <210> 1 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 1 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cgtctggatt caccttcagt agttatggca tgcattgggt ccgccaggct 120 ccaggcaagg ggctggagtg ggtggcagtt atatggtatg atggaagaaa taaatactat 180 acagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatgg acagcctgag agccgaggac acggctgtgt attactgtgc gagagagagg 300 tatatcagca gctattatgg ggggttcgac ccctggggcc agggagccct ggtcaccgtc 360 tcctca 366 <210> 2 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 2 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 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 Arg Asn Lys Tyr Tyr Thr 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 Asp Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Tyr Ile Ser Ser Tyr Tyr Gly Gly Phe Asp Pro Trp 100 105 110 Gly Gln Gly Ala Leu Val Thr Val Ser Ser 115 120 <210> 3 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 3 ggattcacct tcagtagtta tggc 24 <210> 4 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 4 Gly Phe Thr Phe Ser Ser Tyr Gly 1 5 <210> 5 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 5 atatggtatg atggaagaaa taaa 24 <210> 6 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 6 Ile Trp Tyr Asp Gly Arg Asn Lys 1 5 <210> 7 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 7 gcgagagaga ggtatatcag cagctattat ggggggttcg acccc 45 <210> 8 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 8 Ala Arg Glu Arg Tyr Ile Ser Ser Tyr Tyr Gly Gly Phe Asp Pro 1 5 10 15 <210> 9 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 9 gacatccaga tgacccagtc tccatcctcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtattagt agttggttag cctggtatca gcagaaacca 120 gggaaagccc ctaaggtcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttacta ttgtcaacag gctaacagtt tcccattcac tttcggccct 300 gggaccaaac tggatatcaa g 321 <210> 10 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 10 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val 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 Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Leu Asp Ile Lys 100 105 <210> 11 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 11 cagggtatta gtagttgg 18 <210> 12 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 12 Gln Gly Ile Ser Ser Trp 1 5 <210> 13 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 13 gctgcatcc 9 <210> 14 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 14 Ala Ala Ser 1 <210> 15 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 15 caacaggcta acagtttccc attcact 27 <210> 16 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 16 Gln Gln Ala Asn Ser Phe Pro Phe Thr 1 5 <210> 17 <211> 357 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 17 gaggtgcagc tgttggagtc tgggggagac ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagc agctatgcca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagtt attagtggta gtggaagtag cacagactac 180 gcagactccg tgaagggccg gttcaccatt tccagagaca attccaggga cacgctgcat 240 ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaaacgttc 300 tactacttct acggtttgga cgtctggggc caagggacca cggtcaccgt ctcctca 357 <210> 18 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 18 Glu Val Gln Leu Leu Glu Ser Gly Gly Asp 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 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Ser Gly Ser Gly Ser Ser Thr Asp Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Arg Asp Thr Leu His 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 Thr Phe Tyr Tyr Phe Tyr Gly Leu Asp Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115 <210> 19 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 19 ggattcacct tcagcagcta tgcc 24 <210> 20 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 20 Gly Phe Thr Phe Ser Ser Tyr Ala 1 5 <210> twenty one <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> twenty one attagtggta gtggaagtag caca 24 <210> twenty two <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> twenty two Ile Ser Gly Ser Gly Ser Ser Thr 1 5 <210> twenty three <211> 36 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> twenty three gcgaaaacgt tctactactt ctacggtttg gacgtc 36 <210> twenty four <211> 12 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> twenty four Ala Lys Thr Phe Tyr Tyr Phe Tyr Gly Leu Asp Val 1 5 10 <210> 25 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 25 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctttaagaga cagagtcacc 60 atcacttgcc gggcgagtca gggcattagc aattatttag cctggtatca gcagaaacca 120 gggaaagttc ctaaggtcct aatctatgct gcatccactt tgcaatcagg ggtcccatct 180 cggttcagtg gcagtggatc tgggacagtt ttcactctca ccatcagcag cctgcagact 240 gaagatgttg caacttatta ctgtcaaaag tatagcagtg ccccattcac tttcggccct 300 gggaccaaag tggatatcaa a 321 <210> 26 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 26 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Arg 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 Val 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 Val Phe Thr Leu Thr Ile Ser Ser Leu Gln Thr 65 70 75 80 Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Ser Ser Ala Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 <210> 27 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 27 cagggcatta gcaattat 18 <210> 28 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 28 Gln Gly Ile Ser Asn Tyr 1 5 <210> 29 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 29 gctgcatcc 9 <210> 30 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 30 Ala Ala Ser 1 <210> 31 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 31 caaaagtata gcagtgcccc attcact 27 <210> 32 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 32 Gln Lys Tyr Ser Ser Ala Pro Phe Thr 1 5 <210> 33 <211> 351 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 33 caggtgcttc tggtacagtc tggggctgag gtgaagaagc ctggggccac agtgaaggtc 60 tcctgcaagg cttctggatc cactttcacc ggctactata tgcactgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcaacccta acaatggtgg cacaaactat 180 gcacagaagt ttcagggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240 atggaattga gcaggctgag atctgacgac acggccgtat attactgtgc gagagagttg 300 cggtataact ggaagtcctg gggccaggga accctggtca ccgtctcctc a 351 <210> 34 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 34 Gln Val Leu Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Thr Val Lys Val Ser Cys Lys Ala Ser Gly Ser 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 Asn 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 Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Leu Arg Tyr Asn Trp Lys Ser Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 35 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 35 ggatccactt tcaccggcta ctat 24 <210> 36 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 36 Gly Ser Thr Phe Thr Gly Tyr Tyr 1 5 <210> 37 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 37 atcaacccta acaatggtgg caca 24 <210> 38 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 38 Ile Asn Pro Asn Asn Gly Gly Thr 1 5 <210> 39 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 39 gcgagagagt tgcggtataa ctggaagtcc 30 <210> 40 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 40 Ala Arg Glu Leu Arg Tyr Asn Trp Lys Ser 1 5 10 <210> 41 <211> 324 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 41 gaaattgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagtcacc 60 ctctcctgca gggccagtca gagtgttggc aggccctact tagcctggta ccaacagata 120 cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tgacatccca 180 gacaggttca gtggcaatgg gtctgggaca gacttcactc tcaccatcag tagactggag 240 cctgaagatt ttgcagtgta ttactgtcag cagtatgata attcccctta tacttttggc 300 caggggacca ggctggagat caaa 324 <210> 42 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 42 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Val Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Gly Arg Pro 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Ile Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Asp Ile Pro Asp Arg Phe Ser 50 55 60 Gly Asn 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 Asp Asn Ser Pro 85 90 95 Tyr Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 43 <211> twenty one <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 43 cagagtgttg gcaggcccta c 21 <210> 44 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 44 Gln Ser Val Gly Arg Pro Tyr 1 5 <210> 45 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 45 ggtgcatcc 9 <210> 46 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 46 Gly Ala Ser 1 <210> 47 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 47 cagcagtatg ataattcccc ttatact 27 <210> 48 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 48 Gln Gln Tyr Asp Asn Ser Pro Tyr Thr 1 5 <210> 49 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 49 gaggtgcagc tggtggagtc tgggggaggc ttggtacaac ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacctttaga agctttgcca tgagctgggt ccgccaggct 120 ccagggaagg ggctggaatt ggtctcagat ctcaggacta gtggtggtag tacatactac 180 gcagactccg tgaagggccg gctcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaaagccac 300 tatagcacca gctggttcgg gggctttgac tactggggcc agggaaccct ggtcactgtc 360 tcctca 366 <210> 50 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 50 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 Arg Ser Phe 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ser Asp Leu Arg Thr Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Leu 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 Ser His Tyr Ser Thr Ser Trp Phe Gly Gly Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 51 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 51 ggattcacct ttagaagctt tgcc 24 <210> 52 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 52 Gly Phe Thr Phe Arg Ser Phe Ala 1 5 <210> 53 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 53 ctcaggacta gtggtggtag taca 24 <210> 54 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 54 Leu Arg Thr Ser Gly Gly Ser Thr 1 5 <210> 55 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 55 gcgaaaagcc actatagcac cagctggttc gggggctttg actac 45 <210> 56 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 56 Ala Lys Ser His Tyr Ser Thr Ser Trp Phe Gly Gly Phe Asp Tyr 1 5 10 15 <210> 57 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthetic<​​​​​​​​aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcaccaa cctgcagcct 240 gaagattttg caacttacta ttgtcaacag gctaacagtt tccctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 58 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 58 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Phe 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 Thr Asn Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 59 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 59 cagggtttta gcagctgg 18 <210> 60 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 60 Gln Gly Phe Ser Ser Trp 1 5 <210> 61 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 61 gctgcatcc 9 <210> 62 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 62 Ala Ala Ser 1 <210> 63 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 63 caacaggcta acagtttccc tctcact 27 <210> 64 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 64 Gln Gln Ala Asn Ser Phe Pro Leu Thr 1 5 <210> 65 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 65 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacgtttagc agctatgtca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcaagt attagtggta atggtggtag cacaaactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgttt 240 ctggaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaatcactg 300 ggaactacca cgactttttt ggggtttgac tattggggcc agggaaccct ggtcaccgtc 360 tcctca 366 <210> 66 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 66 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 Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Gly Asn Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Leu Gly Thr Thr Thr Thr Phe Leu Gly Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 67 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 67 ggattcacgt ttagcagcta tgtc 24 <210> 68 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 68 Gly Phe Thr Phe Ser Ser Tyr Val 1 5 <210> 69 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 69 attagtggta atggtggtag caca 24 <210> 70 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 70 Ile Ser Gly Asn Gly Gly Ser Thr 1 5 <210> 71 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 71 gcgaaatcac tgggaactac cacgactttt ttggggtttg actat 45 <210> 72 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 72 Ala Lys Ser Leu Gly Thr Thr Thr Thr Phe Leu Gly Phe Asp Tyr 1 5 10 15 <210> 73 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 73 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaacca 120 gggaaagccc ctaaactcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacatat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttacta ttgtcaacag gctaacagtt tccctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 74 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 74 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Tyr 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 Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 75 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 75 cagggtatta gcagctgg 18 <210> 76 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 76 Gln Gly Ile Ser Ser Trp 1 5 <210> 77 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 77 gctgcatcc 9 <210> 78 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 78 Ala Ala Ser 1 <210> 79 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 79 caacaggcta acagtttccc tctcact 27 <210> 80 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 80 Gln Gln Ala Asn Ser Phe Pro Leu Thr 1 5 <210> 81 <211> 363 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 81 caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60 acctgcactg tctctggtgg ctccatcagt agttattact ggagctggat ccggcagccc 120 ccagggaagg gactggagtt gattgggtat atttattaca gtgggagcac caattataac 180 ccctccctca agagtcgagt caccatatct gtagacacgt ccaagaacca cttctccctg 240 aagctgagct ctgtgaccgc tgcggacacg gccgtatatt actgtgcgag atcccagtat 300 accagtagtt ggtacggttc ttttgatatc tggggccaag ggacaatggt caccgtctct 360 tca 363 <210> 82 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <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 Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Tyr 20 25 30 Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Leu Ile 35 40 45 Gly Tyr Ile Tyr Tyr 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 His 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 Ser Gln Tyr Thr Ser Ser Trp Tyr Gly Ser Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 83 <211> 24 <212> DNA <213> Artificial Sequence(Artificial Sequence) <220> <223> synthesis <400> 83 ggtggctcca tcagtagtta ttac 24 <210> 84 <211> 8 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> synthesis <400> 84 Gly Gly Ser Ile Ser Ser Tyr Tyr 1 5 <210> 85 <211> twenty one <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 85 atttattaca gtgggagcac c 21 <210> 86 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 86 Ile Tyr Tyr Ser Gly Ser Thr 1 5 <210> 87 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 87 gcgagatccc agtataccag tagttggtac ggttcttttg atatc 45 <210> 88 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 88 Ala Arg Ser Gln Tyr Thr Ser Ser Trp Tyr Gly Ser Phe Asp Ile 1 5 10 15 <210> 89 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 89 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtattagc acctggttag cctggtttca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccactt tacaaggtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggccagaa ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttacta ttgtcaacag gctaacagtt tcccgtggac gttcggccaa 300 gggaccaagg tggaaatcaa a 321 <210> 90 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 90 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Thr Trp 20 25 30 Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Gln Gly Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Pro 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 Ala Asn Ser Phe Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 91 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 91 cagggtatta gcacctgg 18 <210> 92 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 92 Gln Gly Ile Ser Thr Trp 1 5 <210> 93 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 93 gctgcatcc 9 <210> 94 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 94 Ala Ala Ser 1 <210> 95 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 95 caacaggcta acagtttccc gtggacg 27 <210> 96 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 96 Gln Gln Ala Asn Ser Phe Pro Trp Thr 1 5 <210> 97 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 97 caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cctctggtta cacctttaac agctatggta tcagctgggt gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcagctccc acaatggtaa cagtcactat 180 gtacagaagt tccagggcag agtctccatg accacagaca catccacgag tacagcctac 240 atggaactga ggagccttag atctgacgac acggccgtgt attactgtgc gagacactcg 300 tataccacca gctggtacgg gggttttgac tattggggcc agggaaccct ggtcaccgtc 360 tcctca 366 <210> 98 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 98 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 Asn 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 Ser His Asn Gly Asn Ser His Tyr Val Gln Lys Phe 50 55 60 Gln Gly Arg Val Ser 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 His Ser Tyr Thr Thr Ser Trp Tyr Gly Gly Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 99 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 99 ggttacacct ttaacagcta tggt 24 <210> 100 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 100 Gly Tyr Thr Phe Asn Ser Tyr Gly 1 5 <210> 101 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 101 atcagctccc acaatggtaa cagt 24 <210> 102 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 102 Ile Ser Ser His Asn Gly Asn Ser 1 5 <210> 103 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 103 gcgagacact cgtataccac cagctggtac gggggttttg actat 45 <210> 104 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 104 Ala Arg His Ser Tyr Thr Thr Ser Trp Tyr Gly Gly Phe Asp Tyr 1 5 10 15 <210> 105 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 105 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggttttagc agctggttag cctggtatca gcagaaacca 120 gggaaagccc ctcagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggtcagat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttacta ttgtcaacag gctaacagtt tccctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 106 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 106 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Phe Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Gln 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 Ser 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 Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 107 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 107 cagggtttta gcagctgg 18 <210> 108 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 108 Gln Gly Phe Ser Ser Trp 1 5 <210> 109 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 109 gctgcatcc 9 <210> 110 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 110 Ala Ala Ser 1 <210> 111 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 111 caacaggcta acagtttccc tctcact 27 <210> 112 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 112 Gln Gln Ala Asn Ser Phe Pro Leu Thr 1 5 <210> 113 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 113 gaggtgcagc tggtggagtc cgggggaggc ttggttcagc cggggggggtc cctgagactc 60 tcctgtgcag cctctggaat caccttgagc agctatggca tgagctgggt ccgccaggct 120 ccagggaagg gactggagtg ggtcgcatcc atttttggta gtggtggtgg cccatactac 180 gcagactccg tgaagggccg gttcaccatg tccagagaca attccaagaa cacgctgtat 240 ttgcaaatga acagcctgag agccgaggac acggccgtat attattgtgc gaaagatcga 300 tacagtggga gctactacgg aggttttgac tactggggcc ggggaaccct ggtcaccgtc 360 tcctca 366 <210> 114 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 114 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 Ile Thr Leu Ser Ser Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ser Ile Phe Gly Ser Gly Gly Gly Pro Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Met 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 Asp Arg Tyr Ser Gly Ser Tyr Tyr Gly Gly Phe Asp Tyr Trp 100 105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 115 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 115 ggaatcacct tgagcagcta tggc 24 <210> 116 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 116 Gly Ile Thr Leu Ser Ser Tyr Gly 1 5 <210> 117 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 117 atttttggta gtggtggtgg ccca 24 <210> 118 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 118 Ile Phe Gly Ser Gly Gly Gly Pro 1 5 <210> 119 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 119 gcgaaagatc gatacagtgg gagctactac ggaggttttg actac 45 <210> 120 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 120 Ala Lys Asp Arg Tyr Ser Gly Ser Tyr Tyr Gly Gly Phe Asp Tyr 1 5 10 15 <210> 121 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 121 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtattacc agctggttag cctggtatca gcagaaacca 120 gggaaagccc ctacactcct gatctatgct gcatccagtt tgcaaactgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaacattttg caacttacta ttgtcaacag gctaacagtt tccctcctac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 122 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 122 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Thr Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Thr Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Thr 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 His Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Pro 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 123 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 123 cagggtatta ccagctgg 18 <210> 124 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 124 Gln Gly Ile Thr Ser Trp 1 5 <210> 125 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 125 gctgcatcc 9 <210> 126 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 126 Ala Ala Ser 1 <210> 127 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 127 caacaggcta acagtttccc tcctact 27 <210> 128 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 128 Gln Gln Ala Asn Ser Phe Pro Pro Thr 1 5 <210> 129 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 129 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctaagactc 60 tcctgtgcag cctctggatt cacctttagc agttatgcct tgacctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctctttt attagtggta gtggtggtag gccattctac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa catgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggccatat attactgtgc gaagtccctg 300 tataccacca gctggtacgg ggggttcgac tcctggggcc agggaaccct ggtcaccgtc 360 tcctca 366 <210> 130 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 130 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 Ala Leu Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Phe Ile Ser Gly Ser Gly Gly Arg Pro Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Met Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Lys Ser Leu Tyr Thr Thr Ser Trp Tyr Gly Gly Phe Asp Ser Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 131 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 131 ggattcacct ttagcagtta tgcc 24 <210> 132 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 132 Gly Phe Thr Phe Ser Ser Tyr Ala 1 5 <210> 133 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 133 attagtggta gtggtggtag gcca 24 <210> 134 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 134 Ile Ser Gly Ser Gly Gly Arg Pro 1 5 <210> 135 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 135 gcgaagtccc tgtataccac cagctggtac ggggggttcg actcc 45 <210> 136 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 136 Ala Lys Ser Leu Tyr Thr Thr Ser Trp Tyr Gly Gly Phe Asp Ser 1 5 10 15 <210> 137 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 137 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtgtcgtc agctggttag cctggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttatta ttgtcaacag tctaacagtt tccctttcac tctcggccct 300 gggaccaaag tggatatcaa a 321 <210> 138 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 138 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Val Val 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 Ser Asn Ser Phe Pro Phe 85 90 95 Thr Leu Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 <210> 139 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 139 cagggtgtcg tcagctgg 18 <210> 140 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 140 Gln Gly Val Val Ser Trp 1 5 <210> 141 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 141 gctgcatcc 9 <210> 142 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 142 Ala Ala Ser 1 <210> 143 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 143 caacagtcta acagtttccc tttc 24 <210> 144 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 144 Gln Gln Ser Asn Ser Phe Pro Phe 1 5 <210> 145 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 145 caggtgcagc tggtgcagtc tggggctgaa gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctggata caccttcacc ggccactata tgtactggat gcgacaggcc 120 cctggacaag ggcttgagtg gatgggatgg atcaacccta acagtggtgg cacaaactat 180 gcacagaagt ttcaggacag ggtcaccatg accagggaca cgtccatcag cacagcctac 240 atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagggaga 300 tatggcagta gctggtacgg ggggtttgag tactggggcc agggaaccct ggtcaccgtc 360 tcctca 366 <210> 146 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 146 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 His 20 25 30 Tyr Met Tyr Trp Met 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 Asp 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 Tyr Cys 85 90 95 Ala Arg Gly Arg Tyr Gly Ser Ser Trp Tyr Gly Gly Phe Glu Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 147 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 147 ggatacacct tcaccggcca ctat 24 <210> 148 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 148 Gly Tyr Thr Phe Thr Gly His Tyr 1 5 <210> 149 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 149 atcaacccta acagtggtgg caca 24 <210> 150 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 150 Ile Asn Pro Asn Ser Gly Gly Thr 1 5 <210> 151 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 151 gcgagaggga gatatggcag tagctggtac ggggggtttg agtac 45 <210> 152 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 152 Ala Arg Gly Arg Tyr Gly Ser Ser Trp Tyr Gly Gly Phe Glu Tyr 1 5 10 15 <210> 153 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 153 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgttggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtattacc agctggttag cctggtatca gcagaaacca 120 gggaaagccc ctaacctcct gatctatgct gcagccagtt tacaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacggat ttcactctca ccatcagcag cctgcagcct 240 gaagacttta caacttacta ttgtcaacag gcttacagtc tccctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 154 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 154 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Thr Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn Leu Leu Ile 35 40 45 Tyr Ala Ala Ala 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 Thr Thr Tyr Tyr Cys Gln Gln Ala Tyr Ser Leu Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 155 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 155 cagggtatta ccagctgg 18 <210> 156 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 156 Gln Gly Ile Thr Ser Trp 1 5 <210> 157 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 157 gctgcagcc 9 <210> 158 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 158 Ala Ala Ala 1 <210> 159 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 159 caacaggctt acagtctccc tctcact 27 <210> 160 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 160 Gln Gln Ala Tyr Ser Leu Pro Leu Thr 1 5 <210> 161 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 161 caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt agctatggct tgcactgggt ccgccagtct 120 ccaggcaagg ggctggaatg ggtggcactt atatcatatg acggaagtaa taaatactat 180 gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag acctgaggac acggctggat atttctgtgc gaaatcccta 300 tatacaacca gctggtacgg gggctttgac tattggggcc agggaaccct ggtcaccgtc 360 tcctca 366 <210> 162 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 162 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 Ser Tyr 20 25 30 Gly Leu His Trp Val Arg Gln Ser Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Leu Ile 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 Pro Glu Asp Thr Ala Gly Tyr Phe Cys 85 90 95 Ala Lys Ser Leu Tyr Thr Thr Ser Trp Tyr Gly Gly Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 163 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 163 ggattcacct tcagtagcta tggc 24 <210> 164 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 164 Gly Phe Thr Phe Ser Ser Tyr Gly 1 5 <210> 165 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 165 atatcatatg acggaagtaa taaa 24 <210> 166 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 166 Ile Ser Tyr Asp Gly Ser Asn Lys 1 5 <210> 167 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 167 gcgaaatccc tatatacaac cagctggtac gggggctttg actat 45 <210> 168 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 168 Ala Lys Ser Leu Tyr Thr Thr Ser Trp Tyr Gly Gly Phe Asp Tyr 1 5 10 15 <210> 169 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 169 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtattaga agctggttag cctggtatca gcaaaaacca 120 gggaaagccc ctaacctcct gatctatgct gcgtccagtt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttacta ttgtcaacag gctaacagtt tccctcccac tttcggccct 300 gggaccaaag tggatatcaa a 321 <210> 170 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 170 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn 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 Pro 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 <210> 171 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 171 cagggtatta gaagctgg 18 <210> 172 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 172 Gln Gly Ile Arg Ser Trp 1 5 <210> 173 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 173 gctgcgtcc 9 <210> 174 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 174 Ala Ala Ser 1 <210> 175 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 175 caacaggcta acagtttccc tcccact 27 <210> 176 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 176 Gln Gln Ala Asn Ser Phe Pro Pro Thr 1 5 <210> 177 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 177 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctgggtt caccttcagc aactatgcca tgacctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcaact atcagtggca gtggtgataa cacatactac 180 gcagactccg tgcagggccg gttcaccatc tccagaggcc attccaagaa cacgctgtat 240 ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaacctacg 300 tatagcagaa gctggtacgg tgcttttgat ttctggggcc aagggacaat ggtcaccgtc 360 tcttca 366 <210> 178 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 178 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 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Ile Ser Gly Ser Gly Asp Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Gln Gly Arg Phe Thr Ile Ser Arg Gly His 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 Pro Thr Tyr Ser Arg Ser Trp Tyr Gly Ala Phe Asp Phe Trp 100 105 110 Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 179 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 179 gggttcacct tcagcaacta tgcc 24 <210> 180 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 180 Gly Phe Thr Phe Ser Asn Tyr Ala 1 5 <210> 181 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 181 atcagtggca gtggtgataa caca 24 <210> 182 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 182 Ile Ser Gly Ser Gly Asp Asn Thr 1 5 <210> 183 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 183 gcgaaaccta cgtatagcag aagctggtac ggtgcttttg atttc 45 <210> 184 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 184 Ala Lys Pro Thr Tyr Ser Arg Ser Trp Tyr Gly Ala Phe Asp Phe 1 5 10 15 <210> 185 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 185 gacatccaga tgacccagtc tccatcctcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtattagc agctggttag cctggtatca gcagaaaccg 120 gggaaagccc ctcaactcct gatctatgct gcatccagat tgcaaagtgg ggtcccatca 180 aggttctggg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttacta ttgtcaacag gctaacaatt tcccattcac tttcggccct 300 gggaccaaag tggatatcaa a 321 <210> 186 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 186 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Gln Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Trp 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 Asn Phe Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 <210> 187 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 187 cagggtatta gcagctgg 18 <210> 188 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 188 Gln Gly Ile Ser Ser Trp 1 5 <210> 189 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 189 gctgcatcc 9 <210> 190 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 190 Ala Ala Ser 1 <210> 191 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 191 caacaggcta acaatttccc attcact 27 <210> 192 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 192 Gln Gln Ala Asn Asn Phe Pro Phe Thr 1 5 <210> 193 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 193 caggttcagc tggtgcagtc tggagctgag gtgaagaagc ctggggcctc agtgaaggtc 60 tcctgcaagg cttctggtta cacctttacc agttatggta tcagctgggt gcgacaggcc 120 cctggacaag gccttgagtg gatgggatgg atccgcgctt acaatggtta cacaaactat 180 gcacagaagt ttcagggcag agtcaccatg accacagaca catccacgaa caccgcctac 240 atggagctga ggaccctgaa ttctgacgat acggccgttt attactgtgc gagagatcga 300 tatagtggga gcttccacgg taactttgac tactggggcc agggaaccct ggtcaccgtc 360 tcctca 366 <210> 194 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 194 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 Arg Ala Tyr Asn Gly Tyr Thr Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Thr Leu Asn Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Tyr Ser Gly Ser Phe His Gly Asn Phe Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 195 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 195 ggttacacct ttaccagtta tggt 24 <210> 196 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 196 Gly Tyr Thr Phe Thr Ser Tyr Gly 1 5 <210> 197 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 197 atccgcgctt acaatggtta caca 24 <210> 198 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 198 Ile Arg Ala Tyr Asn Gly Tyr Thr 1 5 <210> 199 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 199 gcgagagatc gatatagtgg gagcttccac ggtaactttg actac 45 <210> 200 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 200 Ala Arg Asp Arg Tyr Ser Gly Ser Phe His Gly Asn Phe Asp Tyr 1 5 10 15 <210> 201 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 201 gacatccaga tgacccagtc tccatcttcc gtgtctgcgt ctgtaggaga cagagtgacc 60 atcacttgtc gggcgagtca gggtattttc agctggttag cctggtatca gcagaaacca 120 gggaaagccc ctaaggtcct aatctatgct gcatccaatt tggaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttacta ttgtcaacag gctaacagtt taccgctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 202 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 202 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Phe Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35 40 45 Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Leu Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 203 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 203 cagggtattt tcagctgg 18 <210> 204 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 204 Gln Gly Ile Phe Ser Trp 1 5 <210> 205 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 205 gctgcatcc 9 <210> 206 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 206 Ala Ala Ser 1 <210> 207 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 207 caacaggcta acagtttacc gctcact 27 <210> 208 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 208 Gln Gln Ala Asn Ser Leu Pro Leu Thr 1 5 <210> 209 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 209 gaggtgcagc tggtggagtc tgggggaggc ttggtccagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt caccttcagt acctattcta tgcactgggt ccgccaggct 120 ccagggaagg gactggaata tgtttcaact attaataata atggggatac cacatattat 180 gcagactctg tgaagggcag attcaccatc tccagagaca attccaagaa cacgctgtat 240 cttcaactgg gcagcctgag acctgaggac atggctgtgt attactgtgc gagacagacg 300 tataccagca gctggtacgg ggggttcgac tcctggggcc agggaaccct ggtcaccgtc 360 tcctca 366 <210> 210 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 210 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 Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45 Ser Thr Ile Asn Asn Asn Gly Asp Thr Thr 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 Leu Gly Ser Leu Arg Pro Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gln Thr Tyr Thr Ser Ser Trp Tyr Gly Gly Phe Asp Ser Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 211 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 211 ggattcacct tcagtaccta ttct 24 <210> 212 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 212 Gly Phe Thr Phe Ser Thr Tyr Ser 1 5 <210> 213 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 213 attaataata atggggatac caca 24 <210> 214 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 214 Ile Asn Asn Asn Gly Asp Thr Thr 1 5 <210> 215 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 215 gcgagacaga cgtataccag cagctggtac ggggggttcg actcc 45 <210> 216 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 216 Ala Arg Gln Thr Tyr Thr Ser Ser Trp Tyr Gly Gly Phe Asp Ser 1 5 10 15 <210> 217 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 217 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggcga cagagtcacc 60 atcacttgtc gggcgagtca gggtattacc agctggttag cctggtatca gcagaaacca 120 gggaaagccc ctaaactcct gatctatgct gcatccaatt tgcaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcaccag cctgcagcct 240 gaggattttg caacttacta ttgtcaacag gctaacagtc tcccattcac tttcggccct 300 gggaccaaag tggatatcaa a 321 <210> 218 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 218 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Thr 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 Asn 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 Thr Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Leu Pro Phe 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105 <210> 219 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 219 cagggtatta ccagctgg 18 <210> 220 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 220 Gln Gly Ile Thr Ser Trp 1 5 <210> 221 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 221 gctgcatcc 9 <210> 222 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 222 Ala Ala Ser 1 <210> 223 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 223 caacaggcta acagtctccc attcact 27 <210> 224 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 224 Gln Gln Ala Asn Ser Leu Pro Phe Thr 1 5 <210> 225 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 225 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacccttagc agctatgcca tgagctgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggcag cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa ctcgctgtat 240 ctgcaattga acagcctgag agccgaggac acggccgtat attactgtgc gaagacgctg 300 tatactacca gctggtacgg gggcttccag cactggggcc agggcaccct ggtcactgtc 360 tcctca 366 <210> 226 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 226 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 Leu Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser 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 Leu Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Thr Leu Tyr Thr Thr Ser Trp Tyr Gly Gly Phe Gln His Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 227 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 227 ggattcaccc ttagcagcta tgcc 24 <210> 228 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 228 Gly Phe Thr Leu Ser Ser Tyr Ala 1 5 <210> 229 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 229 attagtggta gtggtggcag caca 24 <210> 230 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 230 Ile Ser Gly Ser Gly Gly Ser Thr 1 5 <210> 231 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 231 gcgaagacgc tgtatactac cagctggtac gggggcttcc agcac 45 <210> 232 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 232 Ala Lys Thr Leu Tyr Thr Thr Ser Trp Tyr Gly Gly Phe Gln His 1 5 10 15 <210> 233 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 233 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctataggaga cagagtcacc 60 atcacttgtc gggcgagtca gggaatcagc agttggttag cctggtatca gcagaaacca 120 gggaaagtcc ctaagctcct gatctatgct gcgtcctctt tgcaaagtgg gttcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagtag cctgcagccc 240 gaagattttg caacttacta ttgtcaacag actcacagtt tcccgtggac ggtcggccaa 300 gggaccaagg tggaaatcaa a 321 <210> 234 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 234 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Ile 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 Val Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Phe 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 Thr His Ser Phe Pro Trp 85 90 95 Thr Val Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105 <210> 235 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 235 cagggaatca gcagttgg 18 <210> 236 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 236 Gln Gly Ile Ser Ser Trp 1 5 <210> 237 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 237 gctgcgtcc 9 <210> 238 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 238 Ala Ala Ser 1 <210> 239 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 239 caacagactc acagtttccc gtgg 24 <210> 240 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 240 Gln Gln Thr His Ser Phe Pro Trp 1 5 <210> 241 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 241 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacccttagg agctatttca tgacctgggt ccgccaggtt 120 ccagggaagg ggctggaggg ggtctcagct attagtggca ttagtggtgg cacatactac 180 acagactccg ttaagggccg gttcaccatc tccagagaca attccaagaa cacgctgttt 240 ctgcaaatga acagcctgag agccgaggac acggccgtat atttctgtgc gagaacggtg 300 tatagtagta gttactacgg gggcttccag cactggggcc agggcaccct ggtcaccgtc 360 tcctca 366 <210> 242 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 242 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 Leu Arg Ser Tyr 20 25 30 Phe Met Thr Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Gly Val 35 40 45 Ser Ala Ile Ser Gly Ile Ser Gly Gly Thr Tyr Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Thr Val Tyr Ser Ser Ser Tyr Tyr Gly Gly Phe Gln His Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 243 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 243 ggattcaccc ttaggagcta tttc 24 <210> 244 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 244 Gly Phe Thr Leu Arg Ser Tyr Phe 1 5 <210> 245 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 245 attagtggca ttagtggtgg caca 24 <210> 246 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 246 Ile Ser Gly Ile Ser Gly Gly Thr 1 5 <210> 247 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 247 gcgagaacgg tgtatagtag tagttactac gggggcttcc agcac 45 <210> 248 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 248 Ala Arg Thr Val Tyr Ser Ser Ser Tyr Tyr Gly Gly Phe Gln His 1 5 10 15 <210> 249 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 249 gacatccaga tgacccagtc tccatcttcc gtgtctgtat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtattagc agttggttag cctggtatca gcagaaacca 120 gggaaagccc ctaagctcct gatctatgtt gcatccagtt tacaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaagattttg caacttacta ttgtcaacag actaacagtt tccctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 250 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 250 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Val 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 Val 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 Thr Asn Ser Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 251 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 251 cagggtatta gcagttgg 18 <210> 252 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 252 Gln Gly Ile Ser Ser Trp 1 5 <210> 253 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 253 gttgcatcc 9 <210> 254 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 254 Val Ala Ser 1 <210> 255 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 255 caacagacta acagtttccc tctcact 27 <210> 256 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 256 Gln Gln Thr Asn Ser Phe Pro Leu Thr 1 5 <210> 257 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 257 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgtgcag cctctggatt cacccttagg agttatgtca tgtactgggt ccgccagggt 120 ccagggaagg ggctggaggg ggtctcaggt attagtggca gtagtggtgg cacatactac 180 acagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgttt 240 ctgcaaatga acagcctgag agccgaggac acggccgtat atttctgtgc gagatcggtg 300 tatagtacca cctggtacgg gggcttccag cactggggcc agggcaccct ggtcaccgtc 360 tcctca 366 <210> 258 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 258 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 Leu Arg Ser Tyr 20 25 30 Val Met Tyr Trp Val Arg Gln Gly Pro Gly Lys Gly Leu Glu Gly Val 35 40 45 Ser Gly Ile Ser Gly Ser Ser Gly Gly Thr Tyr Tyr Thr Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Ala Arg Ser Val Tyr Ser Thr Thr Trp Tyr Gly Gly Phe Gln His Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 259 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 259 ggattcaccc ttaggagtta tgtc 24 <210> 260 <211> 8 <212> PRT ​​​​​​​​​​​​​​​​​​<213> Artificial Sequence <220> <223> synthesis <400> 261 attagtggca gtagtggtgg caca 24 <210> 262 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 262 Ile Ser Gly Ser Ser Ser Gly Gly Thr 1 5 <210> 263 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 263 gcgagatcgg tgtatagtac cacctggtac gggggcttcc agcac 45 <210> 264 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 264 Ala Arg Ser Val Tyr Ser Thr Thr Trp Tyr Gly Gly Phe Gln His 1 5 10 15 <210> 265 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthesis <400> 265 gacatccaga tgacccagtc tccatcttcc gtgtctgtat ctgtgggaga cagagtcacc 60 atcacttgtc gggcgagtca ggttattagc agttggttag cctggtatca gctgaaacca 120 gggaaagccc ctaaactcct gatctatgct gcatccagtt tacaaagtgg ggtcccatca 180 aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcgg cctgcagcct 240 gaagattttg cagtttacta ttgtcaacag actaacagtt tccctctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 266 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthesis <400> 266 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Val Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Leu 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 Gly Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Thr Asn Ser Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 267 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 267 caggttatta gcagttgg 18 <210> 268 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 268 Gln Val Ile Ser Ser Trp 1 5 <210> 269 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 269 gctgcatcc 9 <210> 270 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 270 Ala Ala Ser 1 <210> 271 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 271 caacagacta acagtttccc tctcact 27 <210> 272 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 272 Gln Gln Thr Asn Ser Phe Pro Leu Thr 1 5 <210> 273 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 273 gaggtgcagc tggtggagtc tgggggaaac ttggaacagc ctggggggtc ccttagactc 60 tcctgtacag cctctggatt cacctttagc agatctgcca tgaactgggt ccgccgggct 120 ccagggaagg ggctggagtg ggtctcagga attagtggta gtggtggtcg aacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa tacgctatat 240 ctgcaaatga acagcctgag cgccgaggac acggccgcat attactgtgc gaaagattcg 300 tatactacca gttggtacgg aggtatggac gtctggggcc acgggaccac ggtcaccgtc 360 tcctca 366 <210> 274 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 274 Glu Val Gln Leu Val Glu Ser Gly Gly Asn Leu Glu Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Arg Ser 20 25 30 Ala Met Asn Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Gly Ser Gly Gly Arg Thr 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 Ser Ala Glu Asp Thr Ala Ala Tyr Tyr Cys 85 90 95 Ala Lys Asp Ser Tyr Thr Thr Ser Trp Tyr Gly Gly Met Asp Val Trp 100 105 110 Gly His Gly Thr Thr Val Thr Val Ser Ser 115 120 <210> 275 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 275 ggattcacct ttagcagatc tgcc 24 <210> 276 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 276 Gly Phe Thr Phe Ser Arg Ser Ala 1 5 <210> 277 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 277 attagtggta gtggtggtcg aaca 24 <210> 278 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 278 Ile Ser Gly Ser Gly Gly Arg Thr 1 5 <210> 279 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 279 gcgaaagatt cgtatactac cagttggtac ggaggtatgg acgtc 45 <210> 280 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 280 Ala Lys Asp Ser Tyr Thr Thr Ser Trp Tyr Gly Gly Met Asp Val 1 5 10 15 <210> 281 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 281 gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggtattttc agctggttag cctggtatca gcagaaacca 120 ggaaaagccc ctaagctcct gatctatgct gcttccagtt tacaaagtgg ggtcccatca 180 agattcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaggattttg caatttacta ttgtcaacag gctaacagtg tcccgatcac cttcggccaa 300 gggacacgac tggagattaa a 321 <210> 282 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 282 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Phe 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 Ile Tyr Tyr Cys Gln Gln Ala Asn Ser Val Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105 <210> 283 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 283 cagggtattt tcagctgg 18 <210> 284 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 284 Gln Gly Ile Phe Ser Trp 1 5 <210> 285 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 285 gctgcttcc 9 <210> 286 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 286 Ala Ala Ser 1 <210> 287 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 287 caacaggcta acagtgtccc gatcacc 27 <210> 288 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 288 Gln Gln Ala Asn Ser Val Pro Ile Thr 1 5 <210> 289 <211> 366 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 289 gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60 tcctgttcag cctctggatt cacctttagc agctatgcca tgaactgggt ccgccaggct 120 ccagggaagg ggctggagtg ggtcaccgct attagtggca gtggtggtgg cacatactac 180 gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa ctcgctgttt 240 ctgcaattga acagcctgag agccgaggac acggccgtgt attactgtgc gaaacaaacg 300 tataccagca gctggtacgg tggctttgat atctggggcc aggggacaat ggtcaccgtc 360 tcttca 366 <210> 290 <211> 122 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 290 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 Ser 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 Thr Ala Ile Ser Gly Ser Gly Gly Gly 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 Phe 65 70 75 80 Leu Gln Leu Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Gln Thr Tyr Thr Ser Ser Trp Tyr Gly Gly Phe Asp Ile Trp 100 105 110 Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 <210> 291 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 291 ggattcacct ttagcagcta tgcc 24 <210> 292 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 292 Gly Phe Thr Phe Ser Ser Tyr Ala 1 5 <210> 293 <211> twenty four <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 293 attagtggca gtggtggtgg caca 24 <210> 294 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 294 Ile Ser Gly Ser Gly Gly Gly Thr 1 5 <210> 295 <211> 45 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 295 gcgaaacaaa cgtataccag cagctggtac ggtggctttg atatc 45 <210> 296 <211> 15 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 296 Ala Lys Gln Thr Tyr Thr Ser Ser Trp Tyr Gly Gly Phe Asp Ile 1 5 10 15 <210> 297 <211> 321 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 297 gacatccaga tgacccagtc gccatcttcc gtgtccgcgt ctgtaggaga cagagtcacc 60 atcacttgtc gggcgagtca gggttttagt tcctggttag cctggtatca gcagatacca 120 gggaaagccc ccaagctcct gatctatgct gcatcaaggt tgcaaagtgg ggtcccatcc 180 aggttccgcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240 gaggattttg caacttacta ttgtcaacag gctaacagtt tcccgctcac tttcggcgga 300 gggaccaagg tggagatcaa a 321 <210> 298 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 298 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Phe Ser Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Ile Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Arg 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 Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 299 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 299 cagggtttta gttcctgg 18 <210> 300 <211> 6 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 300 Gln Gly Phe Ser Ser Trp 1 5 <210> 301 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 301 gctgcatca 9 <210> 302 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 302 Ala Ala Ser 1 <210> 303 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 303 caacaggcta acagtttccc gctcact 27 <210> 304 <211> 9 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> synthesis <400> 304 Gln Gln Ala Asn Ser Phe Pro Leu Thr 1 5 <210> 305 <211> 167 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> synthesis <400> 305 Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Ser Leu Ala Ser Leu Ser 1 5 10 15 Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr 20 25 30 Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Lys Lys Asp Lys Val 35 40 45 Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Ser Glu Ser Gly Asp 50 55 60 Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp 65 70 75 80 Phe Trp Leu Gln Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys 85 90 95 Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Arg 100 105 110 Ser Phe Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe 115 120 125 Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Tyr Ser 130 135 140 Glu Asn Leu Gly Ser Glu Asn Ile Leu Phe Lys Leu Ser Glu Ile Leu 145 150 155 160 Glu His His His His His His 165 <210> 306 <211> 167 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 306 Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Ser Leu Ala Ser Leu Ser 1 5 10 15 Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr 20 25 30 Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Lys Lys Lys Asp Lys Val 35 40 45 Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Ser Glu Ser Gly Asp 50 55 60 Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp 65 70 75 80 Phe Trp Leu Gln Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys 85 90 95 Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Arg 100 105 110 Ser Phe Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe 115 120 125 Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Tyr Ser 130 135 140 Glu Asn Leu Gly Ser Glu Asn Ile Leu Phe Lys Leu Ser Glu Ile Leu 145 150 155 160 Glu His His His His His His 165 <210> 307 <211> 354 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <400> 307 caggtcacct tgaaggagtc tggtcctgtg ctggtgaaac ccacagagag cctcacgctg 60 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu Ser Leu Thr Leu Thr Cys Ser Val Ser Gly Phe Ser Leu Ser Asn Val acctgctccg tctctggatt ctcactcagt aatgttagaa tgggtgtgag ctggatccgt 120 Thr Ala Pro Val Ser Trp Ile Leu Thr Ser Asn Val Arg Met Gly Val Ser Trp Ile Arg cagtccccag ggaaggccct ggagtggctt gcacacattt tttcgaatga cgaaaaatcc 180 Gln Ser Pro Gly Lys Ala Leu Glu Trp Leu Cys His Phe Phe Glu Met Asp Glu Asn Pro tacaccacat ctctgaagac caggctcacc atctccaagg acacctccag aagccaggtg 240 Tyr Thr His Ser Leu Glu Asp Gln Ala Thr Ile Ser Lys Asp Thr Ser Gln Lys Pro Val gtccttacca tgaccgacat ggaccctggg gacacagcca catattactg tgcacggata 300 Val Leu Thr Met Thr Asp Met Asp Pro Gly Asp Thr Ala His Ile Thr Cys His Gly Ile cggaatttgg cctttaatta ctggggccag ggaaccctgg tcaccgtctc ctca 354 Arg Asn Leu Ala Phe Asn Leu Thr Gly Pro Gly Asn Pro Gly Thr Arg Ser Ser <210> 308<210> 308 <211> 118<211> 118 <212> PRT<212> PRT <213> 人工序列(Artificial Sequence)<213> Artificial Sequence <220><220> <223> 合成 <223> Synthetic <400> 308 <400> 308 Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu Gln Val Thr Leu Lys Glu Ser Gly Pro Val Leu Val Lys Pro Thr Glu 1 5 10 15 1 5 10 15 Ser Leu Thr Leu Thr Cys Ser Val Ser Gly Phe Ser Leu Ser Asn Val Ser Leu Thr Leu Thr Cys Ser Val Ser Gly Phe Ser Leu Ser Asn Val 20 25 30 20 25 30 Arg Met Gly Val Ser Trp Ile Arg Gln Ser Pro Gly Lys Ala Leu Glu Arg Met Gly Val Ser Trp Ile Arg Gln Ser Pro Gly Lys Ala Leu Glu 35 40 45 35 40 45 Trp Leu Ala His Ile Phe Ser Asn Asp Glu Lys Ser Tyr Thr Thr Ser 50 55 60 Leu Lys Thr Arg Leu Thr Ile Ser Lys Asp Thr Ser Ser Arg Ser Gln Val 65 70 75 80 Val Leu Thr Met Thr Asp Met Asp Pro Gly Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Ile Arg Asn Leu Ala Phe Asn Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115 <210> 309 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 309 ggattctcac tcagtaatgt tagaatgggt 30 <210> 310 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 310 Gly Phe Ser Leu Ser Asn Val Arg Met Gly 1 5 10 <210> 311 <211> twenty one <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 311 attttttcga atgacgaaaa a 21 <210> 312 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 312 Ile Phe Ser Asn Asp Glu Lys 1 5 <210> 313 <211> 30 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 313 gcacggatac ggaatttggc ctttaattac 30 <210> 314 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 314 Ala Arg Ile Arg Asn Leu Ala Phe Asn Tyr 1 5 10 <210> 315 <211> 339 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 315 gacttcgtga tgacccagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60 atcaactgca agtccagcca gagtgtgtta cacaggtcca gcaataagaa ctacttagct 120 tggtatcagc agaagccagg acagcctcct aacctgctca tttactgggc atctacccgg 180 gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240 atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatggtact 300 ctatttactt tcggccctgg gaccaaagtg gatatcaaa 339 <210> 316 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> Synthetic <400> 316 Asp Phe Val 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 Val Leu His Arg 20 25 30 Ser Ser Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Asn 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 Tyr Gly Thr Leu Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 100 105 110 Lys <210> 317 <211> 36 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 317 cagagtgtgt tacacaggtc cagcaataag aactac 36 <210> 318 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 318 Gln Ser Val Leu His Arg Ser Ser Asn Lys Asn Tyr 1 5 10 <210> 319 <211> 9 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 319 tgggcatct 9 <210> 320 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 320 Trp Ala Ser 1 <210> 321 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> synthesis <400> 321 cagcaatatt atggtactct atttact 27 <210> 322 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> synthesis <400> 322 Gln Gln Tyr Tyr Gly Thr Leu Phe Thr 1 5 <210> 323 <211> 537 <212> PRT <213> Artificial Sequence <220> <223> hST2-hFc <400> 323 Lys Phe Ser Lys Gln Ser Trp Gly Leu Glu Asn Glu Ala Leu Ile Val 1 5 10 15 Arg Cys Pro Arg Gln Gly Lys Pro Ser Tyr Thr Val Asp Trp Tyr Tyr 20 25 30 Ser Gln Thr Asn Lys Ser Ile Pro Thr Gln Glu Arg Asn Arg Val Phe 35 40 45 Ala Ser Gly Gln Leu Leu Lys Phe Leu Pro Ala Ala Val Ala Asp Ser 50 55 60 Gly Ile Tyr Thr Cys Ile Val Arg Ser Pro Thr Phe Asn Arg Thr Gly 65 70 75 80 Tyr Ala Asn Val Thr Ile Tyr Lys Lys Gln Ser Asp Cys Asn Val Pro 85 90 95 Asp Tyr Leu Met Tyr Ser Thr Val Ser Gly Ser Glu Lys Asn Ser Lys 100 105 110 Ile Tyr Cys Pro Thr Ile Asp Leu Tyr Asn Trp Thr Ala Pro Leu Glu 115 120 125 Trp Phe Lys Asn Cys Gln Ala Leu Gln Gly Ser Arg Tyr Arg Ala His 130 135 140 Lys Ser Phe Leu Val Ile Asp Asn Val Met Thr Glu Asp Ala Gly Asp 145 150 155 160 Tyr Thr Cys Lys Phe Ile His Asn Glu Asn Gly Ala Asn Tyr Ser Val 165 170 175 Thr Ala Thr Arg Ser Phe Thr Val Lys Asp Glu Gln Gly Phe Ser Leu 180 185 190 Phe Pro Val Ile Gly Ala Pro Ala Gln Asn Glu Ile Lys Glu Val Glu 195 200 205 Ile Gly Lys Asn Ala Asn Leu Thr Cys Ser Ala Cys Phe Gly Lys Gly 210 215 220 Thr Gln Phe Leu Ala Ala Val Leu Trp Gln Leu Asn Gly Thr Lys Ile 225 230 235 240 Thr Asp Phe Gly Glu Pro Arg Ile Gln Gln Glu Glu Gly Gln Asn Gln 245 250 255 Ser Phe Ser Asn Gly Leu Ala Cys Leu Asp Met Val Leu Arg Ile Ala 260 265 270 Asp Val Lys Glu Glu Asp Leu Leu Leu Gln Tyr Asp Cys Leu Ala Leu 275 280 285 Asn Leu His Gly Leu Arg Arg His Thr Val Arg Leu Ser Arg Lys Asn 290 295 300 Pro Ile Asp His His Ser Asp Lys Thr His Thr Cys Pro Pro Cys Pro 305 310 315 320 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 325 330 335 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 340 345 350 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 355 360 365 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 370 375 380 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 385 390 395 400 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 405 410 415 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 420 425 430 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu 435 440 445 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 450 455 460 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 465 470 475 480 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 485 490 495 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 500 505 510 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 515 520 525 Lys Ser Leu Ser Leu Ser Pro Gly Lys 530 535 <210> 324 <211> 543 <212> PRT <213> Artificial Sequence <220> <223> hST2-mFc <400> 324 Lys Phe Ser Lys Gln Ser Trp Gly Leu Glu Asn Glu Ala Leu Ile Val 1 5 10 15 Arg Cys Pro Arg Gln Gly Lys Pro Ser Tyr Thr Val Asp Trp Tyr Tyr 20 25 30 Ser Gln Thr Asn Lys Ser Ile Pro Thr Gln Glu Arg Asn Arg Val Phe 35 40 45 Ala Ser Gly Gln Leu Leu Lys Phe Leu Pro Ala Ala Val Ala Asp Ser 50 55 60 Gly Ile Tyr Thr Cys Ile Val Arg Ser Pro Thr Phe Asn Arg Thr Gly 65 70 75 80 Tyr Ala Asn Val Thr Ile Tyr Lys Lys Gln Ser Asp Cys Asn Val Pro 85 90 95 Asp Tyr Leu Met Tyr Ser Thr Val Ser Gly Ser Glu Lys Asn Ser Lys 100 105 110 Ile Tyr Cys Pro Thr Ile Asp Leu Tyr Asn Trp Thr Ala Pro Leu Glu 115 120 125 Trp Phe Lys Asn Cys Gln Ala Leu Gln Gly Ser Arg Tyr Arg Ala His 130 135 140 Lys Ser Phe Leu Val Ile Asp Asn Val Met Thr Glu Asp Ala Gly Asp 145 150 155 160 Tyr Thr Cys Lys Phe Ile His Asn Glu Asn Gly Ala Asn Tyr Ser Val 165 170 175 Thr Ala Thr Arg Ser Phe Thr Val Lys Asp Glu Gln Gly Phe Ser Leu 180 185 190 Phe Pro Val Ile Gly Ala Pro Ala Gln Asn Glu Ile Lys Glu Val Glu 195 200 205 Ile Gly Lys Asn Ala Asn Leu Thr Cys Ser Ala Cys Phe Gly Lys Gly 210 215 220 Thr Gln Phe Leu Ala Ala Val Leu Trp Gln Leu Asn Gly Thr Lys Ile 225 230 235 240 Thr Asp Phe Gly Glu Pro Arg Ile Gln Gln Glu Glu Gly Gln Asn Gln 245 250 255 Ser Phe Ser Asn Gly Leu Ala Cys Leu Asp Met Val Leu Arg Ile Ala 260 265 270 Asp Val Lys Glu Glu Asp Leu Leu Leu Gln Tyr Asp Cys Leu Ala Leu 275 280 285 Asn Leu His Gly Leu Arg Arg His Thr Val Arg Leu Ser Arg Lys Asn 290 295 300 Pro Ile Asp His His Ser Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys 305 310 315 320 Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser Val 325 330 335 Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu Ser 340 345 350 Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro Asp 355 360 365 Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala Gln 370 375 380 Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val Ser 385 390 395 400 Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys 405 410 415 Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile 420 425 430 Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu Pro 435 440 445 Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys Met 450 455 460 Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn 465 470 475 480 Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser 485 490 495 Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn 500 505 510 Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly Leu 515 520 525 His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 530 535 540 <210> 325 <211> 884 <212> PRT <213> Artificial Sequence <220> <223> hST2-hIL1RAcP-mFc <400> 325 Lys Phe Ser Lys Gln Ser Trp Gly Leu Glu Asn Glu Ala Leu Ile Val 1 5 10 15 Arg Cys Pro Arg Gln Gly Lys Pro Ser Tyr Thr Val Asp Trp Tyr Tyr 20 25 30 Ser Gln Thr Asn Lys Ser Ile Pro Thr Gln Glu Arg Asn Arg Val Phe 35 40 45 Ala Ser Gly Gln Leu Leu Lys Phe Leu Pro Ala Ala Val Ala Asp Ser 50 55 60 Gly Ile Tyr Thr Cys Ile Val Arg Ser Pro Thr Phe Asn Arg Thr Gly 65 70 75 80 Tyr Ala Asn Val Thr Ile Tyr Lys Lys Gln Ser Asp Cys Asn Val Pro 85 90 95 Asp Tyr Leu Met Tyr Ser Thr Val Ser Gly Ser Glu Lys Asn Ser Lys 100 105 110 Ile Tyr Cys Pro Thr Ile Asp Leu Tyr Asn Trp Thr Ala Pro Leu Glu<00,04239>115 120 125 Trp Phe Lys Asn Cys Gln Ala Leu Gln Gly Ser Arg Tyr Arg Ala His 130 135 140 Lys Ser Phe Leu Val Ile Asp Asn Val Met Thr Glu Asp Ala Gly Asp 145 150 155 160 Tyr Thr Cys Lys Phe Ile His Asn Glu Asn Gly Ala Asn Tyr Ser Val 165 170 175 Thr Ala Thr Arg Ser Phe Thr Val Lys Asp Glu Gln Gly Phe Ser Leu 180 185 190 Phe Pro Val Ile Gly Ala Pro Ala Gln Asn Glu Ile Lys Glu Val Glu 195 200 205 Ile Gly Lys Asn Ala Asn Leu Thr Cys Ser Ala Cys Phe Gly Lys Gly 210 215 220 Thr Gln Phe Leu Ala Ala Val Leu Trp Gln Leu Asn Gly Thr Lys Ile 225 230 235 240 Thr Asp Phe Gly Glu Pro Arg Ile Gln Gln Glu Glu Gly Gln Asn Gln 245 250 255 Ser Phe Ser Asn Gly Leu Ala Cys Leu Asp Met Val Leu Arg Ile Ala 260 265 270 Asp Val Lys Glu Glu Asp Leu Leu Leu Gln Tyr Asp Cys Leu Ala Leu 275 280 285 Asn Leu His Gly Leu Arg Arg His Thr Val Arg Leu Ser Arg Lys Asn 290 295 300 Pro Ile Asp His His Ser Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp 305 310 315 320 Thr Met Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys 325 330 335 Cys Pro Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His 340 345 350 Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp 355 360 365 Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys 370 375 380 Glu Lys Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly 385 390 395 400 Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala 405 410 415 Phe Pro Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met 420 425 430 Lys Leu Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile 435 440 445 Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr 450 455 460 Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val 465 470 475 480 Ile Pro Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn 485 490 495 Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr 500 505 510 Phe His Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys 515 520 525 Asn Ala Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr 530 535 540 Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe 545 550 555 560 Ser Phe Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly 565 570 575 Lys Lys Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile 580 585 590 Ser His Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile 595 600 605 Lys Lys Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala 610 615 620 Arg Ser Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys 625 630 635 640 Val Pro Ala Pro Arg Tyr Thr Val Glu Ser Gly Glu Pro Arg Gly Pro 645 650 655 Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu 660 665 670 Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu 675 680 685 Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser 690 695 700 Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu 705 710 715 720 Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr 725 730 735 Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser 740 745 750 Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro 755 760 765 Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln 770 775 780 Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val 785 790 795 800 Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val 805 810 815 Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu 820 825 830 Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg 835 840 845 Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val 850 855 860 Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg 865 870 875 880 Thr Pro Gly Lys <210> 326 <211> 880 <212> PRT <213> Artificial Sequence <220> <223> mST2‑mIL1RAcP‑mFc <400> 326 Ser Lys Ser Ser Trp Gly Leu Glu Asn Glu Ala Leu Ile Val Arg Cys 1 5 10 15 Pro Gln Arg Gly Arg Ser Thr Tyr Pro Val Glu Trp Tyr Tyr Ser Asp 20 25 30 Thr Asn Glu Ser Ile Pro Thr Gln Lys Arg Asn Arg Ile Phe Val Ser 35 40 45 Arg Asp Arg Leu Lys Phe Leu Pro Ala Arg Val Glu Asp Ser Gly Ile 50 55 60 Tyr Ala Cys Val Ile Arg Ser Pro Asn Leu Asn Lys Thr Gly Tyr Leu 65 70 75 80 Asn Val Thr Ile His Lys Lys Pro Pro Ser Cys Asn Ile Pro Asp Tyr 85 90 95 Leu Met Tyr Ser Thr Val Arg Gly Ser Asp Lys Asn Phe Lys Ile Thr 100 105 110 Cys Pro Thr Ile Asp Leu Tyr Asn Trp Thr Ala Pro Val Gln Trp Phe 115 120 125 Lys Asn Cys Lys Ala Leu Gln Glu Pro Arg Phe Arg Ala His Arg Ser 130 135 140 Tyr Leu Phe Ile Asp Asn Val Thr His Asp Asp Glu Gly Asp Tyr Thr 145 150 155 160 Cys Gln Phe Thr His Ala Glu Asn Gly Thr Asn Tyr Ile Val Thr Ala 165 170 175 Thr Arg Ser Phe Thr Val Glu Glu Lys Gly Phe Ser Met Phe Pro Val 180 185 190 Ile Thr Asn Pro Pro Tyr Asn His Thr Met Glu Val Glu Ile Gly Lys 195 200 205 Pro Ala Ser Ile Ala Cys Ser Ala Cys Phe Gly Lys Gly Ser His Phe 210 215 220 Leu Ala Asp Val Leu Trp Gln Ile Asn Lys Thr Val Val Gly Asn Phe 225 230 235 240 Gly Glu Ala Arg Ile Gln Glu Glu Glu Gly Arg Asn Glu Ser Ser Ser 245 250 255 Asn Asp Met Asp Cys Leu Thr Ser Val Leu Arg Ile Thr Gly Val Thr 260 265 270 Glu Lys Asp Leu Ser Leu Glu Tyr Asp Cys Leu Ala Leu Asn Leu His 275 280 285 Gly Met Ile Arg His Thr Ile Arg Leu Arg Arg Lys Gln Pro Ile Asp 290 295 300 His Arg Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met Arg Gln 305 310 315 320 Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe 325 330 335 Glu His Phe Leu Lys Tyr Asn Tyr Ser Thr Ala His Ser Ser Gly Leu 340 345 350 Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro 355 360 365 Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys Asp Val 370 375 380 Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys 385 390 395 400 Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu 405 410 415 Val Val Gln Lys Asp Ser Cys Phe Asn Ser Ala Met Arg Phe Pro Val 420 425 430 His Lys Met Tyr Ile Glu His Gly Ile His Lys Ile Thr Cys Pro Asn 435 440 445 Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Ser Val Thr Trp Tyr 450 455 460 Lys Gly Cys Thr Glu Ile Val Asp Phe His Asn Val Leu Pro Glu Gly 465 470 475 480 Met Asn Leu Ser Phe Phe Ile Pro Leu Val Ser Asn Asn Gly Asn Tyr 485 490 495 Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Leu Phe His Leu Thr 500 505 510 Arg Thr Val Thr Val Lys Val Val Gly Ser Pro Lys Asp Ala Leu Pro 515 520 525 Pro Gln Ile Tyr Ser Pro Asn Asp Arg Val Val Tyr Glu Lys Glu Pro 530 535 540 Gly Glu Glu Leu Val Ile Pro Cys Lys Val Tyr Phe Ser Phe Ile Met 545 550 555 560 Asp Ser His Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp 565 570 575 Asp Val Thr Val Asp Ile Thr Ile Asn Glu Ser Val Ser Tyr Ser Ser 580 585 590 Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys Val Thr 595 600 605 Pro Glu Asp Leu Arg Arg Asn Tyr Val Cys His Ala Arg Asn Thr Lys 610 615 620 Gly Glu Ala Glu Gln Ala Ala Lys Val Lys Gln Lys Val Ile Pro Pro 625 630 635 640 Arg Tyr Thr Val Glu Ser Gly Glu Pro Arg Gly Pro Thr Ile Lys Pro 645 650 655 Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro Ser 660 665 670 Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser Leu 675 680 685 Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp Pro 690 695 700 Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr Ala 705 710 715 720 Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val Val 725 730 735 Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu Phe 740 745 750 Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg Thr 755 760 765 Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val Leu 770 775 780 Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr Cys 785 790 795 800 Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr Asn 805 810 815 Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu Asp 820 825 830 Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys Lys 835 840 845 Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu Gly 850 855 860 Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly Lys 865 870 875 880 <210> 327 <211> 876 <212> PRT <213> Artificial Sequence <220> <223> hST2-hL1RAcP-hFc <400> 327[[ID=三十五]] [[ID=三十六]]Lys Phe Ser Lys Gln Ser Trp Gly Leu Glu Asn Glu Ala Leu Ile Val[[ID=三十七]] [[ID=三十八]]1 5 10 15[[ID=三十九]] [[ID=四十]]Arg Cys Pro Arg Gln Gly Lys Pro Ser Tyr Thr Val Asp Trp Tyr Tyr[[ID=四十一]] [[ID=四十二]]20 25 30[[ID=四十三]] [[ID=四十四]]Ser Gln Thr Asn Lys Ser Ile Pro Thr Gln Glu Arg Asn Arg Val Phe[[ID=四十五]] [[ID=四十六]]35 40 45 Ala Ser Gly Gln Leu Leu Lys Phe Leu Pro Ala Ala Val Ala Asp Ser 50 55 60 Gly Ile Tyr Thr Cys Ile Val Arg Ser Pro Thr Phe Asn Arg Thr Gly 65 70 75 80 Tyr Ala Asn Val Thr Ile Tyr Lys Lys Gln Ser Asp Cys Asn Val Pro 85 90 95 Asp Tyr Leu Met Tyr Ser Thr Val Ser Gly Ser Glu Lys Asn Ser Lys 100 105 110 Ile Tyr Cys Pro Thr Ile Asp Leu Tyr Asn Trp Thr Ala Pro Leu Glu 115 120 125 Trp Phe Lys Asn Cys Gln Ala Leu Gln Gly Ser Arg Tyr Arg Ala His 130 135 140 Lys Ser Phe Leu Val Ile Asp Asn Val Met Thr Glu Asp Ala Gly Asp 145 150 155 160 Tyr Thr Cys Lys Phe Ile His Asn Glu Asn Gly Ala Asn Tyr Ser Val 165 170 175 Thr Ala Thr Arg Ser Phe Thr Val Lys Asp Glu Gln Gly Phe Ser Leu 180 185 190 Phe Pro Val Ile Gly Ala Pro Ala Gln Asn Glu Ile Lys Glu Val Glu 195 200 205 Ile Gly Lys Asn Ala Asn Leu Thr Cys Ser Ala Cys Phe Gly Lys Gly 210 215 220 Thr Gln Phe Leu Ala Ala Val Leu Trp Gln Leu Asn Gly Thr Lys Ile 225 230 235 240 Thr Asp Phe Gly Glu Pro Arg Ile Gln Gln Glu Glu Gly Gln Asn Gln 245 250 255 Ser Phe Ser Asn Gly Leu Ala Cys Leu Asp Met Val Leu Arg Ile Ala 260 265 270 Asp Val Lys Glu Glu Asp Leu Leu Leu Gln Tyr Asp Cys Leu Ala Leu 275 280 285 Asn Leu His Gly Leu Arg Arg His Thr Val Arg Leu Ser Arg Lys Asn 290 295 300 Pro Ile Asp His His Ser Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp 305 310 315 320 Thr Met Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys 325 330 335 Cys Pro Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His 340 345 350 Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp 355 360 365 Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys 370 375 380 Glu Lys Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly 385 390 395 400 Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala 405 410 415 Phe Pro Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met 420 425 430 Lys Leu Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile 435 440 445 Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr 450 455 460 Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val 465 470 475 480 Ile Pro Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn 485 490 495 Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr 500 505 510 Phe His Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys 515 520 525 Asn Ala Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr 530 535 540 Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe 545 550 555 560 Ser Phe Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly 565 570 575 Lys Lys Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile 580 585 590 Ser His Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile 595 600 605 Lys Lys Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala 610 615 620 Arg Ser Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys 625 630 635 640 Val Pro Ala Pro Arg Tyr Thr Val Glu Asp Lys Thr His Thr Cys Pro 645 650 655 Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 660 665 670 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 675 680 685 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe 690 695 700 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 705 710 715 720 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 725 730 735 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 740 745 750 Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala 755 760 765 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 770 775 780 Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 785 790 795 800 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 805 810 815 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 820 825 830 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 835 840 845 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 850 855 860 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 865 870 875 <210> 328 <211> 310 <\u212> PRT <213> Artificial Sequence <220> <223> Human ST2 Extracellular Domain <400> 328 Lys Phe Ser Lys Gln Ser Trp Gly Leu Glu Asn Glu Ala Leu Ile Val 1 5 10 15 Arg Cys Pro Arg Gln Gly Lys Pro Ser Tyr Thr Val Asp Trp Tyr Tyr 20 25 30 Ser Gln Thr Asn Lys Ser Ile Pro Thr Gln Glu Arg Asn Arg Val Phe 35 40 45 Ala Ser Gly Gln Leu Leu Lys Phe Leu Pro Ala Ala Val Ala Asp Ser 50 55 60 Gly Ile Tyr Thr Cys Ile Val Arg Ser Pro Thr Phe Asn Arg Thr Gly 65 70 75 80 Tyr Ala Asn Val Thr Ile Tyr Lys Lys Gln Ser Asp Cys Asn Val Pro 85 90 95 Asp Tyr Leu Met Tyr Ser Thr Val Ser Gly Ser Glu Lys Asn Ser Lys 100 105 110 Ile Tyr Cys Pro Thr Ile Asp Leu Tyr Asn Trp Thr Ala Pro Leu Glu 115 120 125 Trp Phe Lys Asn Cys Gln Ala Leu Gln Gly Ser Arg Tyr Arg Ala His 130 135 140 Lys Ser Phe Leu Val Ile Asp Asn Val Met Thr Glu Asp Ala Gly Asp 145 150 155 160 Tyr Thr Cys Lys Phe Ile His Asn Glu Asn Gly Ala Asn Tyr Ser Val 165 170 175 Thr Ala Thr Arg Ser Phe Thr Val Lys Asp Glu Gln Gly Phe Ser Leu 180 185 190 Phe Pro Val Ile Gly Ala Pro Ala Gln Asn Glu Ile Lys Glu Val Glu 195 200 205 Ile Gly Lys Asn Ala Asn Leu Thr Cys Ser Ala Cys Phe Gly Lys Gly 210 215 220 Thr Gln Phe Leu Ala Ala Val Leu Trp Gln Leu Asn Gly Thr Lys Ile 225 230 235 240 Thr Asp Phe Gly Glu Pro Arg Ile Gln Gln Glu Glu Gly Gln Asn Gln 245 250 255 Ser Phe Ser Asn Gly Leu Ala Cys Leu Asp Met Val Leu Arg Ile Ala 260 265 270 Asp Val Lys Glu Glu Asp Leu Leu Leu Gln Tyr Asp Cys Leu Ala Leu 275 280 285 Asn Leu His Gly Leu Arg Arg His Thr Val Arg Leu Ser Arg Lys Asn 290 295 300 Pro Ile Asp His His Ser 305 310 <210> 329 <211> 306 <212> PRT <213> Artificial Sequence <220> <223> Mouse ST2 extracellular domain <400> 329 Ser Lys Ser Ser Trp Gly Leu Glu Asn Glu Ala Leu Ile Val Arg Cys 1 5 10 15 Pro Gln Arg Gly Arg Ser Thr Tyr Pro Val Glu Trp Tyr Tyr Ser Asp 20 25 30 Thr Asn Glu Ser Ile Pro Thr Gln Lys Arg Asn Arg Ile Phe Val Ser 35 40 45 Arg Asp Arg Leu Lys Phe Leu Pro Ala Arg Val Glu Asp Ser Gly Ile 50 55 60 Tyr Ala Cys Val Ile Arg Ser Pro Asn Leu Asn Lys Thr Gly Tyr Leu 65 70 75 80 Asn Val Thr Ile His Lys Lys Pro Pro Ser Cys Asn Ile Pro Asp Tyr 85 90 95 Leu Met Tyr Ser Thr Val Arg Gly Ser Asp Lys Asn Phe Lys Ile Thr 100 105 110 Cys Pro Thr Ile Asp Leu Tyr Asn Trp Thr Ala Pro Val Gln Trp Phe 115 120 125 Lys Asn Cys Lys Ala Leu Gln Glu Pro Arg Phe Arg Ala His Arg Ser 130 135 140 Tyr Leu Phe Ile Asp Asn Val Thr His Asp Asp Glu Gly Asp Tyr Thr 145 150 155 160 Cys Gln Phe Thr His Ala Glu Asn Gly Thr Asn Tyr Ile Val Thr Ala 165 170 175 Thr Arg Ser Phe Thr Val Glu Glu Lys Gly Phe Ser Met Phe Pro Val 180 185 190 Ile Thr Asn Pro Pro Tyr Asn His Thr Met Glu Val Glu Ile Gly Lys 195 200 205 Pro Ala Ser Ile Ala Cys Ser Ala Cys Phe Gly Lys Gly Ser His Phe 210 215 220 Leu Ala Asp Val Leu Trp Gln Ile Asn Lys Thr Val Val Gly Asn Phe 225 230 235 240 Gly Glu Ala Arg Ile Gln Glu Glu Glu Gly Arg Asn Glu Ser Ser Ser 245 250 255 Asn Asp Met Asp Cys Leu Thr Ser Val Leu Arg Ile Thr Gly Val Thr 260 265 270 Glu Lys Asp Leu Ser Leu Glu Tyr Asp Cys Leu Ala Leu Asn Leu His 275 280 285 Gly Met Ile Arg His Thr Ile Arg Leu Arg Arg Lys Gln Pro Ile Asp 290 295 300 His Arg 305 <210> 330 <211> 339 <212> PRT <213> Artificial Sequence <220> <223> Human IL1RAcP Extracellular Domain <400> 330 Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln 1 5 10 15 Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His 20 25 30 Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu 35 40 45 Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn 50 55 60 Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp 65 70 75 80 Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu 85 90 95 Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val 100 105 110 Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys 115 120 125 Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp 130 135 140 Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly 145 150 155 160 Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn 165 170 175 Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys 180 185 190 Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr 195 200 205 Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val 210 215 220 Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu 225 230 235 240 Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser 245 250 255 Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile 260 265 270 Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu 275 280 285 Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu 290 295 300 Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu 305 310 315 320 Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr 325 330 335 Thr Val Glu <210> 331 <211> 339 <212> PRT <213> Artificial Sequence <220> <223> Mouse IL1RAcP extracellular domain <400> 331 Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln 1 5 10 15 Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His 20 25 30 Phe Leu Lys Tyr Asn Tyr Ser Thr Ala His Ser Ser Gly Leu Thr Leu 35 40 45 Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn 50 55 60 Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp 65 70 75 80 Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu 85 90 95 Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val 100 105 110 Gln Lys Asp Ser Cys Phe Asn Ser Ala Met Arg Phe Pro Val His Lys 115 120 125 Met Tyr Ile Glu His Gly Ile His Lys Ile Thr Cys Pro Asn Val Asp<\ 130 135 140 Gly Tyr Phe Pro Ser Ser Val Lys Pro Ser Val Thr Trp Tyr Lys Gly 145 150 155 160 Cys Thr Glu Ile Val Asp Phe His Asn Val Leu Pro Glu Gly Met Asn 165 170 175 Leu Ser Phe Phe Ile Pro Leu Val Ser Asn Asn Gly Asn Tyr Thr Cys 180 185 190 Val Val Thr Tyr Pro Glu Asn Gly Arg Leu Phe His Leu Thr Arg Thr 195 200 205 Val Thr Val Lys Val Val Gly Ser Pro Lys Asp Ala Leu Pro Pro Gln 210 215 220 Ile Tyr Ser Pro Asn Asp Arg Val Val Tyr Glu Lys Glu Pro Gly Glu 225 230 235 240 Glu Leu Val Ile Pro Cys Lys Val Tyr Phe Ser Phe Ile Met Asp Ser 245 250 255 His Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Val 260 265 270 Thr Val Asp Ile Thr Ile Asn Glu Ser Val Ser Tyr Ser Ser Thr Glu 275 280 285 Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Pro Glu 290 295 300 Asp Leu Arg Arg Asn Tyr Val Cys His Ala Arg Asn Thr Lys Gly Glu 305 310 315 320 Ala Glu Gln Ala Ala Lys Val Lys Gln Lys Val Ile Pro Pro Arg Tyr 325 330 335 Thr Val Glu <210> 332 <211> 227 <212> PRT <213> Artificial Sequence <220> <223> Human IgG1 Fc <400> 332 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 1 5 10 15 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 20 25 30 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 35 40 45 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 50 55 60 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 65 70 75 80 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 85 90 95 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 100 105 110 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 115 120 125 Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser 130 135 140 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 145 150 155 160 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 165 170 175 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 180 185 190 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 195 200 205 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 210 215 220 Pro Gly Lys 225 <210> 333 <211> 233 <212> PRT <213> Artificial Sequence <220> <223> Mouse IgG2a Fc <400> 333 Glu Pro Arg Gly Pro Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro 1 5 10 15 Ala Pro Asn Leu Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys 20 25 30 Ile Lys Asp Val Leu Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val 35 40 45 Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 50 55 60 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 65 70 75 80 Asp Tyr Asn Ser Thr Leu Arg Val Val Ser Ala Leu Pro Ile Gln His 85 90 95 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 100 105 110 Asp Leu Pro Ala Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser 115 120 125 Val Arg Ala Pro Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met 130 135 140 Thr Lys Lys Gln Val Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro 145 150 155 160 Glu Asp Ile Tyr Val Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn 165 170 175 Tyr Lys Asn Thr Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met 180 185 190 Tyr Ser Lys Leu Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser 195 200 205 Tyr Ser Cys Ser Val Val His Glu Gly Leu His Asn His His Thr Thr 210 215 220 Lys Ser Phe Ser Arg Thr Pro Gly Lys 225 230 <210> 334 <211> 167 <212> PRT <213> Artificial Sequence <220> <223> Cynomolgus IL-33-6His <400> 334 Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Ser Leu Ala Ser Leu Ser 1 5 10 15 Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr 20 25 30 Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Lys Lys Lys Asp Lys Val 35 40 45 Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Ser Glu Ser Gly Asp 50 55 60 Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp 65 70 75 80 Phe Trp Leu Gln Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys 85 90 95 Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Arg 100 105 110 Ser Phe Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe 115 120 125 Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Tyr Ser 130 135 140 Glu Asn Leu Gly Ser Glu Asn Ile Leu Phe Lys Leu Ser Glu Ile Leu 145 150 155 160 Glu His His His His His His 165 <210> 335 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> HCVR - murine surrogate IL - 4R Ab <400> 335 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Arg Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Ile His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Pro Asn Asn Gly Asp Asn Gly Tyr Asn Gln Lys Phe 50 55 60 Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Arg Leu Arg Tyr Phe Asp Val Trp Gly Thr Gly Thr Thr 100 105 110 Val Thr Val Ser Ser 115 <210> 336 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> LCVR - mouse substitute IL - 4R Ab <400> 336 Asn Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr 20 25 30 Gly His Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro 35 40 45 Lys Leu Leu Ile Tyr Leu Ala Ser Asn Leu Glu Ser Gly Val Pro Ala 50 55 60 Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Leu Asp 65 70 75 80 Pro Val Glu Ala Asp Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn 85 90 95 Glu Asp Pro Pro Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 337 <211> 124 <212> PRT <213> Artificial Sequence <220> <223> Dupilumab HCVR <400> 337 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Glu Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Gly Ser Gly Gly Asn Thr 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[[ID=!5]] Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 115 120 <210> 338 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Dupilumab LCVR <400> 338 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Ile Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Ser Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala 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 Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Ala 85 90 95 Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 339 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Dupilumab HCDR1 <400> 339 Gly Phe Thr Phe Arg Asp Tyr Ala 1 5 <210> 340 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Dupilumab HCDR2 <400> 340 Ile Ser Gly Ser Gly Gly Asn Thr 1 5 <210> 341 <211> 18 <212> PRT <213> Artificial Sequence <220> <223> Dupilumab HCDR3 <400> 341 Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu 1 5 10 15 Asp Val <210> 342 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Dupilumab LCDR1 <400> 342 Gln Ser Leu Leu Tyr Ser Ile Gly Tyr Asn Tyr 1 5 10 <210> 343 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> Dupilumab LCDR2 <400> 343 Leu Gly Ser 1 <210> 344 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Dupilumab LCDR3 <400> 344 Met Gln Ala Leu Gln Thr Pro Tyr Thr 1 5 <210> 345 <211> 451 <212> PRT <213> Artificial Sequence <220> <223> Dupilumab heavy chain <400> 345 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Glu Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Gly Ser Gly Phe Thr Phe Arg Asp Tyr 20 25 30 Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser Gly Ser Gly Gly Asn Thr 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 Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu 100 105 110 Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr 115 120 125 Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser 130 135 140 Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu 145 150 155 160 Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His 165 170 175 Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser 180 185 190 Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys 195 200 205 Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu 210 215 220 Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 245 250 255 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 260 265 270 Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu 275 280 285 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr 290 295 300 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 305 310 315 320 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser 325 330 335 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 340 345 350 Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val 355 360 365 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 370 375 380 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr 405 410 415 Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val 420 425 430 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 435 440 445 Ser Leu Gly 450 <210> 346 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> Dupilumab light chain <400> 346 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu Tyr Ser 20 25 30 Ile Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Ser Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Leu Gly Ser Asn Arg Ala 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 Ala Glu Asp Val Gly Phe Tyr Tyr Cys Met Gln Ala 85 90 95 Leu Gln Thr Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 347 <211> 207 <212> PRT <213> Artificial Sequence <220> <223> Human IL-4Rα <400> 347 Met Lys Val Leu Gln Glu Pro Thr Cys Val Ser Asp Tyr Met Ser Ile 1 5 10 15 Ser Thr Cys Glu Trp Lys Met Asn Gly Pro Thr Asn Cys Ser Thr Glu 20 25 30 Leu Arg Leu Leu Tyr Gln Leu Val Phe Leu Leu Ser Glu Ala His Thr 35 40 45 Cys Ile Pro Glu Asn Asn Gly Gly Ala Gly Cys Val Cys His Leu Leu 50 55 60 Met Asp Asp Val Val Ser Ala Asp Asn Tyr Thr Leu Asp Leu Trp Ala 65 70 75 80 Gly Gln Gln Leu Leu Trp Lys Gly Ser Phe Lys Pro Ser Glu His Val 85 90 95 Lys Pro Arg Ala Pro Gly Asn Leu Thr Val His Thr Asn Val Ser Asp 100 105 110 Thr Leu Leu Leu Thr Trp Ser Asn Pro Tyr Pro Pro Asp Asn Tyr Leu 115 120 125 Tyr Asn His Leu Thr Tyr Ala Val Asn Ile Trp Ser Glu Asn Asp Pro 130 135 140 Ala Asp Phe Arg Ile Tyr Asn Val Thr Tyr Leu Glu Pro Ser Leu Arg 145 150 155 160 Ile Ala Ala Ser Thr Leu Lys Ser Gly Ile Ser Tyr Arg Ala Arg Val 165 170 175 Arg Ala Trp Ala Gln Cys Tyr Asn Thr Thr Trp Ser Glu Trp Ser Pro 180 185 190 Ser Thr Lys Trp His Asn Ser Tyr Arg Glu Pro Phe Glu Gln His 195 200 205 <210> 348 <211> 270 <212> PRT <213> Artificial Sequence <220> <223> hIL33_O95760 (Before proteolytic processing) <400> 348 Met Lys Pro Lys Met Lys Tyr Ser Thr Asn Lys Ile Ser Thr Ala Lys 1 5 10 15 Trp Lys Asn Thr Ala Ser Lys Ala Leu Cys Phe Lys Leu Gly Lys Ser 20 25 30 Gln Gln Lys Ala Lys Glu Val Cys Pro Met Tyr Phe Met Lys Leu Arg 35 40 45 Ser Gly Leu Met Ile Lys Lys Glu Ala Cys Tyr Phe Arg Arg Glu Thr 50 55 60 Thr Lys Arg Pro Ser Leu Lys Thr Gly Arg Lys His Lys Arg His Leu 65 70 75 80 Val Leu Ala Ala Cys Gln Gln Gln Ser Thr Val Glu Cys Phe Ala Phe 85 90 95 Gly Ile Ser Gly Val Gln Lys Tyr Thr Arg Ala Leu His Asp Ser Ser 100 105 110 Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu Ser Thr 115 120 125 Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr Glu 130 135 140 Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys Val Leu 145 150 155 160 Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly Asp Gly 165 170 175 Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp Phe 180 185 190 Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys Cys 195 200 205 Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Met His 210 215 220 Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe Ile 225 230 235 240 Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser Ser Glu 245 250 255 Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr 260 265 270 <210> 349 <211> 159 <212> PRT <213> Artificial Sequence <220> <223> hIL33_mature_PEPTIDE (after proteolytic processing) <400> 349 Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu Ser 1 5 10 15 Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser Tyr 20 25 30 Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys Val 35 40 45 Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly Asp 50 55 60 Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys Asp 65 70 75 80 Phe Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His Lys 85 90 95 Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn Met 100 105 110 His Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val Phe 115 120 125 Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser Ser 130 135 140 Glu Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr 145 150 155 <210> 350 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Amino acid residues 1-12 of SEQ ID NO: 349 also correspond to residues 112-123 of SEQ ID NO: 348 (Uniprot O95760). <400> 350 Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu 1 5 10 <210> 351 <211> 87 <212> PRT <213> Artificial Sequence <220> <223> Amino acid residues 50-94 of SEQ ID NO: 349 also correspond to residues 161-205 of SEQ ID NO: 348 (Uniprot O95760). <400> 351 Ile Thr Glu Tyr Leu Ala Ser Leu Ser Thr Tyr Asn Asp Gln Ser Ile 1 5 10 15 Thr Phe Ala Leu Glu Asp Glu Ser Tyr Glu Ile Tyr Val Glu Asp Leu 20 25 30 Lys Lys Asp Glu Lys Lys Asp Lys Val Leu Leu Ser Tyr Tyr Glu Ser 35 40 45 Gln His Pro Ser Asn Glu Ser Gly Asp Gly Val Asp Gly Lys Met Leu 50 55 60 Met Val Thr Leu Ser Pro Thr Lys Asp Phe Trp Leu His Ala Asn Asn 65 70 75 80 Lys Glu His Ser Val Glu Leu 85 <210> 352 <211> 556 <212> PRT <213> Artificial Sequence <220> <223> Human ST2 (see GenBank accession number NP_057316) <400> 352 Met Gly Phe Trp Ile Leu Ala Ile Leu Thr Ile Leu Met Tyr Ser Thr 1 5 10 15 Ala Ala Lys Phe Ser Lys Gln Ser Trp Gly Leu Glu Asn Glu Ala Leu 20 25 30 Ile Val Arg Cys Pro Arg Gln Gly Lys Pro Ser Tyr Thr Val Asp Trp 35 40 45 Tyr Tyr Ser Gln Thr Asn Lys Ser Ile Pro Thr Gln Glu Arg Asn Arg 50 55 60 Val Phe Ala Ser Gly Gln Leu Leu Lys Phe Leu Pro Ala Ala Val Ala 65 70 75 80 Asp Ser Gly Ile Tyr Thr Cys Ile Val Arg Ser Pro Thr Phe Asn Arg 85 90 95 Thr Gly Tyr Ala Asn Val Thr Ile Tyr Lys Lys Gln Ser Asp Cys Asn 100 105 110 Val Pro Asp Tyr Leu Met Tyr Ser Thr Val Ser Gly Ser Glu Lys Asn 115 120 125 Ser Lys Ile Tyr Cys Pro Thr Ile Asp Leu Tyr Asn Trp Thr Ala Pro 130 135 140 Leu Glu Trp Phe Lys Asn Cys Gln Ala Leu Gln Gly Ser Arg Tyr Arg 145 150 155 160 Ala His Lys Ser Phe Leu Val Ile Asp Asn Val Met Thr Glu Asp Ala 165 170 175 Gly Asp Tyr Thr Cys Lys Phe Ile His Asn Glu Asn Gly Ala Asn Tyr 180 185 190 Ser Val Thr Ala Thr Arg Ser Phe Thr Val Lys Asp Glu Gln Gly Phe 195 200 205 Ser Leu Phe Pro Val Ile Gly Ala Pro Ala Gln Asn Glu Ile Lys Glu 210 215 220 Val Glu Ile Gly Lys Asn Ala Asn Leu Thr Cys Ser Ala Cys Phe Gly 225 230 235 240 Lys Gly Thr Gln Phe Leu Ala Ala Val Leu Trp Gln Leu Asn Gly Thr 245 250 255 Lys Ile Thr Asp Phe Gly Glu Pro Arg Ile Gln Gln Glu Glu Gly Gln 260 265 270 Asn Gln Ser Phe Ser Asn Gly Leu Ala Cys Leu Asp Met Val Leu Arg 275 280 285 Ile Ala Asp Val Lys Glu Glu Asp Leu Leu Leu Gln Tyr Asp Cys Leu 290 295 300 Ala Leu Asn Leu His Gly Leu Arg Arg His Thr Val Arg Leu Ser Arg 305 310 315 320 Lys Asn Pro Ile Asp His His Ser Ile Tyr Cys Ile Ile Ala Val Cys 325 330 335 Ser Val Phe Leu Met Leu Ile Asn Val Leu Val Ile Ile Leu Lys Met 340 345 350 Phe Trp Ile Glu Ala Thr Leu Leu Trp Arg Asp Ile Ala Lys Pro Tyr 355 360 365 Lys Thr Arg Asn Asp Gly Lys Leu Tyr Asp Ala Tyr Val Val Tyr Pro 370 375 380 Arg Asn Tyr Lys Ser Ser Thr Asp Gly Ala Ser Arg Val Glu His Phe 385 390 395 400 Val His Gln Ile Leu Pro Asp Val Leu Glu Asn Lys Cys Gly Tyr Thr 405 410 415 Leu Cys Ile Tyr Gly Arg Asp Met Leu Pro Gly Glu Asp Val Val Thr 420 425 430 Ala Val Glu Thr Asn Ile Arg Lys Ser Arg Arg His Ile Phe Ile Leu 435 440 445 Thr Pro Gln Ile Thr His Asn Lys Glu Phe Ala Tyr Glu Gln Glu Val 450 455 460 Ala Leu His Cys Ala Leu Ile Gln Asn Asp Ala Lys Val Ile Leu Ile 465 470 475 480 Glu Met Glu Ala Leu Ser Glu Leu Asp Met Leu Gln Ala Glu Ala Leu 485 490 495 Gln Asp Ser Leu Gln His Leu Met Lys Val Gln Gly Thr Ile Lys Trp 500 505 510 Arg Glu Asp His Ile Ala Asn Lys Arg Ser Leu Asn Ser Lys Phe Trp 515 520 525 Lys His Val Arg Tyr Gln Met Pro Val Pro Ser Lys Ile Pro Arg Lys 530 535 540 Ala Ser Ser Leu Thr Pro Leu Ala Ala Gln Lys Gln 545 550 555 <210> 353 <211> 570 <212> PRT <213> Artificial Sequence <220> <223> Human IL-1RAcP (see GenBank accession number Q9NPH3) <400> 353 Met Thr Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu 1 5 10 15 Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met 20 25 30 Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro 35 40 45 Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala 50 55 60 Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu 65 70 75 80 Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys 85 90 95 Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr 100 105 110 Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro 115 120 125 Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu 130 135 140 Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys 145 150 155 160 Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr 165 170 175 Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro 180 185 190 Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly 195 200 205 Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His 210 215 220 Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala 225 230 235 240 Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys 245 250 255 Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe 260 265 270 Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys 275 280 285 Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His 290 295 300 Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys 305 310 315 320 Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser 325 330 335 Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro 340 345 350 Ala Pro Arg Tyr Thr Val Glu Leu Ala Cys Gly Phe Gly Ala Thr Val 355 360 365 Leu Leu Val Val Ile Leu Ile Val Val Tyr His Val Tyr Trp Leu Glu 370 375 380 Met Val Leu Phe Tyr Arg Ala His Phe Gly Thr Asp Glu Thr Ile Leu 385 390 395 400 Asp Gly Lys Glu Tyr Asp Ile Tyr Val Ser Tyr Ala Arg Asn Ala Glu 405 410 415 Glu Glu Glu Phe Val Leu Leu Thr Leu Arg Gly Val Leu Glu Asn Glu 420 425 430 Phe Gly Tyr Lys Leu Cys Ile Phe Asp Arg Asp Ser Leu Pro Gly Gly 435 440 445 Ile Val Thr Asp Glu Thr Leu Ser Phe Ile Gln Lys Ser Arg Arg Leu 450 455 460 Leu Val Val Leu Ser Pro Asn Tyr Val Leu Gln Gly Thr Gln Ala Leu 465 470 475 480 Leu Glu Leu Lys Ala Gly Leu Glu Asn Met Ala Ser Arg Gly Asn Ile 485 490 495 Asn Val Ile Leu Val Gln Tyr Lys Ala Val Lys Glu Thr Lys Val Lys 500 505 510 Glu Leu Lys Arg Ala Lys Thr Val Leu Thr Val Ile Lys Trp Lys Gly 515 520 525 Glu Lys Ser Lys Tyr Pro Gln Gly Arg Phe Trp Lys Gln Leu Gln Val 530 535 540 Ala Met Pro Val Lys Lys Ser Pro Arg Arg Ser Ser Ser Asp Glu Gln 545 550 555 560 Gly Leu Ser Tyr Ser Ser Leu Lys Asn Val 565 570 <210> 354 <211> 449 <212> PRT <213> Artificial Sequence(Artificial Sequence) <220> <223> HC of H4H9675P <400> 354 Glu Val Gln Leu Val Glu Ser Gly Gly Asn Leu Glu Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Arg Ser 20 25 30 Ala Met Asn Trp Val Arg Arg Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Ser Gly Ser Gly Gly Arg Thr 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 Ser Ala Glu Asp Thr Ala Ala Tyr Tyr Cys 85 90 95 Ala Lys Asp Ser Tyr Thr Thr Ser Trp Tyr Gly Gly Met Asp Val Trp 100 105 110 Gly His Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 115 120 125 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 130 135 140 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr 180 185 190 Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp 195 200 205 His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr 210 215 220 Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro 225 230 235 240 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp 260 265 270 Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285 Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val 290 295 300 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 305 310 315 320 Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys 325 330 335 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350 Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 385 390 395 400 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys 405 410 415 Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly 435 440 445 Lys <210> 355 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> LC of H4H9675P <400> 355 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Phe 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 Ile Tyr Tyr Cys Gln Gln Ala Asn Ser Val Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 356 <211> 166 <212> PRT <213> Artificial Sequence <220> <223> Human IL-33 with the HEXA-HIS tag (amino acid 112-270, GENBANK Registry No. O95760) <400> 356 Met Ser Ile Thr Gly Ile Ser Pro Ile Thr Glu Tyr Leu Ala Ser Leu 1 5 10 15 Ser Thr Tyr Asn Asp Gln Ser Ile Thr Phe Ala Leu Glu Asp Glu Ser 20 25 30 Tyr Glu Ile Tyr Val Glu Asp Leu Lys Lys Asp Glu Lys Lys Asp Lys 35 40 45 Val Leu Leu Ser Tyr Tyr Glu Ser Gln His Pro Ser Asn Glu Ser Gly 50 55 60 Asp Gly Val Asp Gly Lys Met Leu Met Val Thr Leu Ser Pro Thr Lys 65 70 75 80 Asp Phe Trp Leu His Ala Asn Asn Lys Glu His Ser Val Glu Leu His 85 90 95 Lys Cys Glu Lys Pro Leu Pro Asp Gln Ala Phe Phe Val Leu His Asn 100 105 110 Met His Ser Asn Cys Val Ser Phe Glu Cys Lys Thr Asp Pro Gly Val 115 120 125 Phe Ile Gly Val Lys Asp Asn His Leu Ala Leu Ile Lys Val Asp Ser 130 135 140 Ser Glu Asn Leu Cys Thr Glu Asn Ile Leu Phe Lys Leu Ser Glu Thr 145 150 155 160 His His His His His His 165 <210> 357 <211> 51 <212> DNA <213> Artificial Sequence <220> <223> Synthetic <220> <221> n is g or a <222> (26) .. (26) <400> 357 tataccatca caaagcctct cattanactt tgaatccaat gagtattact a 51 <210> 358 <211> 51 <212> DNA <213> Artificial Sequence <220> <223> synthesis <220> <221> n is either g or t <222> (26) .. (26) <400> 358 ccaatctttt ctcatgaaga caccancatg acctcttatt cttatttata t 51

Claims

1. The use of a combination of IL33 antagonists and IL-4R antagonists in the preparation of a medicament for the treatment or inhibition of eosinophilic asthma in a subject, wherein: The subject possesses intronic IL1RL1 variants rs1420101 and IL33 variants rs1342326. Intronic IL1RL1 variant rs1420101 has the nucleotide sequence shown in SEQ ID NO:357, and IL33 variant rs1342326 has the nucleotide sequence shown in SEQ ID NO:

358. The IL33 antagonist comprises an antibody or its antigen-binding fragment that specifically binds to IL33. The antibody or its antigen-binding fragment that specifically binds to IL33 comprises a heavy chain complementarity-determining region 1 (HCDR1) consisting of the amino acid sequence shown in SEQ ID NO:276, an HCDR2 consisting of the amino acid sequence shown in SEQ ID NO:278, and an HCDR3 consisting of the amino acid sequence shown in SEQ ID NO:

280. The antibody or its antigen-binding fragment that specifically binds to IL33 further comprises a light chain complementarity-determining region 1 (LCDR1) consisting of the amino acid sequence shown in SEQ ID NO:284, an LCDR2 consisting of the amino acid sequence shown in SEQ ID NO:286, and an LCDR3 consisting of the amino acid sequence shown in SEQ ID NO:288; and The IL-4R antagonist comprises an antibody or its antigen-binding fragment that specifically binds to IL-4R. The antibody or its antigen-binding fragment that specifically binds to IL-4R comprises a heavy chain complementarity-determining region 1 (HCDR1) consisting of the amino acid sequence shown in SEQ ID NO:339, an HCDR2 consisting of the amino acid sequence shown in SEQ ID NO:340, and an HCDR3 consisting of the amino acid sequence shown in SEQ ID NO:

341. The antibody or its antigen-binding fragment that specifically binds to IL-4R further comprises a light chain complementarity-determining region 1 (LCDR1) consisting of the amino acid sequence shown in SEQ ID NO:342, an LCDR2 consisting of the amino acid sequence shown in SEQ ID NO:343, and an LCDR3 consisting of the amino acid sequence shown in SEQ ID NO:

344.

2. The use according to claim 1, wherein the subject has two risk alleles associated with eosinophilic asthma in the intron IL1RL1 variant rs1420101 having the nucleotide sequence shown in SEQ ID NO:

357.

3. The use according to claim 1, wherein the subject has two risk alleles associated with eosinophilic asthma in the IL33 variant rs1342326 having the nucleotide sequence shown in SEQ ID NO:

358.

4. The use according to any one of claims 1-3, wherein the treatment or inhibition comprises administering to the subject a combination of the IL33 antagonist and the IL-4R antagonist.

5. Use of a combination of IL33 antagonists and IL-4R antagonists in the preparation of a medicament for the treatment or inhibition of hypereosinophilic eosinophilic asthma in a subject, wherein: The subject has an intronic IL1RL1 variant rs1420101 and an IL33 variant rs1342326, the intronic IL1RL1 variant rs1420101 having the nucleotide sequence shown in SEQ ID NO:357, and the IL33 variant rs1342326 having the nucleotide sequence shown in SEQ ID NO:358; The IL33 antagonist comprises an antibody or its antigen-binding fragment that specifically binds to IL33. The antibody or its antigen-binding fragment that specifically binds to IL33 comprises a heavy chain complementarity-determining region 1 (HCDR1) consisting of the amino acid sequence shown in SEQ ID NO:276, an HCDR2 consisting of the amino acid sequence shown in SEQ ID NO:278, and an HCDR3 consisting of the amino acid sequence shown in SEQ ID NO:

280. The antibody or its antigen-binding fragment that specifically binds to IL33 further comprises a light chain complementarity-determining region 1 (LCDR1) consisting of the amino acid sequence shown in SEQ ID NO:284, an LCDR2 consisting of the amino acid sequence shown in SEQ ID NO:286, and an LCDR3 consisting of the amino acid sequence shown in SEQ ID NO:288; and; The IL-4R antagonist comprises an antibody or its antigen-binding fragment that specifically binds to IL-4R. The antibody or its antigen-binding fragment that specifically binds to IL-4R comprises a heavy chain complementarity-determining region 1 (HCDR1) consisting of the amino acid sequence shown in SEQ ID NO:339, an HCDR2 consisting of the amino acid sequence shown in SEQ ID NO:340, and an HCDR3 consisting of the amino acid sequence shown in SEQ ID NO:

341. The antibody or its antigen-binding fragment that specifically binds to IL-4R further comprises a light chain complementarity-determining region 1 (LCDR1) consisting of the amino acid sequence shown in SEQ ID NO:342, an LCDR2 consisting of the amino acid sequence shown in SEQ ID NO:343, and an LCDR3 consisting of the amino acid sequence shown in SEQ ID NO:

344.

6. The use according to claim 5, wherein the subject has two risk alleles associated with hypereosinophilic eosinophilic asthma in the intron IL1RL1 variant rs1420101 having the nucleotide sequence shown in SEQ ID NO:

357.

7. The use according to claim 5, wherein the subject has two risk alleles associated with hypereosinophilic eosinophilic asthma in the IL33 variant rs1342326 having the nucleotide sequence shown in SEQ ID NO:

358.

8. The use according to any one of claims 5-7, wherein the treatment or inhibition comprises administering to the subject a combination of the IL33 antagonist and the IL-4R antagonist.

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