TWI739625B - Methods for treating or preventing asthma by administering an il-4r antagonist - Google Patents

Abstract

The present invention provides methods for treating or preventing asthma and associated conditions in a patient. The methods of the present invention comprise administering to a subject in need thereof a therapeutic composition comprising an interleukin-4 receptor (IL-4R) antagonist, such as an anti-IL-4R antibody.

Description

Methods of administering IL-4R antagonists to treat or prevent asthma

This application is claiming that the United States Provisional Application No. 61/691,625 filed on August 21, 2012; the United States Provisional Application No. 61/758,097 filed on January 29, 2013; the United States filed on February 6, 2013 Provisional Application No. 61/761,279; U.S. Provisional Application No. 61/783,796 filed on March 14, 2013; U.S. Provisional Application No. 61/805,797 filed on March 27, 2013; and July 2013 Priority benefits of French application No. 1357994 filed on the 15th. The content of each of the aforementioned applications is incorporated herein by reference in its entirety.

The present invention relates to the treatment and/or prevention of asthma and related symptoms. More specifically, the present invention relates to the administration of an interleukin-4 receptor (IL-4R) antagonist to treat or prevent asthma in patients in need thereof.

Asthma is a chronic inflammatory disease of the trachea, which is characterized by tracheal overreaction, acute and chronic bronchoconstriction, tracheal edema and mucus blockage. The inflammatory component of asthma is thought to involve many cell types, including mast cells, eosinophils, T lymphocytes, neutrophils and epithelial cells and their biological products. Patients with asthma often experience symptoms of wheezing, shortness of breath, coughing and chest tightness. For most asthmatics, control agent therapy and bronchodilator therapy provide adequate long-term control. Inhaled corticosteroids (ICS) are regarded as the "gold standard" for controlling asthma symptoms, and β2-agonists are currently the most effective bronchodilators available. Studies have shown that the combination therapy of ICS and inhaled long-acting β2-agonist (LABA) provides better asthma control than high-dose ICS alone. Therefore, combination therapy has become the recommended treatment for patients who cannot be controlled by low-dose ICS alone.

However, despite the recommended treatment with the largest combination of anti-inflammatory and bronchodilator drugs, it is estimated that 5% to 10% of the population suffering from asthma have symptomatic disease. Furthermore, this severe asthmatic population accounts for up to 50% of the total health care burden through hospitalization, use of emergency services and irregular doctor visits. Due to some cellular and molecular mechanisms that make many of these patients have a poor response to ICS, the severely asthmatic population has an unmet need for new treatments. In addition, the long-term deleterious effects of systemic and inhaled corticosteroids on bone metabolism, adrenal function, and child growth have led to a tendency to minimize the use of corticosteroids. Although a large proportion of asthma patients are well controlled with current treatments, patients with severe corticosteroids-difficult to treat asthma have very few treatment options to adequately control the disease. No response to treatment or lack of compliance to treatment results in out of control of asthma and finally worsening of asthma.

One of the reasons for the poor response to drugs in some patients with severe asthma may be the heterogeneity of the disease. It is more beneficial to understand these different phenotypes, because for patients with similar underlying pathobiological characteristics, targeted therapy is more likely to be successful. Recent asthma treatments have focused on trying to control the response of T helper cells-2. The up-regulation of interleukin-4 (IL-4) and interleukin-13 (IL-13) has meant that an important inflammatory component in the process of asthmatic disease.

Therefore, there is a need for novel targeted therapies for the treatment and/or prevention of asthma in this technology.

According to one aspect of the present invention, a method for reducing the incidence of exacerbation of asthma is provided in subjects in need. In a related aspect, a method for improving one or more parameters related to the trachea is provided in objects in need. In another aspect of the present invention, a method for treating asthma, such as moderate to severe eosinophilic asthma, is provided in patients in need.

The characteristic method of the present invention includes administering a therapeutically effective amount of a pharmaceutical composition including an interleukin-4 receptor (IL-4R) antagonist to a subject. According to a specific embodiment, the IL-4R antagonist is an antibody or an antigen-binding fragment thereof that specifically binds to IL-4R. An exemplary anti-IL-4R that can be used in the context of the method of the present invention is described elsewhere in the text, including Operation Example 1. For example, in one embodiment, the IL-4R antagonist is an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, and includes the heavy chain variable region (HCVR) and Light chain variable region (LCVR) heavy chain and light chain (complementarity determining region) CDR sequences.

In one example, by administering an antibody or antigen-binding fragment thereof that specifically binds to IL-4R, a method for reducing the incidence of one or more exacerbations of asthma is provided in a subject in need thereof. Asthma worsening can be one or more of the following: (a) The morning maximum expiratory flow (PEF) is reduced by 30% or more compared to baseline for two consecutive days; (b) On two consecutive days, within a 24-hour period (with baseline Compared with) six or more inhalations of additional albuterol or levalbuterol relievers; and (c) exacerbation of asthma requires: (i) systemic (oral and/or non-absorbent) Enteral) steroid therapy, or (ii) inhaled corticosteroids increased to at least 4 times the last dose received before stopping the drug, or hospitalization.

In various embodiments, the method for improving one or more asthma-related parameters includes administering a therapeutically effective amount of IL-4R antagonist to a subject in need thereof, wherein the improvement of the asthma-related parameters is defined as the following One of them: Compared with baseline, FEV1 increased; compared with baseline, AM PEF increased; compared with baseline, PM PEF increased; compared with baseline, the use of salatinol or levosatinol decreased; compared with baseline Reduced nighttime awakening in comparison; and/or reduced SNOT-22 score compared to baseline. Examples of asthma-related parameters include: (a) Forced expiratory volume in 1 second (FEV1); (b) Maximum expiratory flow rate (PEF), including morning PEF (AM PEF) and evening PEF (PM PEF); (c) Use of inhaled bronchodilators, such as salbutamol or levalbuterol; (d) 5 asthma control questionnaire (ACQ5) scores; (e) night awakening; and (f) 22 sinus outcome test (SNOT-22) scores. In one embodiment, the improvement in asthma-related parameters is an increase in FEV1 by at least 0.10 L compared to baseline. In one embodiment, the improvement in asthma-related parameters is an increase in AM PEF by at least 10.0 L/min compared to baseline. In one embodiment, the improvement in asthma-related parameters is an increase in PM PEF by at least 1.0 L/min compared to baseline. In one embodiment, the improvement in asthma-related parameters is a reduction in the use of salbutamol/levosalbutamol by at least 1 dose per day compared to baseline. In one embodiment, the improvement in asthma-related parameters is a decrease in ACQ5 score by at least 0.5 points compared to baseline. In one embodiment, the improvement in asthma-related parameters is a reduction in awakening at least 0.2 times per night compared to baseline. In one embodiment, the improvement in asthma-related parameters is a reduction in SNOT-22 score by at least 5 points compared to baseline.

The present invention also provides methods for reducing the incidence of asthma exacerbation or improving one or more asthma-related parameters in subjects in need, wherein the methods include successively administering a single initial dose to subjects in need A pharmaceutical composition comprising an IL-4R antagonist (for example, an anti-IL 4R antibody or an antigen-binding fragment thereof), followed by one or more second doses of the pharmaceutical composition comprising an IL-4R antagonist. The pharmaceutical composition including IL-4R antagonist can be administered subcutaneously, intranasally or intravenously to a subject in need.

According to a specific embodiment, the present invention provides methods for reducing the incidence of exacerbation of asthma or improving one or more parameters related to asthma in a subject in need thereof, wherein the methods include administering about 75 to about 75% to the subject. 300 mg of a pharmaceutical composition including an antibody or antigen-binding fragment thereof that specifically binds to IL-4R. According to this aspect, the pharmaceutical composition can be administered to the subject at a dosing frequency of, for example, once a week.

The present invention further includes selecting a subject with one or more asthma symptoms or signs, and administering to the patient a pharmaceutical composition comprising an IL-4R antagonist (for example, an anti-IL 4R antibody or an antigen-binding fragment thereof) , For the treatment of asthma (such as eosinophilic asthma, moderate to severe eosinophilic asthma, etc.), wherein the subject has one or more of the following asthma symptoms or signs: (1) The subject is stable before screening A dose of fluticasone/salmeterol combination therapy (250/50 µg BID or 500/50 µg BID), or budesonide/formoterol combination therapy (160/9 µg BID or 320/9 µg BID) treatment for at least 3 months; (2) The subject has blood eosinophils greater than or equal to 300 cells/µL; (3) The subject has phlegm eosinophilia greater than or equal to 3% Cells; (4) The subject has elevated amounts of IgE, thymus and activation regulatory chemotactic hormone (TARC), eosinophil chemotactic hormone-3 (eotaxin-3), carcinoembryonic antigen (CEA), YKL-40 or Periostin; (5) the subject has an elevated expiratory nitric oxide fraction (FeNO); and/or (6) the subject has an asthma control questionnaire (ACQ5) score greater than or equal to 1.0.

A characteristic embodiment of the present invention relates to the above-mentioned treatment method, which further comprises administering a combination of a second therapeutic agent and an IL-4R antagonist. This second therapeutic agent can be administered to a subject in need before, after, or at the same time as the IL-4R antagonist. Exemplary second therapeutic agents include (but are not limited to) one or more of the following combinations: IL-1 inhibitors, IL-5 inhibitors, IL-8 inhibitors, IgE inhibitors, tumor apoptosis factor (TNF) inhibitors, Corticosteroids, long-acting β2-agonists and leukotriene inhibitors.

In another aspect, the present invention provides to reduce or eliminate the dependence of asthma patients on background asthma therapy, which includes selecting patients with moderate to severe asthma that cannot be controlled or partially controlled by background asthma therapy; and a defined dose of IL- The 4R antagonist is administered to the patient while maintaining the patient's background treatment; and during a subsequent treatment period, the dose of one or more components of the background treatment is gradually reduced, while the IL-4R antagonist is continuously administered. In certain embodiments, the background treatment includes inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), or a combination of ICS and LABA. In some embodiments, the background treatment is gradually reduced or withdrawn over a period of 2-8 weeks. In some embodiments, after an initial treatment period, a component of the background treatment is removed. In one embodiment, the background treatment is gradually reduced during a subsequent treatment period.

In yet another aspect, the present invention is based on selection of biomarkers with elevated amounts, such as thymus and activation regulatory chemotactic hormone (TARC), IgE, eotaxin-3 (eotaxin-3), periostin (periostin), carcinoembryonic antigen (CEA) or YKL-40, or patients with increased expiratory nitric oxide fraction (FeNO); and administer a therapeutically effective amount of IL-4R antagonist to the patient To provide a way to identify patients and treat moderate to severe asthma.

In another aspect, the present invention features a method for monitoring the efficacy of treatment of moderate to severe asthma in a subject, for example, by (a) determining a biological sample obtained from the subject before treatment with an IL-4R antagonist The expression level of biomarkers, such as one or two TARC or eosinophil chemoattractant-3, or IgE total serum level; (b) Determine the amount of the biological sample obtained from the subject after treatment with IL-4R antagonist The expression level of the biomarker; (c) compare the expression level measured in step (a) with the amount in step (b), and (d) when the amount measured in step (b) is lower than that in step (a) When the measured amount is determined, it is concluded that the treatment is effective, or when the amount determined in step (b) is equal to or higher than the amount determined in step (a), it is concluded that the treatment is ineffective.

In one embodiment, the biomarker is FeNO, and if FeNO is reduced after administration of the antagonist, it is determined that the treatment with the IL-4R antagonist is effective.

After the IL-4R antagonist is administered, for example, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or more, the expression level of the biomarker can be determined and compared with the expression level before the administration of the antagonist. The dose of IL-4R antagonist (e.g., anti-IL4R antibody) or administration therapy can be adjusted after the determination. For example, if the biomarker performance cannot be reduced within 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks or more after the administration of the antagonist, the treatment of the antagonist can be stopped, or the dose of the antagonist can be increased. If the performance of the biomarker is reduced after the administration of the antagonist, the dose of the antagonist can be maintained or reduced in order to identify the minimum effective dose. In certain embodiments, the treatment is maintained at a minimum effective dose.

In another aspect, the present invention features a method for monitoring the response of a subject to IL-4R antagonist treatment, wherein the subject has moderate to severe asthma, such as obtaining information related to biomarker performance, such as in the administration of After IL-4R antagonist, one or two TARC or eosinophil chemokine-3, or IgE total serum levels in the subject’s biological sample, and when compared with the amount before IL-4R antagonist treatment, If the manifestation of the biomarker decreases, provide an indication that treatment should be continued. In one embodiment, the biomarker is FeNO, and after the antibody is administered, it is determined that the amount of FeNO is reduced, which provides an indication of continued treatment with the IL-4R antagonist.

The present invention also includes the use of IL-4R antagonists as disclosed in the text for the manufacture of pharmaceuticals for the treatment and/or prevention of asthma (for example, eosinophilic asthma, moderate to severe eosinophilic asthma, etc.), or for the treatment of those described in the text Any other indications or symptoms revealed.

The present invention also includes the use of IL-4R antagonists as disclosed in the text for the treatment and/or prevention of asthma (such as eosinophilic asthma, moderate to severe eosinophilic asthma, etc.), or for the treatment of any other Indications or symptoms.

The present invention includes a pharmaceutical composition comprising an anti-IL4R antibody antagonist or an antigen-binding fragment thereof for use in the treatment and/or prevention of asthma and related symptoms.

The present invention also includes a pharmaceutical composition comprising an anti-IL4R antibody antagonist or an antigen-binding fragment thereof for use in a subject in need to reduce the incidence of one or more asthma exacerbations.

In addition, the present invention includes a pharmaceutical composition comprising an anti-IL4R antibody antagonist or an antigen-binding fragment thereof for use in a subject in need to improve one or more parameters related to the trachea.

The present invention includes a pharmaceutical composition comprising an anti-IL4R antibody antagonist or an antigen-binding fragment thereof for use in the treatment of asthma and related symptoms in patients, wherein the patient has an elevated amount of biomarkers selected from the group consisting of : Thymus and activation regulatory chemokine (TARC), IgE, eosinophil chemokine-3 (eotaxin-3), periostin (periostin), carcinoembryonic antigen (CEA) or YKL-40 and exhaled nitric oxide Rate (FeNO).

The present invention further includes a pharmaceutical composition comprising an anti-IL4R antibody antagonist or an antigen-binding fragment thereof for use in the treatment of asthma or moderate to severe eosinophilic asthma in a subject in need, wherein the treatment includes testing the patient Whether there is a blood eosinophil count of at least 300 cells per microliter and/or a sputum eosinophil count of at least 3%, and if this blood eosinophil count and/or sputum eosinophil count is found, start/ Continue to administer this pharmaceutical composition.

From reviewing the detailed description that follows, other embodiments of the present invention will become apparent. Detailed description

Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described, so the methods and conditions can be changed. It should also be understood that the terms used in the text are only for the purpose of describing specific embodiments and are not intended to be limited, because the scope of the present invention will only be limited by the scope of the attached patent application.

Unless otherwise stated, all technical and scientific terms used in the text have the same meanings as normally understood by those skilled in the art to which the present invention belongs.

As used in the text, the term "approximately" when used in relation to a specifically quoted value means that the value can differ from the quoted value by no more than 1%. For example, as used in the text, the term "about 100" includes 99 and 101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the term "treatment" or similar terms refers to alleviating the symptoms, temporarily or permanently eliminating the causes of the symptoms, or preventing or slowing the occurrence of the symptoms of the indicated disease or symptom.

Although any of the methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred methods and materials are currently described. All the publication lines mentioned in the article are incorporated into this article by reference in their entirety. Ways to reduce the incidence of worsening asthma

The present invention includes a method for reducing the incidence of exacerbation of asthma in a subject in need thereof, which comprises administering a pharmaceutical composition including an interleukin-4 receptor (IL-4R) antagonist to the subject. As used in the text, the term "worsening asthma" refers to an increase in the severity and/or frequency and/or duration of one or more symptoms or signs of asthma. "Asthma worsening" also includes the deterioration of the respiratory health of any subject who needs and/or can be treated with therapeutic intervention for asthma (for example, steroid therapy, inhaled corticosteroid therapy, hospitalization, etc.). According to a specific embodiment of the present invention, asthma exacerbation is defined as one or more of the following: (a) The maximum expiratory flow in the morning of two consecutive days (also referred to as "AM PEF" elsewhere in the text) is reduced by 30% compared to the baseline or More; (b) for two consecutive days, six or more additional inhalations of albuterol or levalbuterol in a 24 hour period (compared to baseline); and (c) Exacerbation of asthma (as determined by a physician or other medical practitioner) requires at least one of the following: (i) systemic (oral and/or parenteral) steroid therapy, or (ii) increased inhaled corticosteroids to the base At least 4 times the thread volume, or (iii) hospitalization.

In certain instances, exacerbation of asthma can be classified as "severe exacerbation of asthma". Severe asthma exacerbation refers to an event that requires immediate intervention in the form of systemic corticosteroids or inhaled corticosteroids taking 4 or more times the dose before the event. Therefore, the term "worse asthma" generally includes and covers the more specific subcategory of "worse asthma". Therefore, the present invention includes methods for reducing the incidence of severe asthma exacerbations in subjects in need.

"Reduce the incidence of exacerbation of asthma" means that a subject who has received the pharmaceutical composition of the present invention experiences less exacerbation of asthma than before treatment (for example, reduces at least one exacerbation), or starts treatment with the pharmaceutical composition of the present invention No worsening of asthma occurred at least 4 weeks later (for example, 4, 6, 8, 12, 14 or more weeks). Reducing the incidence of asthma exacerbation also means that compared with subjects who did not receive the pharmaceutical composition of the present invention, after administration of the pharmaceutical composition of the present invention, a subject's exacerbation of asthma may be reduced by at least 10% (for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or more). Methods of improving asthma related parameters

The present invention also includes a method for improving one or more asthma-related parameters in a subject in need thereof, wherein the method includes administering a pharmaceutical composition comprising an interleukin-4 receptor (IL-4R) antagonist The object. For the purpose of the present invention, reducing the incidence of asthma exacerbations (as described above) may be associated with improving one or more asthma-related parameters; however, this association is not necessarily observable in all cases.

Improvement of "asthma-related parameters" includes: (a) Forced expiratory volume in 1 second (FEV1); (b) Maximum expiratory flow rate (PEF), including morning PEF (AM PEF) and evening PEF (PM PEF); (c) ) Use of inhaled bronchodilators, such as salbutamol or levosabutamol; (d) scores on 5 asthma control questionnaires (ACQ5); (d) wake up at night; and (e) scores on 22 sinus outcome tests (SNOT-22) . "Improvement of an asthma-related parameter" refers to the increase in one or more of FEV1, AM PEF or PM PEF compared with baseline, and/or one or more of daily salbutamol/levosalbutamol dosage, ACQ5 score, and/or compared with baseline. The average night time to wake up or SNOT-22 score decreased. As used herein, the term "baseline", in terms of asthma-related parameters, refers to the value of the asthma-related parameters when or before the patient is administered the pharmaceutical composition of the present invention.

To determine whether the asthma-related parameters have improved, this parameter is quantified at baseline and at the time point after administration of the pharmaceutical composition of the present invention. For example, the asthma related parameters can be on the first day, the second day, the third day, the fourth day, the fifth day, the sixth day, the seventh day, the ninth day, and the ninth day after the start of treatment with the pharmaceutical composition of the present invention. Day, Day 10, Day 11, Day 12, Day 14, or Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8 , Week 9, Week 10, Week 11, Week 12, Week 13, Week 14, Week 15, Week 16, Week 17, Week 18, Week 19, Week 20, Week Measured at 21 weeks, 22 weeks, 23 weeks, 24 weeks or longer. The difference between the parameter value at a specific time point after the start of treatment and the baseline parameter value is used to establish whether asthma-related parameters have been "improved" (for example, increase or decrease, depending on the situation, according to the measured parameter Depends).

The term "obtaining" as used in the text refers to obtaining the ownership or value of a physical entity, such as a value, by "obtaining directly" or "indirectly obtaining" the physical entity or value, such as asthma-related parameters. "Direct acquisition" refers to a process (such as a synthesis or analysis method) to obtain a physical entity or value. "Indirect acquisition" refers to receiving the physical entity or value from another party or source (for example, a third-party laboratory that directly obtains the physical entity or value. Direct acquisition of a physical entity includes performing a process that includes a physical substance (such as a starting material) The process of physical change. Illustrated changes include the production of a physical entity from two or more starting materials, shearing or dividing a substance, separating or purifying a substance, combining two or more individual entities into a mixture, and performing chemical reactions (Including destruction or formation of covalent or non-covalent bonds). Obtaining a value directly includes performing a procedure that includes a physical change of a sample or another substance, such as performing a physical change that includes a substance (such as a sample, analyte, or reagent) Analysis procedures (sometimes referred to as physical analysis in the text).

Information obtained indirectly can be provided in the form of reports, for example, in paper or electronic form, such as online databases or applications (App). The report or information can be provided by, for example, a medical institution, such as a hospital or clinic; or a medical provider, such as a doctor or nurse.

Forced expiratory volume in 1 second (FEV1). According to a specific embodiment of the present invention, administering an IL-4R antagonist to a patient increases the forced expiratory volume (FEV1) in 1 second compared to baseline. The method of measuring FEV1 is already known in this technology. For example, a spirometer that complies with the 2005 American Thoracic Society (ATS)/European Respiratory Society (ERS) recommendations can be used to measure the patient's FEV1. The ATS/ERS spirometry standard can be used as a guide. Vital capacity measurement is usually performed between 6 and 10 AM after not taking satineamol for at least 6 hours. The lung function test is generally measured in a sitting position, and the highest measured value of FEV1 (expressed in liters) is recorded.

The present invention includes treatment methods that increase FEV1 by at least 0.05L from baseline at week 12 after starting treatment with a pharmaceutical composition that includes an anti-IL-4R antagonist. For example, according to the present invention, the IL-4R antagonist is administered to a subject in need, so that FEV1 increases by about 0.05L, 0.10L, 0.12L, 0.14L, 0.16L, 0.18L, 0.20 from baseline at week 12 L, 0.22L, 0.24L, 0.26L, 0.28L, 0.30L, 0.32L, 0.34L, 0.36L, 0.38L, 0.40L, 0.42L, 0.44L, 0.46L, 0.48L, 0.50L or more.

Maximum expiratory flow (AM PEF and PM PEF) in the morning and evening. According to a specific embodiment of the present invention, administering an IL-4R antagonist to a patient increases the morning (AM) and/or evening (PM) maximum expiratory flow (AM PEF and/or PM PEF) compared to baseline . The method of measuring PFE is known in this technology. For example, according to the method of measuring PEF, an electronic PEF meter is provided to record the morning (AM) and evening (PM) PEF (as well as the daily use of saltinol, morning and evening asthma symptom scores and the need for asthma symptoms. The number of awakenings during the night after receiving ambulance medicine). Teach patients to use this device, and write down instructions for using the electronic PEF meter and provide them to patients. In addition, medical professionals can teach patients how to record the relevant variables of the electronic PEF meter. AM PEF is generally done 15 minutes after waking up (between 6 am and 10 am) before taking any albuterol. PM PEF is generally done in the evening (between 6 pm and 10 pm) before taking any salatinol. The subject should try to avoid taking salatinol for at least 6 hours before measuring their PEF. The three PEF tasks are performed by patients and all three values are recorded with an electronic PEF meter. Usually the highest value is used for evaluation. The baseline AM PEF can be calculated by the average AM measurement value recorded 7 days before the first dose of the pharmaceutical composition including the IL-4R antagonist, and the baseline PM PEF can be calculated by the first dose of the drug including the IL-4R antagonist The average PM measurement value recorded 7 days before the composition is calculated.

The present invention includes treatment methods that increase AM PEF and/or PM PEF by at least 1.0 L/min from baseline at week 12 after starting treatment with a pharmaceutical composition including an anti-IL-4R antagonist. For example, according to the present invention, the IL-4R antagonist is administered to a subject in need, so that PEF increases by about 0.5 L/min, 1.0 L/min, 1.5 L/min, 2.0 L/min from baseline at week 12 , 2.5 L/min, 3.0 L/min, 3.5 L/min, 4.0 L/min, 4.5 L/min, 5.0 L/min, 5.5 L/min, 6.0 L/min, 6.5 L/min, 7.0 L/min , 7.5 L/min, 8.0 L/min, 8.5 L/min, 9.0 L/min, 9.5 L/min, 10.0 L/min, 10.5 L/min, 11.0 L/min, 12.0 L/min, 15 L/min , 20 L/min or more.

Salatinol/levatamol is used. According to a specific embodiment of the present invention, administering an IL-4R antagonist to a patient can reduce the daily use of saltinol/levalanol compared with baseline. The number of times of use of sartanol/levsartanol can be recorded daily by the patient in a diary, electronic PEF or other recording device. During the treatment period of the pharmaceutical composition of the present invention, the use of saltinol/levartine can typically be based on symptomatic needs, rather than on a regular or preventive basis. The baseline number of times of inhalation of levatamol/levatamol/day can be calculated based on the average of the 7 days before the first dose of the pharmaceutical composition including the IL-4R antagonist is administered.

The present invention includes treatment methods that, after starting treatment with a pharmaceutical composition that includes an anti-IL-4R antagonist, will reduce the daily use of saltamine/levoxatine by at least the baseline at week 12 0.25 suck. For example, according to the present invention, the IL-4R antagonist is administered to a subject in need, so that the use of salatinol/levatamol is reduced by about 0.25 puffs per day and 0.50 puffs per day compared with baseline in the 12th week. 0.75 sucks per day, 1.00 sucks per day, 1.25 sucks per day, 1.5 sucks per day, 1.75 sucks per day, 2.00 sucks per day, 2.25 sucks per day, 2.5 sucks per day, 2.75 sucks per day, 3.00 sucks per day or more.

5-item Asthma Control Questionnaire (ACQ) score. According to a specific embodiment of the present invention, administering an IL-4R antagonist to a patient reduces the score of the 5-item Asthma Control Questionnaire (ACQ) compared to baseline. ACQ5 is a questionnaire for evaluating the effectiveness of asthma control.

The present invention includes treatment methods that, after starting treatment with a pharmaceutical composition that includes an anti-IL-4R antagonist, reduce the ACQ5 score by at least 0.10 points from the baseline at the 12th week. For example, according to the present invention, the IL-4R antagonist is administered to a subject in need, so that the ACQ score decreases by about 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40 points, 0.45 points, 0.50 points, 0.55 points, 0.60 points, 0.65 points, 0.70 points, 0.75 points, 0.80 points, 0.85 points or more.

Wake up at night. According to a specific embodiment of the present invention, administering an IL-4R antagonist to a patient reduces the average number of night awakenings compared to baseline.

The present invention includes treatment methods that, after starting treatment with a pharmaceutical composition that includes an anti-IL-4R antagonist, reduce the average number of night awakenings in the 12th week from baseline by at least 0.10 times per night. For example, according to the present invention, the IL-4R antagonist is administered to a subject in need, so that the average number of night awakenings in the 12th week is reduced from baseline by about 0.10 times per night, 0.20 times per night, 0.25 times per night, 0.30 times per night, 0.35 times per night, 0.40 times per night, 0.45 times per night, 0.50 times per night, 0.55 times per night, 0.60 times per night, 0.65 times per night, 0.70 times per night, 0.75 times per night, 0.80 times per night, 0.85 times per night, 0.90 times per night, 0.95 times per night, 1.0 times per night, 2.0 times per night or more.

Score of 22-items sinus outcome test (SNOT-22). According to a specific embodiment of the present invention, administering an IL-4R antagonist to a patient will reduce the score of 22 sinus outcome tests (SNOT-22) compared to baseline. SNOT-22 is an effective questionnaire for assessing the impact of chronic sinusitis on the quality of life (Hopkins et al. 2009, Clin. Otolaryngol. 34: 447-454).

The present invention includes treatment methods that, after starting treatment with a pharmaceutical composition that includes an anti-IL-4R antagonist, will reduce the SNOT-22 score by at least 1 point from the baseline at the 12th week. For example, according to the present invention, the IL-4R antagonist is administered to a subject in need, so that the SNOT-22 score is reduced by about 1, 2, 3, 4, 5, 6, 7, 8, and 8 in week 12 compared to baseline. 9, 10, 11, 12, 13 points or more. Ways to treat asthma

The present invention, according to a specific embodiment, provides a method for treating asthma, including eosinophilic asthma, in a subject in need thereof, wherein the methods include adding an interleukin-4 receptor (IL-4R) antagonist The pharmaceutical composition is administered to the subject. In a specific embodiment, the method of the present invention can be effectively used to treat moderate to severe eosinophilic asthma in a subject (eg, persistent moderate to severe eosinophilic asthma).

According to the present invention, if a subject has a blood eosinophil count of at least 300 cells per microliter, and/or a sputum eosinophil count of at least 3%, the subject is identified as having moderate to severe eosinophilic asthma. Any known and available method that can be used to measure the amount of blood and/or sputum eosinophils in this technology can be used in the context of the present invention to identify whether a subject has moderate to severe eosinophilic asthma, and its Therefore, it is a suitable target for the treatment method of the present invention.

According to a related aspect of the present invention, the provided method for treating asthma includes: (a) selecting patients with a blood eosinophil count of at least 300 cells per microliter and/or a sputum eosinophil count of at least 3% ; And (b) administering a pharmaceutical composition including an IL-4R antagonist to the patient.

In another aspect, it provides a method for reducing or eliminating the dependence of asthma patients on inhaled corticosteroids (ICS) and/or long-acting beta-agonists (LABA) during the treatment of moderate to severe asthma. In a specific embodiment, these methods include: selecting patients with moderate to severe asthma that cannot be controlled or partially controlled by background asthma treatment; adding a defined dose of IL-4R antagonist, preferably anti-IL -4R antibody is administered to the patient for an initial treatment period, while maintaining the patient's background treatment for an initial treatment period; and gradually reducing the dose of one or more background treatment components during a subsequent treatment period , While continuing to administer IL-4R antagonists. The term "background therapy" refers to standard or conventional therapeutic agents known in the art for the treatment of asthma. In certain embodiments, the background treatment includes ICS, LABA, or a combination of the two. In some embodiments, the dose of ICS and/or LABA is removed or completely withdrawn immediately after the initial treatment period. For example, LABA, such as salmeterol or formoterol, is administered during the initial treatment period and is completely stopped or withdrawn during the subsequent treatment period.

An example of treatment therapy for patients with moderate to severe asthma is shown in Figure 24, in which an IL-4R antagonist is administered to patients with moderate to severe asthma. During the initial treatment period (also called the "stable period"), LABA and ICS are used as background treatments to administer the patient. During the subsequent treatment period (also referred to as the "withdrawal period"), stop the administration of LABA, that is, withdraw or remove the LABA. ICS is gradually reduced during the subsequent treatment period until it is removed.

In related aspects, the department provides treatment methods for asthma including systemic background therapy withdrawal and background therapy adjuvant therapy. In a specific embodiment, the IL-4R antagonist is administered for a specific period of time (e.g., 1 week, 2 weeks, 3 weeks, January, February, May, December, 18 months, 24 months). Or longer) (also known as the "stable period") as an adjuvant therapy for asthma patients who are treated as background. In certain embodiments, the background treatment includes ICS and/or LABA. The stable period is followed by the background treatment withdrawal period, in which one or more components including the background treatment are evacuated, or lowered or removed, while adjuvant treatment is continued. In certain embodiments, the reduction can be about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, or more during the background treatment withdrawal period. The withdrawal period can last for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more. In a preferred embodiment, the background treatment can be reduced by about 5% during the withdrawal period and the withdrawal period can last for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more. In a preferred embodiment, the background treatment can be reduced by about 10% during the withdrawal period and the withdrawal period can last for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more. In a preferred embodiment, the background treatment can be reduced by about 20% during the withdrawal period and the withdrawal period can last for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more. In a preferred embodiment, the background treatment can be reduced by about 30% during the withdrawal period and the withdrawal period can last for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more. In a preferred embodiment, the background treatment can be reduced by about 40% during the withdrawal period and the withdrawal period can last for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more. In a preferred embodiment, the background treatment can be reduced by about 50% during the withdrawal period and the withdrawal period can last for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more.

In certain other embodiments, the present invention covers methods for treating or reducing symptoms or complications related to asthma, such as chronic sinusitis, allergic rhinitis, allergic fungal rhinosinusitis, allergic bronchopulmonary aspergillosis , Combined tracheal disease, Churg-Strauss syndrome, vasculitis, chronic obstructive pulmonary disease (COPD) and exercise-induced bronchospasm.

The present invention also includes methods for treating persistent asthma. As used herein, the term "persistent asthma" means that the subject has symptoms at least once a week during the day and/or night, where the symptoms last from several hours to several days. In certain other embodiments, persistent asthma is "mildly persistent" (e.g., more than twice a week but less than daily, where symptoms are severe enough to interfere with daily activities or sleep and/or where lung function is normal Or it can be eliminated with inhaled bronchodilators), "moderately persistent" (for example, symptoms occur every day, in which sleep is interrupted at least every week and/or there are moderate abnormalities in lung function), or "severely persistent" (for example, just right Use approved medical treatment but symptoms persist and/or lung function is severely affected). Interleukin -4 receptor antagonist

The method of the present invention includes administering a pharmaceutical composition including an interleukin-4 receptor (IL-4R) antagonist to a subject in need thereof. As used herein, "IL-4R antagonist" is any agent that binds or interacts with IL-4R and inhibits the normal biological signal transmission function of IL-4R when IL-4R is expressed on cells in vitro or in vivo. Examples of non-limiting classes of IL-4R antagonists include small molecule IL-4R antagonists, anti-IL-4R aptamers, peptide IL-4R antagonists (eg, "peptibody molecules" and Human IL-4R specifically binds to antibodies or antigen-binding fragments of antibodies.

The term "human IL4R" (hIL-4R) refers to a human cytokine receptor that specifically binds to interleukin-4 (IL-4), such as IL-4Rα (SEQ ID NO: 274).

The term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, and their multimers (eg, IgM). Each heavy chain system includes a heavy chain variable region (hereinafter abbreviated as HCVR or V _H ) and a heavy chain constant region. Heavy chain constant region comprises three regions, C _H 1, C _H 2 and C _H 3. Each system comprises a light chain light chain variable region (abbreviated herein as LCVR or V _L) and a light chain constant region. The light chain constant region includes a region ( _CL ). And V _L, V _H regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs of), interspersed with regions that are more conserved regions referred to as framework regions (FR). Each V _H and V _L, three lines from the four FR and CDR consisting, in the following order from the amino terminus to carboxyl terminus: FR1, CDR1, FR2, CDR2 , FR3, CDR3, FR4. In different embodiments, the FR of the anti-IL-4R antibody (or antigen-binding fragment thereof) can be the same as the human germline sequence, or be modified naturally or artificially. The amino acid consensus sequence can be defined based on the side-by-side analysis of two or more CDRs.

The term "antibody" also includes antigen-binding fragments of whole antibody molecules. The term "antigen-binding portion" of antibody, "antigen-binding fragment" of antibody, etc., as used herein, includes any naturally-occurring, enzyme-prepared, synthetic or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex . Antigen-binding fragments of antibodies can be derived from, for example, whole antibody molecules using any suitable standard techniques, such as proteolytic digestion or recombinant genetic engineering techniques involving DNA manipulation and expression of variable regions and (optionally) constant regions encoding antibodies. This DNA is known and/or can be easily obtained from, for example, market sources, DNA databases (including, for example, obtaining phage-antibody databases) or can be synthesized. This DNA can be sequenced and manipulated chemically or by using molecular biotechnology, such as arranging one or more variable and/or constant regions into a suitable configuration, or introducing codons to generate cysteine residues, Modify, add or delete amino acids, etc.

Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; ( vi) dAb fragments; and (vii) the smallest recognition unit (for example, isolated complementarity determining region (CDR)) or restricted FR3-CDR3-FR4 peptide consisting of amino acid residues in the hypervariable region of an antibody mimicking. Other engineered molecules, such as region-specific antibodies, single-domain antibodies, region-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, tri-antibodies, tetra-antibodies, mini-antibodies, nano-antibodies (e.g. monovalent nano-antibodies, Bivalent nano-antibodies, etc.), small modular immunopharmaceuticals (SMIP) and shark variable IgNAR regions are also included in the term "antigen-binding fragment" used in the text.

Antigen-binding fragments of antibodies typically include at least one variable region. The variable region can be a region of any size or amino acid composition and should generally include CDRs adjacent to or within the framework of one or more framework sequences. Binding fragment having the V _L and V _H region binding the antigen region, V _H and V _L, may be any suitable arrangement region located opposite from each other. For example, the variable region may be a dimerization and contain _{V H -V H, V H -V} L or V _L -V _L dimer. In addition, the antigen-binding fragments of antibodies may contain monomeric VH or VL regions.

In a specific embodiment, the antigen-binding fragment of an antibody may contain at least one variable region and at least one constant region covalently linked. Non-limiting, exemplary configuration of the variable and constant region in the antigen-binding fragment of an antibody of the present invention can be found _{include: (i) V H -C H} 1; (ii) V H -C H 2; ( iii) V _H -C _H 3; (iv) V _H -C _H 1-C _H 2; (v) V _H -C _H 1-C _H 2-C _H 3; (vi) V _H -C _H 2 _{-C H 3; (vii) V} H -C L; (viii) V L -C H 1; (ix) V L -C H 2; (x) V L -C H 3; (xi) V L - _{C H 1-C H 2;} (xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) V _L -C _L. In any configuration of the variable region and the constant region, including any of the exemplary configurations listed above, the variable region and the constant region can be directly connected to each other or can be connected by a complete or partial hinge region or linker region . The hinge region can be composed of at least 2 (for example, 5, 10, 15, 20, 40, 60 or more) amino acids, making the adjacent variable and/or constant regions of a single polypeptide molecule flexible For semi-flexible connection, preferably the hinge region can be composed of 2 to 60 amino acids, preferably 5 to 50, or preferably 10 to 40 amino acids. Furthermore, the antigen-binding fragments of the antibodies of the present invention may include any of the above-listed ones that are non-covalently connected to each other and/or to one or more monomeric VH or VL regions (for example, by disulfide bonds). Homodimer or heterodimer (or other multimer) of variable and constant region configuration.

Like whole antibody molecules, antigen-binding fragments can be single-specific or multi-specific (e.g., dual-specific). The multi-specific antigen-binding fragment of an antibody should typically include at least two different variable regions, where each variable region can specifically bind to a separate antigen or to different epitopes on the same antigen. Any multi-specific antibody model can be modified using conventional techniques available in this technology to make it suitable for the antigen-binding fragment status of the antibody of the present invention.

The constant region of an antibody is important for the antibody's ability to fix complement and vector cell-dependent cytotoxicity. Therefore, the isotype antibody can be selected according to whether it is required for antibody-mediated cytotoxicity.

The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. However, the characteristics of human antibodies in the present invention may include amino acid residues not encoded by human germline immunoglobulin sequences (such as mutations introduced randomly in vitro or site-specific mutagenesis or somatic mutations in vivo). ), for example in CDR, and especially CDR3. However, the term "human antibody" does not include antibodies in which CDR sequences derived from the germline of another mammalian species (such as mouse) have been attached to human framework sequences.

The term "recombinant human antibody" includes all human antibodies prepared, expressed, manufactured or isolated by recombinant methods, such as antibodies expressed by recombinant expression vectors transfected into host cells (further described below), by recombination, combination Antibodies isolated from the human antibody database (further described below), antibodies isolated from human immunoglobulin gene-transgenic animals (such as mice) (see, for example, Taylor et al. (1992) Nucl. Acids Res 20:6287-6295) or by any other method involving the cutting of human immunoglobulin gene sequences into other DNA sequences. These recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, these recombinant human antibodies are mutated in vitro (or somatic mutations in vivo when animal gene transfer is used as human Ig sequences), and therefore the V of recombinant antibodies _H and V _L, the amino acid sequence regions, or when derived from human germline V _H and V _L, sequences not naturally present in the sequence of the antibody germ line repertoire in vivo human.

Human antibodies can exist in two forms related to hinge heterogeneity. In one form, immunoglobulins include a stable four-chain structure of about 150-160 kDa, in which the dimerization system is held together by heavy chain disulfide bonds between the chains. In the second form, the dimer is not connected via disulfide bonds between chains, and forms a molecule of about 75-80 kDa, which is composed of a light chain and a heavy chain (half-antibody) covalently coupled. These forms are extremely difficult to separate, even after affinity purification.

The frequency of the second form among the various intact IgG isotypes is due to (but not limited to) structural differences related to the isotype of the antibody hinge region. A single amino acid substitution in the hinge region of a human IgG4 hinge can significantly reduce the appearance of the second form (Angal et al. (1993) Molecular Immunology 30:105) to the amount typically observed with a human IgG1 hinge. The present invention encompasses the hinge, C _H 2 or C _H 3 region of an antibody having one or more mutations, such as the manufacture thereof to improve the form of the desired yield of antibody may be desirable.

"Isolated antibody" refers to an antibody that has been identified and separated and/or recovered from at least one component of its natural environment. For example, an antibody isolated or removed from at least one organism, or from a component of a tissue or cell, wherein for the purpose of the present invention, the antibody that exists in nature or is naturally produced is an "isolated antibody". Isolated antibodies also include in situ antibodies in recombinant cells. The isolated antibody is an antibody that has undergone at least one purification or separation step. According to certain embodiments, the isolated antibody may be substantially free of other cellular materials and/or chemicals.

The term "specific binding" or similar terms means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is quite stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well-known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and so on. For example, antibodies that "specifically bind" to IL-4R, as used in the context of the present invention, include antibodies that bind to IL-4R or a portion thereof, wherein the K _D is lower than about 1000 nM, lower than about 500 nM, and lower than About 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM or Less than about 0.5 nM, as measured by surface plasmon resonance analysis. However, isolated antibodies that specifically bind to human IL-4R may have cross-reactivity to other antigens, such as IL-4R molecules of other species (non-human).

The anti-IL-4R antibody that can be used in the method of the present invention, compared to the corresponding germline sequence from which the antibody is derived, can include one or more in the framework and/or CDR regions of the heavy and light chain variable regions Amino acid substitutions, insertions or deletions (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 substitutions and/or 1, 2, 3, 4, 5, 6, 7, 8 , 9 or 10 insertions and/or 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 deletions). These mutations can be easily determined by comparing the amino acid sequence disclosed in the text with the germline sequence obtained, for example, from a published antibody sequence database. The present invention includes methods involving the use of antibodies derived from any of the amino acid sequences disclosed herein and antigen-binding fragments thereof, wherein one or more frameworks and/or one or more (for example, tetrameric antibodies are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, or 1, 2, 3, 4, 5, or 6 for the HCVR and LCVR of the antibody) or one of the CDR regions Multiple amino acids (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids) are mutated to the corresponding residues of the germline sequence of the derived antibody, or another human reproduction Corresponding residues of the sequence sequence, or conservative amino acid substitutions corresponding to germline residues (the changes in these sequences are collectively referred to as "germline mutations" in the text). Those of ordinary skill in this technology, starting from the heavy and light chain variable region sequences disclosed in the text, can easily produce many antibodies and antigen-binding fragments or combinations thereof that include one or more individual germline mutations. In a specific embodiment, all framework and/or CDR residues in the VH and/or VL regions are mutated back to residues found in the original germline sequence from which the antibody was derived. In other embodiments, only specific residues are mutated back to the original germline sequence, for example, mutated residues are only found in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or only Mutated residues were found in CDR1, CDR2 or CDR3. In other embodiments, one or more framework and/or CDR residues are mutated to corresponding residues of different germline sequences (ie, germline sequences that are different from the germline sequence from which the antibody was originally derived). Furthermore, the antibody of the present invention may contain any combination of two or more germline mutations in the framework and/or CDR region, for example, where specific individual residues are mutated to the corresponding residues of a specific germline sequence, and Other residues with different primordial germline sequences are maintained as they are or mutated into corresponding residues of different germline sequences. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be easily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, antagonistic or agonistic biological properties, or Increase (depending on the situation), reduce immunity, etc. The antibodies and antigen-binding fragments obtained by this general method are encompassed in the present invention.

The present invention also includes methods involving the use of anti-IL-4R antibodies, wherein the anti-IL-4R antibody system includes any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed in the text with one or more conservative substitutions Variants. For example, the present invention includes the use of anti-IL-4R antibodies, which, relative to any of the HCVR, LCVR and/or CDR amino acid sequences disclosed in the text, have, for example, 10 or less, 8 or less, 6 HCVR, LCVR and/or CDR amino acid sequences with one or fewer, 4 or fewer conservative amino acid substitutions.

The term "surface plasmon resonance" refers to an optical phenomenon that enables real-time biomolecular interaction analysis by detecting changes in the protein concentration in the matrix of a biosensor. For example, using the BIACORE™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

The term "K _D "refers to the equilibrium dissociation constant of a specific antibody-antigen interaction.

The term "epitope" refers to an epitope that interacts with a specific antigen binding site called a paratope in the variable region of an antibody molecule. A single antigen can have more than one epitope. Therefore, different antibodies can bind to different regions of the antigen and can have different biological effects. Epitopes can be conformational or linear. The conformational epitope is generated by the spatially juxtaposed amino acids of different line segments of the linear polypeptide chain. Linear epitopes are generated by adjacent amino acid residues in the polypeptide chain. In a specific embodiment, the epitope may include a carbohydrate group, a phosphate group, or a sulfonyl group on the antigen. Preparation of human antibodies

The method of producing human antibodies in transgenic mice is known in the art. Any of these known methods can be used in the context of the present invention to produce human antibodies that specifically bind to human IL-4R.

Using VELOCIMMUNE™ technology (see, for example, US 6,596,541, Regeneron Pharmaceuticals) or any other known method of producing monoclonal antibodies, first isolate the human variable region and mouse constant region with high affinity to IL-4R.合 Antibody. The VELOCIMMUNE® technology involves the production of genetically transgenic mice that have a gene body containing human heavy and light chain variable regions operatively linked to the endogenous mouse constant region locus, allowing the mouse to respond to antigenic stimuli Able to produce an antibody including human variable regions and mouse constant regions. The DNA encoding the variable regions of the antibody heavy and light chains are separated and operatively linked to the DNA encoding the constant regions of the human heavy and light chains. The DNA is then expressed in cells capable of expressing fully human antibodies.

Generally speaking, VELOCIMMUNE® mice are administrated with related antibodies, and lymphocytes (such as B-cells) expressing the antibodies are recovered from the mice. Lymphocytes can be fused with myeloma cell lines to prepare immortalized hybridoma cell lines, screen and select the hybridoma cell lines, and identify hybridoma cell lines that produce antibodies specific to the relevant antigen. The DNA encoding the variable regions of the heavy and light chains can be isolated and connected to the desired constant regions of the same type of the heavy and light chains. This antibody protein can be produced in cells, such as CHO cells. In addition, the DNA encoding the antigen-specific chimeric antibody or the variable regions of the heavy and light chains can be directly isolated from antigen-specific lymphocytes.

Initially, high-affinity chimeric antibodies with human variable regions and mouse constant regions were isolated. Use the standard manufacturing process known to those familiar with this technology to determine the characteristics of the antibody and make selections for the desired characteristics, including affinity, selectivity, epitope, etc. The mouse constant region is replaced with the desired human constant region to produce a fully human antibody featuring the present invention, such as wild-type or modified IgG1 or IgG4. When the selected constant region can be changed according to the specific application, the high-affinity antigen-binding and target specificity properties remain in the variable region.

Generally speaking, the antibodies that can be used in the method of the present invention, as described above, have high affinity when measured by binding to the antigen by being immobilized on a solid phase or in a solution phase. The mouse constant region is replaced with the desired human constant region to produce the fully human antibody featured in the present invention. When the selected constant region can be changed according to the specific application, the high-affinity antigen-binding and target specificity properties remain in the variable region.

Specific examples of human antibodies or antigen-binding fragments of antibodies that can be used in the method of the present invention that specifically bind to IL-4R include any antibody or antigen-binding fragment that includes three heavy chain CDRs (HCDR1, HCDR2, and HCDR3), and the heavy The chain CDR is contained in a heavy chain variable region (HCVR) having an amino acid sequence selected from the group consisting of: SEQ ID NO: 2, 18, 22, 26, 42, 46, 50, 66, 70 , 74, 90, 94, 98, 114, 118, 122, 138, 142, 146, 162, 166, 170, 186, 190, 194, 210, 214, 218, 234, 238, 242, 258 and 262. The antibody or antigen-binding fragment may include three light chain CDRs (LCVR1, LCVR2, LCVR3), which are contained in a light chain variable region (LCVR) having an amino acid sequence selected from the group consisting of : SEQ ID NO: 10, 20, 24, 34, 44, 48, 58, 68, 72, 82, 92, 96, 106, 116, 120, 130, 140, 144, 154, 164, 168, 178, 188 , 192, 202, 212, 216, 226, 236, 240, 250, 260, and 264. Methods and techniques for identifying CDRs in HCVR and LCVR amino acid sequences are well known in the art, and can be used to identify CDRs in specific HCVR and/or LCVR amino acid sequences disclosed in the text. Exemplary customary usages for identifying CDR boundaries include, for example, Kabat definition, Chothia definition, and AbM definition. Generally speaking, the Kabat definition is based on sequence variability, the Chothia definition is based on the position of the structural loop region, and the AbM definition is a compromise between the Kabat and Chothia methods. See, for example, Kabat, "Sequences of Proteins of Immunological Interest," National Institutes of Health, Bethesda, Md. (1991); Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); and Martin Et al., Proc. Natl. Acad. Sci. USA 86: 9268-9272 (1989). You can also obtain public databases for identifying CDR sequences in antibodies.

In a specific embodiment of the present invention, the antibody or antigen-binding fragment thereof includes six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3), which are derived from the heavy chain selected from the group consisting of and Amino acid sequence pair of light chain variable region: SEQ ID NO: 2/10, 18/20, 22/24, 26/34, 42/44, 46/48, 50/58, 66/68, 70/72 , 74/82, 90/92, 94/96, 98/106, 114/116, 118/120, 122/130, 138/140, 142/144, 146/154, 162/164, 166/168, 170 /178, 186/188, 190/192, 194/202, 210/212, 214/216, 218/226, 234/236, 238/240, 242/250, 258/260 and 262/264.

In a specific embodiment of the present invention, the antibody or antigen-binding fragment thereof includes six CDRs (HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3), which have an amino acid sequence selected from the group consisting of ：SEQ ID NO: 4/6/8/12/14/16; 28/30/32/36/38/40; 52/54/56/60/62/64; 76/78/80/84/86 /88; 100/102/104/108/110/112; 124/126/128/132/134/136; 148/150/152/156/158/160; 172/174/176/180/182/184 ; 196/198/200/204/206/208; 220/222/224/228/230/232; and 244/246/248/252/254/256.

In a specific embodiment of the present invention, the antibody or antigen-binding fragment thereof includes HCVR/LCVR amino acid sequence pairs selected from the group consisting of: SEQ ID NO: 2/10, 18/20, 22/ 24, 26/34, 42/44, 46/48, 50/58, 66/68, 70/72, 74/82, 90/92, 94/96, 98/106, 114/116, 118/120, 122/130, 138/140, 142/144, 146/154, 162/164, 166/168, 170/178, 186/188, 190/192, 194/202, 210/212, 214/216, 218/ 226, 234/236, 238/240, 242/250, 258/260 and 262/264. Pharmaceutical composition

The present invention includes a method comprising administering an IL-4R antagonist to a patient, wherein the IL-4R antagonist is contained in a pharmaceutical composition. The characteristic pharmaceutical composition of the present invention is formulated to provide suitable carriers, excipients and other reagents suitable for transport, delivery, tolerance, etc. Many suitable formulations can be found in all prescriptions known to medicinal chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, glues, waxes, oils, lipids, lipids (cations or anions) containing vesicles (such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes, water-containing Oil and water-in-oil emulsions, carbowax (polyethylene glycol of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbon wax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52: 238-311.

According to the method of the present invention, the dose of antibody administered to the patient may be determined according to the age and size, symptoms, symptoms, route of administration, etc. of the subject to be administered. The preferred dosage is typically calculated based on body weight or body surface area. According to the severity of symptoms, the frequency and duration of treatment can be adjusted. The effective dose and time course of the administration of the pharmaceutical composition including the anti-IL-4R antibody can be determined empirically, for example, to monitor the patient's progress by regular evaluation, and adjust the dose accordingly. Furthermore, the dose estimation between species can be carried out using methods well known in this technology (for example, Mordenti et al., 1991, Pharmaceut. Res. 8:1351).

Various delivery systems are known and can be used to administer the characteristic pharmaceutical composition of the present invention, such as encapsulated liposomes, microparticles, microcapsules, recombinant cells capable of expressing mutant viruses, and receptors for mediator endocytosis ( See, for example, Wu et al., 1987 J. Biol. Chem. 262: 4429-4432). Administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intratracheal, epidural, and oral routes. The composition can be administered by any convenient route, such as by infusion or bolus injection, for absorption through epithelial or mucosal layers (such as oral mucosa, rectum and intestinal mucosa, etc.), and can be co-administered with other biologically active agents.

The pharmaceutical composition of the present invention can be delivered subcutaneously or intravenously with a standard needle or syringe. In addition, in terms of subcutaneous delivery, a pen-type delivery device can be easily used to deliver the pharmaceutical composition of the present invention. The pen-type delivery device can be a reusable type or a disposable type. Reusable pen-type delivery devices generally utilize replaceable refill cartridges containing medical components. Once all the medical components in the cassette are administered and the supplementary cassette is empty, the empty cassette can be easily discarded and replaced with a new supplementary cassette containing the medical composition. Then the pen-type delivery device can be used again. There is no replaceable refill cassette in a disposable pen-type delivery device. Instead, the disposable pen-type delivery device is pre-filled with medical composition and stored in a storage tank in the device. Once the storage tank for the pharmaceutical composition becomes empty, the entire device can be discarded.

Many reusable pen-type and auto-injector delivery devices have been used to deliver the pharmaceutical composition of the present invention subcutaneously. Examples include (but are not limited to) AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUMALOG™ pen, HUMALIN 70/30 ™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™ and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany), to name just a few. Examples of disposable pen-type delivery devices for subcutaneous delivery of the pharmaceutical composition of the present invention include (but are not limited to) SOLOSTAR™ pen (sanofi-aventis), FLEXPEN™ (Novo Nordisk) and KWIKPEN™ (Eli Lilly), SURECLICK™ auto-injector (Amgen, Thousand Oaks, CA), PENLETTM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP) and HUMIRATM pens (Abbott Labs, Abbott Park IL), but only some are proposed.

For direct administration to the sinuses, the pharmaceutical composition of the present invention can use microcatheters (for example, endoscopes and microcatheters), aerosol sprayers, powder dispensers, nebulizers or inhalers. The method includes administering an IL-4R antagonist to a subject in need thereof in an aerosolized formulation. For example, aerosolized IL-4R antibody can be administered to treat asthma in a patient. Aerosolized antibodies can be prepared as described in, for example, US8178098, which is incorporated herein in its entirety.

Under certain circumstances, the pharmaceutical composition can be delivered by a controlled release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In other embodiments, polymeric substances can be used; see Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, the controlled release system can be placed close to the target of the composition, so only a portion of the systemic dose is required (see, Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review of Langer, 1990, Science 249:1527-1533.

Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injection, drip infusion, and the like. These injectable preparations can be prepared by known methods. For example, injectable preparations can be prepared, for example, by dissolving, suspending or emulsifying the above-mentioned antibody or salt thereof in a sterile aqueous or oily vehicle conventionally used for injection. The aqueous vehicles for injection include, for example, physiological saline, isotonic solutions containing glucose and other adjuvants, etc., which can be combined with suitable solubilizers such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol, polyethylene glycol, etc.). ), non-ionic surfactants [for example, polysorbate 80, HCO-50 (polyethylene oxide (50 mol) adduct of hydrogenated castor oil)] and the like are used in combination. As the oily vehicle, sesame oil, soybean oil, etc. can be used, which can be used in combination with a solubilizer such as benzyl benzoate, benzyl alcohol and the like. The injection thus prepared is preferably filled in an appropriate ampoule.

Advantageously, the above-mentioned pharmaceutical composition for oral or parenteral use is prepared into a unit dose dosage form suitable for the dosage of the active ingredient. The dosage form of this unit dose includes, for example, lozenges, tablets, capsules, injections (ampoules), suppositories, and the like.

Exemplary pharmaceutical compositions including anti-IL-4R antibodies that can be used in the context of the present invention are disclosed in U.S. Patent Application Publication No. 2012/0097565. dose

According to the method of the present invention, the amount of IL-4R antagonist (eg, anti-IL-4R antibody) administered to a subject is generally a therapeutically effective amount. As used in the text, "therapeutically effective amount" refers to the amount of IL-4R antagonist that produces one or more of the following: (a) reduces the incidence of exacerbation of asthma; (b) improves one or more asthma-related parameters (such as other parameters in the text) Location definition); and/or (c) Perceptible improvement of one or more symptoms or signs of upper respiratory tract inflammation. "Therapeutically effective amount" also includes the amount of IL-4R antagonist that inhibits, prevents, reduces or delays the progression of asthma in a subject.

In the case of anti-IL-4R antibodies, the therapeutically effective amount can be from about 0.05 mg to about 600 mg, such as about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 5.0 mg, about 7.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg , About 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg , About 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg of anti-IL -4R antibody. In a specific example, 300 mg of anti-IL-4R antibody is administered.

The amount of IL-4R antagonist contained in an individual dose can be expressed in milligrams per kilogram of the patient's body weight (ie, mg/kg). For example, the IL-4R antagonist can be administered to the patient at a dose of about 0.0001 to about 10 mg/kg of the patient's body weight. Combination therapy

The methods of the present invention, according to specific embodiments, include administering to the subject a combination of one or more additional therapeutic agents and an IL-4R antagonist. As used herein, the term "combination" means that the additional therapeutic agent is administered before, after or at the same time as the pharmaceutical composition including the IL-4R antagonist. In certain embodiments, the term "combination" includes the sequential or concomitant administration of the IL-4R antagonist and the second therapeutic agent. The present invention includes a method for treating asthma or related symptoms or complications, or reducing at least one exacerbation, which comprises administering a combination of an IL-4R antagonist and a second therapeutic agent for additive or synergistic activity.

For example, when the pharmaceutical composition including the IL-4R antagonist is administered "before", the additional therapeutic agent may be administered about 72 hours, about 60 hours, or about 48 hours before the pharmaceutical composition including the IL-4R antagonist is administered. Hour, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes or about 10 minutes medicine. When administered "after" the pharmaceutical composition including the IL-4R antagonist, the additional therapeutic agent may be about 10 minutes, about 15 minutes, about 30 minutes, or about 10 minutes after the pharmaceutical composition including the IL-4R antagonist is administered It is administered for about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours. "Simultaneous" administration with the pharmaceutical composition including the IL-4R antagonist means that the additional therapeutic agent is administered within less than 5 minutes (before, after or simultaneously) of the pharmaceutical composition including the IL-4R antagonist The subject is administered in separate dosage forms, or in a dosage formulation that includes a single combination of both the therapeutic agent and the IL-4R antagonist.

This additional therapeutic agent may be, for example, another IL-4R antagonist, IL-1 antagonist (including, for example, the IL-1 antagonist described in U.S. Patent No. 6,927,044), IL-6 antagonist, IL-1 6R antagonists (including, for example, the IL-6 antagonists described in US Patent No. 7,582,298), TNF antagonists, IL-8 antagonists, IL-9 antagonists, IL-17 antagonists, IL-5 antagonists , IgE antagonists, CD48 antagonists, leukotriene inhibitors, anti-fungal agents, NSAIDs, long-acting β2 agonists (e.g., salmeterol or formoterol), inhaled corticosteroids (e.g., fluticasone or Budesonide, systemic corticosteroids (for example, oral or intravenous), methylmethylxanthines, nedocromil sodium, cromolyn sodium, or combinations thereof. For example, in specific In the embodiment, the pharmaceutical composition system including IL-4R antagonist is administered in combination with the composition including long-acting β2-agonist and inhaled corticosteroid (for example, fluticasone or salmeterol [for example, Advair® (GlaxoSmithKline) ]; or budesonide + formoterol [eg Symbicort® (Astra Zeneca)]). Administration therapy

According to a specific embodiment of the present invention, multiple doses of IL-4R antagonist can be administered to a subject within a defined period of time. These methods include sequential administration of multiple doses of IL-4R antagonist to a subject. As used herein, "sequential administration" means that each dose of IL-4R antagonist is administered to the subject at different time points, such as different days separated by expected intervals (eg, hours, days, weeks, or months). The present invention includes the steps of sequentially administering a single initial dose of IL-4R antagonist to the patient, followed by one or more second doses of IL-4R antagonist, and optionally followed by one or more third doses of IL -4R antagonist method.

The present invention includes, including about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every ten A method of administering a pharmaceutical composition including an IL-4R antagonist to a subject at a frequency of once every two weeks or less (as long as a therapeutic response is achieved). In specific embodiments involving the administration of a pharmaceutical composition comprising IL-4R antibody, an amount of about 75 mg, 150 mg, or 300 mg can be used once a week. In other embodiments involving the administration of a pharmaceutical composition including IL-4R antibody, an amount of about 75 mg, 150 mg, or 300 mg administered once every two weeks can be used. In other embodiments involving the administration of pharmaceutical compositions including IL-4R antibodies, an amount of about 75 mg, 150 mg, or 300 mg administered once every three weeks can be used. In other embodiments involving the administration of pharmaceutical compositions including IL-4R antibodies, an amount of about 75 mg, 150 mg, or 300 mg administered once every four weeks can be used. In other embodiments involving the administration of pharmaceutical compositions including IL-4R antibodies, an amount of about 75 mg, 150 mg, or 300 mg administered once every five weeks can be used. In other embodiments involving the administration of pharmaceutical compositions including IL-4R antibodies, an amount of about 75 mg, 150 mg, or 300 mg administered once every six weeks can be used. In other embodiments involving the administration of pharmaceutical compositions including IL-4R antibodies, an amount of about 75 mg, 150 mg, or 300 mg administered once every eight weeks can be used. In other embodiments involving the administration of pharmaceutical compositions including IL-4R antibodies, an amount of about 75 mg, 150 mg, or 300 mg administered once every twelve weeks can be used. The preferred route of administration is subcutaneous.

The term "week" refers to a period of (nx 7 days) ±2 days, preferably (nx 7 days) ±1 day, more preferably (nx 7 days), where "n" refers to the number of weeks, such as 1, 2, 3, 4, 5, 6, 8, 12 or more.

The terms "initial dose", "second dose" and "third dose" refer to the temporary sequence of administration of the IL-4R antagonist. Therefore, the "initial dose" is the dose administered at the beginning of the treatment (also referred to as the "baseline" dose); the "second dose" is the dose administered after the initial dose; and the "third dose" It is the dose administered after the second dose. The initial, second, and third doses can all contain the same amount of IL-4R antagonist, but in terms of frequency of administration, they can generally be different from each other. In certain embodiments, however, the amount of IL-4R antagonist included in the initial, second, and/or third doses may be different during the treatment period (for example, adjusted up or down if appropriate) . In a specific embodiment, two or more (for example, 2, 3, 4, or 5) doses are administered as the "bearer dose" at the beginning of the treatment therapy, and subsequent doses are administered on a lower frequency basis ( For example, "maintenance dose"). In one embodiment, the maintenance dose may be lower than the carrier dose. For example, one or more IL-4R antagonists can be administered at a loading dose of 600 mg, followed by a maintenance dose of about 75 mg to about 300 mg.

In an exemplary embodiment of the present invention, each second and/or third dose is administered 1 to 14 weeks immediately after the previous dose (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½ , 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½ weeks or longer). The term "administered immediately before" means that in a sequence of multiple administrations, the dose of IL-4R antagonist is administered in the sequence without intervening doses before the administration of each adjacent dose Patient.

These methods can include administering any number of second and/or third doses of IL-4R antagonist to a patient. For example, in certain embodiments, only a single second dose is administered to the patient. In other embodiments, two or more (eg, 2, 3, 4, 5, 6, 7, 8, or more) second doses are administered to the patient. Likewise, in certain embodiments, only a single third dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) third doses are administered to the patient.

In embodiments involving multiple second doses, each second dose may be administered at the same frequency as the other second doses. For example, each second dose can be administered to the patient 1 to 2 weeks immediately after the previous dose. Likewise, in embodiments involving multiple third doses, each third dose may be administered at the same frequency as the other third doses. For example, each third dose can be administered to the patient 2 to 4 weeks immediately after the previous dose. In addition, the frequency of administering the second and/or third dose to the patient may be different during the treatment period. During the treatment period, the frequency of administration can also be adjusted by the physician after the clinical examination according to the needs of individual patients.

The present invention includes a method comprising sequentially administering an IL-4R antagonist and a second therapeutic agent to a patient to treat asthma or related symptoms. In certain embodiments, these methods include administering one or more doses of an IL-4R antagonist, followed by one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more). The second therapeutic agent. For example, one or more doses of 75 mg to about 300 mg of IL-4R antagonist can be administered, followed by one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 or more). The second therapeutic agent (e.g., inhaled corticosteroid or β2-agonist or any other therapeutic agent, as described elsewhere in the text) is used to treat, reduce, reduce or ameliorate one or more asthma symptoms. In certain embodiments, one or more doses (eg, 2, 3, 4, 5, 6, 7, 8 or more) of IL-4R antagonist are administered to improve one or more asthma-related parameters , And then administer a second therapeutic agent to prevent at least one asthma symptom from recurring. An alternative embodiment relates to the simultaneous administration of IL-4R antagonist and a second therapeutic agent. For example, one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8 or more) of IL-4R antagonist are administered, and the IL-4R antagonist is separated at a similar or different frequency The dose of the second therapeutic agent. In certain embodiments, the second therapeutic agent is administered before, after, or at the same time as the IL-4R antagonist. Treatment group

The method of the present invention includes administering a therapeutic composition including an IL-4R antagonist to a subject in need thereof. The term "subject in need" refers to a human or non-human animal with one or more symptoms or signs of asthma (such as eosinophilic asthma, including moderate to severe eosinophilic asthma), or a person who has been diagnosed with asthma . For example, "a subject in need" may include one or more asthma-related parameters before treatment, such as reduced FEV1 (for example, lower than 2.0 L), and reduced AM PEF (for example, lower than 400 L/min), reduced PM PEF (for example, less than 400 L/min), ACQ5 score of at least 2.5, nocturnal awakening at least once every night, and/or SNOT-22 score of at least 20. In various embodiments, these methods can be used to treat mild, moderate to severe, and severe asthma in patients in need thereof.

In a related embodiment, the "subject in need" can be a person who has received prescription drugs before receiving IL-4R antagonists or is currently receiving inhaled corticosteroids (ICS)/long-acting β2-adrenergic antagonists ( The object of the combination of LABA). Examples of ICS/LABA treatments include fluticasone/salmeterol combination therapy and budesonide/formoterol combination therapy. For example, the present invention includes a method comprising administering an IL-4R antagonist to a patient, wherein the patient has received a regular course of ICS/LABA for two or more weeks immediately before the IL-4R antagonist is administered (the previous treatment was in Refers to "background therapy" in the text). The present invention includes treatment methods in which the background treatment is interrupted when the IL-4R antagonist is first administered or just before (e.g., 1 day to 2 weeks ago). In addition, background therapy can continue to be combined with IL-4R antagonist administration. In still other embodiments, the amount of the ICS component, the LABA component, or both is gradually reduced before or after the IL-4R antagonist is administered. In certain embodiments, the present invention includes methods for treating patients with persistent asthma for at least 12 months. In one example, patients with persistent asthma may be resistant to treatment with therapeutic agents, such as corticosteroids, and may be administered IL-4R antagonists according to the method of the present invention.

In some embodiments, the "subject in need" may be a subject with an elevated amount of asthma-related biomarkers. Examples of asthma-related biomarkers include (but are not limited to) IgE, thymus and activation regulatory chemotactic hormone (TARC), eosinophil chemotactic hormone-3 (eotaxin-3), CEA, YKL-40, and periostin (periostin) . In some embodiments, the "object in need" may be a subject with blood eosinophils ≥ 300/µl or sputum eosinophils ≥ 3%. In one embodiment, the "object in need" may be, as measured by the expiratory nitric oxide fraction (FeNO), an object with elevated bronchial or tracheal inflammation.

For the purpose of the present invention, the normal amount of IgE in healthy subjects is less than about 100 kU/L (for example, measured using ImmunoCAP® analysis [Phadia, Inc. Portage, MI]). Therefore, the present invention involves selecting subjects with elevated serum IgE levels that are greater than about 100 kU/L, greater than about 150 kU/L, greater than about 500 kU/L, greater than about 1000 kU/L , Greater than about 1500 kU/L, greater than about 2000 kU/L, greater than about 2500 kU/L, greater than about 3000 kU/L, greater than about 3500 kU/L, greater than about 4000 kU/L, greater than about 4500 kU/L or A method of administering a therapeutically effective amount of an IL-4R antagonist to the subject with a pharmaceutical composition greater than about 5000 kU/L.

The amount of TARC in healthy subjects ranges from 106 ng/L to 431 ng/L, with an average of about 239 ng/L. (The exemplary analysis system for measuring the amount of TARC is the TARC quantitative ELISA kit, such as supplied by R&D Systems, Minneapolis, MN, model DDN00). Therefore, the present invention involves selecting subjects with elevated TARC levels, whose serum TARC levels are greater than about 431 ng/L, greater than about 500 ng/L, greater than about 1000 ng/L, greater than about 1500 ng/L, greater than about 2000 ng/L, greater than about 2500 ng/L, greater than about 3000 ng/L, greater than about 3500 ng/L, greater than about 4000 ng/L, greater than about 4500 ng/L or greater than about 5000 ng/L, and here A method of administering a pharmaceutical composition comprising a therapeutically effective amount of an IL-4R antagonist to a subject.

Eosinophil chemokine-3 (eotaxin-3) belongs to the group of chemotactic hormones released by tracheal epithelial cells, which is upregulated by the Th2 cytokines IL-4 and IL-13 (Lilly# et al. 1999, J. Allergy Clin. Immunol. 104: 786-790). The present invention includes including the administration of IL-4R antagonists to treat patients with elevated amounts of eosinophil chemoattractant-3, for example, greater than about 100 pg/ml, greater than about 150 pg/ml, greater than about 200 pg/ml , Methods for objects greater than about 300 pg/ml or greater than about 350 pg/ml. The amount of serum eosinophil chemoattractant-3 can be measured, for example, by ELISA.

Periostin is an extracellular matrix protein involved in Th2-mediated inflammation. Up-regulation of periostin can be found in patients with asthma (Jia et al. 2012 J Allergy Clin Immunol. 130:647-654.e10. doi: 10.1016/j.jaci.2012.06.025. Epub 2012 Aug 1) . The present invention includes methods comprising administering IL-4R antagonists to treat patients with elevated amounts of periostin.

The expiratory NO fraction (FeNO) is a biomarker of inflammation in a trachea or trachea. FeNO is produced by tracheal epithelial cells in response to inflammatory cytokines, including IL-4 and IL-13 (Alwing et al. 1993, Eur. Respir. J. 6: 1368-1370). The amount of FeNO in healthy adults ranges from 2 to 30 parts per billion (ppb). The exemplary analysis for measuring FeNO is by using the NIOX instrument of Aerocrine AB, Solna, Sweden. This assessment can be performed before spirometry and after fasting for at least 1 hour. The present invention includes administering an IL-4R antagonist with an elevated amount of expiratory NO (FeNO), for example, greater than about 30 ppb, greater than about 31 ppb, greater than about 32 ppb, greater than about 33 ppb, greater than about 34 ppb, greater than The method for patients with about 35ppb.

Carcinoembryonic antigen (CEA) is a tumor marker that has been found to be associated with non-neoplastic diseases of the lung (Marechal et al. 1988, Anticancer Res. 8: 677-680). The amount of CEA in serum can be measured by ELISA. The present invention includes administering an IL-4R antagonist with an elevated amount of CEA, for example, greater than about 1.0 ng/ml, greater than about 1.5 ng/ml, greater than about 2.0 ng/ml, greater than about 2.5 ng /ml, higher than about 3.0 ng/ml, higher than about 4.0 ng/ml or higher than about 5.0 ng/ml.

YKL-40 [named after its N-terminal amino acids tyrosine (Y), lysine (K) and leucine (L) and its molecular weight 40kD] is a class of chitinase protein, which can be found to be up-regulated And it is associated with worsening asthma, IgE and eosinophils (Tang et al. 2010 Eur. Respir. J. 35: 757-760). The amount of serum YKL-40 is measured by, for example, ELISA. The present invention includes administering an IL-4R antagonist with an elevated amount of YKL-40, such as greater than about 40 ng/ml, greater than about 50 ng/ml, greater than about 100 ng/ml, greater than about Method for patients with 150 ng/ml, higher than about 200 ng/ml or higher than about 250 ng/ml.

Induced sputum eosinophils and neutrophils are established direct markers of tracheal inflammation (Djukanovic et al. 2002, Eur. Respire. J. 37: 1S-2S). The sputum is induced by inhalation of a hypertonic salt solution and the cell count is performed according to methods known in this technology, such as the guidelines of the European Respiratory Association. The present invention includes methods comprising administering an IL-4R antagonist to patients with elevated amounts of sputum eosinophils, for example, greater than about 2.5% or greater than about 3%. Method for evaluating asthma-related parameters in pharmacodynamics

The present invention also includes a method for evaluating one or more pharmacodynamic asthma-related parameters caused by the administration of a pharmaceutical composition including an interleukin-4 receptor (IL-4R) antagonist in a subject in need thereof . The decrease in the incidence of asthma exacerbation (as described above) or the improvement of one or more asthma-related parameters (as described above) may be related to the improvement of one or more pharmacodynamic asthma-related parameters; however, this correlation is not necessarily Observed in all cases.

Examples of "pharmacodynamic parameters related to asthma" include, for example, the following: (a) biomarker expression level; (b) serum protein and RNA analysis; (c) induced sputum eosinophils and neutrophils; (d) Exhaled nitric oxide (FeNO); and (e) the number of blood eosinophils. "Pharmacodynamic improvement in asthma-related parameters" refers to, for example, a decrease in one or more biomarkers, such as TARC, eosinophil chemokine-3 or IgE, sputum eosinophils or neutrophils compared to baseline , FeNO or decreased blood eosinophil count. As used herein, the term "baseline", in terms of pharmacodynamic asthma-related parameters, refers to the value of the patient's pharmacodynamic asthma-related parameters at or before the administration of the characteristic pharmaceutical composition of the present invention.

The evaluation of pharmacodynamic parameters related to asthma is to quantify the parameters of the baseline and the time point after administration of the pharmaceutical composition of the present invention. For example, pharmacodynamic parameters related to asthma can be set on the first day, the second day, the third day, the fourth day, the fifth day, the sixth day, the seventh day, and the seventh day after the initial treatment of the pharmaceutical composition of the present invention. Day 8, Day 9, Day 10, Day 11, Day 12, Day 14, or Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9 , Week 10, Week 11, Week 12, Week 13, Week 14, Week 15, Week 16, Week 17, Week 18, Week 19, Week 20, Week 21, Week 22 Week, 23rd week, 24th week or longer. Use the difference between the parameter value at a specific time point after the initial treatment and the baseline parameter value to establish whether there is a change in the pharmacodynamic asthma-related parameter, such as "improvement" (for example, increase or decrease according to the specific parameter measured , Depending on the situation).

In a specific embodiment, the IL-4R antagonist is administered to the patient to cause a change in the performance of a specific biomarker, such as a decrease or an increase. Asthma-related biomarkers include the following: (a) total IgE; (b) thymus and activated regulatory chemokine (TARC); (c) YKL-40; and (d) serum carcinoembryonic antigen (CEA, known as CEA cell adhesion molecule 5 [CEACAM5]) and (e) Eosinophil chemoattractant-3 in plasma. For example, administration of IL-4R antagonists to asthmatic patients can cause a decrease in the amount of one or more TARC or eosinophil chemokine-3, or a decrease in the amount of total serum IgE. This decrease can be detected in the first week, the second week, the third week, the fourth week, the fifth week or longer after the IL-4R antagonist is administered. Biomarker performance can be evaluated by methods known in this technology. For example, the amount of protein can be measured by ELISA (enzyme linked immunosorbent assay), or the amount of RNA can be measured by reverse transcription combined with polymerase chain reaction (RT-PCR).

Biomarker performance, as discussed above, can be analyzed by detecting protein or RNA in serum. Serum samples can also be used to monitor additional protein or RNA biomarkers related to response to IL-4R antagonist therapy, L 4/IL-13 signaling, asthma, specific reactions, or eosinophilic diseases (e.g., by measuring soluble IL-4Rα , IL 4,, IL-13, protein). In some embodiments, RNA samples are used to determine the amount of RNA (non-genetic analysis), such as the amount of RNA for biomarkers; and in other embodiments, RNA samples are used for transcript sequencing (eg, genetic analysis).

Instance

The following examples are presented to provide a complete disclosure and description of how those skilled in the art can make and use the methods and compositions of the present invention, but do not intend to limit the scope of the invention as considered by the inventors. Although every effort has been made to ensure the correctness of the relevant figures (such as quantity, temperature, etc.) used, some experimental errors and deviations should still be considered. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is expressed in degrees Celsius, and pressure is at or near atmospheric pressure. Example 1. Human antibody production of human IL-4R

The human anti-hIL-4R antibody system was produced as described in US Patent No. 7,608,693. Table 1 describes the selected anti-IL-4R antibodies and their corresponding antibody names of the heavy chain and light chain variable region amino acid sequence pairs and the sequence identification symbols of the CDR amino acid sequences. Table 1 SEQ ID NOs: Antibody name HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 H1H095-a 2 4 6 8 10 12 14 16 H1H095-b 18 4 6 8 20 12 14 16 H1H095-c twenty two 4 6 8 twenty four 12 14 16 H1H097-a 26 28 30 32 34 36 38 40 H1H097-b 42 28 30 32 44 36 38 40 H1H097-c 46 28 30 32 48 36 38 40 H1H093-a 50 52 54 56 58 60 62 64 H1H093-b 66 52 54 56 68 60 62 64 H1H093-c 70 52 54 56 72 60 62 64 H1H093-d 74 76 78 80 82 84 86 88 H1H093-e 90 76 78 80 92 84 86 88 H1H093-f 94 76 78 80 96 84 86 88 H1H094-a 98 100 102 104 106 108 110 112 H1H094-b 114 100 102 104 116 108 110 112 H1H094-c 118 100 102 104 120 108 110 112 H1H096-a 122 124 126 128 130 132 134 136 H1H096-b 138 124 126 128 140 132 134 136 H1H096-c 142 124 126 128 144 132 134 136 H1H098-a 146 148 150 152 154 156 158 160 H1H098-b 162 148 150 152 164 156 158 160 H1H098-c 166 148 150 152 168 156 158 160 H1H099-a 170 172 174 176 178 180 182 184 H1H099-b 186 172 174 176 188 180 182 184 H1H099-c 190 172 174 176 192 180 182 184 H4H083-a 194 196 198 200 202 204 206 208 H4H083-b 210 196 198 200 212 204 206 208 H4H083-c 214 196 198 200 216 204 206 208 H4H121-a 218 220 222 224 226 228 230 232 H4H121-b 234 220 222 224 236 228 230 232 H4H121-c 238 220 222 224 240 228 230 232 H4H118-a 242 244 246 248 250 252 254 256 H4H118-b 258 244 246 248 260 252 254 256 H4H118-c 262 244 246 248 264 252 254 256

An exemplary IL-4R antagonist used in the following examples is the human anti-IL-4R antibody designated H1H098-b in Table 1 (also referred to herein as "mAb1"). Example 2 : Clinical trial of subcutaneous administration of anti-IL-4R antibody (mAb1) in patients with persistent moderate to severe eosinophilic asthma, including patients with chronic proliferative eosinophilic sinusitis A. Research goals and overview

Inhaled corticosteroids (ICS) and long-acting beta 2 agonists (LABA) were administered subcutaneously with 300 mg mAb1 or placebo once a week for 12 weeks in the treatment of partially controlled or uncontrollable patients with persistent moderate to severe addiction For patients with acid cell asthma, a randomized, placebo-controlled, double-blind, parallel group study was conducted. The main goal of this study was to investigate the effect of mAb1 administered subcutaneously once a week for 12 weeks compared with placebo on reducing the incidence of asthma exacerbation in patients with persistent moderate to severe eosinophilic asthma. The second goal of this study is to evaluate the safety and tolerability of mAb1 administered subcutaneously once a week for 12 weeks in patients with persistent moderate to severe eosinophilic asthma, and to evaluate the safety and tolerability of mAb1 administered once a week for 12 weeks. The serum concentration of mAb1 in patients with persistent moderate to severe eosinophilic asthma after 12 weeks of subcutaneous administration.

Before screening, patients must have received stable doses of the following ICS/LABA combination therapy (also known as background therapy) and formulations for at least 1 month: Fluticasone/salmeterol combination therapy -Advair® Diskus-Dry Powder Inhaler (DPI): 250/50 ug BID or 500/50 ug BID; or -Advair® HFA-MDI: 230/42 ug BID or 460/42 ug BID; or Budesonide/formoterol combination therapy (Symbicort® 160/9 ug BID or 320/9 ug BID); or Mometasone/formoterol combination therapy (Dulera® 200/10 ug BID or 400/10 ug BID).

Randomized (day 1) patients receiving budesonide/formoterol or mometasone/formoterol were replaced with equivalent doses of fluticasone/salmeterol while patients receiving fluticasone/salmeterol remained the same As background treatment.

Patients who meet the inclusion and exclusion criteria (see below) are randomly assigned to one of the following treatments: 300 mg of mAb1, administered subcutaneously once a week for 12 weeks; or placebo, administered subcutaneously once a week for 12 weeks .

The study included a 2-week screening period, a 12-week treatment period, which included a 4-week background treatment stabilization period and an 8-week background treatment withdrawal period after random assignment, followed by an 8-week post-treatment follow-up period. The algorithm of background therapy (ICS/LABA) withdrawal:

Patients were still on BID fluticasone/salmeterol background treatment for 4 weeks after starting the add-on therapy or treatment with 300 mg mAb1 (or placebo). After random allocation in the 4th week, the patients were replaced by fluticasone/salmeterol combination therapy with equivalent ICS dose fluticasone monotherapy (including 250ug or 500 ug BID Flovent® Diskus-DPI formulation; or 220 ug or 440 ug BID's Flovent® HFA-MDI formulation). Discontinue the LABA component (that is, salmeterol). In the follow-up visit, the fluticasone dose was reduced by about 50% from the 6th week, provided that the patient did not meet any criteria for asthma exacerbation (as defined below). If no asthma worsening occurs, ICS evacuation is performed according to the following dosing schedule: Background treatment stable period Background treatment withdrawal period Week 4 Week 6 Week 7 Week 8 Week 9 Fluticasone/Salmeterol (DPI): 250/50μg BID Fluticasone/Salmeterol (DPI): 500/50μg BID Fluticasone (DPI): 250 BID Fluticasone (DPI): 500 BID 100μg BID 250μg BID 50μg BID 100μg BID 0μg BID 50μg BID 0μg BID 0μg BID Fluticasone/Salmeterol (MDI): 230/42μg BID Fluticasone/Salmeterol (MDI): 460/42μg BID Fluticasone (MDI): 220μg Fluticasone (MDI): 440μg 110μg BID 220μg BID 44μg BID 110μg BID 0μg BID 44μg BID 0μg BID 0μg BID

After completing the 12-week study product treatment (or after early discontinuation), let the patient receive their original dose of fluticasone/salmeterol, budesonide/formoterol or mometasone/formoterol (enter the study) Time-dose) and salatinol or levosatinol, if needed to control the symptoms, will be administered outside the study for another 8 weeks, after which the final safety assessment will be carried out.

Adult patients were included in the study based on the following criteria: (1) Based on the Global Asthma Initiative (GINA) 2009 guidelines, the physician diagnosed persistent asthma for at least 12 months, and the inflammation of the trachea may be eosinophils (2) According to the following criteria, their asthma is partially controlled or uncontrollable with corticosteroid/long-acting beta-agonist combination therapy: (i) Before screening, a stable dose of fluticasone/salmeterol combination therapy (DPI) Formulation: 250/50 μg BID or 500/50 μg BID or MDI Formulation: 230/42 μg BID (460/42 μg BID), or budesonide/formoterol combination therapy (160/9 μg BID or 320/9 μg BID), or mometasone/formoterol combination therapy (200/10 μg BID or 400/10 μg BID) for at least 1 month; (ii) blood eosinophils ≥ 300 during the screening period Cells/μl or sputum eosinophils ≥ 3%; (iii) Juniper asthma control questionnaire (5-item version, ACQ) score ≥ 1.5 and ≤ 3.0 at the time of screening; (iv) during the screening period (up to 3 times) Attempts) and on the day of random assignment before the first dose (up to 3 attempts), FEV1 ≥ 50% is predicted to be normal; (v) One or more systemic (oral and/or parenteral) steroids have been taken before screening Intensive treatment of worsening asthma or the patient’s hospitalization or emergency care visits for worsening asthma; and (vi) The recovery history published in the 12-month screening meets the following criteria-200 µg to 400 µg (2 to 4 inhalations) during the screening period At least 12% and 200 mL of FEV1 (maximum 3 attempts) after the satineamol, or a positive methylcholine challenge (PD20 methylcholine ≤ 8 mg) within 12 months before screening. Combination therapy with medium or high doses of inhaled corticosteroids/long-acting β-agonists (ADVAIR®, SYMBICORT® or DULERA®) will partially control or uncontrollable moderate to severe asthma, and blood habit during screening Patients with acid cells greater than or equal to 300 cells per milliliter, or patients with sputum eosinophils greater than or equal to 3% were included in this study.

All patients who meet the inclusion criteria are screened with the following exclusion criteria: (1) Patients under 18 and over 65; (2) Clinically relevant abnormal laboratory values, showing unknown diseases and requiring further evaluation; (3) Chronic pulmonary obstructive pulmonary disease (COPD) and/or other lung diseases impaired lung function test; (4) Patients who need β-adrenoreceptor blockers for any reason; (5) Current smoking or screening Those who quit smoking in the first 6 months; (6) Previously smoked, with a history of smoking> 10 packs-years; (7) Hospitalized or emergency care visits due to worsening asthma within 2 months before screening; (8) Plan during the study period Start allergen immunotherapy; (9) Receive another research antibody within a period of time before the screening, which is less than 5 half-lives of the antibody but not less than 30 days, or if the half-life of the antibody is unknown, then the pre-screening The duration is at least 6 months; (10) Previously logged into the current study; (11) The patient is a researcher, and his family or employees at the research location; (12) Known or suspected disobedience, alcohol or drug addiction; (13) Failure to follow research procedures (for example, due to language problems or mental illness); (14) Reversed sleep patterns (for example, night shift workers); (15) Treatment with drugs known to extend the QTc interval; (16) Accompanying serious illness Therefore, it is forbidden to use ICS (such as active or inactive tuberculosis) or LABA (such as diabetes, cardiovascular disease, hypertension, hyperthyroidism, thyrotoxicosis, etc.); (17) It can be used within 2 months before screening. Injection of glucocorticoids or oral systemic corticosteroids, or more than 3 courses within 6 months before screening; (18) Pre-treatment of various doses of ICS, alone or in combination with non-steroid control agents (fluticasone/salmeterol combination therapy , Budesonide/formoterol combination therapy or mometasone/formoterol combination therapy); (19) patients receiving prohibited concomitant medical treatment (listed below); (20) known to doxil Allergies to doxycycline or related compounds; (21) pregnancy or planning to become pregnant, breast-feeding or unwilling to use effective contraceptive methods during the study period; and (22) recent history of parasitic infections or up to 6 months before screening Travel to areas where parasites are prevalent.

In the first four weeks of the study, patients who continued to receive a constant dose of background asthma therapy, then gradually reduced the background therapy dose. First, withdraw the long-acting beta-agonist component of the background treatment in the 4th week, and then halve the inhaled corticosteroid dose every 2 weeks until the 12th week. Patients will continue the study treatment until the end of the study or until they withdraw due to worsening asthma or any other factors. B. Research treatment

Research product: The sterile mAb1 150 mg/mL solution for SC injection is provided in a 5 mL glass vial. Each vial contains an extractable volume of 2 mL. The 300 mg dose was administered subcutaneously once a week in the morning at the study site for 12 weeks. Placebo: The sterile placebo for SC injection is provided in the same size 5 mL glass vial. Each vial contains an extractable volume of 2 mL. The placebo was administered subcutaneously once a week in the morning at the study site for a total of 12 weeks.

The following concomitant medical treatments are not allowed during the duration of the study: any other fluticasone/salmeterol combination therapy or fluticasone administration (or budesonide/formoterol or mometasone/formoterol during the screening period) Inhaled steroids other than those listed above; systemic or ocular steroids; LABAs other than the salmeterol component of fluticasone/salmeterol combination therapy that meets the plan; any other ICS/LABA combination products other than those given above; any Inhaled anti-cholinergic agents (such as Ipratropium bromide or tiotropium); methylxanthines (theophylline, aminophylline); g Cromone; anti-IgE treatment; lipoxygenase inhibitor; and leukotriene receptor antagonist or leukotriene synthesis inhibitor. C. Therapeutic effect

The primary efficacy endpoint of this study is the occurrence of any exacerbation of asthma as defined by: (1) The morning peak expiratory flow (PEF) is reduced by 30% or more compared to baseline for two consecutive days; (2) On two consecutive days, Within a 24-hour period (compared to baseline) six or more additional sastin or levartine relievers; and (3) worsening of asthma, as determined by the investigator, requires: (a) Systemic (oral and/or parenteral) steroid therapy, or (b) ICS increased ≥4 times from the last dose received before the study was discontinued, or (c) hospitalization.

The secondary efficacy endpoints of this study include the average changes in the following parameters compared to baseline: (1) Forced expiratory volume (FEV1) within 1 second measured at each return to the clinic is expressed in liters; (2) The morning sum and sum of daily measurements The maximum expiratory flow rate in the evening (AM PEF and PM PEF) is expressed in liters/minute; (3) Daily use of salbutamol/levosalbutamol, expressed in inhalations/day; (4) 5 asthma control questionnaires for each visit (ACQ5) ) Score; and (5) wake up at night (number of times per night); and (6) 22-item sinus outcome test (SNOT-22) evaluated at baseline and at the end of treatment to assess upper respiratory symptoms. The secondary efficacy endpoint also includes the ratio of patients with a comprehensive asthmatic event, which is a 30% or more reduction in morning peak expiratory flow (PEF) compared to baseline on two consecutive days, and a 24-hour period for two consecutive days. During the period (compared to baseline) ≥ 6 six breaths or more as defined by additional salatinol or levosatinol relievers. PEF, ACQ5, asthma symptom score, night awakening and medical use of relievers are recorded in an electronic diary. Wake up every night on average, ranging from 0-10, which is the average of the previous 7 days. The morning and evening asthma symptom scores are composed of ineffective patient report results assessed on the 5-point Likert scale. The higher the score, the worse the result (Table 2). Before PEF, patients recorded all symptom scores twice a day. The data is described as the average of the 7 days prior to a specific time point (see, for example, Figures 26A and 26B). Table 2 : Assessment of Asthma Symptom Score A) Morning symptom score: 0 = no asthma symptoms, sleep all night 1 = good sleep, but some complaints in the morning. No night awakening 2 = Woke up once because of asthma (including early waking) 3 = Woke up several times because of asthma (including early waking) 4 = Poor sleep, because asthma is mostly awake at night B) Night symptom score: 0 = Very good, No wheezing symptoms 1 = one wheezing, coughing, or dyspnea 2 = more than one wheezing, coughing, or dyspnea that does not interfere with normal activities 3 = most wheezing, coughing, or dyspnea throughout the day, which interferes with normal activities to some extent 4 = Asthma is very severe. Unable to carry out daily activities as usual D. Adverse event monitoring

Safety is assessed by monitoring adverse events and serious adverse events through this study.

An adverse event (AE) is any adverse medical occurrence in a subject who has administered a pharmaceutical product or a clinical research subject. AE can therefore be any unfavorable and undesirable phenomenon (including abnormal laboratory examination findings), symptoms or diseases that are temporarily related to the use of medical products, regardless of whether relevant medical (research) products are considered. AE also includes: any worsening of existing symptoms (ie, any clinically significant change in frequency and/or intensity) that is temporarily related to the use of the study drug; the abnormal laboratory test findings considered by the researcher are clinically significant的; and any bad medical treatment occurs.

A serious adverse event (SAE) is any adverse medical treatment that causes death at any dose; life-threatening; requires hospitalization or prolongs the current hospital stay; causes sustained or significant disability; congenital anomalies/birth defects; or is an important medical event . E. Statistical methods

For the primary analysis of the proportion of patients with experiential asthma exacerbation, a logistic regression model was used to compare the SAR group and placebo. The model includes treatment duration and statistical factors (previous ICS/LABA combined treatment dose). The primary analysis is based on the modified intention-to-treat (mITT) cohort and includes all patients who were randomly assigned and received at least one dose of investigational medicinal product (IMP). A stratified chi-square test was also used to confirm this primary analysis.

With regard to the secondary efficacy endpoints, except for SNOT-22, the mixed-effects model was used to analyze changes from baseline by repeated measures (MMRM). This model includes changes up to 12 weeks compared to baseline values as response variables and treatment, stratification factors, return visits, return visits treatment interactions, baseline values and return visits baseline interaction factors (fixed effects). The statistical inferences that compare the changes from the baseline at week 12 are derived from the mixed effects model. The change of SNOT-22 compared with the baseline was analyzed by analysis of covariance (ANCOVA), and the measurement at the end of treatment was used to estimate the missing data. The pharmacodynamic effect is evaluated in a post hoc fashion using the MMRM model. No adjustment was made for multiplicity because there is only one primary efficacy endpoint and analysis. The safety variables including AE, test parameters, vital signs, ECG, clinical test observations and physical examinations are summarized using descriptive statistics.

Demographic and clinical characteristics are summarized using narrative characteristics. The mapping of the secondary and pharmacodynamic variables is expressed in terms of the mean change and standard error over time compared with the baseline. The comparison of treatment efficacy from the MMRM analysis is based on the least square mean change from baseline at week 12 (95% confidence interval [CI]). F. Results

The observation results of all 104 randomly assigned patients (selected from 491) who completed or discontinued the treatment period of this study are summarized below. All randomly assigned patients received study treatment and were included in the mITT group. The baseline characteristics between the groups are similar. The demographic and clinical characteristics of the two groups were also similar (Table 3). As mentioned above, patients were treated with 300 mg subcutaneous mAb1 once a week or with placebo. 86.5% and 67.3% of mAb1 and placebo patients, respectively, completed the study treatment period (Figure 25). The most common interruption factor was lack of utility, with placebo (21.2%) more frequently than mAb1 (1.9%). Table 3. Baseline demographics and clinical characteristics of the treatment group * variable Placebo (N=52) mAb1 300 mg (N = 52) age) 41.6 ± 13.1 37.8 ± 13.2 Number of males (%) 26 (50.0) 26 (50.0) Race or ethnicity (%) Whites 38 (73.1) 45 (86.5) Black or African American 9 (17.3) 5 (9.6) Asian 3 (5.8) 1 (1.9) other 2 (3.8) 1 (1.9) Body mass index Average (kg/m ² ) 31.6 ± 7.0 31.3 ± 8.0 ≥ 30, number (%) 25 (48.1) 24 (46.2) Duration of asthma (years) 26.9 ± 14.8 24.2 ± 12.6 Number of asthma exacerbations in the first 2 years 1.4 ± 1.3 1.4 ± 1.0 Previous ICS/LABA combined therapeutic dose, number (%) High dose 41 (78.8) 42 (80.8) Low dose 11 (21.2) 10 (19.2) Blood eosinophils (x10 ^-9 /l) 0.47 ± 0.21 0.55 ± 0.19 FEV ₁ (l) 2.54 ± 0.66 2.47 ± 0.65 FEV ₁ (% of stated value) 72.0 ± 12.7 72.0 ± 12.6 PEF (l/min) morning 406.9 ± 110.7 393.0 ± 101.1 evening 416.6 ± 116.8 414.6 ± 102.3 ACQ5 score 2.1 ± 0.5 2.1 ± 0.5 Asthma symptom score morning 0.73 ± 0.63 0.75 ± 0.81 evening 1.12 ± 0.73 0.92 ± 0.71 Wake up every night 0.21 ± 0.50 0.44 ± 0.80 SNOT-22 26.2 ± 15.6 30.9 ± 14.8 Inhalation of sartanol or levsartanol/24-hour period 2.0 ± 1.8 2.2 ± 2.4 FeNO (ppb) 35.0 ± 27.1 37.6 ± 28.1 TARC (pg/ml) 470.5 ± 204.7 496.1 ± 342.4 Eosinophil chemokine-3 (pg/ml) 117.3 ± 349.2 75.4 ± 44.0 IgE (IU/ml) 694.7 ± 1837.8 657.7 ± 1482.3 *Unless otherwise stated, ± values are average ± SD. ACQ5 refers to the asthma control questionnaire (5 questions version), FeNO expiratory nitric oxide fraction, FEV ₁ forced expiratory volume within 1 second, IgE immunoglobulin E, PEF maximum expiratory volume, SNOT-2222-item Results of the sinus test, and TARC thymus and activation regulating chemokines. (i) Primary efficacy endpoint

The incidence of asthma exacerbation in the placebo and mAb1 treatment groups is shown in Table 4. Table 4 : Incidence of exacerbation of asthma in the mITT population Placebo (N=52) mAb1 (N=52) No worsening of asthma 29 (55.8%) 49 (94.2%) Patients with worsening asthma 23 (44.2%) 3 (5.8%) Odds ratio and placebo (95% CI) - 0.077 (0.021, 0.279)

A total of 26 asthma exacerbations during the treatment period, and no patients were hospitalized due to exacerbation of asthma. In the placebo group, 23 patients experienced exacerbation of asthma, of which only 3 patients (5.8%) experienced exacerbation of asthma were in the mAb1 treatment group. The odds ratio is 0.077 (p <0.0001) and the relative risk is reduced by about 87%.

Of the 26 asthma exacerbations experienced during the study, 9 were considered severe, as indicated by the need for immediate intervention in the form of systemic corticosteroids at 4 times the dose received before the event or in the form of inhaled corticosteroids. The summary of the incidence of severe asthma exacerbation is shown in Table 5. Table 5: Incidence of severe asthma in the mITT population Placebo (N=52) mAb1 (N=52) Patients with no worsening asthma 29 (55.8%) 49 (94.2%) Patients with worsening severe asthma 8 (15.4%) 1 (1.9%) Patients with non-severe asthma worsening 15 (28.8%) 2 (3.8%)

As shown in Table 5, worsening of severe asthma was observed in eight patients in the placebo group, while worsening of severe asthma was observed in only one in the mAb1 treatment group. The remaining 15 asthma exacerbations in the placebo group and 2 in the mAb1 group met the definition of an exacerbation treatment regimen based on a decrease in morning PEF and/or an increase in the dosage of salatinol/levartine. As shown in Table 6, in the active treatment group, despite the withdrawal of steroids, continuous improvement was observed for all parameters against the baseline during the study period. Table 6. Deteriorating events result Placebo (N=52) mAb1 (N = 52) For 2 consecutive days, the morning PEF decreased by ≥ 30% compared to the baseline during the 24-hr period 10* (19.2) 1 (1.9) For 2 consecutive days, ≥ 6 inhalations of extra salatinol/levexatinol in a 24-hr period 10 (19.2) 1 (1.9) Systemic steroid therapy 5 (9.6) 1 (1.9) ICS increased ≥ 4-fold from the previous dose 3 (5.8) 0 Be hospitalized 0 0 *4 placebo patients met the treatment criteria for both PEF and systemic cholesterol, and 1 placebo patient met both PEF and the additional use of salatinol/levexatinol.

In the case of mAb1, the worsening time is longer (Figure 1), and the risk of worsening relative to placebo is reduced (risk ratio 0,10; 95% CI 0.03, 0.34; P <0.001). The analysis of the deterioration time based on the Kaplan-Meier chart shows that when the patient is at a higher risk of deterioration due to steroid withdrawal, the therapeutic effect of mAb1 continues over time, including 8 weeks later (Figure 1).

Only one patient in the placebo group had a compound asthma event. A compound asthma event is defined as a reduction in PEF of 30% or more in the morning of 2 consecutive days compared to baseline, and ≥ 6 inhalation of extra salatinol or levexartine for 2 consecutive days during a 24-hr period. Inhalation (compared to baseline). (ii) Other efficacy endpoints

At the time of return visit, the patients were evaluated for pulmonary function parameters (FEV1, AM PEF and PM PEF), the efficacy endpoints (ACQ score, night wake up) and the use of saltamineol, mainly for asthma symptoms. Observations of these parameters (weekly changes compared to baseline) are depicted in Figures 2-7, respectively. In addition, SNOT-22 scores at baseline and at the end of treatment were evaluated. For all the parameters, the baseline and week 12 (LOCF) averages and the average difference between treatment groups (SNOT-22 is an ANOVA model) are summarized in Table 7. In Table 7, the column labeled "Difference vs. Placebo" refers to the placebo-corrected value of the response compared with the baseline, which takes into account the observed changes in the parameter values and compares it with the placebo-treated group The parameter changes are compared. Table 7 : Secondary parameters and symptom scores of lung function N Baseline average (SD) Least Square Mean Change (SD) Difference and placebo p value FEV1 (L) Placebo 52 2.54 (0.66) -0.22 (0.06) - mAb1 52 2.47 (0.65) 0.05 (0.06) 0.27 (0.11, 0.42) 0.0009 AM PEF (L/min) Placebo 52 406.9 (110.7) -20.7 (9.1) - mAb1 51 393.0 (101.1) 13.9 (8.8)† 34.6 (10.6, 58.5) 0.0051 PM PEF (L/min) Placebo 51 416.6 (116.8) -18.4 (8.9)† - mAb1 52 414.6 (102.3) 4.3 (8.5) 22.7 (-0.7, 46.0) 0.0567 Salatinol use ( inhalation / day ) Placebo 52 2.0 (1.8) 0.7 (0.3) - mAb1 50 2.2 (2.4) -1.3 (0.3)‡ -2.0 (-2.9, -1.2) ＜0.0001 ACQ score Placebo 52 2.08 (0.52) -0.27 (0.16) - mAb1 52 2.09 (0.46) -1.00 (0.16) -0.73 (-1.15, -0.30) 0.0011 Wake up at night ( times / night ) Placebo 52 0.2 (0.5) 0.1 (0.1) - mAb1 52 0.4 (0.8) -0.2 (0.1) -0.2 (-0.5, -0.0) 0.0518 SNOT22 average score Placebo 51 26.24 (15.62) 0.23 (2.15)† - mAb1 50 30.92 (14.77) -8.26 (2.20)‡ -8.49 (-13.96, -3.03) 0.0027 † 51 patients underwent at least one post-dose evaluation. ‡ 50 patients were evaluated after at least one medication.

In the first week, treatment with mAb1 produced a significant change in FEV1 compared with baseline. Although LABA and ICS were withdrawn, this change was maintained until the 12th week (Figure 2), where the fifth week coincided with the withdrawal of LABA, and FEV1 decreased slightly. A similar improvement was observed in the morning PEF, but the evening PEF was smaller (Figures 3 and 4). The least square (LS) mean change from baseline to week 12, FEV1 was -0.22 L in placebo and 0.05 L in mAb1 group (p=0.0009).

In the first week, ACQ5 scores improved in both groups (Figure 6). However, when the ACQ5 of mAb1 improved more from the 1st to the 4th week, the placebo effect remained stable until the 12th week.

From baseline to week 12, the placebo morning symptom score increased. As for mAb1, there was a decrease at first and it remained below baseline until week 12 (Figure 26A). A similar pattern (with larger variation) was observed for the nighttime asthma symptom score (Figure 26B).

In the placebo group, awakening at night was stable from week 6 to week 6 and increased from week 6 to week 12. On the contrary, in the control baseline mAb1 group, awakening at night in the first week decreased and continued to improve until the 12th week (Figure 7).

The change in the use of salatinol/levatamol (Figure 5) was similar to other secondary efficacy endpoints: placebo initially declined and then returned to baseline. In the case of mAb1, the initial decline remained over time.

There was a non-significant difference between the SNOT-22 values at baseline, where the placebo score was 26.24 and the average mAb1 score was 39.02. At week 12, the average change in LS in the placebo group increased slightly by 0.23 points, while the mAb1 group decreased (improved) by an average of 8.26 points. This represents a significant improvement of 8.49 points in the mAb1 group (p=0.0027). Table 8. Secondary efficacy endpoints result Placebo (N=52) mAb1 (N = 52) Difference with placebo (95% CI)** P value Kaplan-Meier estimate for week 12 46.0 (31.8, 60.2) 5.8 (0.0, 2.1) 0.10 (0.03 to 0.34) ＜0.001 Change in morning asthma symptom score from baseline to week 12 0.3 ± 0.1 -0.4 ± 0.1 -0.7 (-0.9 to -0.4) ＜0.001 Change in asthma symptom score from baseline to week 12 0.1 ± 0.1 -0.6 ± 0.1 -0.7 (-0.9 to -0.4) ＜0.001 Table 9. Changes in SNOT-22 items related to the upper respiratory tract compared to baseline at week 12 SNOT-22 scale Least square mean change ± standard error Difference with placebo (95% CI) P value Placebo (N=52) mAb1 (N = 52) Need to blow your nose -0.25 ± 0.17* 0.95 ± 0.17† -0.70 (-1.13, -0.26) 0.002 Stuffy nose -0.20 ± 0.19* -0.94 ± 0.19† 0.75 (-1.22, -0.28) 0.002 Reduced smell/taste 0.04 ± 0.18* -1.13 ± 0.18† -1.16 (-1.62, -0.71) ＜ 0.001 *51 and †50 patients were evaluated after at least one medication.

For all secondary efficacy endpoints, with the exception of evening PEF and nocturnal awakening, the measurement at week 12 was beneficial to mAb1 treatment and was significant (Tables 7 and 8). Regarding mAb1, significant improvement was also observed in the three SNOT-22 items related to upper respiratory tract diseases (Table 9). (iii) Security

mAb1 is generally safe and well tolerated. Treatment-emergent adverse events (TEAE) reports were similar, with 40 (76.9%) placebo-treated patients and 42 (80.8) mAb1-treated patients (Table 10). TEAE is non-specific, generally moderate to severe, and most of them recover before the end of the study. Compared with placebo, the follow-up TEAE reports observed with mAb1 increased: injection site reactions were reported by 15 (28.8%) mAb1 patients and 5 (9.6%) placebo patients; and 7 (13.5%) patients with nasopharyngitis ) mAb1 patients and 2 (3.8%) placebo patients presented; headaches in 6 (11.5%) mAb1 patients and 3 (5.85) placebo patients, and nausea in 4 (7.7%) mAb1 The patient and 1 (1.9%) placebo patient presented. Table 10. Adverse events Adverse events Placebo (N=52) mAb1 300 mg (N = 52) Number of patients (%) Adverse events 40 (76.9) 42 (80.8) Any serious adverse events 3 (5.8) 1 (1.9) Study discontinued due to adverse events 3 (5.8) 3 (5.8) die 0 0 The most common AE* Reaction at the injection site† 5 (9.6) 15 (28.8) Nasopharyngitis 2 (3.8) 7 (13.5) Upper respiratory tract infection 9 (17.3) 7 (13.5) Headache 3 (5.8) 6 (11.5) nausea 1 (1.9) 4 (7.7) Arthropod bites 0 3 (5.8) Muscle cramps 0 3 (5.8) Nasal congestion 1 (1.9) 3 (5.8) rash 1 (1.9) 3 (5.8) Urticaria 0 3 (5.8) Viral upper respiratory tract infection 0 3 (5.8) * ≥ 3 † bit first item at the injection site of the patient in any treatment group events proposed for the reaction include: injection site pain, injection site reaction, injection site redness, injection site rash from the injection site hematoma, injection site urticaria , Dermatitis at the injection site, inflammation at the injection site, nodules at the injection site, itching at the injection site, and swelling at the injection site.

No deaths were reported during the study period. Among them, 4 treatment emergency serious adverse events (SAE) proposed: 1 mAb1 patient experienced bipolar disorder and 3 placebo patients experienced pneumonia, gunshot wounds with left pneumothorax and right ankle fractures and asthma SAE. It is not believed that these SAEs are related to IMP, and all (except for ankle fractures) recovered before the end of the study. There are no dead.

A total of 6 patients discontinued the study due to TEAE: 3 patients in the mAb1 group (bipolar disorder, asthma with wheezing and angioedema) and 3 patients in the placebo group (upper respiratory tract infection, psoriasis, and asthma). TEAE of angioedema occurred in a 42-year-old African American woman who observed itching and generalized rash at the injection site and far away after the ninth study treatment administration. It lasted for one week, the study treatment was discontinued and he recovered after treatment with prednisome and diphenhydramine. It seems to be related to treatment. This AE was continued after a slight rash at the injection site after the first and sixth study treatment doses.

Among the most common AEs that occurred in ≥3 patients in any treatment group (Table 10), the frequency of mAb1 at injection site reactions, nasopharyngitis, nausea, and headaches was higher than that of placebo. It was proposed that there were no clinically significant changes in life symbols, physical examination, clinical laboratory examination or ECG findings in any group. G. Results

Significant improvements were observed with regard to lung function and other asthma control parameters. Despite the withdrawal of background treatment, efficacy was still observed early and continued. Compared with placebo (44.2%), after 12-week treatment with 300 mg mAb1 once a week, the incidence of asthma exacerbation (5.8 %) The relative reduction of the primary efficacy endpoint was about 87% (p <0.0001). As shown in Table 7, compared with placebo, the clinically significant and statistically significant (none) Multiple adjustments) to improve. A positive trend was observed for PEF PM (p=0.0567) and night awakening (p=0.0518). Regarding the SNOT-22 score, a statistically significant (no multiple adjustment) improvement was also observed. In the active treatment group, continuous improvement from baseline was observed for all parameters during the study, despite the withdrawal of LABA and ICS. mAb1 is generally safe and well tolerated. Example 3 : Biomarker research

The biomarker analysis was performed on samples collected from subjects participating in the mAb1 clinical trial (see Example 2 above). In particular, at different time points after baseline and initial study treatment, measure serum/plasma biomarkers related to TH2 inflammation in patient samples, such as thymus and activated chemotactic hormone (TARC; CCL17), immunoglobulin E (IgE), eosinophil chemoattractant-3, periostin, carcinoembryonic antigen (CEA), YKL-40 and blood eosinophils. Evaluate the baseline amount of these biomarkers as a possible predictor of treatment response. In addition, measure the fraction of expiratory NO (FeNO) and induce sputum eosinophils and neutrophils as biomarkers of bronchial inflammation. The expiratory nitric oxide assessment was performed using the NIOX instrument (Aerocrine AB, Solna, Sweden) before spirometry and after fasting for at least 1 hour. The biomarker system uses a mixed model to analyze and the least square mean system derived from this model is recorded below.

Asthmatic subjects (N=104) received mAb1 (300 mg) or placebo on the first 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 days of the study (i.e. Weekly administration for 12 weeks) was administered subcutaneously (see Example 2 in the text). The samples for biomarker analysis were collected by antibody-treated and placebo-treated subjects at 0, 1, 4, 8 and 12 weeks. Use the Phadiatop® test to detect antigen-specific IgE.

In response to placebo, TARC, eosinophil chemokine-3 and IgE remained unchanged (Figures 8, 9 and 10). In contrast, in patients treated with mAb1, TARC (mean% change-22.7% vs. +0.3%; p = 0.0003 (Figure 8) and eosinophil chemokine-3 (mean% change- 39.62% vs. 12.69%; p<0.0001) (Figure 9) The rapid decline and continued to the 12th week: TARC: -26.0% vs. +7.6% placebo (p=0.0005); Eosinophil chemokine-3: 45.67 % Vs +5.13% placebo (p<0.0001).

The amount of TARC responds within one week after subcutaneous administration of 300 mg mAb1. In mAb1-treated subjects, TARC reached a plateau at about 50% of the baseline amount, regardless of ICS withdrawal. The data shows that TARC performance is more directly related to IL-4R signal transmission than FEV1 changes (it fell to the equivalent of ICS withdrawal [after 4th week]) and IL-4R blockade caused a shift toward TH1 signal, such as, for example IFNγ administration was observed. It is possible to use TARC (and, for example, CXCL10) to titrate the mAb1 dose, especially in patients who require long-term treatment and are at risk for TH1 immune diseases.

After mAb1 treatment, total serum IgE also decreased. Compared with the TARC response, the total serum IgE response is more different and delayed. The mean (SD) baseline IgE value of the placebo group (n=52) was 694.68 IU/L (1837.82) and the mAb1 group (n=52) was 657.66 (1482.25), while the placebo group had a median of 169.95 and mAb1 The group is 206.15. Despite this heterogeneity, compared to placebo, a downward trend toward IgE was observed in mAb1-exposed patients – however, only starting at week 4. Compared with placebo, from the 4th week, the serum IgE decreased significantly in the mAb1 group (mean% change-10.1% vs. +13.5%; p=0.0325) and continued until the 12th week (average% for REGN668/SAR231893) Change -36.8% vs. placebo -5.5%; p<0.0001) (Figure 10).

The changes in FeNO, TARC, eosinophil chemokine-3, and IgE at week 12 compared to baseline and placebo were all in favor of mAb1 (all P<0.001) (Table 11). In YKL-40 or CEA, no difference compared with baseline or between treatments was observed. Table 11. The percentage change of the pharmacodynamic efficacy endpoint compared to baseline at week 12 result Least square mean percentage change ± standard error P value Placebo (N=52) mAb1 (N = 52) FeNO 35.0 ± 10.8 28.7 ± 11.2 ＜ 0.001 TARC 7.6 ± 6.9 -26.0 ± 6.9 ＜ 0.001 Eosinophil chemoattractant-3 5.1 ± 4.7 -45.7 ± 4.7 ＜ 0.001 IgE 5.5 ± 3.6 -36.8 ± 3.6 ＜ 0.001 Blood eosinophils 2.7 ± 15.8 41.6 ± 15.7 0.078

There was a transitional decrease in the amount of periostin, and then increased with the withdrawal of LABA/ICS (Figure 11). Administration of mAb1 delayed the increase, but did not prevent it from increasing above the baseline. Regarding CEA (Figure 12) and YKL-40 (Figure 13), no consistent therapeutic effect was observed. The number of blood eosinophils remained unchanged until the 6th week, but increased at the 8th and 12th weeks (Figure 14). In the placebo, the number of peripheral blood eosinophils remained unchanged throughout the treatment. The difference between treatments was not significant, only a slight increase in patients treated with mAb1 was caused by an increase in larger blood eosinophils. Little or no increase was observed in most patients (Table 12). Table 12. Proportion of patients reaching the threshold of blood eosinophilic changes Changes in eosinophils Number of patients (%) Placebo (n = 52) mAb1 (n = 52) ＞ 15% reduction 13 (30.2) 21 (47.7) 15% reduction-0% change 7 (16.3) 6 (13.6) 0%-15% increase 8 (18.6) 4 (9.1) 15%-100% increase 13 (30.2) 6 (13.6) 100%-200% increase 2 (4.7) 3 (6.8) ＞ 200% increase 0 4 (9.1)

Because only 3 mAb1 patients experienced exacerbation of asthma in this study, no conclusion can be made about the correlation between baseline biomarkers and exacerbation of asthma.

mAb1 treatment was also associated with a significant decrease in FeNO compared to baseline at week 4, and FeNo was still below baseline by week 12, not related to ICS withdrawal (mean% change at week 12: mAb1 was -28.7 vs. 35.0 for placebo ; P<0.0001) (Figure 15). On the contrary, the placebo FeNo value remained stable until the 8th week, and then increased at the 12th week, which coincided with the withdrawal of ICS.

At the 12th week, the _{improvement of forced expiratory volume (FEV 1} ) within 1 second was obviously related to the decrease of FeNO (r=-0.408, p=0.009) (Figure 16). Similarly, the improvement of AM-PEF and PM-PEF is related to the decrease of FeNO (Figures 17 and 18). The other correlations of FeNO are not significant. See Table 13. Table 13. Correlation _{between FEV 1} and PD efficacy endpoint result Correlation P value FeNO -0.408 -0.248 -0.146 -0.279 0.165 ＜0.009 TARC 0.10 Eosinophil chemoattractant-3 0.34 IgE 0.06 Blood eosinophils 0.28

The scatter plot of baseline eosinophils vs. FEV1 change from baseline at week 12 does not seem to suggest the correlation between baseline eosinophils and therapeutic efficacy, such as the change in FEV1 compared to baseline measured in the study population (baseline eosinophils) ≥ 0.3 Giga/L) (Figure 19). Baseline eosinophils were associated with a decrease in ACQ (Figure 20) and the use of salatinol/levatamol (Figure 21). Periostin and YKL-40 were associated with a decrease in ACQ at baseline (Figures 22 and 23).

The change in FEV1 compared to baseline at week 12 was more complicated by ICS withdrawal (starting from week 4). In this study population, similar analysis does not recommend the association between baseline TARC or IgE and the change in FEV1 from baseline at week 12 (baseline eosinophils ≥ 0.3 Giga/L). Summarize

These results show that mAb1 significantly reduces serum biomarkers related to Th2 inflammation (TARC, eosinophil chemokine-3 and IgE) and bronchial inflammation (FeNO) in adult asthmatic patients. The correlation between FeNO reduction and FEV ₁ improvement shows the relationship between IL-4/IL-13 mediated anti-inflammatory activity and improved lung function in moderate to severe uncontrollable asthma.

The scope of the present invention is not limited to the specific embodiments described herein. In fact, in addition to those described in the text, various modifications are obvious to those skilled in the art from the foregoing description and accompanying drawings. These amendments are hoped to fall within the scope of the attached patent application.

Figure 1 shows a Kaplan-Meier plot of time versus asthma exacerbation in patients treated with placebo (open circles) compared to patients treated with anti-IL-4R antibody mAb1 (asterisks). When patients are at a higher risk of worsening due to withdrawal of steroids, the efficacy of treatment with anti-IL-4R antibody mAb1 continues over time, including 8 weeks later. The vertical dashed line indicates the evacuation of the LABA.

Figure 2 shows the forced expiratory volume in 1 second (FEV1) in liters in patients treated with placebo (open triangles) compared to patients treated with anti-IL-4R antibody mAb1 (closed circles) Graph of average change compared to baseline. The vertical dashed line indicates the evacuation of the LABA.

Figure 3 shows the highest morning expiratory flow rate expressed in liters per minute in patients treated with placebo (open triangles) compared to patients treated with anti-IL-4R antibody mAb1 (closed circles) ( AM PEF) A graph of the average change compared to the baseline.

Figure 4 shows the maximum evening expiratory flow rate in liters per minute in patients treated with placebo (open triangles) compared to patients treated with anti-IL-4R antibody mAb1 (closed circles) ( PM PEF) Mean change graph compared to baseline.

Figure 5 shows the average daily use of inhaled albuterol compared to baseline in patients treated with placebo (open triangles) compared to patients treated with anti-IL-4R antibody mAb1 (closed circles) Change graph. The vertical dashed line indicates the evacuation of the LABA.

Figure 6 shows the scores of the five asthma control questionnaires (ACQ5) in patients treated with placebo (open triangles) compared to patients treated with anti-IL-4R antibody mAb1 (closed circles) compared with baseline The average change graph. The vertical dashed line indicates the evacuation of the LABA.

Figure 7 is a graph showing the average change in the number of night awakenings per night in patients treated with placebo (open triangles) compared to patients treated with anti-IL-4R antibody mAb1 (closed circles) compared to baseline. The vertical dashed line indicates the evacuation of the LABA.

Figure 8 shows that patients in the mITT group who were treated with placebo (closed circles) were compared with patients treated with anti-IL-4R antibody mAb1 (closed squares) at 0, 1, 4, 8 and 12 weeks. A graph of the average percentage change of TARC compared to baseline. The vertical dashed line indicates the evacuation of the LABA.

Figure 9 shows that patients in the mITT group who were treated with placebo (closed circles) were compared with patients treated with anti-IL-4R antibody mAb1 (closed squares) at 0, 1, 4, 8 and 12 weeks. A graph of the average percentage change of eosinophil chemokine-3 compared to baseline. The vertical dashed line indicates the evacuation of the LABA.

Figure 10 shows that patients in the mITT population treated with placebo (closed circles) compared to patients treated with anti-IL-4R antibody mAb1 (closed squares) at 0, 1, 4, 8 and 12 weeks of return visits A graph of the average percentage change in total IgE compared to baseline. The vertical dashed line indicates the evacuation of the LABA.

Figure 11 shows that patients in the mITT group treated with placebo (closed circles) compared to patients treated with anti-IL-4R antibody mAb1 (closed squares) at 0, 1, 4, 8 and 12 weeks. Periostin (periostin) average percentage change from baseline.

Figure 12 shows that patients in the mITT group who were treated with placebo (closed circles) were compared with patients treated with anti-IL-4R antibody mAb1 (closed squares) at 0, 1, 4, 8 and 12 weeks. The average percentage change of carcinoembryonic antigen (CEA) compared to baseline.

Figure 13 shows that patients in the mITT group treated with placebo (closed circles) compared to patients treated with anti-IL-4R antibody mAb1 (closed squares) at 0, 1, 4, 8 and 12 weeks of return visits The average percentage change of YKL-40 compared to the baseline.

Figure 14 shows that patients in the mITT population treated with placebo (closed circles) compared to patients treated with anti-IL-4R antibody mAb1 (closed squares) at 0, 1, 2, 4, 6, 8 and A graph of the average percentage change of blood eosinophils compared with baseline in the 12-week return visit.

Figure 15 shows the patients who were treated with placebo (closed circles) in the mITT group compared to patients treated with anti-IL-4R antibody mAb1 (closed squares) at the 0, 4, 8 and 12 week visits. The graph of the average percentage change of the nitrogen monoxide (NO) fraction compared with the baseline. The vertical dashed line indicates the evacuation of the LABA.

Figure 16 shows the FEV1 of patients treated with placebo (open circles and solid lines) in the mITT population compared to patients treated with anti-IL-4R antibody mAb1 (plus signs and dashed lines) at week 12 compared to baseline Scatter plot of changes versus baseline expiratory nitric oxide fraction (FeNO) (PPB).

Figure 17 shows the AM of placebo-treated patients (open circles and solid lines) in the mITT population compared to patients treated with anti-IL-4R antibody mAb1 (plus signs and dashed lines) at week 12 compared to baseline -Scatter plot of PEF change versus baseline FeNO (PPB).

Figure 18 shows the PM of patients treated with placebo (open circles and solid lines) in the mITT population compared to patients treated with anti-IL-4R antibody mAb1 (plus signs and dashed lines) at week 12 compared to baseline -Scatter plot of PEF change versus baseline FeNO (PPB).

Figure 19 shows the FEV1 of patients treated with placebo (open circles and solid lines) in the mITT population compared to patients treated with anti-IL-4R antibody mAb1 (plus signs and dashed lines) at week 12 compared to baseline Scatter plot of changes in blood eosinophil count (GIGA/L).

Figure 20 shows the ACQ of patients treated with placebo (open circles and solid lines) in the mITT population compared to patients treated with anti-IL-4R antibody mAb1 (plus signs and dashed lines) at week 12 compared to baseline Scatter plot of changes in blood eosinophil count (GIGA/L).

Figure 21 shows the daily comparison of placebo-treated patients (open circles and solid lines) in the mITT population with patients treated with anti-IL-4R antibody mAb1 (plus signs and dashed lines) at week 12 compared to baseline The scatter plot of the changes in the use of salatinol/levatamol versus the number of blood eosinophils (GIGA/L).

Figure 22 shows the ACQ of patients treated with placebo (open circles and solid lines) in the mITT population compared to patients treated with anti-IL-4R antibody mAb1 (plus signs and dashed lines) at week 12 compared to baseline Scatter plot of change versus baseline periostin.

Figure 23 shows the ACQ of patients treated with placebo (open circles and solid lines) in the mITT population compared to patients treated with anti-IL-4R antibody mAb1 (plus signs and dashed lines) at week 12 compared to baseline Change the scatter diagram of YKL-40.

Figure 24 is a flow chart showing an example of background treatment withdrawal time during treatment of an asthmatic patient.

Figure 25 depicts the treatment of patients with persistent moderate to severe eosinophilic asthma who are partially controlled or uncontrollable with inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA). A chart of patient treatment in a randomized, placebo-controlled, double-blind, parallel group study with 300 mg mAb1 or placebo administered subcutaneously once a week for 12 weeks.

Figures 26A and 26B are scatter diagrams of morning (A) and evening (B) asthma symptoms measured during 12 weeks after administration of placebo (open triangles) or mAb1 (closed circles).

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                REGENERON PHARMACEUTICALS, INC.
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           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 22]]>
          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 Arg 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 Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Glu Gly Arg Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu
                      100 105 110
          Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 23]]>
           <![CDATA[ <211> 322]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 23]]>
          gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60
          atcacttgtc gggcgagtca ggtcataaac aattatttag cctggtttca gcagaaacca 120
          gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
          aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
          gaagattttg caacttatta ctgccaacag tataatagtc acccgtggac gttcggccaa 300
          gggaccaagg tggaaatcaa ac 322
           <![CDATA[ <210> 24]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 24]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Asn Asn Tyr
                      20 25 30
          Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser 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 Tyr Asn Ser His Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 25]]>
           <![CDATA[ <211> 351]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 25]]>
          caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
          tcctgtgcag cctctggatt caccttcaga agctatggca tacactgggt ccgccaggct 120
          ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180
          gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacactgtat 240
          ctgcaaatga acagcctgat aactgaggac acggctgtgt attattgtgt gaaagagggg 300
          aggggggggt ttgactactg gggccaggga accacggtca ccgtctcctc a 351
           <![CDATA[ <210> 26]]>
           <![CDATA[ <211> 117]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 26]]>
          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 Arg Ser Tyr
                      20 25 30
          Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser 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 Ile Thr Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Val Lys Glu Gly Arg Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr Thr
                      100 105 110
          Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 27]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 27]]>
          ggattcacct tcagaagcta tggc 24
           <![CDATA[ <210> 28]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 28]]>
          Gly Phe Thr Phe Arg Ser Tyr Gly
           1 5
           <![CDATA[ <210> 29]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 29]]>
          atatcatatg atggaagtaa taaa 24
           <![CDATA[ <210> 30]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 30]]>
          Ile Ser Tyr Asp Gly Ser Asn Lys
           1 5
           <![CDATA[ <210> 31]]>
           <![CDATA[ <211> 30]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 31]]>
          gtgaaagagg ggaggggggg gtttgactac 30
           <![CDATA[ <210> 32]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 32]]>
          Val Lys Glu Gly Arg Gly Gly Phe Asp Tyr
           1 5 10
           <![CDATA[ <210> 33]]>
           <![CDATA[ <211> 324]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 33]]>
          gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60
          atcacttgtc gggcgagtca ggtcattaat aattatttag cctggtttca gcagaaacca 120
          gggaaagtcc ctaagtccct gatccatgct gcatccagtt tgcaaagagg ggtcccatca 180
          aagttcagcg gcagtggatc tgggacagat ttcactctca ccatcaacag cctgcagcct 240
          gaagattttg caacttatta ctgccaacaa tataatagtt acccgtggac gttcggccaa 300
          gggaccaagg tggaaatcaa acga 324
           <![CDATA[ <210> 34]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 34]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Asn Asn Tyr
                      20 25 30
          Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Ser Leu Ile
                  35 40 45
          His Ala Ala Ser Ser Leu Gln Arg Gly Val Pro Ser Lys Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
                      100 105
           <![CDATA[ <210> 35]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <21]]>3> Artificial sequence]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;220&gt;]]&gt;
           <br/> &lt;![CDATA[ &lt;223&gt;Synthetic]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;400&gt;35]]&gt;
           <br/> <![CDATA[caggtcatta ataattat 18
           <![CDATA[ <210> 36]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 36]]>
          Gln Val Ile Asn Asn Tyr
           1 5
           <![CDATA[ <210> 37]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 37]]>
          gctgcatcc 9
           <![CDATA[ <210> 38]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 38]]>
          Ala Ala Ser
           1          
           <![CDATA[ <210> 39]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 39]]>
          caacaatata atagttaccc gtggacg 27
           <![CDATA[ <210> 40]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 40]]>
          Gln Gln Tyr Asn Ser Tyr Pro Trp Thr
           1 5
           <![CDATA[ <210> 41]]>
           <![CDATA[ <211> 351]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 41]]>
          caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
          tcctgtgcag cctctggatt caccttcaga agctatggca tacactgggt ccgccaggct 120
          ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180
          gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacactgtat 240
          ctgcaaatga acagcctgat aactgaggac acggctgtgt attattgtgt gaaagagggg 300
          aggggggggt ttgactactg gggccaggga accctggtca ccgtctcctc a 351
           <![CDATA[ <210> 42]]>
           <![CDATA[ <211> 117]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 42]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr
                      20 25 30
          Gly Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Val Ile Ser Tyr Asp Gly Ser 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 Ile Thr Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Val Lys Glu Gly Arg Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu
                      100 105 110
          Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 43]]>
           <![CDATA[ <211> 321]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 43]]>
          gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60
          atcacttgtc gggcgagtca ggtcattaat aattatttag cctggtttca gcagaaacca 120
          gggaaagtcc ctaagtccct gatccatgct gcatccagtt tgcaaagagg ggtcccatca 180
          aagttcagcg gcagtggatc tgggacagat ttcactctca ccatcaacag cctgcagcct 240
          gaagattttg caacttatta ctgccaacaa tataatagtt acccgtggac gttcggccaa 300
          gggaccaagg tggaaatcaa a 321
           <![CDATA[ <210> 44]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 44]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Asn Asn Tyr
                      20 25 30
          Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Val Pro Lys Ser Leu Ile
                  35 40 45
          His Ala Ala Ser Ser Leu Gln Arg Gly Val Pro Ser Lys Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 45]]>
           <![CDATA[ <211> 351]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 45]]>
          caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
          tcctgtgcag cctctggatt caccttcaga agctatggca tgcactgggt ccgccaggct 120
          ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaagtaa taaatactat 180
          gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtgt gaaagagggg 300
          aggggggggt ttgactactg gggccaggga accctggtca ccgtctcctc a 351
           <![CDATA[ <210> 46]]>
           <![CDATA[ <211> 117]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 46]]>
          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 Arg 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 Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Val Lys Glu Gly Arg Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu
                      100 105 110
          Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 47]]>
           <![CDATA[ <211> 322]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 47]]>
          gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60
          atcacttgtc gggcgagtca ggtcattaat aattatttag cctggtttca gcagaaacca 120
          gggaaagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180
          aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
          gaagattttg caacttatta ctgccaacaa tataatagtt acccgtggac gttcggccaa 300
          gggaccaagg tggaaatcaa ac 322
           <![CDATA[ <210> 48]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 48]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Val Ile Asn Asn Tyr
                      20 25 30
          Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser 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 Tyr Asn Ser Tyr Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 49]]>
           <![CDATA[ <211> 375]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 49]]>
          caggtgcagc tggtggagtc tgggggaggc ttggaacagc cgggggggtc cttgagactc 60
          tcctgtgcag gctctggatt cacgtttaga gactatgcca tgacctgggt ccgccaggct 120
          ccagggaagg ggctggagtg ggtcgcatcg attagtggtt ccggtggtaa cacatacttc 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatcga 300
          ctctctataa caattcgccc acgctattat ggtttggacg tctggggcca agggtccacg 360
          gtcaccgtct cctca 375
           <![CDATA[ <210> 50]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 50]]>
          Gln 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
          Ala Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Phe 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 Ser Thr Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 51]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 51]]>
          ggattcacgt ttagagacta tgcc 24
           <![CDATA[ <210> 52]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 52]]>
          Gly Phe Thr Phe Arg Asp Tyr Ala
           1 5
           <![CDATA[ <210> 53]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 53]]>
          attagtggtt ccggtggtaa caca 24
           <![CDATA[ <210> 54]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 54]]>
          Ile Ser Gly Ser Gly Gly Asn Thr
           1 5
           <![CDATA[ <210> 55]]>
           <![CDATA[ <211> 54]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 55]]>
          gcgaaagatc gactctctat aacaattcgc ccacgctatt atggtttgga cgtc 54
           <![CDATA[ <210> 56]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 56]]>
          Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu
           1 5 10 15
          Asp Val
           <![CDATA[ <210> 57]]>
           <![CDATA[ <211> 324]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 57]]>
          gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgttggaga cagagtcacc 60
          atcacttgtc gggcgagtca ggccattaac aatcatttag cctggtttca gcagaaacca 120
          gggaaagccc ctaagtccct gatctttgct gtatccagtt tgcaaagtgg ggtcccatca 180
          aagttcagcg gcagtggatc tgggacagac ttcactctca ccatcagcag cctgcagcct 240
          gaagattttg caacttatta ctgccaacag tataatagtt acccgtggac gttcggccaa 300
          gggaccaagg tggaaatcaa acga 324
           <![CDATA[ <210> 58]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 58]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Asn Asn His
                      20 25 30
          Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Phe Ala Val Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
                      100 105
           <![CDATA[ <210> 59]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 59]]>
          caggccatta acaatcat 18
           <![CDATA[ <210> 60]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 60]]>
          Gln Ala Ile Asn Asn His
           1 5
           <![CDATA[ <210> 61]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 61]]>
          gctgtatcc 9
           <![CDATA[ <210> 62]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 62]]>
          Ala Val Ser
           1          
           <![CDATA[ <210> 63]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 63]]>
          caacagtata atagttaccc gtggacg 27
           <![CDATA[ <210> 64]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 64]]>
          Gln Gln Tyr Asn Ser Tyr Pro Trp Thr
           1 5
           <![CDATA[ <210> 65]]>
           <![CDATA[ <211> 372]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 65]]>
          gaggtgcagc tggtggagtc tgggggaggc ttggaacagc cgggggggtc cttgagactc 60
          tcctgtgcag gctctggatt cacgtttaga gactatgcca tgacctgggt ccgccaggct 120
          ccagggaagg ggctggagtg ggtcgcatcg attagtggtt ccggtggtaa cacatacttc 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatcga 300
          ctctctataa caattcgccc acgctattat ggtttggacg tctggggcca agggaccacg 360
          gtcaccgtct cc 372
           <![CDATA[ <210> 66]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 66]]>
          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
          Ala Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Phe 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
                  115 120
           <![CDATA[ <210> 67]]>
           <![CDATA[ <211> 321]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 67]]>
          gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgttggaga cagagtcacc 60
          atcacttgtc gggcgagtca ggccattaac aatcatttag cctggtttca gcagaaacca 120
          gggaaagccc ctaagtccct gatctttgct gtatccagtt tgcaaagtgg ggtcccatca 180
          aagttcagcg gcagtggatc tgggacagac ttcactctca ccatcagcag cctgcagcct 240
          gaagattttg caacttatta ctgccaacag tataatagtt acccgtggac gttcggccaa 300
          gggaccaagg tggaaatcaa a 321
           <![CDATA[ <210> 68]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 68]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Asn Asn His
                      20 25 30
          Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Phe Ala Val Ser Ser Leu Gln Ser Gly Val Pro Ser Lys Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 69]]>
           <![CDATA[ <211> 373]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 69]]>
          gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
          tcctgtgcag cctctggatt cacgtttaga gactatgcca tgagctgggt ccgccaggct 120
          ccagggaagg ggctggagtg ggtctcagct attagtggtt ccggtggtaa cacatactac 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatcga 300
          ctctctataa caattcgccc acgctattat ggtttggacg tctggggcca agggaccacg 360
          gtcaccgtct cct 373
           <![CDATA[ <210> 70]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 70]]>
          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 Asp Tyr
                      20 25 30
          Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala 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
                  115 120
           <![CDATA[ <210> 71]]>
           <![CDATA[ <211> 322]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <21]]>3> Artificial sequence]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;220&gt;]]&gt;
           <br/> &lt;![CDATA[ &lt;223&gt;Synthetic]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;400&gt;71]]&gt;
           <br/> <![CDATA[gacatccaga tgacccagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60
          atcacttgtc gggcgagtca ggccattaac aatcatttag cctggtttca gcagaaacca 120
          gggaaagccc ctaagtccct gatctatgct gtatccagtt tgcaaagtgg ggtcccatca 180
          aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
          gaagattttg caacttatta ctgccaacag tataatagtt acccgtggac gttcggccaa 300
          gggaccaagg tggaaatcaa ac 322
           <![CDATA[ <210> 72]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 72]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ala Ile Asn Asn His
                      20 25 30
          Leu Ala Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu Ile
                  35 40 45
          Tyr Ala Val Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Pro Trp
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 73]]>
           <![CDATA[ <211> 375]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 73]]>
          caggtgcagc tggtggagtc tgggggaggc ttggaacagc cgggggggtc cttgagactc 60
          tcctgtgcag gctctggatt cacgtttaga gactatgcca tgacctgggt ccgccaggct 120
          ccagggaagg ggctggagtg ggtcgcatcg attagtggtt ccggtggtaa cacatacttc 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatcga 300
          ctctctataa caattcgccc acgctattat ggtttggacg tctggggcca agggtccacg 360
          gtcaccgtct cctca 375
           <![CDATA[ <210> 74]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 74]]>
          Gln 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
          Ala Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Phe 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 Ser Thr Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 75]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 75]]>
          ggattcacgt ttagagacta tgcc 24
           <![CDATA[ <210> 76]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 76]]>
          Gly Phe Thr Phe Arg Asp Tyr Ala
           1 5
           <![CDATA[ <210> 77]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 77]]>
          attagtggtt ccggtggtaa caca 24
           <![CDATA[ <210> 78]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 78]]>
          Ile Ser Gly Ser Gly Gly Asn Thr
           1 5
           <![CDATA[ <210> 79]]>
           <![CDATA[ <211> 54]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 79]]>
          gcgaaagatc gactctctat aacaattcgc ccacgctatt atggtttgga cgtc 54
           <![CDATA[ <210> 80]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 80]]>
          Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu
           1 5 10 15
          Asp Val
           <![CDATA[ <210> 81]]>
           <![CDATA[ <211> 339]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 81]]>
          gaaatagtgt tgacgcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
          atctcctgca ggtctagtca gagcctcctg tatagtattg gatacaacta tttggattgg 120
          tacctgcaga agtcagggca gtctccacag ctccttatct atttgggttc taatcgggcc 180
          tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240
          agcagagtgg aggctgagga tgttgggttt tattactgca tgcaagctct acaaactccg 300
          tacacttttg gcccggggac caagctggag atcaaacga 339
           <![CDATA[ <210> 82]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 82]]>
          Glu Ile Val Leu 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 Pro Gly Thr Lys Leu Glu Ile Lys
                      100 105 110
          Arg
           <![CDATA[ <210> 83]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 83]]>
          cagagcctcc tgtatagtat tggatacaac tat 33
           <![CDATA[ <210> 84]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> ]]>84
          Gln Ser Leu Leu Tyr Ser Ile Gly Tyr Asn Tyr
           1 5 10
           <![CDATA[ <210> 85]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 85]]>
          ttgggttct 9
           <![CDATA[ <210> 86]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 86]]>
          Leu Gly Ser
           1          
           <![CDATA[ <210> 87]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 87]]>
          atgcaagctc tacaaactcc gtacact 27
           <![CDATA[ <210> 88]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 88]]>
          Met Gln Ala Leu Gln Thr Pro Tyr Thr
           1 5
           <![CDATA[ <210> 89]]>
           <![CDATA[ <211> 372]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 89]]>
          gaggtgcagc tggtggagtc tgggggaggc ttggaacagc cgggggggtc cttgagactc 60
          tcctgtgcag gctctggatt cacgtttaga gactatgcca tgacctgggt ccgccaggct 120
          ccagggaagg ggctggagtg ggtcgcatcg attagtggtt ccggtggtaa cacatacttc 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatcga 300
          ctctctataa caattcgccc acgctattat ggtttggacg tctggggcca agggaccacg 360
          gtcaccgtct cc 372
           <![CDATA[ <210> 90]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 90]]>
          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
          Ala Ser Ile Ser Gly Ser Gly Gly Asn Thr Tyr Phe 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
                  115 120
           <![CDATA[ <210> 91]]>
           <![CDATA[ <211> 336]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 91]]>
          gatattgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
          atctcctgca ggtctagtca gagcctcctg tatagtattg gatacaacta tttggattgg 120
          tacctgcaga agtcagggca gtctccacag ctccttatct atttgggttc taatcgggcc 180
          tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240
          agcagagtgg aggctgagga tgttgggttt tattactgca tgcaagctct acaaactccg 300
          tacacttttg gcccggggac caagctggag atcaaa 336
           <![CDATA[ <210> 92]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 92]]>
          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 Pro Gly Thr Lys Leu Glu Ile Lys
                      100 105 110
           <![CDATA[ <210> 93]]>
           <![CDATA[ <211> 373]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 93]]>
          gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
          tcctgtgcag cctctggatt cacgtttaga gactatgcca tgagctgggt ccgccaggct 120
          ccagggaagg ggctggagtg ggtctcagct attagtggtt ccggtggtaa cacatactac 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatcga 300
          ctctctataa caattcgccc acgctattat ggtttggacg tctggggcca agggaccacg 360
          gtcaccgtct cct 373
           <![CDATA[ <210> 94]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 94]]>
          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 Asp Tyr
                      20 25 30
          Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala 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
                  115 120
           <![CDATA[ <210> 95]]>
           <![CDATA[ <211> 337]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 95]]>
          gatattgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
          atctcctgca ggtctagtca gagcctcctg tatagtattg gatacaacta tttggattgg 120
          tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc 180
          tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240
          agcagagtgg aggctgagga tgttggggtt tattactgca tgcaagctct acaaactccg 300
          tacacttttg gccaggggac caagctggag atcaaac 337
           <![CDATA[ <210> 96]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 96]]>
          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 Pro 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 Val 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
           <![CDATA[ <210> 97]]>
           <![CDATA[ <211> 375]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 97]]>
          caggtgcagc tggtggagtc tgagggactc ttggaacagc ctggggggtc cctgagactc 60
          tcctgtgcag cctctggatt caactttaga gactttgcca tgacctgggt ccgccaggct 120
          ccagggaagg ggctggagtg ggtctcatct attagtggta gtggtagtaa tacatactac 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaacca cacgctgtat 240
          ctgcgaatga acagcctgag agccgaagac acggccgtgt attactgtgc gaaagatcga 300
          ctctctataa caattcgccc acgctattac ggtctggacg tctggggcca agggtccacg 360
          gtcaccgtct cctca 375
           <![CDATA[ <210> 98]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 98]]>
          Gln Val Gln Leu Val Glu Ser Glu Gly Leu Leu Glu Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Phe Arg Asp Phe
                      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 Ser Asn Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Asn His Thr Leu Tyr
          65 70 75 80
          Leu Arg 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 Ser Thr Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 99]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 99]]>
          ggattcaact ttagagactt tgcc 24
           <![CDATA[ <210> 100]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 100]]>
          Gly Phe Asn Phe Arg Asp Phe Ala
           1 5
           <![CDATA[ <210> 101]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 101]]>
          attagtggta gtggtagtaa taca 24
           <![CDATA[ <210> 102]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 102]]>
          Ile Ser Gly Ser Gly Ser Asn Thr
           1 5
           <![CDATA[ <210> 103]]>
           <![CDATA[ <211> 54]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 103]]>
          gcgaaagatc gactctctat aacaattcgc ccacgctatt acggtctgga cgtc 54
           <![CDATA[ <210> 104]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 104]]>
          Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu
           1 5 10 15
          Asp Val
           <![CDATA[ <210> 105]]>
           <![CDATA[ <211> 324]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 105]]>
          gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
          atcacttgcc gggcgagtca ggacattagc aattattttg cctggtatca gcagaagcca 120
          gggaaagttc ctaagctcct gatctttgct gcatccactt tgcatccagg ggtcccatct 180
          cggttcagtg gcagtggatc tgggacagat ttcactctca ccattcgcag cctgcagcct 240
          gaagatgttg caacttatta ctgtcaaaaa tatgacagtg ccccgtacac ttttggccag 300
          gggaccaagg tggaaatcaa acga 324
           <![CDATA[ <210> 106]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 106]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
                      20 25 30
          Phe Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
                  35 40 45
          Phe Ala Ala Ser Thr Leu His Pro Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asp Ser Ala Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
                      100 105
           <![CDATA[ <210> 107]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 107]]>
          caggacatta gcaattat 18
           <![CDATA[ <210> 108]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 108]]>
          Gln Asp Ile Ser Asn Tyr
           1 5
           <![CDATA[ <210> 109]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 109]]>
          gctgcatcc 9
           <![CDATA[ <210> 110]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 110]]>
          Ala Ala Ser
           1          
           <![CDATA[ <210> 111]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 111]]>
          caaaaatatg acagtgcccc gtacact 27
           <![CDATA[ <210> 112]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 112]]>
          Gln Lys Tyr Asp Ser Ala Pro Tyr Thr
           1 5
           <![CDATA[ <210> 113]]>
           <![CDATA[ <211> 372]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 113]]>
          gaggtgcagc tggtggagtc tgagggactc ttggaacagc ctggggggtc cctgagactc 60
          tcctgtgcag cctctggatt caactttaga gactttgcca tgacctgggt ccgccaggct 120
          ccagggaagg ggctggagtg ggtctcatct attagtggta gtggtagtaa tacatactac 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaacca cacgctgtat 240
          ctgcgaatga acagcctgag agccgaagac acggccgtgt attactgtgc gaaagatcga 300
          ctctctataa caattcgccc acgctattac ggtctggacg tctggggcca agggaccacg 360
          gtcaccgtct cc 372
           <![CDATA[ <210> 114]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 114]]>
          Glu Val Gln Leu Val Glu Ser Glu Gly Leu Leu Glu Glu Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Phe Arg Asp Phe
                      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 Ser Asn Thr Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Asn His Thr Leu Tyr
          65 70 75 80
          Leu Arg 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
                  115 120
           <![CDATA[ <210> 115]]>
           <![CDATA[ <211> 321]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 115]]>
          gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
          atcacttgcc gggcgagtca ggacattagc aattattttg cctggtatca gcagaagcca 120
          gggaaagttc ctaagctcct gatctttgct gcatccactt tgcatccagg ggtcccatct 180
          cggttcagtg gcagtggatc tgggacagat ttcactctca ccattcgcag cctgcagcct 240
          gaagatgttg caacttatta ctgtcaaaaa tatgacagtg ccccgtacac ttttggccag 300
          gggaccaagc tggagatcaa a 321
           <![CDATA[ <210> 116]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 116]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
                      20 25 30
          Phe Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
                  35 40 45
          Phe Ala Ala Ser Thr Leu His Pro Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asp Ser Ala Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 117]]>
           <![CDATA[ <211> 373]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 117]]>
          gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
          tcctgtgcag cctctggatt caactttaga gactttgcca tgagctgggt ccgccaggct 120
          ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtagtaa tacatactac 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatcga 300
          ctctctataa caattcgccc acgctattac ggtctggacg tctggggcca agggaccacg 360
          gtcaccgtct cct 373
           <![CDATA[ <210> 118]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 118]]>
          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 Asn Phe Arg Asp Phe
                      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 Ser 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
                  115 120
           <![CDATA[ <210> 119]]>
           <![CDATA[ <211> 322]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 119]]>
          gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
          atcacttgcc gggcgagtca ggacattagc aattatttag cctggtatca gcagaaacca 120
          gggaaagttc ctaagctcct gatctatgct gcatccactt tgcaatcagg ggtcccatct 180
          cggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
          gaagatgttg caacttatta ctgtcaaaaa tatgacagtg ccccgtacac ttttggccag 300
          gggaccaagc tggagatcaa ac 322
           <![CDATA[ <210> 120]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 120]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asp Ser Ala Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 121]]>
           <![CDATA[ <211> 357]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 121]]>
          caggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
          tcctgtgtag cttctggatt cacccttaac aactttgtca tgaactgggt ccgccaggtt 120
          ccagggaagg gactggagtg ggtctctttt attagtgcta gtggtggtag tatatactac 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca cttccaagaa cacattatat 240
          ctgcaaatga acagcctgag agccgacgac acggccgtct attactgtgc gaaatccccg 300
          tataactgga acccctttga ctattggggc cagggaacca cggtcaccgt ctcctca 357
           <![CDATA[ <210> 122]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <22]]>3> Synthetic]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;400&gt;122]]&gt;
           <br/> <![CDATA[Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Leu Asn Asn Phe
                      20 25 30
          Val Met Asn Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Ser Ala Ser Gly Gly Ser Ile Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ser Pro Tyr Asn Trp Asn Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Thr Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 123]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 123]]>
          ggattcaccc ttaacaactt tgtc 24
           <![CDATA[ <210> 124]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 124]]>
          Gly Phe Thr Leu Asn Asn Phe Val
           1 5
           <![CDATA[ <210> 125]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 125]]>
          attagtgcta gtggtggtag tata 24
           <![CDATA[ <210> 126]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 126]]>
          Ile Ser Ala Ser Gly Gly Ser Ile
           1 5
           <![CDATA[ <210> 127]]>
           <![CDATA[ <211> 36]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 127]]>
          gcgaaatccc cgtataactg gaaccccttt gactat 36
           <![CDATA[ <210> 128]]>
           <![CDATA[ <211> 12]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 128]]>
          Ala Lys Ser Pro Tyr Asn Trp Asn Pro Phe Asp Tyr
           1 5 10
           <![CDATA[ <210> 129]]>
           <![CDATA[ <211> 327]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 129]]>
          gacatccagt tgacccagtc tccagccacc ctgtctgtgt ctccagggga acgagccacc 60
          ctctcctgca gggccagtct gagtgttagc agcaaattag cctggtacca gcagacacct 120
          ggccaggctc ccagactcct catctatagt gcctccaccc gggccactgg tatcccagtc 180
          aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
          gaagattttg cggtttatta ctgtcagcag tataatcatt ggcctccgta cacttttggc 300
          caggggacca aggtggagat caaacga 327
           <![CDATA[ <210> 130]]>
           <![CDATA[ <211> 109]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 130]]>
          Asp Ile Gln Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
           1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Leu Ser Val Ser Ser Lys
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Thr Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Thr Arg Ala Thr Gly Ile Pro Val Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn His Trp Pro Pro
                          85 90 95
          Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
                      100 105
           <![CDATA[ <210> 131]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 131]]>
          ctgagtgtta gcagcaaa 18
           <![CDATA[ <210> 132]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 132]]>
          Leu Ser Val Ser Ser Lys
           1 5
           <![CDATA[ <210> 133]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 133]]>
          agtgcctcc 9
           <![CDATA[ <210> 134]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 134]]>
          Ser Ala Ser
           1          
           <![CDATA[ <210> 135]]>
           <![CDATA[ <211> 30]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 135]]>
          cagcagtata atcattggcc tccgtacact 30
           <![CDATA[ <210> 136]]>
           <![CDATA[ <211> 10]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 136]]>
          Gln Gln Tyr Asn His Trp Pro Pro Tyr Thr
           1 5 10
           <![CDATA[ <210> 137]]>
           <![CDATA[ <211> 357]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 137]]>
          gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
          tcctgtgtag cttctggatt cacccttaac aactttgtca tgaactgggt ccgccaggtt 120
          ccagggaagg gactggagtg ggtctctttt attagtgcta gtggtggtag tatatactac 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca cttccaagaa cacattatat 240
          ctgcaaatga acagcctgag agccgacgac acggccgtct attactgtgc gaaatccccg 300
          tataactgga acccctttga ctattggggc cagggaaccc tggtcaccgt ctcctca 357
           <![CDATA[ <210> 138]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 138]]>
          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 Val Ala Ser Gly Phe Thr Leu Asn Asn Phe
                      20 25 30
          Val Met Asn Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Phe Ile Ser Ala Ser Gly Gly Ser Ile Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Asp Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Ala Lys Ser Pro Tyr Asn Trp Asn Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 139]]>
           <![CDATA[ <211> 324]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 139]]>
          gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga acgagccacc 60
          ctctcctgca gggccagtct gagtgttagc agcaaattag cctggtacca gcagacacct 120
          ggccaggctc ccagactcct catctatagt gcctccaccc gggccactgg tatcccagtc 180
          aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
          gaagattttg cggtttatta ctgtcagcag tataatcatt ggcctccgta cacttttggc 300
          caggggacca agctggagat caaa 324
           <![CDATA[ <210> 140]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 140]]>
          Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
           1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Leu Ser Val Ser Ser Lys
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Thr Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Thr Arg Ala Thr Gly Ile Pro Val Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn His Trp Pro Pro
                          85 90 95
          Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 141]]>
           <![CDATA[ <211> 357]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 141]]>
          gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
          tcctgtgcag cctctggatt cacccttaac aactttgtca tgagctgggt ccgccaggct 120
          ccagggaagg ggctggagtg ggtctcagct attagtgcta gtggtggtag tatatactac 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaatccccg 300
          tataactgga acccctttga ctattggggc cagggaaccc tggtcaccgt ctcctca 357
           <![CDATA[ <210> 142]]>
           <![CDATA[ <211> 119]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 142]]>
          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 Asn Asn Phe
                      20 25 30
          Val Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Ala Ser Gly Gly Ser Ile 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 Ser Pro Tyr Asn Trp Asn Pro Phe Asp Tyr Trp Gly Gln Gly
                      100 105 110
          Thr Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 143]]>
           <![CDATA[ <211> 325]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 143]]>
          gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60
          ctctcctgca gggccagtct gagtgttagc agcaaattag cctggtacca gcagaaacct 120
          ggccaggctc ccaggctcct catctatagt gcctccacca gggccactgg tatcccagcc 180
          aggttcagtg gcagtgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240
          gaagattttg cagtttatta ctgtcagcag tataatcatt ggcctccgta cacttttggc 300
          caggggacca agctggagat caaac 325
           <![CDATA[ <210> 144]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 144]]>
          Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly
           1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Leu Ser Val Ser Ser Lys
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Ser Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn His Trp Pro Pro
                          85 90 95
          Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 145]]>
           <![CDATA[ <211> 375]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 145]]>
          caggtgcagc tggtggagtc tgggggaggc ttggaacagc cgggggggtc cctgagactc 60
          tcctgtgcag gctctggatt cacctttaga gactatgcca tgacctgggt ccgccaggct 120
          ccagggaagg gactggagtg ggtctcatct attagtggtt ccggtggtaa cacatactac 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatcga 300
          ctctctataa caattcgccc acgctattat ggtttggacg tctggggcca agggtccacg 360
          gtcaccgtct cctca 375
           <![CDATA[ <210> 146]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 146]]>
          Gln 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 Ser Thr Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 147]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 147]]>
          ggattcacct ttagagacta tgcc 24
           <![CDATA[ <210> 148]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 148]]>
          Gly Phe Thr Phe Arg Asp Tyr Ala
           1 5
           <![CDATA[ <210> 149]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 149]]>
          attagtggtt ccggtggtaa caca 24
           <![CDATA[ <210> 150]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 150]]>
          Ile Ser Gly Ser Gly Gly Asn Thr
           1 5
           <![CDATA[ <210> 151]]>
           <![CDATA[ <211> 54]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 151]]>
          gcgaaagatc gactctctat aacaattcgc ccacgctatt atggtttgga cgtc 54
           <![CDATA[ <210> 152]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 152]]>
          Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu
           1 5 10 15
          Asp Val
           <![CDATA[ <210> 153]]>
           <![CDATA[ <211> 339]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 153]]>
          gacatcgtgt tgacccagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
          atctcctgca ggtctagtca gagcctcctg tatagtattg gatacaacta tttggattgg 120
          tacctgcaga agtcagggca gtctccacag ctccttatct atttgggttc taatcgggcc 180
          tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240
          agcagagtgg aggctgagga tgttgggttt tattactgca tgcaagctct acaaactccg 300
          tacacttttg gccaggggac caagctggag atcaaacga 339
           <![CDATA[ <210> 154]]>
           <![CDATA[ <211> 113]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 154]]>
          Asp Ile Val Leu 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
           <![CDATA[ <210> 155]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 155]]>
          cagagcctcc tgtatagtat tggatacaac tat 33
           <![CDATA[ <210> 156]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 156]]>
          Gln Ser Leu Leu Tyr Ser Ile Gly Tyr Asn Tyr
           1 5 10
           <![CDATA[ <210> 157]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 157]]>
          ttgggttct 9
           <![CDATA[ <210> 158]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 158]]>
          Leu Gly Ser
           1          
           <![CDATA[ <210> 159]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 159]]>
          atgcaagctc tacaaactcc gtacact 27
           <![CDATA[ <210> 160]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 160]]>
          Met Gln Ala Leu Gln Thr Pro Tyr Thr
           1 5
           <![CDATA[ <210> 161]]>
           <![CDATA[ <211> 372]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 161]]>
          gaggtgcagc tggtggagtc tgggggaggc ttggaacagc cgggggggtc cctgagactc 60
          tcctgtgcag gctctggatt cacctttaga gactatgcca tgacctgggt ccgccaggct 120
          ccagggaagg gactggagtg ggtctcatct attagtggtt ccggtggtaa cacatactac 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatcga 300
          ctctctataa caattcgccc acgctattat ggtttggacg tctggggcca agggaccacg 360
          gtcaccgtct cc 372
           <![CDATA[ <210> 162]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 162]]>
          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
                  115 120
           <![CDATA[ <210> 163]]>
           <![CDATA[ <211> 336]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 163]]>
          gacatcgtga tgacccagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
          atctcctgca ggtctagtca gagcctcctg tatagtattg gatacaacta tttggattgg 120
          tacctgcaga agtcagggca gtctccacag ctccttatct atttgggttc taatcgggcc 180
          tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240
          agcagagtgg aggctgagga tgttgggttt tattactgca tgcaagctct acaaactccg 300
          tacacttttg gccaggggac caagctggag atcaaa 336
           <![CDATA[ <210> 164]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 164]]>
          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
           <![CDATA[ <210> 165]]>
           <![CDATA[ <211> 373]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 165]]>
          gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
          tcctgtgcag cctctggatt cacctttaga gactatgcca tgagctgggt ccgccaggct 120
          ccagggaagg ggctggagtg ggtctcagct attagtggtt ccggtggtaa cacatactac 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatcga 300
          ctctctataa caattcgccc acgctattat ggtttggacg tctggggcca agggaccacg 360
          gtcaccgtct cct 373
           <![CDATA[ <210> 166]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 166]]>
          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 Asp Tyr
                      20 25 30
          Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala 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
                  115 120
           <![CDATA[ <210> 167]]>
           <![CDATA[ <211> 337]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 167]]>
          gatattgtga tgactcagtc tccactctcc ctgcccgtca cccctggaga gccggcctcc 60
          atctcctgca ggtctagtca gagcctcctg tatagtattg gatacaacta tttggattgg 120
          tacctgcaga agccagggca gtctccacag ctcctgatct atttgggttc taatcgggcc 180
          tccggggtcc ctgacaggtt cagtggcagt ggatcaggca cagattttac actgaaaatc 240
          agcagagtgg aggctgagga tgttggggtt tattactgca tgcaagctct acaaactccg 300
          tacacttttg gccaggggac caagctggag atcaaac 337
           <![CDATA[ <210> 168]]>
           <![CDATA[ <211> 112]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 168]]>
          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 Pro 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 Val 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
           <![CDATA[ <210> 169]]>
           <![CDATA[ <211> 375]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 169]]>
          caggtgcagc tggtggagtc tgggggagtc ttggagcagc ctggggggtc cctgagactc 60
          tcctgtacag cctctggatt cacctttaga gactatgcca tgacctgggt ccgccaggct 120
          ccagggaagg ggctggagtg ggtctcatct attagtggta gtggtggtaa tacatactac 180
          gcagactccg tgaggggccg gttcaccatc tccagagaca actccaacca cacgctgtat 240
          ctgcaaatga acagcctgag agccgaagac acggccgtat attactgtgc gaaagatcga 300
          ctctccataa caattcgccc acgctattac ggtttggacg tctggggcca agggtccacg 360
          gtcaccgtct cctca 375
           <![CDATA[ <210> 170]]>
           <![CDATA[ <211> 125]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 170]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Val Leu Glu Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Thr Ala 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
          Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Asn His 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 Ser Thr Val Thr Val Ser Ser
                  115 120 125
           <![CDATA[ <210> 171]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 171]]>
          ggattcacct ttagagacta tgcc 24
           <![CDATA[ <210> 172]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 172]]>
          Gly Phe Thr Phe Arg Asp Tyr Ala
           1 5
           <![CDATA[ <210> 173]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 173]]>
          attagtggta gtggtggtaa taca 24
           <![CDATA[ <210> 174]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 174]]>
          Ile Ser Gly Ser Gly Gly Asn Thr
           1 5
           <![CDATA[ <210> 175]]>
           <![CDATA[ <211> 54]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 175]]>
          gcgaaagatc gactctccat aacaattcgc ccacgctatt acggtttgga cgtc 54
           <![CDATA[ <210> 176]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Human process]]> column
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 176]]>
          Ala Lys Asp Arg Leu Ser Ile Thr Ile Arg Pro Arg Tyr Tyr Gly Leu
           1 5 10 15
          Asp Val
           <![CDATA[ <210> 177]]>
           <![CDATA[ <211> 324]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 177]]>
          gatattgtga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
          attacttgcc gggcgagtca ggacattagc aattattttg cctggtatca gcagaagcca 120
          gggaaagttc ctaaactcct gatctttgct gcatccactt tgcatccagg ggtcccatct 180
          cggttcagtg gcagtggatc tgggacagat ttcactctca ccattagtag cctgcagcct 240
          gaagatgttg caacttatta ctgtcaaaag tataacagtg ccccgtacac ttttggccag 300
          gggaccaagg tggaaatcaa acga 324
           <![CDATA[ <210> 178]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 178]]>
          Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
                      20 25 30
          Phe Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
                  35 40 45
          Phe Ala Ala Ser Thr Leu His Pro Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
                      100 105
           <![CDATA[ <210> 179]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 179]]>
          caggacatta gcaattat 18
           <![CDATA[ <210> 180]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 180]]>
          Gln Asp Ile Ser Asn Tyr
           1 5
           <![CDATA[ <210> 181]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 181]]>
          gctgcatcc 9
           <![CDATA[ <210> 182]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 182]]>
          Ala Ala Ser
           1          
           <![CDATA[ <210> 183]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 183]]>
          caaaagtata acagtgcccc gtacact 27
           <![CDATA[ <210> 184]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 184]]>
          Gln Lys Tyr Asn Ser Ala Pro Tyr Thr
           1 5
           <![CDATA[ <210> 185]]>
           <![CDATA[ <211> 372]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 185]]>
          gaggtgcagc tggtggagtc tgggggagtc ttggagcagc ctggggggtc cctgagactc 60
          tcctgtacag cctctggatt cacctttaga gactatgcca tgacctgggt ccgccaggct 120
          ccagggaagg ggctggagtg ggtctcatct attagtggta gtggtggtaa tacatactac 180
          gcagactccg tgaggggccg gttcaccatc tccagagaca actccaacca cacgctgtat 240
          ctgcaaatga acagcctgag agccgaagac acggccgtat attactgtgc gaaagatcga 300
          ctctccataa caattcgccc acgctattac ggtttggacg tctggggcca agggaccacg 360
          gtcaccgtct cc 372
           <![CDATA[ <210> 186]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 186]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Leu Glu Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Thr Ala 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
          Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Asn His 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
                  115 120
           <![CDATA[ <210> 187]]>
           <![CDATA[ <211> 321]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 187]]>
          gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
          attacttgcc gggcgagtca ggacattagc aattattttg cctggtatca gcagaagcca 120
          gggaaagttc ctaaactcct gatctttgct gcatccactt tgcatccagg ggtcccatct 180
          cggttcagtg gcagtggatc tgggacagat ttcactctca ccattagtag cctgcagcct 240
          gaagatgttg caacttatta ctgtcaaaag tataacagtg ccccgtacac ttttggccag 300
          gggaccaagc tggagatcaa a 321
           <![CDATA[ <210> 188]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 188]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
                      20 25 30
          Phe Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
                  35 40 45
          Phe Ala Ala Ser Thr Leu His Pro Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 189]]>
           <![CDATA[ <211> 373]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 189]]>
          gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60
          tcctgtgcag cctctggatt cacctttaga gactatgcca tgagctgggt ccgccaggct 120
          ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtggtaa tacatactac 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagatcga 300
          ctctccataa caattcgccc acgctattac ggtttggacg tctggggcca agggaccacg 360
          gtcaccgtct cct 373
           <![CDATA[ <210> 190]]>
           <![CDATA[ <211> 124]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 190]]>
          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 Asp Tyr
                      20 25 30
          Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala 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
                  115 120
           <![CDATA[ <210> 191]]>
           <![CDATA[ <211> 322]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 191]]>
          gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60
          atcacttgcc gggcgagtca ggacattagc aattatttag cctggtatca gcagaaacca 120
          gggaaagttc ctaagctcct gatctatgct gcatccactt tgcaatcagg ggtcccatct 180
          cggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
          gaagatgttg caacttatta ctgtcaaaag tataacagtg ccccgtacac ttttggccag 300
          gggaccaagc tggagatcaa ac 322
           <![CDATA[ <210> 192]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Manual]]> Sequence
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 192]]>
          Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
           1 5 10 15
          Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile
                  35 40 45
          Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr Asn Ser Ala Pro Tyr
                          85 90 95
          Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 193]]>
           <![CDATA[ <211> 355]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 193]]>
          gaagtgcacc tggtggaatc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
          tcctgtgagg cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
          ccggggaagg gcctggaatg ggtctcaggt cttagtcgga caagtgtcag tataggctat 180
          gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctttat 240
          ttggaaatga acagtctgag acctgaggac acggccttat attactgtgc aaaatggggg 300
          acccgggggt attttgacta ctggggccag ggaaccctgg tcaccgtctc ctcag 355
           <![CDATA[ <210> 194]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 194]]>
          Glu Val His Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Asp Asp Tyr
                      20 25 30
          Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Leu Ser Arg Thr Ser Val Ser Ile Gly Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Glu Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
                          85 90 95
          Ala Lys Trp Gly Thr Arg Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 195]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 195]]>
          ggattcacct ttgatgatta tgcc 24
           <![CDATA[ <210> 196]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 196]]>
          Gly Phe Thr Phe Asp Asp Tyr Ala
           1 5
           <![CDATA[ <210> 197]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 197]]>
          cttagtcgga caagtgtcag tata 24
           <![CDATA[ <210> 198]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 198]]>
          Leu Ser Arg Thr Ser Val Ser Ile
           1 5
           <![CDATA[ <210> 199]]>
           <![CDATA[ <211> 33]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 199]]>
          gcaaaatggg ggacccgggg gtattttgac tac 33
           <![CDATA[ <210> 200]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 200]]>
          Ala Lys Trp Gly Thr Arg Gly Tyr Phe Asp Tyr
           1 5 10
           <![CDATA[ <210> 201]]>
           <![CDATA[ <211> 322]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 201]]>
          gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtgggaga cagagtcacc 60
          atcacttgtc gggcgagtca ggatattagt atttggttag cctggtatca gcagagtcca 120
          gggaaagccc ctaaactcct gatcaatgtt gcatcccgtt tgcaaagtgg ggtcccatca 180
          aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcaacag tctgcagcct 240
          gaagattttg taacttacta ttgtcaacag gctaacagtt tcccgatcac cttcggccaa 300
          gggacacgac tggcgaccaa ac 322
           <![CDATA[ <210> 202]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <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 Asp Ile Ser Ile Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Ser Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Asn Val Ala Ser Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Val Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile
                          85 90 95
          Thr Phe Gly Gln Gly Thr Arg Leu Ala Thr Lys
                      100 105
           <![CDATA[ <210> 203]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 203]]>
          caggatatta gtatttgg 18
           <![CDATA[ <210> 204]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 204]]>
          Gln Asp Ile Ser Ile Trp
           1 5
           <![CDATA[ <210> 205]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 205]]>
          gttgcatcc 9
           <![CDATA[ <210> 206]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 206]]>
          Val Ala Ser
           1          
           <![CDATA[ <210> 207]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 207]]>
          caacaggcta acagtttccc gatcacc 27
           <![CDATA[ <210> 208]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 208]]>
          Gln Gln Ala Asn Ser Phe Pro Ile Thr
           1 5
           <![CDATA[ <210> 209]]>
           <![CDATA[ <211> 355]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 209]]>
          gaggtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
          tcctgtgagg cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
          ccggggaagg gcctggaatg ggtctcaggt cttagtcgga caagtgtcag tataggctat 180
          gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctttat 240
          ttggaaatga acagtctgag acctgaggac acggccttat attactgtgc aaaatggggg 300
          acccgggggt attttgacta ctggggccag ggaaccctgg tcaccgtctc ctcag 355
           <![CDATA[ <210> 210]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 210]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Glu Ala Ser Gly Phe Thr Phe Asp Asp Tyr
                      20 25 30
          Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Leu Ser Arg Thr Ser Val Ser Ile Gly Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Glu Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Leu Tyr Tyr Cys
                          85 90 95
          Ala Lys Trp Gly Thr Arg Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 211]]>
           <![CDATA[ <211> 322]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 211]]>
          gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtgggaga cagagtcacc 60
          atcacttgtc gggcgagtca ggatattagt atttggttag cctggtatca gcagagtcca 120
          gggaaagccc ctaaactcct gatcaatgtt gcatcccgtt tgcaaagtgg ggtcccatca 180
          aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcaacag tctgcagcct 240
          gaagattttg taacttacta ttgtcaacag gctaacagtt tcccgatcac cttcggccaa 300
          gggacacgac tggagattaa ac 322
           <![CDATA[ <210> 212]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 212]]>
          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 Asp Ile Ser Ile Trp
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Ser Pro Gly Lys Ala Pro Lys Leu Leu Ile
                  35 40 45
          Asn Val Ala Ser Arg Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro
          65 70 75 80
          Glu Asp Phe Val Thr Tyr Tyr Cys Gln Gln Ala Asn Ser Phe Pro Ile
                          85 90 95
          Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 213]]>
           <![CDATA[ <211> 355]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 213]]>
          gaagtgcagc tggtggagtc tgggggaggc ttggtacagc ctggcaggtc cctgagactc 60
          tcctgtgcag cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct 120
          ccagggaagg gcctggagtg ggtctcaggt cttagtcgga caagtgtcag tataggctat 180
          gcggactctg tgaagggccg attcaccatc tccagagaca acgccaagaa ctccctgtat 240
          ctgcaaatga acagtctgag agctgaggac acggccttgt attactgtgc aaaatggggg 300
          acccgggggt attttgacta ctggggccaa ggaaccctgg tcaccgtctc ctcag 355
           <![CDATA[ <210> 214]]>
           <![CDATA[ <211> 118]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 214]]>
          Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
                      20 25 30
          Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ser Gly Leu Ser Arg Thr Ser Val Ser Ile Gly Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
          65 70 75 80
          Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys
                          85 90 95
          Ala Lys Trp Gly Thr Arg Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr
                      100 105 110
          Leu Val Thr Val Ser Ser
                  115
           <![CDATA[ <210> 215]]>
           <![CDATA[ <211> 322]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 215]]>
          gacatccaga tgacccagtc tccatcttcc gtgtctgcat ctgtaggaga cagagtcacc 60
          atcacttgtc gggcgagtca ggatattagt atttggttag cctggtatca gcagaaacca 120
          gggaaagccc ctaagctcct gatctatgtt gcatccagtt tgcaaagtgg ggtcccatca 180
          aggttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240
          gaagattttg caacttacta ttgtcaacag gctaacagtt tcccgatcac cttcggccaa 300
          gggacacgac tggagattaa ac 322
           <![CDATA[ <210> 216]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 216]]>
          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 Asp Ile Ser Ile 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 Ala Asn Ser Phe Pro Ile
                          85 90 95
          Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
                      100 105
           <![CDATA[ <210> 217]]>
           <![CDATA[ <211> 363]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 217]]>
          gaggtgcagc tgttggagtc tgggggaggc ttgctacagc cgggggggtc cctgagactc 60
          tcctgtgcag cctctggaat cacctttagc acctatgcca tgagctgggt ccgtcaggct 120
          ccagggaggg ggctggagtg ggtctcagct attagtggta gtggtgatag cacatcctac 180
          gcagactccg tgaagggccg gttcaccagc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagtcata 300
          gcagctcgtc ctcactggaa cttcgatctc tggggccgtg gcaccctggt cactgtctcc 360
          tca 363
           <![CDATA[ <210> 218]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 218]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Leu Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Phe Ser Thr Tyr
                      20 25 30
          Ala Met Ser Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Asp Ser Thr Ser Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ser 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 Val Ile Ala Ala Arg Pro His Trp Asn Phe Asp Leu Trp Gly
                      100 105 110
          Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 219]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 219]]>
          ggaatcacct ttagcaccta tgcc 24
           <![CDATA[ <210> 220]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 220]]>
          Gly Ile Thr Phe Ser Thr Tyr Ala
           1 5
           <![CDATA[ <210> 221]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 221]]>
          attagtggta gtggtgatag caca 24
           <![CDATA[ <210> 222]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 222]]>
          Ile Ser Gly Ser Gly Asp Ser Thr
           1 5
           <![CDATA[ <210> 223]]>
           <![CDATA[ <211> 42]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 223]]>
          gcgaaagtca tagcagctcg tcctcactgg aacttcgatc tc 42
           <![CDATA[ <210> 224]]>
           <![CDATA[ <211> 14]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 224]]>
          Ala Lys Val Ile Ala Ala Arg Pro His Trp Asn Phe Asp Leu
           1 5 10
           <![CDATA[ <210> 225]]>
           <![CDATA[ <211> 324]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 225]]>
          gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
          ctctcctgca gggccagtca gagtgttagt agatatttag cctggtatca acagaaacct 120
          ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180
          aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
          gaagattttg gagtttatta ctgtcagcag cgtagtgact ggccgctcac tttcggcgga 300
          gggaccaagg tggagatcaa acgg 324
           <![CDATA[ <210> 226]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 226]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
           1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
          65 70 75 80
          Glu Asp Phe Gly Val Tyr Tyr Cys Gln Gln Arg Ser Asp Trp Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 227]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 227]]>
          cagagtgtta gtagatat 18
           <![CDATA[ <210> 228]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 228]]>
          Gln Ser Val Ser Arg Tyr
           1 5
           <![CDATA[ <210> 229]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 229]]>
          gatgcatcc 9
           <![CDATA[ <210> 230]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 230]]>
          Asp Ala Ser
           1          
           <![CDATA[ <210> 231]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 231]]>
          cagcagcgta gtgactggcc gctcact 27
           <![CDATA[ <210> 232]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 232]]>
          Gln Gln Arg Ser Asp Trp Pro Leu Thr
           1 5
           <![CDATA[ <210> 233]]>
           <![CDATA[ <211> 363]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 233]]>
          gaggtgcagc tgttggagtc tgggggaggc ttgctacagc cgggggggtc cctgagactc 60
          tcctgtgcag cctctggaat cacctttagc acctatgcca tgagctgggt ccgtcaggct 120
          ccagggaggg ggctggagtg ggtctcagct attagtggta gtggtgatag cacatcctac 180
          gcagactccg tgaagggccg gttcaccagc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagtcata 300
          gcagctcgtc ctcactggaa cttcgatctc tggggccgtg gcaccctggt cactgtctcc 360
          tca 363
           <![CDATA[ <210> 234]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 234]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Leu Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Phe Ser Thr Tyr
                      20 25 30
          Ala Met Ser Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Val
                  35 40 45
          Ser Ala Ile Ser Gly Ser Gly Asp Ser Thr Ser Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ser 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 Val Ile Ala Ala Arg Pro His Trp Asn Phe Asp Leu Trp Gly
                      100 105 110
          Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 235]]>
           <![CDATA[ <211> 324]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 235]]>
          gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
          ctctcctgca gggccagtca gagtgttagt agatatttag cctggtatca acagaaacct 120
          ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180
          aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
          gaagattttg gagtttatta ctgtcagcag cgtagtgact ggccgctcac tttcggcgga 300
          gggaccaagg tggagatcaa acgg 324
           <![CDATA[ <210> 236]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 236]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
           1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
          65 70 75 80
          Glu Asp Phe Gly Val Tyr Tyr Cys Gln Gln Arg Ser Asp Trp Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 237]]>
           <![CDATA[ <211> 363]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 237]]>
          gaggtgcagc tgttggagtc tgggggaggc ttggtacagc cgggggggtc cctgagactc 60
          tcctgtgcag cctctggaat cacctttagc acctatgcca tgagctgggt ccgtcaggct 120
          ccagggaagg ggctggagtg ggtctcagct attagtggta gtggtgatag cacatactac 180
          gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaagtcata 300
          gcagctcgtc ctcactggaa cttcgatctc tggggccgtg gcaccctggt cactgtctcc 360
          tca 363
           <![CDATA[ <210> 238]]>
           <![CDATA[ <211> 121]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 238]]>
          Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
           1 5 10 15
          Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Ile Thr Phe Ser Thr 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 Asp Ser 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 Val Ile Ala Ala Arg Pro His Trp Asn Phe Asp Leu Trp Gly
                      100 105 110
          Arg Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 239]]>
           <![CDATA[ <211> 324]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 239]]>
          gaaattgtgt tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
          ctctcctgca gggccagtca gagtgttagt agatatttag cctggtatca acagaaacct 120
          ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180
          aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
          gaagattttg cagtttatta ctgtcagcag cgtagtgact ggccgctcac tttcggcgga 300
          gggaccaagg tggagatcaa acgg 324
           <![CDATA[ <210> 240]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 240]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
           1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asp Trp Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
                      100 105
           <![CDATA[ <210> 241]]>
           <![CDATA[ <211> 366]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 241]]>
          caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
          acctgtgcag cctctggatt caccttcagt agtaatggca tgcactgggt ccgccaggct 120
          ccaggcaagg ggctggagtg ggtggcaatt atatcatatg atggaaataa tcaatactat 180
          gcagactccg tgaagggccg attcaccatc tccagagaca attccaagca cacgctgtat 240
          ctggaaatga acagcctgag agctgaggac acggctgtgt attactgtac aaaagccatc 300
          tctataagtg gaacttacaa ctggttcgat tcctggggcc agggaaccct ggtcaccgtc 360
          tcctca 366
           <![CDATA[ <210> 242]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 242]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
           1 5 10 15
          Ser Leu Arg Leu Thr Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Asn
                      20 25 30
          Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Ile Ile Ser Tyr Asp Gly Asn Asn Gln Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys His Thr Leu Tyr
          65 70 75 80
          Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Lys Ala Ile Ser Ile Ser Gly Thr Tyr Asn Trp Phe Asp Ser Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 243]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 243]]>
          ggattcacct tcagtagtaa tggc 24
           <![CDATA[ <210> 244]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <22]]>3> Synthetic]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;400&gt;244]]&gt;
           <br/> <![CDATA[Gly Phe Thr Phe Ser Ser Asn Gly
           1 5
           <![CDATA[ <210> 245]]>
           <![CDATA[ <211> 24]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 245]]>
          atatcatatg atggaaataa tcaa 24
           <![CDATA[ <210> 246]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 246]]>
          Ile Ser Tyr Asp Gly Asn Asn Gln
           1 5
           <![CDATA[ <210> 247]]>
           <![CDATA[ <211> 45]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 247]]>
          acaaaagcca tctctataag tggaacttac aactggttcg attcc 45
           <![CDATA[ <210> 248]]>
           <![CDATA[ <211> 15]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 248]]>
          Thr Lys Ala Ile Ser Ile Ser Gly Thr Tyr Asn Trp Phe Asp Ser
           1 5 10 15
           <![CDATA[ <210> 249]]>
           <![CDATA[ <211> 324]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 249]]>
          gaaattgtat tgacacagtc tccagccatc ctgtctttgt ctccagggga aagagccacc 60
          ctctcctgca gggccagtca gagtgttagc aggtacttag cctggtacca acagaaacct 120
          ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180
          aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
          gaagattttg cagtttatta ctgtcaacag cgtagcaact ggccgctcac tttcggcgga 300
          gggaccaagg tggagatcaa acgg 324
           <![CDATA[ <210> 250]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 250]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ala Ile Leu Ser Leu Ser Pro Gly
           1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 251]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 251]]>
          cagagtgtta gcaggtac 18
           <![CDATA[ <210> 252]]>
           <![CDATA[ <211> 6]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 252]]>
          Gln Ser Val Ser Arg Tyr
           1 5
           <![CDATA[ <210> 253]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 253]]>
          gatgcatcc 9
           <![CDATA[ <210> 254]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 254]]>
          Asp Ala Ser
           1          
           <![CDATA[ <210> 255]]>
           <![CDATA[ <211> 27]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 255]]>
          caacagcgta gcaactggcc gctcact 27
           <![CDATA[ <210> 256]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 256]]>
          Gln Gln Arg Ser Asn Trp Pro Leu Thr
           1 5
           <![CDATA[ <210> 257]]>
           <![CDATA[ <211> 366]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 257]]>
          caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
          acctgtgcag cctctggatt caccttcagt agtaatggca tgcactgggt ccgccaggct 120
          ccaggcaagg ggctggagtg ggtggcaatt atatcatatg atggaaataa tcaatactat 180
          gcagactccg tgaagggccg attcaccatc tccagagaca attccaagca cacgctgtat 240
          ctggaaatga acagcctgag agctgaggac acggctgtgt attactgtac aaaagccatc 300
          tctataagtg gaacttacaa ctggttcgat tcctggggcc agggaaccct ggtcaccgtc 360
          tcctca 366
           <![CDATA[ <210> 258]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 258]]>
          Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
           1 5 10 15
          Ser Leu Arg Leu Thr Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Asn
                      20 25 30
          Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
                  35 40 45
          Ala Ile Ile Ser Tyr Asp Gly Asn Asn Gln Tyr Tyr Ala Asp Ser Val
              50 55 60
          Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys His Thr Leu Tyr
          65 70 75 80
          Leu Glu Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
                          85 90 95
          Thr Lys Ala Ile Ser Ile Ser Gly Thr Tyr Asn Trp Phe Asp Ser Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 259]]>
           <![CDATA[ <211> 324]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 259]]>
          gaaattgtat tgacacagtc tccagccatc ctgtctttgt ctccagggga aagagccacc 60
          ctctcctgca gggccagtca gagtgttagc aggtacttag cctggtacca acagaaacct 120
          ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180
          aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
          gaagattttg cagtttatta ctgtcaacag cgtagcaact ggccgctcac tttcggcgga 300
          gggaccaagg tggagatcaa acgg 324
           <![CDATA[ <210> 260]]>
           <![CDATA[ <211> 107]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 260]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ala Ile Leu Ser Leu Ser Pro Gly
           1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
                      100 105
           <![CDATA[ <210> 261]]>
           <![CDATA[ <211> 366]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 261]]>
          caggtgcagc tggtggagtc tgggggaggc gtggtccagc ctgggaggtc cctgagactc 60
          tcctgtgcag cctctggatt caccttcagt agtaatggca tgcactgggt ccgccaggct 120
          ccaggcaagg ggctggagtg ggtggcagtt atatcatatg atggaaataa tcaatactat 180
          gcagactccg tgaagggccg attcaccatc tccagagaca attccaagaa cacgctgtat 240
          ctgcaaatga acagcctgag agctgaggac acggctgtgt attactgtac aaaagccatc 300
          tctataagtg gaacttacaa ctggttcgat tcctggggcc agggaaccct ggtcaccgtc 360
          tcctca 366
           <![CDATA[ <210> 262]]>
           <![CDATA[ <211> 122]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 262]]>
          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 Asn
                      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 Ser Tyr Asp Gly Asn Asn Gln 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
          Thr Lys Ala Ile Ser Ile Ser Gly Thr Tyr Asn Trp Phe Asp Ser Trp
                      100 105 110
          Gly Gln Gly Thr Leu Val Thr Val Ser Ser
                  115 120
           <![CDATA[ <210> 263]]>
           <![CDATA[ <211> 324]]>
           <![CDATA[ <212> DNA]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 263]]>
          gaaattgtat tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60
          ctctcctgca gggccagtca gagtgttagc aggtacttag cctggtacca acagaaacct 120
          ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180
          aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240
          gaagattttg cagtttatta ctgtcaacag cgtagcaact ggccgctcac tttcggcgga 300
          gggaccaagg tggagatcaa acgg 324
           <![CDATA[ <210> 264]]>
           <![CDATA[ <211> 108]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 264]]>
          Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly
           1 5 10 15
          Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Arg Tyr
                      20 25 30
          Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile
                  35 40 45
          Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly
              50 55 60
          Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro
          65 70 75 80
          Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu
                          85 90 95
          Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
                      100 105
           <![CDATA[ <210> 265]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <21]]>3> Artificial sequence]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;220&gt;]]&gt;
           <br/> &lt;![CDATA[ &lt;223&gt;Synthetic]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;220&gt;]]&gt;
           <br/> &lt;![CDATA[ &lt;221&gt; Variations ]]&gt;
           <br/> &lt;![CDATA[ &lt;222&gt;(1)...(8)]]&gt;
           <br/> &lt;![CDATA[ &lt;223&gt; Xaa = any amino acid]]&gt;
           <br/>
           <br/> &lt;![CDATA[ &lt;400&gt;265]]&gt;
           <br/> <![CDATA[Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
           1 5
           <![CDATA[ <210> 266]]>
           <![CDATA[ <211> 8]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> Variations ]]>
           <![CDATA[ <222> (1)...(8))]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 266]]>
          Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
           1 5
           <![CDATA[ <210> 267]]>
           <![CDATA[ <211> 18]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> Variations ]]>
           <![CDATA[ <222> (1)...(18))]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 267]]>
          Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
           1 5 10 15
          Xaa Xaa
           <![CDATA[ <210> 268]]>
           <![CDATA[ <211> 11]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> Variations ]]>
           <![CDATA[ <222> (1)...(11))]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 268]]>
          Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
           1 5 10
           <![CDATA[ <210> 269]]>
           <![CDATA[ <211> 3]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> Variations ]]>
           <![CDATA[ <222> (1)...(3))]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 269]]>
          Xaa Xaa Xaa
           1          
           <![CDATA[ <210> 270]]>
           <![CDATA[ <211> 9]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <221> Variations ]]>
           <![CDATA[ <222> (1)...(9))]>
           <![CDATA[ <223> Xaa = any amino acid]]>
           <![CDATA[ <400> 270]]>
          Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
           1 5
           <![CDATA[ <210> 271]]>
           <![CDATA[ <211> 330]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 271]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
           1 5 10 15
          Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
          65 70 75 80
          Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
                      100 105 110
          Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
                  115 120 125
          Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
              130 135 140
          Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
          145 150 155 160
          Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
                          165 170 175
          Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
                      180 185 190
          His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
                  195 200 205
          Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
              210 215 220
          Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
          225 230 235 240
          Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
                          245 250 255
          Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
                      260 265 270
          Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
                  275 280 285
          Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
              290 295 300
          Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
          305 310 315 320
          Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
                          325 330
           <![CDATA[ <210> 272]]>
           <![CDATA[ <211> 327]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 272]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
           1 5 10 15
          Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
          65 70 75 80
          Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro
                      100 105 110
          Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
                  115 120 125
          Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
              130 135 140
          Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
          145 150 155 160
          Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
                          165 170 175
          Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
                      180 185 190
          Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
                  195 200 205
          Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
              210 215 220
          Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
          225 230 235 240
          Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
                          245 250 255
          Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
                      260 265 270
          Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
                  275 280 285
          Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
              290 295 300
          Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
          305 310 315 320
          Leu Ser Leu Ser Leu Gly Lys
                          325
           <![CDATA[ <210> 273]]>
           <![CDATA[ <211> 327]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Artificial sequence]]>
           <![CDATA[ <220> ]]>
           <![CDATA[ <223> Synthetic]]>
           <![CDATA[ <400> 273]]>
          Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
           1 5 10 15
          Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
                      20 25 30
          Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
                  35 40 45
          Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
              50 55 60
          Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
          65 70 75 80
          Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
                          85 90 95
          Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
                      100 105 110
          Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
                  115 120 125
          Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
              130 135 140
          Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
          145 150 155 160
          Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
                          165 170 175
          Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
                      180 185 190
          Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
                  195 200 205
          Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
              210 215 220
          Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
          225 230 235 240
          Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
                          245 250 255
          Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
                      260 265 270
          Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
                  275 280 285
          Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
              290 295 300
          Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
          305 310 315 320
          Leu Ser Leu Ser Leu Gly Lys
                          325
           <![CDATA[ <210> 274]]>
           <![CDATA[ <211> 207]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Homo sapiens]]>
           <![CDATA[ <400> 274]]>
          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
           <![CDATA[ <210> 275]]>
           <![CDATA[ <211> 231]]>
           <![CDATA[ <212> PRT]]>
           <![CDATA[ <213> Crab-eating macaque]]>
           <![CDATA[ <400> 275]]>
          Met Gly Trp Leu Cys Ser Gly Leu Leu Phe Pro Val Ser Cys Leu Val
           1 5 10 15
          Leu Leu Gln Val Ala Ser Ser Ser Gly Ser Met Lys Val Leu Gln Glu Pro
                      20 25 30
          Thr Cys Val Ser Asp Tyr Met Ser Ile Ser Thr Cys Glu Trp Lys Met
                  35 40 45
          Gly Gly Pro Thr Asn Cys Ser Ala Glu Leu Arg Leu Leu Tyr Gln Leu
              50 55 60
          Val Phe Gln Ser Ser Glu Thr His Thr Cys Val Pro Glu Asn Asn Gly
          65 70 75 80
          Gly Val Gly Cys Val Cys His Leu Leu Met Asp Asp Val Val Ser Met
                          85 90 95
          Asp Asn Tyr Thr Leu Asp Leu Trp Ala Gly Gln Gln Leu Leu Trp Lys
                      100 105 110
          Gly Ser Phe Lys Pro Ser Glu His Val Lys Pro Arg Ala Pro Gly Asn
                  115 120 125
          Leu Thr Val His Thr Asn Val Ser Asp Thr Val Leu Leu Thr Trp Ser
              130 135 140
          Asn Pro Tyr Pro Pro Asp Asn Tyr Leu Tyr Asn Asp Leu Thr Tyr Ala
          145 150 155 160
          Val Asn Ile Trp Ser Glu Asn Asp Pro Ala Tyr Ser Arg Ile His Asn
                          165 170 175
          Val Thr Tyr Leu Lys Pro Thr Leu Arg Ile Pro Ala Ser Thr Leu Lys
                      180 185 190
          Ser Gly Ile Ser Tyr Arg Ala Arg Val Arg Ala Trp Ala Gln His Tyr
                  195 200 205
          Asn Thr Thr Trp Ser Glu Trp Ser Pro Ser Thr Lys Trp Tyr Asn Ser
              210 215 220
          Tyr Arg Glu Pro Phe Glu Gln
          225 230
          40
          
      

Claims (16)

The use of a pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), which is used to manufacture a drug as an additional therapy for treating severe asthma in an individual, the individual Having oral corticosteroid-dependent asthma, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the heavy chain complementarity determining region (HCDR) sequence of SEQ ID NO: 148, 150 and 152, respectively, and comprising a heavy chain comprising SEQ ID NO: 156, 158 and 160 light chain complementarity determining region (LCDR) sequence light chain. The use according to claim 1, wherein the oral corticosteroid is administered to the individual before, after or at the same time as the medical composition. Such as the use of claim 1, wherein the pharmaceutical composition reduces the occurrence of one or more asthma exacerbations selected from the group consisting of: (A) Peak expiratory flow (PEF) decreased by 30% or more from baseline in the morning for two consecutive days; (B) Six or more additional albuterol or levalbuterol reliever inhalations (reliever puffs) within 24 hours (compared to baseline) on two consecutive days; and (C) Asthma worsens, which requires: (I) Systemic (oral or parenteral or both) steroid therapy, or (Ii) The inhaled corticosteroid is increased to at least 4 times the last dose received before the interruption, or (Iii) Hospitalization. Such as the use of claim 1, wherein the pharmaceutical composition improves one or more asthma-related parameters selected from the group consisting of: (A) Forced expiratory volume (FEV1) within 1 second increased from baseline by at least 0.10 L; (B) The morning peak expiratory flow rate (AM PEF) increased from baseline by at least 10.0 L/min; (C) The evening peak expiratory flow rate (PM PEF) increased from baseline by at least 1.0 L/min; (D) Daily use of salbutamol/lev-salbutamol is reduced from baseline by at least 1 inhalation/day; (E) Five-item Asthma Control Questionnaire (ACQ5) score, reduced by at least 0.5 points from baseline; (F) Nocturnal awakenings measured daily (number of times per night) decreased from baseline by at least 0.2 times per night; and (G) 22 mid-nasal outcome tests (SNOT-22) reduced by at least 5 points from baseline. The use of a pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), which is used to manufacture a drug as an additional therapy for treating severe asthma in an individual, the individual With oral corticosteroid-dependent asthma, the use includes: (A) Select individuals with elevated levels of biomarkers selected from the group consisting of: thymus and activation-regulated chemokine (TARC), IgE, eosinophil-activated chemokine-3 , Periostin, carcinoembryonic antigen (CEA), YKL-40 and graded exhaled nitric oxide (FeNO); and (B) administer the pharmaceutical composition to the individual, Wherein the antibody or antigen-binding fragment thereof comprises a heavy chain containing the heavy chain complementarity determining region (HCDR) sequence of SEQ ID NO: 148, 150 and 152, respectively, and a light chain containing SEQ ID NO: 156, 158 and 160, respectively The light chain of the complementarity determining region (LCDR) sequence. The use of a pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof that specifically binds to interleukin-4 receptor (IL-4R), which is used to manufacture a drug as an additional therapy for treating severe asthma in an individual, the individual With oral corticosteroid-dependent asthma, the use includes: (A) Select individuals that exhibit the following: The blood eosinophil level is at least 300 cells per microliter, or Sputum eosinophil level is at least 3%, or The blood eosinophil level is at least 300 cells per microliter and the sputum eosinophil level is at least 3%; and (B) administer the pharmaceutical composition to the individual, Wherein the antibody or antigen-binding fragment thereof comprises a heavy chain containing the heavy chain complementarity determining region (HCDR) sequence of SEQ ID NO: 148, 150 and 152, respectively, and a light chain containing SEQ ID NO: 156, 158 and 160, respectively The light chain of the complementarity determining region (LCDR) sequence. The use according to any one of claims 1 to 6, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain variable region (HCVR)/light chain variable region (LCVR) sequence pair of SEQ ID NO: 162/164. The use according to any one of claims 1 to 6, wherein the pharmaceutical composition comprises 75 mg to 600 mg of the antibody or antigen-binding fragment thereof. Such as the use of any one of claims 1 to 6, wherein the pharmaceutical composition is administered once every other week. Such as the use of claim 9, wherein the pharmaceutical composition is administered with an initial dose of 600 mg, followed by one or more second doses of 300 mg each. Such as the use of claim 9, wherein the pharmaceutical composition is administered with an initial dose of 400 mg, followed by one or more second doses of 200 mg each. The use according to any one of claims 1 to 6, wherein the individual has an eosinophil phenotype. The use according to any one of claims 1 to 6, wherein the individual has bronchial inflammation. Such as the use of any one of claims 1 to 6, where the system is at least 12 years old. Such as the use of any one of claims 1 to 6, wherein the anti-system dupilumab (dupilumab). Such as the use of any one of claims 1 to 6, wherein the medical composition is administered subcutaneously using a needle and a syringe, a pen delivery device or an auto-injector.

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