CN116963776A

CN116963776A - Methods of treating GPP

Info

Publication number: CN116963776A
Application number: CN202280019132.1A
Authority: CN
Inventors: C·托马; D·B·霍尔; B·朗
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2021-03-04
Filing date: 2022-03-03
Publication date: 2023-10-27

Abstract

The present application relates to the use of anti-IL 36R antibodies to treat or ameliorate signs and symptoms of Generalized Pustular Psoriasis (GPP) or acute phase complications of GPP.

Description

Methods of treating GPP

Sequence listing

The present application comprises a sequence listing that has been submitted in ASCII format by EFS-Web and is incorporated herein by reference in its entirety. The ASCII copy was created on 1 month 31 of 2022 under the name 09-0719-WO-1-2022-03-03-SL.txt, of size 147,456 bytes.

Technical Field

The present application relates to the use of anti-IL-36R antibodies in methods and compositions for treating patients with Generalized Pustular Psoriasis (GPP). More specifically, the present application relates to GPP or GPP burst (fire) for treating patients by: administering to the patient two 900mg intravenous (i.v.) doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose. More specifically, the application relates to GPP for treating patients by: the patient was administered a single 900mg intravenous dose of pessary Li Shan antibody, if the GPP symptoms persisted one week after the initial dose, an additional 900mg intravenous dose was administered.

Background

GPP is a serious skin disease characterized by repeated acute bursts caused by systemic inflammation affecting the skin and viscera. The typical manifestations of acute GPP were first described by von Zumbusch in 1909 as recurrent pustular psoriasis. While GPP and plaque psoriasis may occur simultaneously in individual patients, GPP differs from plaque psoriasis in clinical manifestations, pathophysiology, histopathology, response to therapy, epidemiology and genetics.

Therefore, it is extremely critical to distinguish GPP from plaque-type or red skin-type psoriasis with secondary pustules. The clinical manifestations of GPP are very different from Psoriasis Vulgaris (PV) in their paroxysmal nature, often between extremely acute and severe outbreaks, with normal skin appearance. GPP is clinically characterized by pustules as the primary lesions on a erythema basis, rather than red plaque covered with psoriasis, which represents the primary lesions of typical plaque psoriasis. In addition, the histopathological markers of GPP are unique Kogoj spongiform pustules located in the lower part of the stratum corneum of the epidermis. GPP can be associated with systemic symptoms (fever, CRP increase and neutrophilia) and severe external organ manifestations of the skin (liver, renal failure, CV shock). Although GPP patients may pre-exist or co-exist with PV, primary plaque disease (PV) patients with secondary pustule components can be clinically distinguished from primary pustule disease (GPP) patients with concomitant plaque components based on the order of performance (primary lesion pustule rather than plaque) and that GPP pustules are located on an erythema basis rather than on a PsO plaque.

Since the descriptions of GPP are inconsistent between standard dermatological textbooks, the european rare and severe psoriasis expert network (European Rare And Severe Psoriasis Expert Network, eraspn) defines consensus criteria, including as critical diagnostic criteria for acute GPP: non-acroskin presents with primary, sterile, macroscopically visible pustules (excluding the case where pustules are limited to psoriatic plaques), with or without systemic inflammation, with or without plaque psoriasis, recurrent (> 1 episode) or persistent (> 3 months).

Chronic GPP describes a state between outbreaks of disease that may be characterized by the complete absence of symptoms or the persistence of residual skin symptoms such as erythema and scaling and minor pustules.

Current treatment options for controlling acute GPP and subcutaneous reactions are limited and do not provide sustained efficacy. Currently there is no approval for treatment of GPP in the United states and European Union, but retinoids (retinoids), cyclosporine (cyclosporine) or methotrexate (methotrextrate) are suggested. Although these treatments were described as "significantly effective or effective" in 70% to 84% of patients (J Am Acad Dermatol.2012;67 (2): 279-88), these data were based on retrospective cohort studies from Japan (retrospective cohort study) with no well-defined endpoint (Japanese Journal of Dermatology.2010;120 (4): 815-39). In addition, these treatments are not long-term use due to side effects or contraindications (retinoids: teratogenicity, hair loss; cyclosporine: hair overgrowth, nephrotoxicity; MTX: hepatotoxicity).

Based on a small number of published case families, biologicals (mostly TNF inhibitors, occasionally IL-1 or IL-17 inhibitors) are increasingly being used to treat more severe, extensive or therapeutic resistant GPP patients. However, these drugs are also associated with efficacy limitations (frequent incomplete and delayed response) and safety and contraindications (infusion responses, tuberculosis, cardiovascular disease). Thus, there is a need in the art for novel targeted therapies for the treatment and/or prevention of GPP.

Disclosure of Invention

The present invention addresses the above needs by providing a biologic therapeutic, particularly an antibody, that binds to IL-36R and provides a therapeutic or prophylactic therapy for GPP and related signs and symptoms (such as GPP outbreaks) including acute GPP.

In one aspect, the invention relates to the treatment of a patient's GPP by administering to the patient two 900mg intravenous (i.v.) doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

In another aspect, the invention relates to the treatment of GPP in a patient by administering a single 900mg intravenous dose of an anti-IL-36R antibody to the patient, if GPP symptoms persist one week after the initial dose, an additional 900mg intravenous dose of the anti-IL-36R antibody is administered.

In one aspect, the invention relates to a method of treating an outbreak of Generalized Pustular Psoriasis (GPP) in a patient, the method comprising administering to the patient two 900mg intravenous (i.v.) doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

In one aspect, the invention relates to a method of treating GPP in a patient, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

In one aspect, the invention relates to a method of reducing or alleviating the signs and symptoms of acute phase disease onset (fire-up) in GPP in a patient, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

In one aspect, the invention relates to a method of reducing the severity and duration of GPP symptoms, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

In one aspect, the invention relates to a method of treating a skin disorder associated with GPP comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

In one aspect, the invention relates to a method of preventing a relapse of an GPP outbreak in a patient, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

In one aspect, the invention relates to a method of reducing pain by at least 10% in a patient suffering from GPP, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

In one aspect, the invention relates to a method of improving the quality of life of a patient suffering from moderate to severe GPP symptoms by at least 10%, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

In one embodiment directed to any of the above aspects, the patient's GPP practitioner overall evaluation (GPPGA) total score is ≡2.

In one embodiment involving any of the above aspects, the patient's GPP physician overall assessment (GPPGA) total score is ≡2 and GPPGA pustule score is ≡2.

In one embodiment involving any of the above aspects, prior to administration of the first intravenous dose, the patient's GPP physician overall evaluation (GPPGA) total score is ≡2 and GPPGA pustule score is ≡2.

In one embodiment directed to any of the above aspects, after administration of the first intravenous dose, the patient's GPP physician overall evaluation (GPPGA) total score is ≡2 and GPPGA pustule score is ≡2.

In one embodiment involving any of the above aspects, the patient's GPP physician overall evaluation (GPPGA) total score is ≡2 and GPPGA pustule score is ≡2 before and after administration of the first intravenous dose.

In one embodiment involving any of the above aspects, the second dose is administered 1 week but less than 2 weeks after the first dose.

In one aspect, the invention relates to a method of treating a GPP patient having a GPPGA pustule score of ∈2, the method comprising the steps of: (a) Administering to the patient a first 900mg intravenous (i.v.) dose of an anti-IL-36R antibody; (b) The GPPGA pustule score for the patient is assessed, and if the GPPGA pustule score for the patient ∈2 persists after 1 week after the first dose, a second 900mg (i.v.) dose of pessary Li Shan antibody is administered to the patient less than 2 weeks after the first dose.

In one aspect, the present invention relates to a method of treating a GPP patient having a general assessment of GPP physicians (GPPGA) total score of > 2, the method comprising the steps of: (a) Administering to the patient a first 900mg intravenous (i.v.) dose of an anti-IL-36R antibody; (b) The patient's total GPPGA score is assessed, and if the patient's total GPPGA score of ∈2 persists after 1 week after the first dose, a second 900mg (i.v.) dose of pessary Li Shan antibody is administered to the patient less than 2 weeks after the first dose.

In one aspect, the present invention relates to a method of treating a GPP patient having a GPP practitioner general assessment (GPPGA) total score of > 2 and a GPPGA pustule score of > 2, the method comprising the steps of: (a) Administering to the patient a first 900mg intravenous (i.v.) dose of an anti-IL-36R antibody; (b) The patient's GPPGA score is assessed, and if the patient's GPPGA total score ∈2 and the GPPGA pustular score ∈2 persists after 1 week after the first dose, a second 900mg (i.v.) dose of pessary Li Shan antibody is administered to the patient less than 2 weeks after the first dose.

In one embodiment directed to any one of the above aspects or embodiments, the optional third 900mg intravenous dose of the anti-IL-36R antibody is administered 2 to 12 weeks after the second intravenous dose.

In an embodiment with respect to any of the above aspects or embodiments, two dose administrations achieve one or more of the following results:

(a) A Generalized Pustular Psoriasis Global Assessment (GPPGA) pustular score of 0 shown within one week after administration of the second intravenous dose; and/or

(b) Within one week after administration of this second intravenous dose, the GPPGA total score was 0 or 1.

In one embodiment directed to any one of the above aspects or embodiments, the result is maintained for up to and at least 12 weeks after administration of the second intravenous dose.

In one embodiment directed to any one of the above aspects or embodiments, the method comprises administering to the patient a prophylactically effective amount of the anti-IL-36R antibody in one or more subcutaneous doses after administration of the last intravenous dose.

In an embodiment directed to any one of the above aspects or embodiments, each of the one or more subcutaneous doses comprises 150mg, 225mg, 300mg, 450mg, or 600mg of the anti-IL-36R antibody.

In an embodiment directed to any one of the above aspects or embodiments, 1, 2, 3 or more subcutaneous doses are administered to the patient and wherein a first subcutaneous dose is administered after the last intravenous dose.

In an embodiment directed to any of the above aspects or embodiments, a first subcutaneous dose is administered 2 to 8 weeks, 4 to 6 weeks, 2 weeks, 4 weeks, 6 weeks or 8 weeks, 12 weeks, 16 weeks, 20 weeks after the last intravenous dose, and a subsequent subcutaneous dose is administered at 2, 4, 6, 8, 10 or 12 week intervals after the first subcutaneous dose.

In one embodiment directed to any one of the above aspects or embodiments, the patient maintains clinical relief at least 12, 24, 36, 48, 60, or 72 weeks after the last intravenous or subcutaneous dose, as measured by a GPPGA total score of 0 or 1.

In one embodiment directed to any one of the above aspects or embodiments, the anti-IL-36R antibody comprises: a) A light chain variable region comprising the amino acid sequence SEQ ID NO. 26 (L-CDR 1); amino acid sequence SEQ ID NO:35, 102, 103, 104, 105, 106 or 140 (L-CDR 2); the amino acid sequence SEQ ID NO. 44 (L-CDR 3); and b) a heavy chain variable region comprising the amino acid sequence SEQ ID NO:53 (H-CDR 1); the amino acid sequence SEQ ID NO. 62, 108, 109, 110 or 111 (H-CDR 2); the amino acid sequence SEQ ID NO:72 (H-CDR 3).

In one embodiment directed to any one of the above aspects or embodiments, the anti-IL-36R antibody comprises:

a) a light chain variable region comprising the amino acid sequence SEQ ID NO. 26 (L-CDR 1); amino acid sequence SEQ ID NO. 102 (L-CDR 2); the amino acid sequence SEQ ID NO. 44 (L-CDR 3); and b) a heavy chain variable region comprising the amino acid sequence SEQ ID NO:53 (H-CDR 1); the amino acid sequence SEQ ID NO. 62, 108, 109, 110 or 111 (H-CDR 2); the amino acid sequence SEQ ID NO:72 (H-CDR 3);

II.a) a light chain variable region comprising the amino acid sequence SEQ ID NO. 26 (L-CDR 1); amino acid sequence SEQ ID NO. 103 (L-CDR 2); the amino acid sequence SEQ ID NO. 44 (L-CDR 3); and b) a heavy chain variable region comprising the amino acid sequence SEQ ID NO:53 (H-CDR 1); the amino acid sequence SEQ ID NO. 62, 108, 109, 110 or 111 (H-CDR 2); the amino acid sequence SEQ ID NO:72 (H-CDR 3);

a) a light chain variable region comprising the amino acid sequence SEQ ID NO. 26 (L-CDR 1); amino acid sequence SEQ ID NO 104 (L-CDR 2); the amino acid sequence SEQ ID NO. 44 (L-CDR 3); and b) a heavy chain variable region comprising the amino acid sequence SEQ ID NO:53 (H-CDR 1); the amino acid sequence SEQ ID NO. 62, 108, 109, 110 or 111 (H-CDR 2); the amino acid sequence SEQ ID NO:72 (H-CDR 3);

A) a light chain variable region comprising the amino acid sequence SEQ ID NO. 26 (L-CDR 1); amino acid sequence SEQ ID NO. 105 (L-CDR 2); the amino acid sequence SEQ ID NO. 44 (L-CDR 3); and b) a heavy chain variable region comprising the amino acid sequence SEQ ID NO:53 (H-CDR 1); the amino acid sequence SEQ ID NO. 62, 108, 109, 110 or 111 (H-CDR 2); the amino acid sequence SEQ ID NO:72 (H-CDR 3);

v.a) a light chain variable region comprising the amino acid sequence SEQ ID NO. 26 (L-CDR 1); amino acid sequence SEQ ID NO. 106 (L-CDR 2); the amino acid sequence SEQ ID NO. 44 (L-CDR 3); and b) a heavy chain variable region comprising the amino acid sequence SEQ ID NO:53 (H-CDR 1); the amino acid sequence SEQ ID NO. 62, 108, 109, 110 or 111 (H-CDR 2); the amino acid sequence SEQ ID NO:72 (H-CDR 3);

a) a light chain variable region comprising the amino acid sequence SEQ ID NO. 26 (L-CDR 1); the amino acid sequence SEQ ID NO:140 (L-CDR 2); the amino acid sequence SEQ ID NO. 44 (L-CDR 3); and b) a heavy chain variable region comprising the amino acid sequence SEQ ID NO:53 (H-CDR 1); the amino acid sequence SEQ ID NO. 62, 108, 109, 110 or 111 (H-CDR 2); the amino acid sequence SEQ ID NO:72 (H-CDR 3).

(i) A light chain variable region comprising the amino acid sequence SEQ ID NO. 77; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO. 87; or (b)

(ii) A light chain variable region comprising the amino acid sequence SEQ ID NO. 77; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO 88; or (b)

(iii) A light chain variable region comprising the amino acid sequence SEQ ID NO. 77; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO. 89; or (b)

(iv) A light chain variable region comprising the amino acid sequence SEQ ID NO. 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO. 87; or (b)

(v) A light chain variable region comprising the amino acid sequence SEQ ID NO. 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO 88; or (b)

(vi) A light chain variable region comprising the amino acid sequence SEQ ID NO. 80; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO. 89; or (b)

(vii) A light chain variable region comprising the amino acid sequence SEQ ID NO. 85; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO. 100; or (b)

(viii) A light chain variable region comprising the amino acid sequence SEQ ID NO. 85; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO. 101; or (b)

(ix) A light chain variable region comprising the amino acid sequence SEQ ID NO 86; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO. 100; or (b)

(x) A light chain variable region comprising the amino acid sequence SEQ ID NO 86; and a heavy chain variable region comprising the amino acid sequence SEQ ID NO. 101.

i. a light chain comprising the amino acid sequence SEQ ID NO. 115; and a heavy chain comprising the amino acid sequence SEQ ID NO. 125; or (b)

A light chain comprising the amino acid sequence SEQ ID NO. 115; and a heavy chain comprising the amino acid sequence SEQ ID NO. 126; or (b)

A light chain comprising the amino acid sequence SEQ ID NO. 115; and a heavy chain comprising the amino acid sequence SEQ ID NO. 127; or (b)

A light chain comprising the amino acid sequence SEQ ID NO. 118; and a heavy chain comprising the amino acid sequence SEQ ID NO. 125; or (b)

v. a light chain comprising the amino acid sequence SEQ ID NO. 118; and a heavy chain comprising the amino acid sequence SEQ ID NO. 126; or (b)

A light chain comprising the amino acid sequence SEQ ID NO. 118; and a heavy chain comprising the amino acid sequence SEQ ID NO. 127; or (b)

A light chain comprising the amino acid sequence SEQ ID NO. 123; and a heavy chain comprising the amino acid sequence SEQ ID NO 138; or (b)

Light chain comprising the amino acid sequence SEQ ID NO. 123; and a heavy chain comprising the amino acid sequence SEQ ID NO 139; or (b)

A light chain comprising the amino acid sequence SEQ ID NO 124; and a heavy chain comprising the amino acid sequence SEQ ID NO. 138.

In one embodiment directed to any one of the above aspects or embodiments, the anti-IL-36R antibody is a pendant Li Shan antibody

Additional features and advantages of the application will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by practice of the technology. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the application as claimed.

Brief Description of Drawings

The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate aspects of the technology of the application and together with the description serve to explain the principles of the application.

Figure 1 shows a confrt flow chart of the experiment described in example 1. * Other exclusions include trial completion, completion of the overall recruitment objective, and no outbreak of patients within the 6 month screening period.Patients were blinded to randomized block treatment, but could meet the conditions of open-label dose of peacable Li Shan antibody on day 8. / >Patients who did not complete the remaining 16 weeks after the last administration of the drug of peaked Li Shan were not enrolled in the OLE trial. Patients who do not continue the OLE trial will follow-up for 16 weeks after the last dose of trial drug, which is the latest time point during the trial at which the trial drug was given (e.g., day 1 if OL pexole Li Shan antibody was given and day 8 if OL pexole Li Shan anti-rescue was given). OL, open label; OLE, open label extension; soC, standard of care.

Figure 2 shows a test design as described in example 1. * Day 2 to 7: an adverse treatment (SoC) may be provided in the event of a disease exacerbation (defined as a clinical state as defined by the researcher or exacerbation of GPP skin and/or systemic symptoms).After day 8-week 12: if patients who have previously achieved clinical response (GPPGA 0/1) to initial treatment (with day 1 peacable Li Shan resistance or placebo, or day 8 pest-avoidance drug or OL peacable Li Shan resistance) experience GPP burst recurrence (GPPGA score > 2 score increase and GPPGA pustule component > 2), then only one OL peacable Li Shan anti-rescue dose is allowed. Subsequent bursts will followThe physician chooses to treat with SoC. / >Until week 12 (EoT), patients not requiring anti-rescue treatment with OL-pendant Li Shan should be followed before entering OLE trial. Until week 12 (EoT), patients receiving OL-pendant Li Shan anti-rescue treatment between week 2 and week 6 should be followed before entering OLE trial. If it fits into the OLE trial at week 12, eoT of these patients will be considered. Patients not suitable for entering an OLE trial will follow up for 16 weeks (EoT/16 th to 28 th weeks) after the last dose of trial drug, which is the latest time point given the trial drug during the trial (e.g. day 1 if OL eupatorium Li Shan antibody is given, and day 8 if OL eupatorium Li Shan anti-rescue is given). EoT, the test is ended; GPP, generalized pustular psoriasis; GPPGA, overall evaluation by the pan-pustular psoriasis physician; v. intravenous; OL, open label, OLE, open label extension; r, randomly grouping; SD, single dose; soC, standard of care.

Fig. 3 shows primary and key secondary results. Panel a shows the percentage of patients with a global evaluation (GPPGA) of the pustular score of 0 (complete pustular clearance) for pan-pustular psoriasis physicians following week 1 pessary Li Shan antibody or placebo treatment. Panel B shows the percentage of patients with an overall GPPGA score of 0 or 1 (cleared or nearly cleared skin) following a single intravenous dose of 900mg pexol Li Shan antibody or placebo treatment at week 1. CI, confidence interval.

Figure 4 shows GPPGA pustule score over time for randomized group treatment on day 1. Panels a and B show the proportion of patients scored on the global evaluation of pustular scores (GPPGA) by the general pustular psoriasis physician at week 1 (day 8) and over time after receiving a single intravenous dose of placebo (panel a) or 900mg pessary Li Shan antibody (panel B), respectively. The dashed line indicates the proportion of patients who achieved GPPGA pustule score of 0. * For this analysis, any use of the pest-resistant drug or open-label-pendant Li Shan antibody at day 8 or open-label-pendant Li Shan anti-rescue drug treatment at each time point was classified separately (gray bars).

Figure 5 shows GPPGA total scores over time for the day 1 randomized group treatment. Panels a and B show the proportion of patients scored overall by the overall evaluation of the total score of the pan-pustular psoriasis physician (GPPGA) at week 1 (day 8) and over time after receiving a single intravenous dose of placebo (panel a) or 900mg of pessary Li Shan antibody (panel B), respectively. The dashed line indicates the proportion of patients who achieved a GPPGA total score of 0 or 1. * For this analysis, any use of the pest-resistant drug or open-label-pendant Li Shan antibody at day 8 or open-label-pendant Li Shan anti-rescue drug treatment at each time point was classified separately (gray bars).

Figure 6 shows GPPGA pustule score over time for randomized group treatment on day 1 and open label pessary Li Shan anti-treatment on day 8. On day 8, patients with a GPPGA total score of > 2 and a generalized impetigo psoriasis physician overall evaluation (GPPGA) impetigo score of > 2 received the open label petiole Li Shan resistance. The following GPPGA pustule score relative to baseline is displayed: random grouping to eupatorium Li Shan antibody, all patients receiving or not receiving open label eupatorium Li Shan antibody dose on day 8 (panel a); patients who were randomized to the peacable Li Shan antibody and did not receive the open label peacable Li Shan antibody dose on day 8 (panel B); patients who received an open label eupatorium Li Shan antibody dose on day 8 (panel C) were randomized to eupatorium Li Shan antibody; and placebo patients receiving an open label pessary Li Shan anti-dose on day 8 (panel D). The dashed line indicates the proportion of patients who achieved a GPPGA pustule score of 0. * For this analysis, any use of the pest-resistant drug or open-label-pendant Li Shan antibody at day 8 or open-label-pendant Li Shan anti-rescue drug treatment at each time point was classified separately (gray bars).

Figure 7 shows GPPGA total scores over time for the 1 st randomized group treatment and the 8 th open label pessary Li Shan anti-treatment. On day 8, patients with a GPPGA total score of > 2 and a GPPGA pustule score of > 2 received open-label pendant Li Shan resistance. The following GPPGA total scores relative to baseline are shown: random grouping to eupatorium Li Shan antibody, all patients receiving or not receiving open label eupatorium Li Shan antibody dose on day 8 (panel a); patients who were randomized to the peacable Li Shan antibody and did not receive the open label peacable Li Shan antibody dose on day 8 (panel B); patients who received an open label eupatorium Li Shan antibody dose on day 8 (panel C) were randomized to eupatorium Li Shan antibody; and placebo patients receiving an open label pessary Li Shan anti-dose on day 8 (panel D). The dashed line indicates the proportion of patients who achieved a GPPGA total score of 0 or 1. * For this analysis, any use of the pest-resistant drug or open-label-pendant Li Shan antibody at day 8 or open-label-pendant Li Shan anti-rescue drug treatment at each time point was classified separately (gray bars). GPP, generalized pustular psoriasis; GPPGA, overall evaluation by the physician of generalized pustular psoriasis.

Figure 8 shows the therapeutic response of patients in the eupatorium Li Shan antibody group receiving up to two doses of eupatorium Li Shan antibody on day 1 and optionally a dose on day 8. Panel A shows GPPASI results; panel B shows GPPASI 75 results; panel C shows pain VAS results; plot D shows DLQI results; panel E shows neutrophils over time in patients with a baseline exceeding the upper normal limit (. Gtoreq.7X109/L); panel F shows levels of C-reactive protein over time in patients with baseline exceeding the upper normal limit (. Gtoreq.10 mg/L). The dataset included patients randomly grouped into peacable Li Shan antibodies, receiving up to two doses of peacable Li Shan antibodies, including those observed in patients receiving day 8 open label peacable Li Shan antibodies. Arrows indicate the days of intravenous pessary Li Shan anti-administration. For this analysis, any value after the day 8 open label pendant Li Shan resistance was used, but any value after treatment with the pest-avoidance drug, or pendant Li Shan anti-rescue drug, was not used and was estimated as the worst result in the calculation of median and quartiles. DLQI, dermatological quality of life index; GPPASI, area and severity index of generalized pustular psoriasis; GPPASI 75, 75% or greater improvement in psoriasis area and severity index of generalized pustular psoriasis; IQR, quartile range; pain VAS, pain visual analog scale.

Figure 9 shows the change from baseline in GPPGA scores (including GPPGA pustule score and GPPGA total score) in three patients after receiving first and second doses of peacable Li Shan antibodies on days 1 and 8, respectively. Panel A shows the change in GPPGA score (and skin erythema, scaling/crusting) in patient 1250001012 after receiving a first intravenous (i.v.) dose of 900mg of pexol Li Shan antibody and a second intravenous dose of 900mg of pexol Li Shan antibody after 1 week. Panel B shows the change in GPPGA score (and skin erythema, scaling/crusting) in patient 1276007001 after receiving a first intravenous dose of 900mg of pexol Li Shan and a second intravenous dose of 900mg of pexol Li Shan after 1 week. Panel C shows the change in GPPGA score (and skin erythema, scaling/crusting) in patient 1458001002 after receiving a first intravenous dose of 900mg of pexol Li Shan and a second intravenous dose of 900mg of pexol Li Shan after 1 week.

Fig. 10 shows PRO surveys for PSS, pain VAS, facility-fatigue and DLQI scores. A high overall score indicates a greater disorder or a strong severity, with a higher score indicating less fatigue in addition to facility-fatigue. DLQI, dermatological quality of life index; FACIT-fatigue, functional assessment of chronic pain therapy-fatigue; PRO, patient reported outcome; PSS, psoriasis disorder scale; VAS, visual analog scale.

Fig. 11 shows the absolute change in PRO score over time from baseline. Panel A shows the change in pain VAS score from baseline, panel B shows the change in PSS score from baseline, panel C shows the change in FACIT-fatigue score from baseline, and panel D shows the change in DLQI score from baseline. Using the intended treatment analysis, efficacy results for all randomized group patients showed all four PRO duration improvements over time; however, no statistical significance with respect to placebo was observed during period 1. The placebo curve began to converge with the peacable Li Shan antibody curve after administration of the OL peacable Li Shan antibody on day 8. CI, confidence interval; DLQI, dermatological quality of life index; FACIT-fatigue, functional assessment of chronic pain therapy-fatigue; IV, intravenous; OL, open label; PRO, patient reported outcome; PSS, psoriasis disorder scale; VAS, visual analog scale.

Fig. 12 shows the distribution of maximum ADA titers after intravenous administration of pessary Li Shan antibodies in female and male patients with GPP.

Detailed Description

In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. It will be apparent, however, to one skilled in the art that the present technology may be practiced without some of these specific details. In other instances, well-known structures and techniques have not been shown in detail in order not to obscure the invention.

A phrase such as an "aspect" does not imply that such aspect is essential to the invention or that such aspect applies to all configurations of the present technology. The disclosure relating to an aspect may apply to all configurations or one or more configurations. Aspects may provide one or more examples of the invention. A phrase such as an "aspect" may refer to one or more aspects and vice versa. Phrases such as "an embodiment" do not imply that such an embodiment is essential to the present technology or that such an embodiment is applicable to all configurations of the present technology. The disclosure relating to an embodiment may apply to all embodiments or one or more embodiments. Implementations may provide one or more examples of the invention.

The inventors have unexpectedly found that, inter alia, the interleukin-36 pathway inhibition using a single dose of the humanized anti-interleukin-36R (anti-IL-36R) monoclonal antibody of the invention causes rapid and sustained relief of clinical symptoms in patients with acute generalized pustular psoriasis, and no recurrence of GPP outbreaks is observed within 20 weeks after single dose administration.

Accordingly, the present invention relates to compositions and methods for treating and/or preventing GPP and its signs and symptoms. More particularly, the invention relates to compositions and methods for treating and/or preventing moderate to severe GPP, acute GPP, chronic GPP, and/or GPP burst in mammals with an anti-IL 36R antibody or antigen binding fragment thereof of the invention. Compositions and methods include administering to a mammal a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof, wherein the anti-IL-36R antibody is administered in an intravenous dose. In one embodiment, the anti-IL-36R antibody is administered in one or more intravenous doses, optionally followed by one or more subcutaneous doses.

Without wishing to be bound by this theory, it is believed that the anti-IL-36R antibody or antigen-binding fragment thereof binds to human anti-IL-36R and thus blocks the binding of IL-36 agonists and thus, at least partially blocks the signaling cascade of IL-36R to inflammatory mediators. The anti-IL 36R antibodies of the invention are disclosed in U.S. patent No. 9,023,995 or WO2013/074569, the entire contents of each of which are incorporated herein by reference.

Acute GPP bursts of varying severity occur in most patients and may be idiopathic or triggered by external stimuli such as infection, corticosteroid use or withdrawal, stress, or pregnancy. Moderate or severe GPP outbreaks cause significant morbidity and mortality due to tenderness, painful skin lesions, extreme fatigue, hyperthermia, peripheral blood neutrophilia and acute phase reactions, and sepsis. The acute phase is associated with a 10 balance average hospitalization duration (ranging from 3 to 44 days). The 7% observed mortality reported in the retrospective study of 102 GPP cases seen in tertiary hospitals of Malaysia soft (Johor, malaysia) may underestimate because not all GPP patients are included in the study. Mortality may also be underestimated due to the lack of identification of the cause of death from GPP and is driven to a large extent by infectious complications and external organs of the skin, such as kidney, liver, respiratory system, and heart failure. After response to treatment or cessation of spontaneous outbreaks, it is estimated that up to 50% of patients may suffer from chronic GPP, which is characterized by persistent erythema and scaling, which may also include joint symptoms.

Based on the limitations described above, current treatment options are not applicable to long-term treatment and do not provide a sustained response in most patients. Thus, there is a high need to develop the following: (i) High-efficiency therapies that rapidly act on patients exhibiting acute GPP outbreaks; and (ii) effective treatment of chronic GPP, which reliably prevents outbreaks from occurring and is safe and tolerable for lifetime treatment.

Typical manifestations of GPP bursts as described by von Zumbusch are strongly related to polymorphisms in the IL36-R signaling pathway. Individuals with loss of function mutations in the IL36RN gene encoding an endogenous IL36R antagonist (IL-36 RN) have significantly higher GPP morbidity, indicating that uncontrolled upregulation of IL36 signaling due to defective IL36RN antagonism leads to inflammatory episodes observed in GPP. Genetic human studies have demonstrated that GPP occurs in clusters in families with loss-of-function mutations in IL36 RNs that result in uncontrolled IL36R signaling. Mutations in other genes linked to the IL36 pathway, such as CARD14, also cause GPP. Recently published gene expression studies indicate that IL-1 and IL-36 are continuously activated in GPP, inducing neutrophil chemokine expression, infiltration, and pustule formation, indicating that the IL-1/IL-36 inflammatory axis is a powerful driver of disease pathology in GPP. In addition, a recent integrated analysis investigated 233 published GPP cases. It was found that 49 out of 233 cases (21.0%) carried a recessive IL36RN dual gene. These 49 recessive IL36RN dual genes define the GPP phenotype, characterized by early onset and high risk of systemic inflammation.

IL36R is a cell surface receptor involved in inflammatory reactions in the skin and intestinal tract. Which are novel members of the IL1R family, form heterodimeric complexes with IL1R accessory proteins. Heterodimeric IL36R systems with stimulatory (IL 36. Alpha., IL 36. Beta., IL 36. Gamma.) and inhibitory ligands (IL 36 Ra) share a variety of structural and functional similarities with other members of the IL1/IL1R family, such as IL1, IL18, and IL33 (R17-3602). All IL1 family members (il1α, il1β, IL18, il36α, il36β, il36γ and IL 38) signal via unique cognate receptor proteins that, upon ligand binding, recruit the common IL1RacP subunit and activate NFkB and MAP kinase pathways in receptor positive cell types. In human skin tissue, IL36R is expressed in keratinocytes, dermal fibroblasts, and infiltrating myeloid cells. IL36R activation in skin tissue drives production of inflammatory mediators (e.g., CCL20, MIP-1. Beta., TNF- α, IL12, IL17, IL23, TGF- β) and regulates expression of tissue remodeling genes (e.g., MMP, TGF- β). Thus, the link between GPP and mutations in IL36RN is somewhat analogous to the well-recognized aseptic multifocal osteomyelitis, periostitis, and impetigo that result from neonatal onset in the absence of interleukin-1-receptor antagonist. In this case, the absence of receptor antagonists leaves the effects of interleukin-1 unchecked, causing life-threatening systemic inflammation of the skin and bone. These clinical features are responsive to empirical treatment with the recombinant interleukin-1 receptor antagonist anakinra.

I. Definition of the definition

The term "about" shall generally mean an acceptable degree of error or deviation of the measured quantity in view of the nature or accuracy of the measurement. Typically, exemplary degrees of error or deviation are within 5% or within 3% or within 1% of a given value or range of values. For example, the expression "about 100" includes 105 and 95, or 103 and 97, or 101 and 99, and all values therebetween (e.g., 95.1, 95.2, etc. for the range of 95 to 105, or 97.1, 97.2, etc. for the range of 97 to 103, 99.1, 99.2, etc. for the range of 99 to 101). Unless otherwise stated, the numerical quantities given herein are approximations, by which the term "about" may be inferred when not explicitly stated.

In this context, "pharmaceutical composition" refers to a liquid or powder formulation, which is in such form as to allow the biological activity of one or more active ingredients to be clearly effective, and which does not contain additional components that are significantly toxic to the individual to whom the composition is administered. Such compositions are sterile. "powder" refers to a lyophilized or freeze-dried or spray-dried pharmaceutical composition for parenteral use. Powders are typically reconstituted or dissolved in water. Lyophilization is a low temperature dehydration process that involves freezing the product, reducing the pressure, and subsequently removing the ice by sublimation. Lyophilization produces high quality products due to the low temperatures used in processing. For well developed lyophilized formulations, the shape and appearance of the product remains unchanged over time and the quality of the rehydrated product is excellent. Spray drying is another method of producing dry powders from liquids or slurries by rapid drying with hot gas and aims to achieve a constant particle size distribution.

As used herein, the terms "intravenous dose," "subcutaneous dose," and the like, refer to the temporal order of administration of an anti-IL-36R antibody, except for their ordinary meaning. Thus, an "intravenous dose" is the dose administered at the beginning of a treatment regimen (also referred to as the "baseline dose"); it may also be referred to as an "initial dose" or "induction dose". A "subcutaneous dose" is a dose administered after an intravenous dose, which may also be referred to as a "subsequent dose" or "maintenance dose". Both intravenous and subcutaneous doses may contain the same amount of anti-IL-36R antibody or antigen-binding fragment thereof, but may generally differ from each other in the amount of antibody administered or the frequency of administration. In one embodiment, the intravenous dose is equal to or greater than the subcutaneous dose. An "intravenous dose" interchangeably referred to as an "initial dose" or "induction dose" may be a single dose, or alternatively, a set of doses. Subcutaneous doses, which may also be referred to as "subsequent doses" or "maintenance doses," may be single doses for administration, or alternatively, a set of doses.

In certain embodiments, the amount of anti-IL-36R antibody contained in the induction/initial/intravenous and maintenance/subsequent/subcutaneous doses is different from each other during the course of treatment. In certain embodiments, the one or more initial/induction/intravenous doses each comprise a first amount of the antibody or antigen-binding fragment thereof, and the one or more maintenance/subsequent/subcutaneous doses each comprise a second amount of the antibody or antigen-binding fragment thereof. In some embodiments, the first amount of antibody or fragment thereof is 1.5×, 2×, 2.5×, 3×, 3.5×, 4×, or 5× of the second or subsequent amount of antibody or antigen binding fragment thereof. In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5 or more) initial doses are administered as a "loading dose" or "lead dose" at the beginning of a treatment regimen, followed by subsequent doses (e.g., a "maintenance dose") administered less frequently. In one embodiment, the intravenous dose, induction dose, or initial dose is about 210mg, 300mg, 350mg, 450mg, 600mg, 700mg, 750mg, 800mg, 850mg, or 900mg of the anti-IL-36R antibody. In one embodiment, the subcutaneous dose, maintenance dose, or subsequent dose is about 150, 225, or 300mg. In another embodiment, the subcutaneous dose or maintenance or subsequent dose is administered at least two weeks after the intravenous, induction or initial dose.

The terms "antibody", "anti-IL-36R antibody", "humanized anti-IL-36R epitope antibody" and "variant humanized anti-IL-36R epitope antibody" specifically encompass monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), antibodies with minor modifications (such as N and/or C-terminal truncations), and antibody fragments such as the variable domains and other portions of the antibodies that exhibit the desired biological activity (e.g., IL-36R binding).

The term "monoclonal antibody" (mAb) refers to an antibody that has a high degree of specificity for a single epitope. Thus, the modifier "monoclonal" indicates the antibody as being directed against the same epitope and is not to be construed as requiring production of the antibody by any particular method. It is understood that monoclonal antibodies can be made by any technique or method known in the art; including, for example, the hybridoma method (Kohler et al, 1975, nature 256:495), or recombinant DNA methods known in the art (see, e.g., U.S. Pat. No. 4,816,567), or methods for isolating a monoclonal recombinantly produced using phage antibody libraries using techniques described in Clackson et al, 1991,Nature 352:624-628 and Marks et al, 1991, J.mol. Biol. 222:581-597.

The term "monomer" refers to a homogeneous form of an antibody. For example, for a full length antibody, a monomer means a monomeric antibody having two identical heavy chains and two identical light chains.

Chimeric antibodies consist of heavy and light chain variable regions from antibodies of one species (e.g., non-human mammals such as mice) and heavy and light chain constant regions of antibodies of another species (e.g., human) and can be obtained as follows: a DNA sequence encoding the variable region of an antibody from a first species (e.g., mouse) is ligated to a DNA sequence encoding the constant region of an antibody from a second (e.g., human) species, and the host is transformed with an expression vector containing the ligated sequences to produce a chimeric antibody. Alternatively, a chimeric antibody may also be an antibody in which one or more regions or domains of the heavy and/or light chain are identical, homologous, or a variant thereof to a corresponding sequence in a monoclonal antibody from another immunoglobulin class or isotype or from a consensus or germline sequence. Chimeric antibodies may include fragments of such antibodies, provided that the antibody fragment exhibits the desired biological activity of its parent antibody, e.g., binds to the same epitope (see, e.g., U.S. Pat. No. 4,816,567; and Morrison et al, 1984,Proc.Natl.Acad.Sci.USA 81:6851-6855).

The term "intravenous infusion" refers to the introduction of a medicament into the vein of an animal or human patient over a period of time exceeding about 15 minutes, typically between about 30 to 90 minutes.

The term "intravenous bolus" (intravenous bolus/intravenosus push) "refers to administration of a drug into the vein of an animal or human such that the body receives the drug in about 15 minutes or less, typically 5 minutes or less.

The term "subcutaneous administration" refers to the introduction of an agent under the skin of an animal or human patient, preferably in a pouch between the skin and subcutaneous tissue, by relatively slow sustained delivery from a drug container. Pinching or pulling up the skin and away from the subcutaneous tissue may create a pouch.

As used herein, the terms "treatment" and "therapy" and similar terms are meant to include treatment of a disease or condition as well as prophylactic or inhibitory measures, such that any clinically desirable or beneficial effect is produced, including, but not limited to, alleviation or relief of one or more symptoms, regression, slowing or halting the progression of the disease or condition. Thus, for example, the term treatment includes administration of an agent prior to or after the onset of symptoms of a disease or disorder, thereby preventing or removing one or more signs of the disease or disorder. As another example, the term includes administration of an agent following a clinical manifestation of a disease to combat symptoms of the disease. Furthermore, where a clinical parameter affecting a disease or disorder, such as the extent of tissue damage or the amount or extent of metastasis, is administered, whether or not treatment results in an improvement in the disease, administration of the agent after onset and after clinical symptoms have developed includes "treatment" or "therapy" as used herein. In addition, as long as the composition of the invention alone or in combination with another therapeutic agent reduces or ameliorates at least one symptom of the disorder being treated compared to the symptoms in the absence of the use of the humanized anti-IL-36R antibody composition, the result should be considered an effective treatment of the underlying disorder, whether or not all symptoms of the disorder are reduced.

The term "prophylactically effective amount" is used to refer to an amount effective to achieve the desired prophylactic result at the dosages and for periods of time required. Typically, a prophylactic dose is used in an individual prior to the onset of an outbreak of GPP and/or prior to the onset of symptoms of GPP, e.g., to prevent or inhibit the occurrence of an acute outbreak. In an embodiment, the subcutaneous dose as contemplated herein is a prophylactic dose for use in patients with acute GPP following intravenous dose to prevent possible recurrence of GPP outbreaks in patients.

Antibodies II

The anti-IL 36R antibodies of the present invention are disclosed in U.S. patent No. 9,023,995 or WO2013/074569, the entire contents of each of which are incorporated herein by reference.

In one aspect, anti-IL-36R antibodies, particularly humanized anti-IL-36R antibodies, and compositions and articles of manufacture comprising one or more anti-IL-36R antibodies, particularly one or more humanized anti-IL-36R antibodies of the invention are described and disclosed herein. Binding agents comprising antigen binding fragments of anti-IL-36 antibodies (particularly humanized anti-IL-36R antibodies) are also described.

Mode of action

The anti-IL-36R antibodies of the invention are humanized antagonistic monoclonal IgG1 antibodies that block human IL36R signaling. The binding of the anti-IL-36R antibodies of the invention to IL36R is expected to prevent subsequent activation of IL36R via cognate ligands (IL 36 a, β and γ), and downstream activation of pro-inflammatory and pro-fibrotic pathways, with the aim of reducing epithelial/fibroblast/immune cell-mediated inflammation in Generalized Pustular Psoriasis (GPP) and interrupting inflammatory responses driving pathogenic cytokine production. As provided herein, the anti-IL-36R antibodies of the invention have been tested and demonstrated to be effective in treating patients with acute Generalized Pustular Psoriasis (GPP), a severe inflammatory skin disease driven by uncontrolled IL36 activity.

IL-36R is also known as IL-1RL2 and IL-1Rrp2. It has been reported that an agonistic IL-36 ligand (α, β or γ) initiates a signaling cascade by engaging the IL-36 receptor, which subsequently forms heterodimers with the IL-1 receptor accessory protein (IL-1 RAcP). IL-36 antagonist ligands (IL-36 RA/IL1F5, IL-38/ILF 10) inhibit the signaling cascade.

The variable regions and CDRs of representative antibodies of the invention are disclosed below:

anti-IL-36R mouse antibody sequences

The variable regions and CDRs of representative mouse lead antibodies (mouse lead) of the invention are shown below:

light chain variable region (VK) amino acid sequence

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Heavy chain variable region (VH) amino acid sequence

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Light chain CDR-1 (L-CDR 1) amino acid sequence

>33D10G1 L-CDR1

TASSSVSSSYLH(SEQ ID NO：21)

>172C8B12 L-CDR1

LASQTIGTWLA(SEQ ID NO：22)

>67E7E8 L-CDR1

LASQTIGTWLG(SEQ ID NO：23)

>78C8D1 L-CDR1

RSSQNIVHSNGNTYLQ(SEQ ID NO：24)

>81A1D1 L-CDR1

RASQDIYKYLN(SEQ ID NO：25)

>81B4E11 L-CDR1

TASSSVSSSYFH(SEQ ID NO：26)

>73C5C10 L-CDR1

KASQDVGTNVL(SEQ ID NO：27)

>73F6F8 L-CDR1

KASQDVGTNVL(SEQ ID NO：27)

>76E10E8 L-CDR1

KASQNVGRAVA(SEQ ID NO：28)

>89A12B8 L-CDR1

LASQTIGTWLG(SEQ ID NO：29)

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Light chain CDR-2 (L-CDR 2) amino acid sequence

>33D10B12 L-CDR2

STSNLAS(SEQ ID NO：30)

>172C8B12 L-CDR2

AATSLAD(SEQ ID NO：31)

>67E7E8 L-CDR2

RSTTLAD(SEQ ID NO：32)

>78C8D1 L-CDR2

KVSNRFS(SEQ ID NO：33)

>81A1D1 L-CDR2

YTSGLHS(SEQ ID NO：34)

>81B4E11 L-CDR2

RTSNLAS(SEQ ID NO：35)

>73C5C10 L-CDR2

SASYRHS(SEQ ID NO：36)

>73F6F8 L-CDR2

SASYRHS(SEQ ID NO：36)

>76E10E8 L-CDR2

SASNRYT(SEQ ID NO：37)

>89A12B8 L-CDR2

RATSLAD(SEQ ID NO：38)

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Light chain CDR-3 (L-CDR 3) amino acid sequence

>33D10B12 L-CDR3

HQHHRSPVT(SEQ ID NO：39)

>172C8B12 L-CDR3

QQVYTTPLT(SEQ ID NO：40)

>67E7E8 L-CDR3

QQLYSAPYT(SEQ ID NO：41)

>78C8D1 L-CDR3

FQGSHVPFT(SEQ ID NO：42)

>81A1D1 L-CDR3

QQDSKFPWT(SEQ ID NO：43)

>81B4E11 L-CDR3

HQFHRSPLT(SEQ ID NO：44)

>73C5C10 L-CDR3

QQYSRYPLT(SEQ ID NO：45)

>73F6F8 L-CDR3

QQYSRYPLT(SEQ ID NO：45)

>76E10E8 L-CDR3

QQYSSYPLT(SEQ ID NO：46)

>89A12B8 L-CDR3

QQLYSGPYT(SEQ ID NO：47)

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Heavy chain CDR-1 (H-CDR 1) amino acid sequence

>33D10B12 H-CDR1

GNTVTSYWMH(SEQ ID NO：48)

>172C8B12 H-CDR1

GYTFTDNYMN(SEQ ID NO：49)

>67E7E8 H-CDR1

GFNIKDDYIH(SEQ ID NO：50)

>78C8D1 H-CDR1

GFSLTKFGVH(SEQ ID NO：51)

>81A1D1 H-CDR1

GFSLSSYEIN(SEQ ID NO：52)

>81B4E11 H-CDR1

GYSFTSSWIH(SEQ ID NO：53)

>73C5C10 H-CDR1

GFSLTNYAVH(SEQ ID NO：54)

>73F6F8 H-CDR1

GFSLTNYAVH(SEQ ID NO：54)

>76E10E8 H-CDR1

GFSLTNYGVH(SEQ ID NO：55)

>89A12B8 H-CDR1

GFNIKDDYIH(SEQ ID NO：56)

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Heavy chain CDR-2 (H-CDR 2) amino acid sequence

>33D10B12 H-CDR2

EILPSTGRTNYNENFKG(SEQ ID NO：57)

>172C8B12 H-CDR2

RVNPSNGDTKYNQNFKG(SEQ ID NO：58)

>67E7E8 H-CDR2

RIDPANGNTKYAPKFQD(SEQ ID NO：59)

>78C8D1 H-CDR2

VIWAGGPTNYNSALMS(SEQ ID NO：60)

>81A1D1 H-CDR2

VIWTGITTNYNSALIS(SEQ ID NO：61)

>81B4E11 H-CDR2

EINPGNVRTNYNENF(SEQ ID NO：62)

>73C5C10 H-CDR2

VIWSDGSTDFNAPFKS(SEQ ID NO：63)

>73F6F8 H-CDR2

VIWSDGSTDYNAPFKS(SEQ ID NO：64)

>76E10E8 H-CDR2

VIWPVGSTNYNSALMS(SEQ ID NO：65)

>89A12B8 H-CDR2

RIDPANGNTKYDPRFQD(SEQ ID NO：66)

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Heavy chain CDR-3 (H-CDR 3) amino acid sequences

>33D10B12 H-CDR3

VYFGNPWFAY(SEQ ID NO：67)

>172C8B12 H-CDR3

TKNFYSSYSYDDAMDY(SEQ ID NO：68)

>67E7E8 H-CDR3

SFPNNYYSYDDAFAY(SEQ ID NO：69)

>78C8D1 H-CDR3

QIYYSTLVDY(SEQ ID NO：70)

>81A1D1 H-CDR3

GTGTGFYYAMDY(SEQ ID NO：71)

>81B4E11 H-CDR3

VFYGEPYFPY(SEQ ID NO：72)

>73C5C10 H-CDR3

KGGYSGSWFAY(SEQ ID NO：73)

>73F6F8 H-CDR3

KGGYSGSWFAY(SEQ ID NO：73)

>76E10E8 H-CDR3

MDWDDFFDY(SEQ ID NO：74)

>89A12B8 H-CDR3

SFPDNYYSYDDAFAY(SEQ ID NO：75)

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anti-IL-36R mouse CDR sequences

An overview of the CDR sequences of the lead mouse antibodies is shown below:

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anti-IL-36R humanizationAntibody sequences

Human framework sequences were selected for murine leader based on framework homology, CDR structure, conserved canonical residues, conserved interfacial stuffer residues, and other parameters to generate humanized variable regions (see example 5).

Representative humanized variable regions derived from antibodies 81B4 and 73C5 are shown below.

Light chain variable region (VK) amino acid sequence

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Heavy chain variable region (VH) amino acid sequence

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CDR sequences from the humanized variable regions of antibodies 81B4 and 73C5 shown above are depicted below.

L-CDR1 amino acid sequence

>81B4vK32_3 L-CDR1

TASSSVSSSYFH(SEQ ID NO：26)

>81B4vK32_105 L-CDR1

TASSSVSSSYFH(SEQ ID NO：26)

>81B4vK32_116 L-CDR1

TASSSVSSSYFH(SEQ ID NO：26)

>81B4vK32_127 L-CDR1

TASSSVSSSYFH(SEQ ID NO：26)

>81B4vK32_138 L-CDR1

TASSSVSSSYFH(SEQ ID NO：26)

>81B4vK32_140 L-CDR1

TASSSVSSSYFH(SEQ ID NO：26)

>81B4vK32_141 L-CDR1

TASSSVSSSYFH(SEQ ID NO：26)

>81B4vK32_147 L-CDR1

TASSSVSSSYFH(SEQ ID NO：26)

>73C5vK39_2 L-CDR1

KASQDVGTNVL(SEQ ID NO：27)

>73C5vK39_7 L-CDR1

KASQDVGTNVL(SEQ ID NO：27)

>73C5vK39_15 L-CDR1

KASQDVGTNVL(SEQ ID NO：27)

L-CDR2 amino acid sequence

>81B4vK32_3 L-CDR2(SEQ ID 102)

RTSTLAS

>81B4vK32_105 L-CDR2(SEQ ID 103)

RTSILAS

>81B4vK32_116 L-CDR2(SEQ ID 104)

RTSRLAS

>81B4vK32_127 L-CDR2(SEQ ID 104)

RTSRLAS

>81B4vK32_138 L-CDR2(SEQ ID 104)

RTSRLAS

>81B4vK32_140 L-CDR2(SEQ ID 105)

RTSQLAS

>81B4vK32_141 L-CDR2(SEQ ID 106)

RTSKLAS

>81B4vK32_147 L-CDR2(SEQ ID 140)

RTSHLAS

>73C5vK39_2 L-CDR2

SASYRHS(SEQ ID NO：36)

>73C5vK39_7 L-CDR2

SASYRHS(SEQ ID NO：36)

>73C5vK39_15 L-CDR2

SASYRHS(SEQ ID NO：36)

L-CDR3 amino acid sequence

>81B4vK32_3 L-CDR3

HQFHRSPLT(SEQ ID NO：44)

>81B4vK32_105 L-CDR3

HQFHRSPLT(SEQ ID NO：44)

>81B4vK32_116 L-CDR3

HQFHRSPLT(SEQ ID NO：44)

>81B4vK32_127 L-CDR3

HQFHRSPLT(SEQ ID NO：44)

>81B4vK32_138 L-CDR3

HQFHRSPLT(SEQ ID NO：44)

>81B4vK32_140 L-CDR3

HQFHRSPLT(SEQ ID NO：44)

>81B4vK32_141 L-CDR3

HQFHRSPLT(SEQ ID NO：44)

>81B4vK32_147 L-CDR3

HQFHRSPLT(SEQ ID NO：44)

>73C5vK39_2 L-CDR3

QQYSRYPLT(SEQ ID NO：45)

>73C5vK39_7 L-CDR3

QQYSRYPLT(SEQ ID NO：45)

>73C5vK39_15 L-CDR3

QQYSRYPLT(SEQ ID NO：45)

H-CDR1 amino acid sequence

>81B4vH33_49 H-CDR1

GYSFTSSWIH(SEQ ID NO：53)

>81B4vH33_85T H-CDR1

GYSFTSSWIH(SEQ ID NO：53)

>81B4vH33_90 H-CDR1

GYSFTSSWIH(SEQ ID NO：53)

>81B4vH33_93 H-CDR1

GYSFTSSWIH(SEQ ID NO：53)

>81B4vH50_22 H-CDR1

GYSFTSSWIH(SEQ ID NO：53)

>81B4vH50_30 H-CDR1

GYSFTSSWIH(SEQ ID NO：53)

>81B4vH51_13 H-CDR1

GYSFTSSWIH(SEQ ID NO：53)

>81B4vH51_15 H-CDR1

GYSFTSSWIH(SEQ ID NO：53)

>81B4vH52_83 H-CDR1

GYSFTSSWIH(SEQ ID NO：53)

>73C5vH46_4 H-CDR1

GFSLTDYAVH(SEQ ID NO：107)

>73C5vH46_19 H-CDR1

GFSLTDYAVH(SEQ ID NO：107)

>73C5vH46_40 H-CDR1

GFSLTDYAVH(SEQ ID NO：107)

>73C5vH47_65 H-CDR1

GFSLTDYAVH(SEQ ID NO：107)

>73C5vH47_77 H-CDR1

GFSLTDYAVH(SEQ ID NO：107)

>73C5vH58_91 H-CDR1

GFSLTDYAVH(SEQ ID NO：107)

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H-CDR2 amino acid sequence

>81B4vH33_49 H-CDR2

EINPGNVRTNYNENF(SEQ ID NO：62)

>81B4vH33_85T H-CDR2

EINPGNVRTNYNENF(SEQ ID NO：62)

>81B4vH33_90 H-CDR2

EINPGNVRTNYNENF(SEQ ID NO：62)

>81B4vH33_93 H-CDR2

EINPGNVRTNYNENF(SEQ ID NO：62)

>81B4vH50_22 H-CDR2

EILPGVVRTNYNENF(SEQ ID NO：108)

>81B4vH50_30 H-CDR2

EINPGAVRTNYNENF(SEQ ID NO：109)

>81B4vH51_13 H-CDR2

EINPGLVRTNYNENF(SEQ ID NO：110)

>81B4vH51_15 H-CDR2

EINPGAVRTNYNENF(SEQ ID NO：109)

>81B4vH52_83 H-CDR2

EINPGSVRTNYNENF(SEQ ID NO：111)

>73C5vH46_4 H-CDR2

VIWSDGSTDYNAPFKS(SEQ ID NO：64)

>73C5vH46_19 H-CDR2

VIWSDGSTDYNAPFKS(SEQ ID NO：64)

>73C5vH46_40 H-CDR2

VIWSDGSTDYNAPFKS(SEQ ID NO：64)

>73C5vH47_65 H-CDR2

VIWSDGSTDYNAPFKS(SEQ ID NO：64)

>73C5vH47_77 H-CDR2

VIWSDGSTDFNAPFKS(SEQ ID NO：63)

>73C5vH58_91 H-CDR2

VIWSDGSTDYNAPFKS(SEQ ID NO：64)

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H-CDR3 amino acid sequence

>81B4vH33_49 H-CDR3

VFYGEPYFPY(SEQ ID NO：72)

>81B4vH33_85T H-CDR3

VFYGEPYFPY(SEQ ID NO：72)

>81B4vH33_90 H-CDR3

VFYGEPYFPY(SEQ ID NO：72)

>81B4vH33_93 H-CDR3

VFYGEPYFPY(SEQ ID NO：72)

>81B4vH50_22 H-CDR3

VFYGEPYFPY(SEQ ID NO：72)

>81B4vH50_30 H-CDR3

VFYGEPYFPY(SEQ ID NO：72)

>81B4vH51_13 H-CDR3

VFYGEPYFPY(SEQ ID NO：72)

>81B4vH51_15 H-CDR3

VFYGEPYFPY(SEQ ID NO：72)

>81B4vH52_83 H-CDR3

VFYGEPYFPY(SEQ ID NO：72)

>73C5vH46_4 H-CDR3

KGGYSGSWFAY(SEQ ID NO：73)

>73C5vH46_19 H-CDR3

KGGYSGSWFAY(SEQ ID NO：73)

>73C5vH46_40 H-CDR3

KGGYSGSWFAY(SEQ ID NO：73)

>73C5vH47_65 H-CDR3

KGGYSGSWFAY(SEQ ID NO：73)

>73C5vH47_77 H-CDR3

KGGYSGSWFAY(SEQ ID NO：73)

>73C5vH58_91 H-CDR3

KGGYSGSWFAY(SEQ ID NO：73)

In one aspect, the variable region of the invention is linked to a constant region. For example, the variable regions of the invention are linked to constant regions as shown below to form the heavy or light chain of an antibody.

Representative light chain and heavy chain sequences of the invention are shown below (humanized variable regions derived from antibodies 81B4 and 73C5 are linked to constant regions).

Light chain amino acid sequence

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Heavy chain amino acid sequence

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The CDRs listed above are defined using the Chothia numbering system (Al-Lazikani et Al (1997) JMB 273, 927-948).

In one aspect, an antibody of the invention comprises 3 light chain CDRs and 3 heavy chain CDRs, e.g., as set forth above.

In one aspect, the antibodies of the invention comprise light and heavy chain variable regions as set forth above. In one aspect, the light chain variable region of the invention is fused to a light chain constant region (e.g., a kappa or lambda constant region). In one aspect, the heavy chain variable region of the invention is fused to a heavy chain constant region (e.g., igA, igD, igE, igG or IgM, particularly IgG1, igG2, igG3 or IgG 4).

The invention provides an anti-IL-36R antibody comprising: a light chain comprising the amino acid sequence SEQ ID NO. 115; and a heavy chain comprising the amino acid sequence SEQ ID NO. 125 (antibody B1).

The invention provides an anti-IL-36R antibody comprising: a light chain comprising the amino acid sequence SEQ ID NO. 115; and a heavy chain comprising the amino acid sequence SEQ ID NO. 126 (antibody B2).

The invention provides an anti-IL-36R antibody comprising: a light chain comprising the amino acid sequence SEQ ID NO. 115; and a heavy chain comprising the amino acid sequence SEQ ID NO:127 (antibody B3).

The invention provides an anti-IL-36R antibody comprising: a light chain comprising the amino acid sequence SEQ ID NO. 118; and a heavy chain comprising the amino acid sequence SEQ ID NO. 125 (antibody B4).

The invention provides an anti-IL-36R antibody comprising: a light chain comprising the amino acid sequence SEQ ID NO. 118; and a heavy chain comprising the amino acid sequence SEQ ID NO. 126 (antibody B5).

The invention provides an anti-IL-36R antibody comprising: a light chain comprising the amino acid sequence SEQ ID NO. 118; and a heavy chain comprising the amino acid sequence SEQ ID NO:127 antibody B6).

The invention provides an anti-IL-36R antibody comprising: a light chain comprising the amino acid sequence SEQ ID NO. 123; and a heavy chain comprising the amino acid sequence SEQ ID NO. 138 (antibody C3).

The invention provides an anti-IL-36R antibody comprising: a light chain comprising the amino acid sequence SEQ ID NO. 123; and a heavy chain comprising the amino acid sequence SEQ ID NO 139 (antibody C2).

The invention provides an anti-IL-36R antibody comprising: a light chain comprising the amino acid sequence SEQ ID NO. 124; and a heavy chain comprising the amino acid sequence SEQ ID NO. 138 (antibody C1)

Representative antibodies of the invention are shown below.

Table B

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Table C

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In some aspects, the humanized antibody exhibits blocking activity, whereby it reduces binding of an IL-36 ligand to an IL-36 receptor by at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. The ability of an antibody to block the binding of an IL-36 ligand to an IL-36 receptor can be measured using competitive binding assays known in the art. Alternatively, the blocking activity of an antibody can be measured by assessing the biological effects of IL-36 (such as IL-8, IL-6, and GM-CSF production) to determine whether IL-36 receptor-mediated signaling is inhibited.

In another aspect, the invention provides a humanized anti-IL-36R antibody with advantageous physiological properties. In one aspect, the humanized anti-IL-36R antibodies of the invention are present in the buffer in at least 90% monomeric form, or in at least 92% monomeric form, or in at least 95% monomeric form. In another aspect, the humanized anti-IL-36R antibodies of the invention remain in buffer for at least 90% of the monomeric form, or at least 92% of the monomeric form, or at least 95% of the monomeric form, for one or four months.

In one aspect, the humanized antibody of the invention is antibody B1, antibody B2, antibody B3, antibody B4, antibody B5, antibody B6, antibody C1, antibody C2 or antibody C3. Thus, in one embodiment, the humanized antibody of the invention comprises light chain sequence SEQ ID NO:115 and heavy chain sequence SEQ ID NO:125 (antibody B1). In another embodiment, the humanized antibody of the invention comprises light chain sequence SEQ ID NO. 115 and heavy chain sequence SEQ ID NO. 126 (antibody B2). In another embodiment, the humanized antibody of the invention comprises light chain sequence SEQ ID NO:115 and heavy chain sequence SEQ ID NO:127 (antibody B3). In another embodiment, the humanized antibody of the invention comprises light chain sequence SEQ ID NO:118 and heavy chain sequence SEQ ID NO:125 (antibody B4). In another embodiment, the humanized antibody of the invention comprises light chain sequence SEQ ID NO:118 and heavy chain sequence SEQ ID NO:126 (antibody B5). In another embodiment, the humanized antibody of the invention comprises light chain sequence SEQ ID NO:118 and heavy chain sequence SEQ ID NO:127 (antibody B6). In another embodiment, the humanized antibody of the invention comprises light chain sequence SEQ ID NO. 124 and heavy chain sequence SEQ ID NO. 138 (antibody C1). In another embodiment, the humanized antibody of the invention comprises light chain sequence SEQ ID NO. 123 and heavy chain sequence SEQ ID NO. 139 (antibody C2). In another embodiment, the humanized antibody of the invention comprises light chain sequence SEQ ID NO. 123 and heavy chain sequence SEQ ID NO. 138 (antibody C3).

In another embodiment, the humanized antibody of the invention consists of: light chain sequence SEQ ID NO. 115 and heavy chain sequence SEQ ID NO. 125 (antibody B1). In another embodiment, the humanized antibody of the invention consists of: light chain sequence SEQ ID NO. 115 and heavy chain sequence SEQ ID NO. 126 (antibody B2). In another embodiment, the humanized antibody of the invention consists of: light chain sequence SEQ ID NO. 115 and heavy chain sequence SEQ ID NO. 127 (antibody B3). In another embodiment, the humanized antibody of the invention consists of: light chain sequence SEQ ID NO. 118 and heavy chain sequence SEQ ID NO. 125 (antibody B4). In another embodiment, the humanized antibody of the invention consists of: light chain sequence SEQ ID NO. 118 and heavy chain sequence SEQ ID NO. 126 (antibody B5). In another embodiment, the humanized antibody of the invention consists of: light chain sequence SEQ ID NO. 118 and heavy chain sequence SEQ ID NO. 127 (antibody B6). In another embodiment, the humanized antibody of the invention consists of: light chain sequence SEQ ID NO. 124 and heavy chain sequence SEQ ID NO. 138 (antibody C1). In another embodiment, the humanized antibody of the invention consists of: light chain sequence SEQ ID NO. 123 and heavy chain sequence SEQ ID NO. 139 (antibody C2). In another embodiment, the humanized antibody of the invention consists of: light chain sequence SEQ ID NO. 123 and heavy chain sequence SEQ ID NO. 138 (antibody C3).

In some embodiments, humanized anti-IL-36R antibodies, including antigen-binding fragments thereof, such as heavy and light chain variable regions, comprise amino acid sequences derived from residues of antibody B1, antibody B2, antibody B3, antibody B4, antibody B5, antibody B6, antibody C1, antibody C2, or antibody C3.

In another embodiment, the invention provides an anti-IL-36R antibody or antigen binding fragment thereof that competitively binds to human anti-IL-36R with an antibody of the invention, e.g., antibody B1, antibody B2, antibody B3, antibody B4, antibody B5, antibody B6, antibody C1, antibody C2, or antibody C3 described herein. The ability of an antibody or antigen binding fragment to competitively bind to IL-36R can be measured using competitive binding assays known in the art.

The humanized anti-IL-36R antibody optionally comprises specific amino acid substitutions in a consensus or germline framework region. Specific substitutions of amino acid residues at these framework positions may improve various aspects of antibody performance, including binding affinity and/or stability, relative to performance exhibited in humanized antibodies formed by "direct exchange" of CDRs or HVLs into human germline framework regions.

In some embodiments, the invention describes other monoclonal antibodies whose light chain variable region has the amino acid sequence set forth in any one of SEQ ID NOs 1 to 10. In some embodiments, the invention describes other monoclonal antibodies whose heavy chain variable region has the amino acid sequence set forth in any one of SEQ ID NOs 11 to 20. Placing such CDRs in FR of human consensus heavy and light chain variable domains will yield useful humanized antibodies of the invention.

Specifically, the invention provides monoclonal antibodies having a combination of light chain variable regions and heavy chain variable regions of SEQ ID NOS 1/11, 2/12, 3/13, 4/14, 5/15, 6/16, 7/17, 8/18, 9/19, 10/20. Such variable regions may be combined with human constant regions.

In some embodiments, the invention describes other humanized antibodies whose light chain variable region sequences have the amino acid sequences set forth in any one of SEQ ID NOs 76 to 86. In some embodiments, the present invention describes other humanized antibodies whose heavy chain variable region sequence has the amino acid sequence set forth in any one of SEQ ID NOs 87 to 101. In particular, the invention provides monoclonal antibodies having a combination of light chain variable regions and heavy chain variable regions of SEQ ID NOS 77/89, 80/88, 80/89, 77/87, 77/88, 80/87, 86/100, 85/101, 85/100. Such variable regions may be combined with human constant regions.

In another embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising: a humanized light chain variable domain comprising the CDR of SEQ ID No. 77 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain light chain amino acid sequence of SEQ ID No. 77; and a humanized heavy chain variable domain comprising the CDRs of SEQ ID NO. 89 and a framework region having an amino acid sequence at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain heavy chain amino acid sequence of SEQ ID NO. 89. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In another embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising: a humanized light chain variable domain comprising the CDRs of SEQ ID No. 80 and a framework region having an amino acid sequence at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain light chain amino acid sequence of SEQ ID No. 80; and a humanized heavy chain variable domain comprising the CDR of SEQ ID NO. 88 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain heavy chain amino acid sequence of SEQ ID NO. 88. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In another embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising: a humanized light chain variable domain comprising the CDRs of SEQ ID No. 80 and a framework region having an amino acid sequence at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain light chain amino acid sequence of SEQ ID No. 80; and a humanized heavy chain variable domain comprising the CDRs of SEQ ID NO. 89 and a framework region having an amino acid sequence at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain heavy chain amino acid sequence of SEQ ID NO. 89. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In another embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising: a humanized light chain variable domain comprising the CDR of SEQ ID No. 77 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain light chain amino acid sequence of SEQ ID No. 77; and a humanized heavy chain variable domain comprising the CDR of SEQ ID NO. 87 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain heavy chain amino acid sequence of SEQ ID NO. 87. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In another embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising: a humanized light chain variable domain comprising the CDR of SEQ ID No. 77 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain light chain amino acid sequence of SEQ ID No. 77; and a humanized heavy chain variable domain comprising the CDR of SEQ ID NO. 88 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain heavy chain amino acid sequence of SEQ ID NO. 88. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In another embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising: a humanized light chain variable domain comprising the CDRs of SEQ ID No. 80 and a framework region having an amino acid sequence at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain light chain amino acid sequence of SEQ ID No. 80; and a humanized heavy chain variable domain comprising the CDR of SEQ ID NO. 87 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain heavy chain amino acid sequence of SEQ ID NO. 87. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In another embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising: a humanized light chain variable domain comprising the CDR of SEQ ID No. 86 and a framework region having an amino acid sequence that is at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain light chain amino acid sequence of SEQ ID No. 86; and a humanized heavy chain variable domain comprising the CDRs of SEQ ID NO. 100 and a framework region having an amino acid sequence at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain heavy chain amino acid sequence of SEQ ID NO. 100. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In another embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising: a humanized light chain variable domain comprising the CDRs of SEQ ID No. 85 and a framework region having an amino acid sequence at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain light chain amino acid sequence of SEQ ID No. 85; and a humanized heavy chain variable domain comprising the CDRs of SEQ ID NO. 101 and a framework region having an amino acid sequence at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain heavy chain amino acid sequence of SEQ ID NO. 101. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In another embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising: a humanized light chain variable domain comprising the CDRs of SEQ ID No. 85 and a framework region having an amino acid sequence at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain light chain amino acid sequence of SEQ ID No. 85; and a humanized heavy chain variable domain comprising the CDRs of SEQ ID NO. 100 and a framework region having an amino acid sequence at least 90% identical, at least 93% identical or at least 95% identical to the amino acid sequence of the framework region of the variable domain heavy chain amino acid sequence of SEQ ID NO. 100. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In some specific embodiments, the humanized anti-IL-36R antibodies disclosed herein comprise at least one heavy or light chain variable domain comprising CDRs or HVL of a murine monoclonal antibody or humanized antibody as disclosed herein and FR of human germline heavy and light chain variable domains.

In another aspect, the invention provides an anti-IL-36R antibody or antigen-binding fragment thereof comprising: a light chain CDR1 (L-CDR 1) sequence of any one of SEQ ID NO's 21 to 29; a light chain CDR2 (L-CDR 2) sequence of any one of SEQ ID NO's 30 to 38; a light chain CDR3 (L-CDR 3) sequence of any one of SEQ ID NOs 39 to 47; a heavy chain CDR1 (H-CDR 1) sequence of any one of SEQ ID NOs 48 to 56; a heavy chain CDR2 (H-CDR 2) sequence of any one of SEQ ID NOs 57 to 66; and the heavy chain CDR3 (H-CDR 3) sequence of any one of SEQ ID NOS 67 to 75. In one aspect, an anti-IL-36R antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising an L-CDR1 listed above, an L-CDR2 listed above, and an L-CDR3 listed above; and a heavy chain variable region comprising an H-CDR1 as set forth above, an H-CDR2 as set forth above, and an H-CDR3 as set forth above.

In another aspect, the invention provides an anti-IL-36R antibody or antigen-binding fragment thereof comprising:

a) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO's 21, 30, 39, 48, 57 and 67, respectively; or (b)

b) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO's 22, 31, 40, 49, 58 and 68, respectively; or (b)

c) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO's 23, 32, 41, 50, 59 and 69, respectively; or (b)

d) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO's 24, 33, 42, 51, 60 and 70, respectively; or (b)

e) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO's 25, 34, 43, 52, 61 and 71, respectively; or (b)

f) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO's 26, 35, 44, 53, 62 and 72, respectively; or (b)

g) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO's 27, 36, 45, 54, 63 and 73, respectively; or (b)

h) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO's 27, 36, 45, 54, 64 and 74, respectively; or (b)

i) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO's 27, 36, 45, 54, 64 and 73, respectively; or (b)

j) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO 28, 37, 46, 55, 65 and 74, respectively; or (b)

k) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO's 29, 38, 47, 56, 66 and 75, respectively.

a) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO's 26, 103, 44, 53, 62 and 72, respectively; or (b)

b) The L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO's 26, 104, 44, 53, 62 and 72, respectively; or (b)

c) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO's 27, 36, 45, 107, 63 and 73, respectively; or (b)

d) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequences of SEQ ID NO 27, 36, 45, 107, 64 or 73, respectively.

In one aspect, an anti-IL-36R antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising the combination of L-CDR1, L-CDR2, and L-CDR3 listed above; and a heavy chain variable region comprising the H-CDR1, H-CDR2 and H-CDR3 combinations listed above.

In particular embodiments, chimeric antibodies having CDR regions exchanged between these exemplary immunoglobulins (i.e., e.g., exchanging one or both CDRs of one of the mouse antibodies or a humanized antibody derived therefrom with similar CDRs from another mouse antibody or a humanized antibody derived therefrom) are expected to produce useful antibodies.

In certain embodiments, the humanized anti-IL-36R antibody is an antibody fragment. Various antibody fragments have been generally discussed above and there are techniques that have been developed for producing antibody fragments. Fragments may be derived via proteolytic digestion of the intact antibody (see, e.g., morimoto et al, 1992,Journal of Biochemical and Biophysical Methods 24:107-117; and Brennan et al, 1985,Science 229:81). Alternatively, the fragment may be produced directly in the recombinant host cell. For example, fab '-SH fragments can be recovered directly from E.coli (E.coli) and chemically coupled to form F (ab') 2 fragments (see, e.g., carter et al, 1992, bio/Technology 10:163-167). By another approach, F (ab') 2 fragments can be isolated directly from recombinant host cell cultures. Other techniques for generating antibody fragments will be apparent to those skilled in the art. Accordingly, in one aspect, the present invention provides an antibody fragment comprising a CDR as described herein, in particular an antibody fragment of one of the combinations of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 as described herein. In another aspect, the invention provides an antibody fragment comprising a variable region described herein, e.g., an antibody fragment of one of the combinations of light chain variable regions and heavy chain variable regions described herein.

Certain embodiments include a F (ab') 2 fragment of a humanized anti-IL-36R antibody comprising the light chain sequence of any one of SEQ ID NOS: 115 or 118 in combination with the heavy chain sequence of SEQ ID NOS: 125, 126 or 127. Such embodiments may include intact antibodies comprising such F (ab') 2.

Certain embodiments include F (ab') 2 fragments of humanized anti-IL-36R antibodies comprising the light chain sequence of either of SEQ ID NOS: 123 or 124 in combination with the heavy chain sequence of SEQ ID NOS: 138 or 139. Such embodiments may include intact antibodies comprising such F (ab') 2.

In some embodiments, the antibody or antibody fragment comprises a constant region that mediates effector function. The constant region may provide antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and/or complement-dependent cytotoxicity (CDC) response against a target cell expressing anti-IL-36R. The effector domain may be, for example, the Fc region of an Ig molecule.

The effector domains of the antibodies may be from any suitable vertebrate species and isotype. Isoforms from different animal species differ in their ability to mediate effector functions. For example, the ability of human immunoglobulins to mediate CDC and ADCC/ADCP is generally ordered by IgM≡IgG1≡IgG3> IgG2> IgG4 and IgG1≡IgG3> IgG2/IgM/IgG4, respectively. Murine immunoglobulins typically mediate CDC and ADCC/ADCP in the murine IgM.apprxeq.IgG 3> > IgG2b > IgG2a > > IgG1 and IgG2b > IgG2a > IgG1> > IgG3 sequences, respectively. In another example, murine IgG2a mediates ADCC, while murine IgG2a and IgM mediate CDC.

III pharmaceutical dosage and administration

The anti-IL-36R antibodies of the invention are typically administered to a patient in the form of a pharmaceutical composition in which the antagonist is admixed with a pharmaceutically acceptable carrier or excipient, see, e.g., remington's Pharmaceutical Sciences and US Pharmacopeia: national Formulary, mack Publishing company, easton, pa. (1984). The pharmaceutical compositions may be formulated in any manner suitable for the intended route of administration. Examples of pharmaceutical formulations include lyophilized powders, slurries, aqueous solutions, suspensions and sustained release formulations (see, e.g., hardman et al (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, mcGraw-Hill, new York, N.Y., gennaro (2000) Remington: the Science and Practice of Pharmacy, lippincott, williams and Wilkins, new York, N.Y., avis et al (eds.) (1993) Pharmaceutical Dosage Forms: parenteral Medications, marcel Dekker, NY, lieberman et al (ex.) (1990) Pharmaceutical Dosage Forms: tablets, marcel Dekker, NY, lieberman et al (ex.) (1990) Pharmaceutical Dosage Forms: disperSystems, marcel Dekker, NY, weiner and Kotkoskie (2000) Excipient Toxicity and Safety, marcel Dekker, new York, N.Y.). Suitable routes of administration include intravenous injection (including intra-arterial injection) and subcutaneous injection.

Representative examples of dosages and dosing regimens according to the present invention are disclosed in table a. Although doses of 900mg and 750mg have been exemplified, similar dosing regimens apply equally to doses of 210mg, 300mg, 350mg, 450mg, 600mg, 700mg and 800mg.

Table a: dosage and dosing regimen

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In one embodiment, 1, 2, or 3 or more intravenous doses are administered to a patient in the dosing regimen set forth in table a, wherein a first subcutaneous dose is administered 2 to 8 weeks, 4 to 6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks, 12 weeks, 16 weeks, 20 weeks after the last intravenous dose, and a subsequent subcutaneous dose is administered at 2, 4, 6, 8, 10, or 12 week intervals after the first subcutaneous dose.

In one aspect, the invention relates to the treatment of GPP in a patient by administering to the patient two 900mg intravenous (i.v.) doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

In one aspect, the invention relates to a method of reducing or alleviating the signs and symptoms of an acute phase disorder of GPP in a patient, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

In one embodiment involving any of the above aspects or embodiments, two dose administrations achieve one or more of the following results:

In an embodiment directed to any one of the above aspects or embodiments, the mammal or patient is evaluated for improvement in clinical remission as defined by: (a) Global evaluation of impetigo general (GPPGA) score of 0 or 1 at week 1; (b) Week 1 GPPGA pustule score of 0, indicating no visible pustules; (c) Psoriasis Area and Severity Index (GPPASI) 75 for week 4 generalized pustular psoriasis; (d) Change in pain Visual Analog Scale (VAS) score from baseline at week 4; (e) Change in psoriasis condition scale (PSS) score from baseline at week 4; (f) Changes in chronic pain therapy functional assessment (facility) fatigue score from baseline at week 4; (g) week 4 GPPGA 0 or 1; (h) Week 4 GPPGA pustule score of 0, indicating no visible pustules; (i) week 1 and week 4 GPPASI 50; or (j) change in GPPASI pustule, erythema or desquamation severity score at week 1 and week 4 from baseline. In a related embodiment, for any of the listed endpoints, the proportion of patients who responded to administration is statistically significantly higher compared to patients taking placebo.

Pharmaceutical composition and administration thereof

The antibodies of the invention may be administered alone or in combination with other agents. Examples of antibodies for use in such pharmaceutical compositions are those comprising: an antibody or antibody fragment having the amino acid sequence of the light chain variable region of any one of SEQ ID NOs 1 to 10. Examples of antibodies for use in such pharmaceutical compositions are also those comprising: a humanized antibody or antibody fragment having the heavy chain variable region amino acid sequence of any one of SEQ ID NOs 11 to 20.

Other examples of antibodies for use in such pharmaceutical compositions are also those comprising: a humanized antibody or antibody fragment having the amino acid sequence of the light chain variable region of any one of SEQ ID NOs 76-86. Preferred antibodies for use in such pharmaceutical compositions are also those comprising: a humanized antibody or antibody fragment having the heavy chain variable region amino acid sequence of any one of SEQ ID NOs 87 to 101.

Other examples of antibodies for use in such pharmaceutical compositions are also those comprising: humanized antibodies or antibody fragments having the light chain variable region and heavy chain variable region of any one of SEQ ID NOS: 77 and 89, SEQ ID NOS: 80 and 88, SEQ ID NOS: 80 and 89, SEQ ID NOS: 77 and 87, SEQ ID NOS: 77 and 88, SEQ ID NOS: 80 and 87, SEQ ID NOS: 86 and 100, SEQ ID NOS: 85 and 101 or SEQ ID NOS: 85 and 10.

Other examples of antibodies for use in such pharmaceutical compositions are also those comprising: a humanized antibody having the light chain region amino acid sequence of any one of SEQ ID NOs 115, 118, 123 or 124. Preferred antibodies for use in such pharmaceutical compositions are also those comprising: a humanized antibody having the heavy chain variable region amino acid sequence of any one of SEQ ID NOs 125, 126, 127, 138 or 139.

Other examples of antibodies for use in such pharmaceutical compositions are also those comprising: antibody B1, antibody B2, antibody B3, antibody B4, antibody B5, antibody B6, antibody C1, antibody C2 or antibody C3.

Various delivery systems are known and may be used to administer the IL-36R binding agent. Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The IL-36R binding agent may be administered, for example, by infusion, bolus injection, or injection, and may be administered with other bioactive agents, such as chemotherapeutic agents. Can be administered systemically or locally. In a preferred embodiment, administration is by subcutaneous injection. Formulations for such injections may be prepared, for example, as prefilled syringes, which may be administered once every other week.

In one aspect, the invention provides an article of manufacture comprising a subcutaneous administration device that delivers a fixed dose of an antibody of the invention to a patient. In some embodiments, the subcutaneous administration device is pre-formedFill syringe, auto-injector, or high volume infusion device. For example, myDose from Roche ^TM The product (single use infusion device enabling subcutaneous administration of large amounts of liquid drug) may be used as an administration device. Many reusable pen and auto-injector delivery devices are applicable for subcutaneous delivery of the pharmaceutical compositions of the present invention. Examples include, but are not limited to, AUTOPEN, to name a few ^TM (Owen Mumford Co., woodstock, UK), DISETRONIC ^TM Pen (Disetronic Medical Systems, bergdorf, switzerland), HUMALOG MIX 75/25 ^TM Pen, HUMALOG ^TM Pen, HUMALIN 70/30 ^TM Pen (Eli Lilly Co., indianapolis, ind.), NOVOPEN ^TM I. II and III (Novo Nordisk, copenhagen, denmark), NOVOPEN JUNIOR ^TM (Novo Nordisk,Copenhagen,Denmark)，BD ^TM Pen (Becton Dickinson, franklin Lakes, N.J.), OPTIPEN ^TM ，OPTIPEN PRO ^TM ，OPTIPEN STARLET ^TM OPTICLIK ^TM (Sanofi-Aventis, frankfurt, germany). Examples of disposable pen delivery devices that may be used to subcutaneously deliver the pharmaceutical compositions of the present invention include, but are not limited to, SOLOSTAR ^TM Pen (Sanofi-Aventis), FLEXPEN ^TM (Novo Nordisk) KWIKPEN ^TM (Eli Lilly), SURECICKTM autoinjector (Amgen, thonsand Oaks, calif.), PENLETTM (Haselmeier, stuttgart, germany), EPIPEN (Dey, L.P.), and HUMIRATM pen (Abbott Labs, abbott Park, ill.), YSOMATE ^TM 、YPSOMATE 2.25 ^TM 、VAIROJECT ^TM (Ypsimed AG, burgdorf, switzerland). Additional information relating to exemplary delivery devices that may be used with the antibodies of the invention may be found, for example, in CH705992A2, WO2009/040602, WO2016/169748, WO 2016/179713.

In particular embodiments, the IL-36R binding agent composition is administered by injection, by catheter, by suppository, or by implant that is a porous, non-porous, or gelatinous material, including membranes, such as silicone rubber membranes, or fibers. Typically, when the composition is administered, materials are used that are not absorbed by the anti-IL-36R antibody or agent.

In other embodiments, the anti-IL-36R antibody or agent is delivered in a controlled release system. In one embodiment, a pump may be used (see, e.g., langer,1990,Science 249:1527-1533;Sefton,1989,CRC Crit.Ref.Biomed.Eng.14:201;Buchwald et al, 1980,Surgery 88:507;Saudek et al, 1989, N.Engl. J. Med. 321:574). In another embodiment, a polymeric material may be used. (see, e.g., medical Applications of Controlled Release (Langer and Wise, CRC Press, boca Raton, fla., 1974), controlled Drug Bioavailability, drug Product Design and Performance (Smolen and Ball, wiley, new York, 1984), ranger and Peppas,1983, macromol. Sci. Rev. Macromol. Chem.23:61. See also Levy et al, 1985,Science 228:190;During et al, 1989, ann. Neurol.25:351; howard et al, 1989, J. Neurosurg. 71:105.) other controlled release systems are discussed, e.g., in Langer, supra.

The IL-36R binding agent (e.g., anti-IL-36R antibody) may be administered in the form of a pharmaceutical composition comprising a therapeutically effective amount of the binding agent and one or more pharmaceutically compatible ingredients.

In one embodiment, the anti-IL-36R antibody or antigen-binding fragment thereof (disclosed herein) is present in a pharmaceutical formulation (as described in co-pending PCT application No. 20200185479, published at 9/17 of 2020, the entire contents of which are incorporated herein by reference in their entirety) that is suitable for administration to a mammal or patient according to any of the aspects described herein. For convenience, various examples of this embodiment are described as numbered items (1, 2, 3, etc.) as follows. These items are provided as examples and do not limit the techniques of the present disclosure. It should be noted that any of the subsidiary items may be combined in any combination and placed in the respective independent item (e.g., item 1). Other items may be presented in a similar manner.

1. A method of treating an outbreak of Generalized Pustular Psoriasis (GPP) in a patient, the method comprising administering to the patient two 900mg intravenous (i.v.) doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

2. A method of treating GPP in a patient by administering a single 900mg intravenous dose of an anti-IL-36R antibody to the patient, if symptoms of GPP persist one week after the initial dose, then administering an additional 900mg intravenous dose of the anti-IL-36R antibody.

3. A method of treating GPP in a patient, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

4. A method of reducing or alleviating signs and symptoms of an acute phase disorder of GPP in a patient, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

5. A method of reducing the severity and duration of a GPP symptom, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

6. A method of treating a skin disorder associated with GPP, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

7. A method of preventing recurrence of a GPP outbreak in a patient, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

8. A method of reducing pain by at least 10% in a patient having GPP, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

9. A method of improving the quality of life of a patient suffering from moderate to severe GPP symptoms by at least 10%, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

10. The method of any one of the preceding claims, wherein the patient's GPP physician overall evaluation (GPPGA) total score is ≡2.

11. The method of any one of the preceding claims, wherein the patient's GPP physician overall assessment (GPPGA) total score ∈2 and GPPGA pustule score ∈2.

12. The method of any one of the preceding claims, wherein the patient's GPP physician overall evaluation (GPPGA) total score ∈2 and GPPGA pustule score ∈2 prior to administration of the first intravenous dose.

13. The method of any one of the preceding claims, wherein after administration of the first intravenous dose, the patient's GPP physician overall evaluation (GPPGA) total score ∈2 and GPPGA pustule score ∈2.

14. The method of any one of the preceding claims, wherein the patient's GPP physician overall evaluation (GPPGA) total score ∈2 and GPPGA pustule score ∈2, before and after administration of the first intravenous dose.

15. The method of any one of the preceding claims, wherein the second dose is administered 1 week but less than 2 weeks after the first dose.

16. A method of treating a GPP patient having a GPPGA pustule score of ∈2, the method comprising the steps of: (a) Administering to the patient a first 900mg intravenous (i.v.) dose of an anti-IL-36R antibody; (b) The GPPGA pustule score for the patient is assessed, and if the GPPGA pustule score for the patient ∈2 persists after 1 week after the first dose, a second 900mg (i.v.) dose of pessary Li Shan antibody is administered to the patient less than 2 weeks after the first dose.

17. A method of treating a GPP patient having a general rating of GPPGA equal to or greater than 2 for a global assessment by a GPP physician, the method comprising the steps of: (a) Administering to the patient a first 900mg intravenous (i.v.) dose of an anti-IL-36R antibody; (b) The patient's total GPPGA score is assessed, and if the patient's total GPPGA score of ∈2 persists after 1 week after the first dose, a second 900mg (i.v.) dose of pessary Li Shan antibody is administered to the patient less than 2 weeks after the first dose.

18. A method of treating a GPP patient having a general GPPGA score of > 2 and a GPPGA pustule score of > 2 by general GPP physician assessment (GPPGA), the method comprising the steps of: (a) Administering to the patient a first 900mg intravenous (i.v.) dose of an anti-IL-36R antibody; (b) The patient's GPPGA score is assessed, and if the patient's GPPGA total score ∈2 and the GPPGA pustular score ∈2 persists after 1 week after the first dose, a second 900mg (i.v.) dose of pessary Li Shan antibody is administered to the patient less than 2 weeks after the first dose.

19. The method of any one of the preceding claims, wherein an optional third 900mg intravenous dose of the anti-IL-36R antibody is administered 2 to 12 weeks after the second intravenous dose.

20. The method of any one of the preceding claims, wherein two dose administrations achieve one or more of the following results:

21. The method of claim 20, wherein the result is maintained for up to and at least 12 weeks after administration of the second intravenous dose.

22. The method of any one of the preceding claims, wherein the method further comprises administering to the patient a prophylactically effective amount of the anti-IL-36R antibody in one or more subcutaneous doses after administration of the last intravenous dose.

23. The method of claim 22, wherein each of the one or more subcutaneous doses comprises 150mg, 225mg, 300mg, 450mg, or 600mg of the anti-IL-36R antibody.

24. The method of claim 23, wherein 1, 2, 3 or more subcutaneous doses are administered to the patient and wherein a first subcutaneous dose is administered after the last intravenous dose.

25. The method of claim 24, wherein a first subcutaneous dose is administered 2 to 8 weeks, 4 to 6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks, 12 weeks, 16 weeks, 20 weeks after the last intravenous dose, and a subsequent subcutaneous dose is administered at 2, 4, 6, 8, 10, or 12 week intervals after the first subcutaneous dose.

26. The method of any one of the preceding claims, wherein the patient remains clinically relieved for at least 12, 24, 36, 48, 60, or 72 weeks after the last intravenous or subcutaneous dose, as measured by a GPPGA total score of 0 or 1.

27. The method of any one of the preceding claims, wherein the anti-IL-36R antibody comprises: a) A light chain variable region comprising the amino acid sequence SEQ ID NO. 26 (L-CDR 1); amino acid sequence SEQ ID NO:35, 102, 103, 104, 105, 106 or 140 (L-CDR 2); the amino acid sequence SEQ ID NO. 44 (L-CDR 3); and b) a heavy chain variable region comprising the amino acid sequence SEQ ID NO:53 (H-CDR 1); the amino acid sequence SEQ ID NO. 62, 108, 109, 110 or 111 (H-CDR 2); the amino acid sequence SEQ ID NO:72 (H-CDR 3).

28. The method of any one of the preceding claims, wherein the anti-IL-36R antibody comprises:

a) a light chain variable region comprising the amino acid sequence SEQ ID NO. 26 (L-CDR 1); amino acid sequence SEQ ID NO. 102 (L-CDR 2); the amino acid sequence SEQ ID NO. 44 (L-CDR 3); and b) a heavy chain variable region comprising the amino acid sequence SEQ ID NO:53 (H-CDR 1); the amino acid sequence SEQ ID NO. 62, 108, 109, 110 or 111 (H-CDR 2); the amino acid sequence SEQ ID NO:72 (H-CDR 3).

II.a) a light chain variable region comprising the amino acid sequence SEQ ID NO. 26 (L-CDR 1); amino acid sequence SEQ ID NO. 103 (L-CDR 2); the amino acid sequence SEQ ID NO. 44 (L-CDR 3); and b) a heavy chain variable region comprising the amino acid sequence SEQ ID NO:53 (H-CDR 1); the amino acid sequence SEQ ID NO. 62, 108, 109, 110 or 111 (H-CDR 2); the amino acid sequence SEQ ID NO:72 (H-CDR 3).

A) a light chain variable region comprising the amino acid sequence SEQ ID NO. 26 (L-CDR 1); amino acid sequence SEQ ID NO 104 (L-CDR 2); the amino acid sequence SEQ ID NO. 44 (L-CDR 3); and b) a heavy chain variable region comprising the amino acid sequence SEQ ID NO:53 (H-CDR 1); the amino acid sequence SEQ ID NO. 62, 108, 109, 110 or 111 (H-CDR 2); the amino acid sequence SEQ ID NO:72 (H-CDR 3).

A) a light chain variable region comprising the amino acid sequence SEQ ID NO. 26 (L-CDR 1); amino acid sequence SEQ ID NO. 105 (L-CDR 2); the amino acid sequence SEQ ID NO. 44 (L-CDR 3); and b) a heavy chain variable region comprising the amino acid sequence SEQ ID NO:53 (H-CDR 1); the amino acid sequence SEQ ID NO. 62, 108, 109, 110 or 111 (H-CDR 2); the amino acid sequence SEQ ID NO:72 (H-CDR 3).

V.a) a light chain variable region comprising the amino acid sequence SEQ ID NO. 26 (L-CDR 1); amino acid sequence SEQ ID NO. 106 (L-CDR 2); the amino acid sequence SEQ ID NO. 44 (L-CDR 3); and b) a heavy chain variable region comprising the amino acid sequence SEQ ID NO:53 (H-CDR 1); the amino acid sequence SEQ ID NO. 62, 108, 109, 110 or 111 (H-CDR 2); the amino acid sequence SEQ ID NO:72 (H-CDR 3).

29. The method of any one of the preceding claims, wherein the anti-IL-36R antibody comprises:

30. The method of any one of the preceding claims, wherein the anti-IL-36R antibody comprises:

31. The method of any one of the preceding clauses wherein the anti-IL-36R antibody is a pessary Li Shan antibody.

32. A method of treating an outbreak of Generalized Pustular Psoriasis (GPP) in a patient, the method comprising administering to the patient two intravenous (i.v.) doses of 900mg pessary Li Shan; wherein the second dose is administered less than 2 weeks after the first dose.

33. A method of treating GPP in a patient, the method comprising administering to the patient two intravenous doses of 900mg pessary Li Shan antibody; wherein the second dose is administered less than 2 weeks after the first dose.

34. A method of reducing or alleviating signs and symptoms of an acute phase disorder of GPP in a patient, the method comprising administering to the patient two intravenous doses of 900mg pessary Li Shan antibody; wherein the second dose is administered less than 2 weeks after the first dose.

35. A method of reducing the severity and duration of a GPP symptom, the method comprising administering to the patient two intravenous doses of 900mg pessary Li Shan antibody; wherein the second dose is administered less than 2 weeks after the first dose.

36. A method of treating a skin disorder associated with GPP, said method comprising administering to the patient two intravenous doses of 900mg pessary Li Shan antibody; wherein the second dose is administered less than 2 weeks after the first dose.

37. A method of preventing recurrence of a GPP outbreak in a patient, the method comprising administering to the patient two intravenous doses of 900mg pessary Li Shan antibody; wherein the second dose is administered less than 2 weeks after the first dose.

38. A method of reducing pain by at least 10% in a patient suffering from GPP, the method comprising administering to the patient two intravenous doses of 900mg pessary Li Shan antibody; wherein the second dose is administered less than 2 weeks after the first dose.

39. A method of improving the quality of life of a patient suffering from moderate to severe GPP symptoms by at least 10%, the method comprising administering to the patient two intravenous doses of 900mg pessary Li Shan antibody; wherein the second dose is administered less than 2 weeks after the first dose.

40. The method of any one of the preceding claims, wherein the patient's GPP physician overall evaluation (GPPGA) total score is ≡2.

41. The method of any one of the preceding claims, wherein the patient's GPP physician overall assessment (GPPGA) total score ∈2 and GPPGA pustule score ∈2.

42. The method of any one of the preceding claims, wherein the patient's GPP physician overall evaluation (GPPGA) total score ∈2 and GPPGA pustule score ∈2 prior to administration of the first intravenous dose.

43. The method of any one of the preceding claims, wherein after administration of the first intravenous dose, the patient's GPP physician overall evaluation (GPPGA) total score ∈2 and GPPGA pustule score ∈2.

44. The method of any one of the preceding claims, wherein the patient's GPP physician overall evaluation (GPPGA) total score ∈2 and GPPGA pustule score ∈2, before and after administration of the first intravenous dose.

45. The method of any one of the preceding claims, wherein the second dose is administered 1 week but less than 2 weeks after the first dose.

46. A method of treating a GPP patient having a GPPGA pustule score of ∈2, the method comprising the steps of: (a) Administering to the patient a first intravenous (i.v.) dose of 900mg of pessary Li Shan antibody; (b) The patient's GPPGA pustule score is evaluated, and if the patient's GPPGA pustule score ∈2 persists after 1 week after the first dose, a second (i.v.) dose of 900mg pessary Li Shan antibody is administered to the patient less than 2 weeks after the first dose.

47. A method of treating a GPP patient having a general rating of GPPGA equal to or greater than 2 for a global assessment by a GPP physician, the method comprising the steps of: (a) Administering to the patient a first intravenous (i.v.) dose of 900mg of pessary Li Shan antibody; (b) The patient's total GPPGA score is assessed and if the patient's total GPPGA score of ∈2 persists after 1 week after the first dose, then a second (i.v.) dose of 900mg pessary Li Shan antibody is administered to the patient less than 2 weeks after the first dose.

48. A method of treating a GPP patient having a general GPPGA score of > 2 and a GPPGA pustule score of > 2, the method comprising the steps of: (a) Administering to the patient a first intravenous (i.v.) dose of 900mg of pessary Li Shan antibody; (b) The patient's GPPGA score is assessed, and if the patient's GPPGA total score ∈2 and the GPPGA pustular score ∈2 persists after 1 week after the first dose, a second (i.v.) dose of 900mg pessary Li Shan antibody is administered to the patient less than 2 weeks after the first dose.

49. The method of any one of the preceding claims, wherein the optional third intravenous dose of 900mg of pessary Li Shan antibody is administered 2 to 12 weeks after the second intravenous dose.

50. The method of any one of the preceding claims, wherein two dose administrations achieve one or more of the following results:

51. The method of clause 50, wherein the result is maintained for up to and at least 12 weeks after the administration of the second intravenous dose.

52. The method of any one of the preceding claims, wherein the method further comprises administering to the patient a prophylactically effective amount of pessary Li Shan antibody in one or more subcutaneous doses after administration of the last intravenous dose.

53. The method of claim 52, wherein each of the one or more subcutaneous doses comprises 150mg, 225mg, 300mg, 450mg, or 600mg of pessary Li Shan antibody.

54. The method of claim 53, wherein 1, 2, 3 or more subcutaneous doses are administered to the patient and wherein a first subcutaneous dose is administered after the last intravenous dose.

55. The method of claim 54, wherein a first subcutaneous dose is administered 2 to 8 weeks, 4 to 6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks, 12 weeks, 16 weeks, 20 weeks after the last intravenous dose, and a subsequent subcutaneous dose is administered at 2, 4, 6, 8, 10, or 12 week intervals after the first subcutaneous dose.

56. The method of any one of the preceding claims, wherein the patient remains clinically relieved for at least 12, 24, 36, 48, 60, or 72 weeks after the last intravenous or subcutaneous dose, as measured by a GPPGA total score of 0 or 1.

57. The method of any one of the preceding claims, wherein the patient experiences an improvement in psoriasis condition scale (PSS) score within 1, 4 or 12 weeks after receiving one or more doses of the peacable Li Shan antibody; wherein the improvement is at least 10% when the PSS score after anti-IL-36R antibody or pessary Li Shan anti-administration is compared to the PSS score of the patient at baseline prior to the administration.

58. The method of any one of the preceding claims, wherein the patient experiences an improvement in chronic pain therapy functional assessment-fatigue (facility-fatigue) score within 1, 4, or 12 weeks after receiving one or more doses of eupatorium Li Shan resistance; wherein the improvement is at least 10% when the facility-fatigue score after anti-IL-36R antibody or pessary Li Shan anti-administration is compared to the facility-fatigue score at the patient's baseline prior to the administration.

59. The method of any one of the preceding claims, wherein the patient experiences an improvement in dermatological quality of life index (DLQI), psoriasis System Scale (PSS), visual Analog Scale (VAS) or chronic pain therapy functional assessment-fatigue (facility-fatigue) score within 1, 4 or 12 weeks after receiving one or more doses of eupatorium Li Shan resistance; wherein the improvement is at least 10% when compared to a DQLI, PSS, VAS or facility-fatigue score at week 1, 4 or 12 after anti-IL-36R antibody or pendant Li Shan anti-administration to a DQLI, PSS, VAS or facility-fatigue score at the patient's baseline prior to the administration.

60. A method of improving the psoriasis condition status scale (PSS), skin student quality index (DLQI), visual Analog Scale (VAS) or chronic pain therapy functional assessment-fatigue (facility-fatigue) score of a patient suffering from GPP, said method comprising administering to the patient a 900mg intravenous (i.v.) dose of pessary Li Shan antibody and optionally a second 900mg intravenous dose of pessary Li Shan antibody; wherein if the GPP symptoms (e.g., GPPGA total score > 2 and/or GPPGA pustule score > 2) persist in the patient, then a second optional dose of peacable Li Shan is administered less than 2 weeks after the first dose.

61. A method of improving the chronic pain therapy functional assessment-fatigue (facility-fatigue) score of a patient suffering from GPP, said method comprising administering to the patient a 900mg intravenous (i.v.) dose of pexol Li Shan antibody and optionally a second 900mg intravenous dose of pexol Li Shan antibody; wherein if the GPP symptoms (e.g., GPPGA total score > 2 and/or GPPGA pustule score > 2) persist in the patient, then a second optional dose of peacable Li Shan is administered less than 2 weeks after the first dose.

62. A method of improving the dermatological quality of life index (DLQI) score of a patient having GPP, said method comprising administering to the patient a 900mg intravenous (i.v.) dose of pexol Li Shan antibody and optionally a second 900mg intravenous dose of pexol Li Shan antibody; wherein if the GPP symptoms (e.g., GPPGA total score > 2 and/or GPPGA pustule score > 2) persist in the patient, then a second optional dose of peacable Li Shan is administered less than 2 weeks after the first dose.

63. The method of any one of claims 59 to 61, wherein the improvement is at least 10% when comparing the score at week 1, 4 or 12 after administration of the peacable Li Shan antibody to the score at the patient's baseline prior to the administration.

64. The method of any one of the preceding claims, wherein the administration of peacable Li Shan against the subject results in a lower maximum ADA titer at week 2, week 4, week 6, week 8, week 10 and/or week 12 of treatment.

Furthermore, the pharmaceutical composition may be provided as a pharmaceutical kit comprising (a) a container containing the IL-36R binding agent (e.g., an anti-IL-36R antibody) in lyophilized form; and (b) a second container containing a pharmaceutically acceptable diluent (e.g., sterile water) for injection. Pharmaceutically acceptable diluents may be used to reconstitute or dilute the lyophilized anti-IL-36R antibodies or agents. Optionally, associated with such containers may be a notice in the form prescribed by a government agency regulating the manufacture, use or sale of pharmaceutical or biological products, which notice reflects agency approval for manufacture, use or sale for human administration.

Such combination therapy administration may have additive or synergistic effects on disease parameters (e.g., severity of symptoms, number of symptoms, or frequency of recurrence).

With respect to the therapeutic regimen of the combination administration, in a particular embodiment, the anti-IL-36R antibody or IL-36R binding agent is administered concurrently with the therapeutic agent. In another specific embodiment, at least one hour and a plurality of months before or after administration of the anti-IL-36R antibody or IL-36R binding agent, e.g., at least one hour, five hours, 12 hours, one day, one week, one month, or three months before or after administration of the anti-IL-36R antibody or IL-36R binding agent.

The present invention is further described in the following examples, which are not intended to limit the scope of the invention.

Examples

Example 1: test of Paxol Li Shan against generalized pustular psoriasis

Abstract

Background: generalized pustular psoriasis is a rare life threatening inflammatory skin disease characterized by a broad burst of sterile pustules. Its pathogenesis involves dysregulated interleukin-36 signaling. We compared the humanized anti-interleukin-36 receptor monoclonal antibody pessary Li Shan with placebo in patients with an outbreak of generalized pustular psoriasis in phase 2 trials.

The method comprises the following steps: patients with outbreaks of generalized pustular psoriasis were randomly assigned to a single 900mg intravenous dose of pexol Li Shan antibody or placebo at a 2:1 ratio. The primary endpoint was a global impetigo psoriasis doctor overall evaluation (GPPGA) impetigo score of 0 at week 1 (range 0 to 4,0 indicating no impetigo and 4 indicating severe impetigo). The key secondary endpoint was a week 1 GPPGA total score of 0 or 1 (cleared or almost cleared) (range 0 to 4, higher scores indicating greater disease severity).

Results: a total of 85 patients were screened and 53 enrolled: 35 were assigned to receive pessary Li Shan antibodies and 18 received placebo. The baseline GPPGA pustule score for the pearsoid Li Shan antibody and placebo groups were 46% and 39% 3 and 37% and 33% 4, respectively. At the end of week 1, a pustular score of 0 (difference, 49 percentiles; 95% confidence interval [ CI ]21.5 to 67.2]; P < 0.001) was achieved in 19/35 (54%) of patients receiving pessary Li Shan antibody compared to 1/18 (6%) receiving placebo. At the end of week 1, 15/35 (43%) of the patients in the peacable Li Shan resistant group and 2/18 (11%) of the patients in the placebo group achieved a GPPGA total score of 0 or 1 (difference, 32 percentage points; 95% CI,2.2 to 52.7]; p=0.024). Drug responses with eosinophilia and systemic symptoms were reported in two patients treated with pexol Li Shan. Infection occurred in 17% of patients treated with peacable Li Shan at week 1. Anti-drug antibodies were detected in 23/50 (46%) patients receiving at least one dose of peacable Li Shan antibody.

Conclusion: in phase 2 trials of 1 week, the IL-36 receptor inhibitor pessary Li Shan resistance caused lesions with higher clearance rate than placebo in patients with an outbreak of generalized pustular psoriasis, but associated with more infection and systemic drug response. Longer and larger experiments are needed to determine the effect and risk of pessary Li Shan resistance in pustular psoriasis. (Boehringer Ingelheim sponsored; clinicalTrials. Gov identifier: NCT 03782792).

Introduction to the invention

Generalized Pustular Psoriasis (GPP) is a rare potentially life threatening autoinflammatory dermatological condition characterized by a broad burst of sterile visible pustules with or without systemic symptoms of pain, fever, general malaise, fatigue, and extra-dermal manifestations such as arthritis and neutrophil cholangitis. The clinical course of GPP can be recurrent with recurrent bursts, or persistent with intermittent bursts. Mortality is in the range of 2% to 16% and is due to septic shock and heart lung failure. The frequency of bursts varies from patient to patient and bursts may be spontaneous or triggered by upper respiratory tract infections, stress, medications, withdrawal and pregnancy. The disease has an adverse effect on the quality of life.

There is no approved therapy for this disease in the united states or europe and management includes cyclosporine, retinoids, methotrexate, and biologicals. Biological agents that inhibit tumor necrosis factor- α (adalimumab), infliximab, pegylated cetuximab (certolizumab pegol), interleukin (IL) -17/IL-17 receptor (secukinumab), brodamab (brodalumab), ixekizumab), and IL-23 (risenkelizumab, guselkuumab) have been approved for use in japan, taiwan, and thailand based on small-scale trials and studies of these agents in plaque psoriasis and small-scale non-random grouping GPP trials.

The role of the IL-36 pathway in GPP is supported by the following findings: overexpression of IL-36 cytokine in IL-36 receptor antagonist gene (IL 36 RN) and related genes (CARD 14, AP1S3, SERPINA3, MPO) in GPP skin lesions. Clinical improvement was observed in open label phase 1 studies in seven patients exhibiting GPP outbreaks using the humanized anti-IL-36 receptor monoclonal antibody pessary Li Shan antibody.

We performed a 2-phase randomized group trial to investigate efficacy and safety of pessary Li Shan against placebo in patients exhibiting GPP outbreaks. Because the acute and severe outbreaks of this condition are life threatening, a single dose of drug was selected for the trial design with a placebo control phase of 1 week, and patients from both groups were provided with an opportunity to receive open label petiole Li Shan antibodies on day 8. At week 12, the end of the trial, the patient was provided with an opportunity to enroll in a separate eupatorium Li Shan anti-open label extension trial (ClinicalTrials gov identifier: NCT 03886246).

Method

Test design

This 2-phase, multicentric, randomized group, double-blind, placebo-controlled trial was performed between day 20 of 2 in 2019 and day 5 of 1 in 2021, and patients were recruited from 37 sites in 12 countries. Patients exhibiting GPP outbreaks were randomly allocated to receive a single intravenous dose of 900mg pessary Li Shan antibody or placebo at a 2:1 ratio (fig. 1). Random grouping is performed using an interactive reaction system using layering factors of japanese ethnicities relative to non-japanese ethnicities. The treatment group assignments administered on day 1 were kept hidden from the patient and the investigator throughout the trial until the database was locked for analysis. On day 8, patients from both groups were eligible to receive an open-label single intravenous dose of 900mg of pessary Li Shan antibody (for some patients this caused a crossover from placebo to pessary Li Shan antibody) if they had persistent symptoms based on a predefined threshold consisting of: the overall evaluation of the GPP practitioner (GPPGA) at the end of week 1 is greater than or equal to 2 (in the range of 0[ clean skin ] to 4[ severe disease ]) and the GPP severity clinician evaluation based on modified PGA, and the GPPGA pustule score is greater than or equal to 2 (in the range of 0[ no visible pustules ] to 4[ severe pustules ]). GPPGA total score is the average of the score [ pustules, erythema and desquamation ]; see supplemental information below.) after week 1, a single intravenous dose of 900mg of pessary Li Shan resistant rescue therapy can be administered with a burst recurrence (defined as a total score of GPPGA and a score increase of greater than or equal to 2 score after the first time to reach GPPGA total score of 0 or 1), and a patient who achieves clinical improvement and completes the test without burst symptoms is eligible to enter a 5 year open label extension test (ClinicalTrials. Gov identifier: NCT 03886246) according to the choice of the main therapy, for patients who need to undergo immediate treatment during week 1 and for a patient who does not receive any critical drug protection from the critical drug evaluation in the week 2, as a critical care plan for the need of the performance of the drug protection against the critical drug in the patient's need of the drug protection against the critical drug protection against the deterioration in week 1.

Patients aged 18-75 years qualify for inclusion if they have a GPP medical history that meets diagnostic guidelines according to European rare and severe psoriasis expert network (ERASPEN) guidelines 1. DNA extracts from blood samples were analyzed for coding sequences of three major GPP-related genes (IL 36RN, CARD14, AP 1S 3) and patient enrollment did not take into account IL36RN mutation status. The patient must have a moderate to severe intensity GPP burst (defined as a total GPPGA score of > 3, a new or worsening pustule, a GPPGA pustule score of > 2, and > 5% body surface area with erythema and pustules present). The key exclusion criteria include: patients with plaque psoriasis do not have pustules or are limited to psoriatic plaques, drug-triggered acute systemic eruption impetigo, immediate life threatening outbreaks of GPP requiring intensive care therapy, and currently require treatment with methotrexate, cyclosporine, or retinoids, or any limited drug.

Endpoint (endpoint)

The primary endpoint was to achieve a GPPGA pustule score of 0 (clearance) at the end of week 1. The key secondary endpoint was a GPPGA score of 0 or 1 (cleared or almost cleared) at the end of week 1. The secondary endpoint was primarily at week 4, and some patients may have received open label pendant Li Shan resistance at day 8. Week 4 secondary endpoints included: psoriasis area and severity index of the generalized pustular psoriasis is 75% or greater (GPPASI 75; GPPASI is an adaptation of PASI score, wherein induration is replaced by pustule component; score in the range of 0[ least severe ] to 72[ most severe ], visual simulated pain scale (VAS, 0[ no pain ] to 100[ severe pain ]) changes from baseline, psoriasis symptoms scale (PSS; patients report psoriasis pain, redness, itching and burning pain; in the range of 0 to 16, higher score indicates more severe symptoms) changes from baseline, and chronic pain therapy functionality assessment-fatigue (fasit-fatigue; patient reports effects of fatigue; in the range of 0 to 52, lower score indicates more impact) changes from baseline.

Details of the test results and the list of exploratory endpoints are listed in supplementary table S3 below.

Safety events at week 1 (day 8 of study) and week 12 include treatment initiation and serious adverse events. Adverse events were assessed by test researchers, and treatment assignments were withheld from the researchers until after the database was locked for final analysis of the test. During the course of the trial, the adverse events that occurred were collected, recorded on an electronic case report, and reported by the researcher to the sponsor. The intensity of adverse events was assessed by researchers and ranked according to RCTC version 2.0 developed by the rheumatology outcome measure (ome act) organization.

Statistical analysis

Estimating the sample size of 51 patients provides ≡90% ability to detect any differences between pessary Li Shan antibody and placebo with a hypothetical response rate of 0.6 and 0.1 for both primary and key secondary endpoints, respectively, and <0.025 type I error (single sided), which can be considered <0.05 type I error under double sided detection. Primary endpoint and key secondary endpoint were analyzed using a random set with the precision Suissa-cluster Z mix test. This is a single-sided detection; double sided P values are reported by doubling the single sided P value. The 30 confidence intervals (95% CI) for risk differences were calculated using the Chan and Zhang method for the primary and all binary secondary endpoints. Fixed sequence testing was used to control type I family errors. Primary and key secondary endpoints (both assessed on day 8 [ week 1 ]) were tested in a hierarchical fashion at bilateral levels of P < 0.05. If the primary endpoint fails to achieve a significant difference between the test groups, then the critical secondary results will not be tested. The protocol and statistical analysis program required hierarchical testing of 4 subsequent secondary endpoints (GPPASI 75 and following changes from baseline: pain VAS; PSS; and FACIT-fatigue) all at week 4; however, the randomized group was no longer relevant after week 1 of the trial group, as 15/18 patients allocated as placebo received the day 8 open label petiole Li Shan antibody and were estimated as non-responsive or worst possible outcome. Thus, comparisons of randomized group treatments as originally planned are not informative and the change in these endpoints at weeks 1 and 4 of the following groups are reported in descriptive fashion: all patients with resistance to guy Li Shan (patients receiving one or two doses), patients with resistance to guy Li Shan with only a single dose (patients receiving only guy Li Shan on day 1), patients with resistance to guy Li Shan, patients with resistance to guy Li Shan on day 8 (patients eligible for a second dose on day 8), and patients with resistance to guy Li Shan on day 8 (patients with resistance to guy Li Shan on day 8) with a random grouping to placebo. For binary results, patients missing data are considered to not achieve the corresponding endpoint. For continuous results, the last observed case of the forward run is used for setup.

Post-hoc sensitivity analysis of primary and key secondary endpoints using linear regression with modulation of baseline imbalance covariates (including gender, race and GPPASI) was not conclusive from these data.

Results

Patient(s)

Of the 85 patients screened, 53 were enrolled in the group: 35 were assigned to 900mg of pessary Li Shan antibody and 18 to placebo (FIG. 1; table 1). Baseline demographics and disease characteristics varied between groups in terms of percentage of female participants (60.0% and 83.3% in the peacable Li Shan resistant and placebo groups, respectively) and proportion of asian participants (45.7% and 72.2%, respectively). The baseline median GPPASI total score was peacable Li Shan anti-group 27.4 and placebo group 20.9 (table 1). At random groupings, 18.9% of patients had a GPPGA total score of 4 (severe), and most patients had a GPPGA pustule score of 3 or 4 (high or very high density pustules) and impaired quality of life and clinical burden as indicated by dermatological quality of life index (DLQI), pain VAS, facility-fatigue and PSS (supplementary table S3). Seven patients in the five pessary Li Shan resistant group and the two placebo groups had IL36RN mutations (table 1). Most patients had no CARD14 (38 patients none) or AP1S3 (42 none) mutations (supplementary table S4).

TABLE 1 demographic data and baseline characteristics of the current outbreak

* The patient reports the ethnic group.

The overall evaluation by the pan-pustular psoriasis physician (GPPGA) scores ranged from 0 (clean skin) to 4 (severe disease).

GPPGA pustule score ranges from 0 (no visible pustules) to 4 (very high density pustules with purulent lakes).

Psoriasis Area and Severity Index (GPPASI) scores for extensive pustular psoriasis ranging from 0 (least severe) to 72 (most severe).

Five patients had homozygotic mutations (four p.Leu27Pro; one p.Ser113Leu), and two patients had heterozygotic mutations (p.Ser113Leu; p.Ser113Leu/p.Val44Met). On the date of database locking (day 18 of 1 month 2021), DNA assays were not completed in three patients (targeted re-sequencing Illumina Miseq, illumina corporation, san Diego, CA) and samples from seven patients were absent. IQR, quartile range; SD, standard deviation.

A total of 52 out of 53 enrolled patients completed the first week trial. The primary and key secondary endpoints of one patient in the peacable Li Shan antibody group were missing data and were attributed to non-response. On day 8, 12 patients (34.3%) in the eupatorium Li Shan resistant group and 15 patients (83.3%) in the placebo group received an open-label dose of eupatorium Li Shan resistant. After day 8, 32 patients (91.4%) initially randomized to the peacable Li Shan antibody and 17 patients (94.4%) initially randomized to the placebo were completed a 12 week follow-up period during which four and two patients, respectively, needed rescue treatment with the peacable Li Shan antibody. After 12 weeks of treatment was completed, 39 patients entered the group open label extension trial (fig. 1).

Efficacy of

Primary and key secondary efficacy endpoints

At the end of week 1, 19 patients (54.3%) randomized to pessary Li Shan antibody achieved a GPPGA pustule score of 0 (no visible pustules) versus one patient (5.6%) randomized to placebo; (difference, 48.7 percentiles; 95% confidence interval [ CI ],21.5 to 67.2; P <0.001; table 2, FIG. 3A). 15 patients (42.9%) randomized to peacable Li Shan antibody achieved a total GPPGA score of 0 or 1 (clear or nearly clear skin) at week 1 (difference, 31.7 percentage points; 95% CI,2.2 to 52.7; p=0.024; table 2, fig. 3B) relative to two patients (11.1%) randomized to placebo. The GPPGA pustule score and GPPGA total score over time considering only day 1 randomized block treatment are shown in figures 4 and 5.

TABLE 2 Primary and Critical Secondary efficacy endpoints

* Double sided P-value by Suissa-share Z mix test.

CI, confidence interval; GPPGA, overall evaluation by the physician of generalized pustular psoriasis.

Post hoc sensitivity analysis of primary and key secondary endpoints of baseline imbalances observed in gender, ethnic group and GPPASI are consistent with primary analysis. (supplement tables S5 and S6).

Post-8 exploratory efficacy endpoint for day 1 randomized block therapy and day 8 open label pendant Li Shan anti-therapy

After week 1, 15/18 patients assigned placebo received the open label petiole Li Shan antibody on day 8, so the planned stratum test of the comparative secondary endpoint at week 4 failed to provide information. Instead, secondary endpoints of four groups reflecting the post-8 day treatment route were reported in descriptive fashion: all patients with resistance to guggul Li Shan (patients receiving either one [ day 1 only ] or two doses [ day 1 plus day 8 ]; n=35), patients with resistance to guggul Li Shan in only a single dose (day 1; n=23), patients with resistance to guggul Li Shan, patients with resistance to guggul Li Shan on day 8 of open label (day 1 plus day 8; n=12), and patients with resistance to guggul Li Shan on day 8 of open label (n=15) were randomized to a placebo. Descriptive analysis of GPPGA pustule score of 0 and GPPGA total score of 0 or 1 over time for these subgroups is reported in the supplemental information (below) and fig. 6 and 7, and secondary endpoints including the following are reported in the supplemental information below: week 4 GPPASI 75 and following changes from baseline: pain VAS; PSS; FACIT-fatigue.

In addition, for patients randomized to the peacable Li Shan antibody, groups receiving either one (day 1) or two doses (day 1 plus day 8; n=35 day) of peacable Li Shan antibody, descriptive results of GPPASI, GPPASI 75, pain VAS, DLQI, neutrophil count, and C-reactive protein content over 12 weeks are reported in fig. 8. Changes in GPPGA scores (including GPPGA pustule, erythema and scaling/crusting score and GPPGA total score) from baseline for three patients after receiving first and second doses of peacable Li Shan antibody on days 1 and 8, respectively, are shown in figure 9.

Safety of

Adverse events were reported in 65.7% of patients assigned to pessary Li Shan resistance and 55.6% of placebo group during the first week of randomized group treatment. Fever occurred in 5.7% and 22.2% of patients receiving pessary Li Shan antibody and placebo, respectively; all fever events occurred in the case of a basal GPP burst, but it cannot be excluded that the drug causes fever (table 3). In the first week, infections were reported in 17.1% and 5.6% of patients with pexol Li Shan antibody and placebo group, respectively (supplementary table S8); at week 1, there were two cases of urinary tract infection in the peacable Li Shan resistant group, one for each of all other infections (see footnotes supplementing table S8). Serious adverse events were reported in 5.7% of pessary Li Shan resistant patients, and no placebo-receiving patients.

Table 3. Adverse event overview

* All adverse events occurring between the beginning of the treatment and the end of the residual action phase (16 weeks after the last dose tested) were considered "treatment-induced". Adverse events were encoded using the pharmaceutical regulatory active medical dictionary (Medical Dictionary for Drug Regulatory Activities) version 23.1. Adverse event severity was graded according to the rheumatology common toxicity guidelines (Rheumatology Common Toxicity Criteria, RCTC) version 2.0 safety analysis group. Pustular psoriasis is excluded from this safety analysis as an adverse event.

The dataset included patients receiving up to three doses of peacable Li Shan antibody randomized to peacable Li Shan antibody at week 12, and patients initially randomized to placebo, receiving open label peacable Li Shan antibody at or after day 8. Including all adverse events from the first peaked line Li Shan anti-use to the residual action phase of the last peaked line Li Shan anti-dose.

Common adverse events were reported in greater than or equal to 10% of patients in any treatment group.

Drug-induced liver injury is reflected by an increase in transaminase and is considered an systemic symptom of drug response accompanied by eosinophilia and systemic symptoms. Chronic plaque psoriasis exacerbation captures events reflecting non-pustular psoriasis; these events were not captured in the efficacy results.

At week 12, 82.4% of patients receiving at least one dose of pessary Li Shan antibody (including those who received the open label pessary Li Shan antibody on day 8 initially randomized to placebo) had adverse events, and 11.8% had severe adverse events; within the euphausiid Li Shan antibody group, the proportion of patients with adverse events remained unchanged or increased from week 1 to week 12, while the incidence of time adjustment decreased (table 3). Infection was reported in 47.1% of patients; three cases of urinary tract infection and influenza are respectively present; there are two examples of each: folliculitis, otitis externa, upper respiratory tract infections, pustules; for all other infections, there is one case (see footnotes supplementing table S8). The symptoms observed in the two patients receiving the pessary Li Shan antibody were reported as Drug Response (DRESS) with eosinophilia and systemic symptoms, with a RegiSCAR score of 1 and 3.33. Additional details of these two examples of reports can be found in the supplemental information below. Anti-drug antibodies (ADA) were detected at a median time of 2.3 weeks after administration of the peacable Li Shan antibody. ADA was detected in 23/50 (46%) patients receiving at least one dose of pessary Li Shan antibody. Most (87%) ADA positive patients (40% of total treated patients) were also Nab positive and Nab status appears to be related to efficacy value. No dose dependence was observed; surprisingly, however, the maximum ADA titers appeared to be reduced in GPP patients receiving two doses by day 8 (n=4|) relative to only 1 dose.

Discussion of the invention

This randomized block trial of a single intravenous dose of the humanized anti-IL-36 receptor monoclonal antibody pessary Li Shan antibody in patients with GPP outbreaks showed better lesion clearance at 1 week compared to placebo. Overall, pexol Li Shan is more frequent against infection, although there is no obvious pattern of pathogens and affected organs, and two patients treated with pexol Li Shan resistance have drug responses with eosinophilia and systemic symptoms, with a RegiSCAR score of 1 and 3.

At the end of the 1 week period of randomization, one third of the patients in the eupatorium Li Shan resistant group and the majority of the patients in the placebo group received the open label eupatorium Li Shan resistant and were followed for 12 weeks. Since 15 of the 18 randomized, placebo patients received the open-label pessary Li Shan antibody, the actual effect of the pessary Li Shan antibody relative to placebo was not reflected after week 1 in this trial. This highlighting one of the challenges inherent in performing a randomized, placebo-controlled trial in patients with this disease; the nature and severity of the bursts of GPP outbreaks (potentially life threatening) present several challenges in the design of this study, including the limitation in the duration of time that patients can be expected to undergo placebo treatment in this trial; furthermore, the clinical course is heterogeneous and can be characterized as recurrent disease with recurrent outbreaks, or persistent disease with intermittent outbreaks, making it difficult to select an appropriate time for the endpoint of the study.

As noted above, this trial has limitations, including a small number of enrolled patients (typical for rare diseases); however, the effects of the primary and key secondary endpoints at week 1 are large and significant in magnitude. The randomized block phase is limited to 1 week and if the pre-specified threshold of severity is still met, the patient has the option to receive an open label eupatorium Li Shan anti-treatment at week 1, meaning that most placebo patients receive eupatorium Li Shan anti, and thus the comparative analysis after week 1 cannot provide information; the hierarchical tests of the secondary endpoints defined at week 4 are therefore not reported here. There was some baseline imbalance (gender, race, GPPASI) that occurred randomly between treatment groups; however, post hoc sensitivity analysis of primary and key secondary endpoints of regulatory imbalance is consistent with primary analysis.

Despite these challenges, single pexol Li Shan anti-infusion rapid control burst attacks in this study, builds on the results of previous pexol Li Shan anti-open label studies, and supports the hypothesis that IL-36 is the central driver of pathogenesis of GPP. The improvement in measurements including CRP, neutrophil count, pain, PSS, facility-fatigue, DLQI over time indicates that pexol Li Shan is acting systemically beyond the skin and that pexol Li Shan is potentially improving the quality of life of patients experiencing GPP outbreaks. Long term administration of pessary Li Shan resistance was evaluated with subcutaneous formulations in an ongoing 5 year open label extension (clinical Trials. Gov identifier: NCT 03886246) and burst prevention test Effiliail 2 (clinical Trials. Gov identifier: NCT 04399837).

In summary, in this phase 2 trial, anti-treatment of GPP outbreaks with intravenous pessary Li Shan resulted in higher impetigo clearance than placebo, but was associated with infection and systemic reactions. Longer and larger experiments are needed to determine the effect and safety of the pendant Li Shan resistance in GPP.

Supplemental information

Overall evaluation of pan-onset pustular psoriasis doctor (GPPGA)

GPPGA relies on clinical assessment of patient skin manifestations. It is a modified Physician Global Assessment (PGA), a psoriasis lesions physician assessment adapted to evaluate patients with Generalized Pustular Psoriasis (GPP). The investigator (or qualified field personnel) scored from 0 to 4 for erythema, pustules, and desquamation of all psoriatic lesions (see table below). Each component was graded separately, the mean was calculated and the final GPPGA was determined from this composite score (composite mean score = (erythema + pustule + desquamation)/3; total GPPGA score 0 means = 0 for all three components, 1 score means 0 to <1.5,2 score means 1.5 to <2.5,3 score means 2.5 to <3.5, and 4 score means ≡3.5). Lower scores indicate lower severity, where 0 relates to 'clear', and 1 relates to 'almost clear'. To receive a score of 0 or 1, the patient should have no fever in addition to the skin performance requirements.

Psoriasis Area and Severity Index (GPPASI) of generalized pustular psoriasis

GPPASI is an adaptation of PASI for patients with GPP, PASI being an established measure of the severity and area of psoriasis lesions in psoriasis patients. Similar adaptations have been used for palmoplantar psoriasis. In GPPASI, the sclerotic component is replaced by the pustule component. It is a tool to provide a numerical score ranging from 0 to 72 for the overall generalized pustular psoriasis disease state of a patient. It is a linear combination of the percentage of affected skin surface area (body area score) of four body areas (head, upper limb, torso and lower limb) and the severity of erythema, pustules and desquamation (desquamation) (five-point scale score, ranging from 0[ least severe ] to 4[ most severe ]).

* Individual score for each body region = body region factor (head = 0.1, upper limb = 0.2, torso = 0.3, lower limb = 0.4) x body region area score x component severity score sum of body region.

Total GPPASI score = sum of individual scores for all body regions.

Inclusion and exclusion criteria

Inclusion criteria

Patients were enrolled (screened) into the trial if they met the following criteria:

Patient GPPGA score of 0 or 1 and with a known and documented medical history of GPP independent of the mutation status of IL36RN (according to ERASPEN guidelines), and additionally prior signs of fever and/or weakness and/or myalgia and/or elevated C-reactive protein and/or leukocytosis with peripheral blood neutrophilia (above the upper normal limit [ ULN ]), or

Patient suffering from moderate to severe intensity burst meeting the ERASPEN standard of GPP and having a known and documented medical history of GPP independent of the mutated state of IL36RN (according to the ERASPEN standard), and additionally prior signs of fever and/or weakness and/or myalgia and/or elevated C-reactive protein and/or leukocytosis with peripheral blood neutrophilia (above ULN), or

Patients experience a first onset of a GPP burst of moderate to severe intensity with fever and/or weakness and/or myalgia and/or elevated C-reactive protein and/or signs of leukocytosis (above ULN) with peripheral blood hypereosinophilia. For these patients, diagnosis will be retrospectively confirmed by the central external expert/committee.

2. The patient may or may not be receiving a background treatment of retinoids and/or methotrexate and/or cyclosporine. Patients must discontinue retinoids/methotrexate/cyclosporine prior to receiving the first dose of pexol Li Shan antibody or placebo.

3. Male or female patients, the age at screening is 18-75 years.

4. Prior to starting any screening procedure, informed consent was written and dated in accordance with ICH-GCP and local regulations prior to entering the trial.

5. Women with fertility potential must be ready and able to use a highly efficient method of birth control according to ICH M3 (R2), which when used continuously and properly, results in a low failure rate of less than 1% per year. Women are considered to have fertility potential (WOCBP) after the beginner, are fertile, and until become postmenopausal unless permanently sterile. Permanent sterilization procedures include hysterectomy, bilateral tubectomy, and bilateral ovariectomy. Tubal ligation is not a permanent sterilization method. Postmenopausal status is defined as no menstruation for 12 months, no alternative medical reasons.

Exclusion criteria

Patients will not be screened or treated if any of the following criteria apply:

1. the patient had synovitis-acne-impetigo-hypertrophic bone-osteomyelitis syndrome.

2. The patient had primary red skin psoriasis vulgaris.

3. Patients suffer from primary plaque psoriasis vulgaris, with no pustules present or limited to psoriatic plaques.

4. Drug-triggered acute systemic eruption impetigo.

5. At the discretion of the investigator, the immediate life threatening outbreak of GPP or the need for intensive care therapy. Life threatening complications mainly include, but are not limited to, cardiovascular/cytokine driven shock, lung distress syndrome or renal failure.

6. Severe, progressive or uncontrolled liver disease, defining an increase in aspartate aminotransferase or alanine aminotransferase or alkaline phosphatase > 3-fold ULN, or an increase in total bilirubin > 2-fold ULN.

7. The following treatments were used:

a. as assessed by the investigator, any drug that is limited or believed to interfere with the safe performance of the test.

b. Any previous exposure of the peaked Li Shan to the other IL36R inhibitor.

8. The patient had an elevated dose of cyclosporine and/or methotrexate and/or retinoid maintenance therapy within 2 weeks prior to receiving the first dose of pexoline Li Shan anti/placebo.

9. Systemic agents such as cyclosporine and/or retinoids and/or methotrexate are initiated 2 weeks before receiving the first dose of the pexoline Li Shan anti/placebo.

10. As assessed by the investigator, the patient had congestive heart disease.

11. Active systemic infection (fungal and bacterial disease) during the last 2 weeks prior to receiving the first drug administration, as assessed by the investigator.

12. As assessed by researchers, the risk of infectious complications (e.g., recent suppurative infection, any congenital or acquired immunodeficiency [ e.g., human Immunodeficiency Virus (HIV) ], past organ or stem cell transplantation) is increased.

13. Related chronic or acute infections, including HIV or viral hepatitis. For patients screened concurrently with outbreaks (incorporating criteria 1b or 1 c), if the HIV or viral hepatitis results of the 1 st visit are not timely available for randomized group, these patients may receive randomized group treatment, provided that the investigator has excluded active disease (i.e., negative HIV and viral hepatitis test results) based on the recorded medical history available 3 months prior to the 2 nd visit. If the patient is treating and curing the acute infection, the patient may be rescreened.

14. Active or latent Tuberculosis (TB):

will be performed during screening(or if applicable, if appropriate)>) And (5) testing TB. If the result is positive, the patient may participate in the trial with further processing (according to local practice/guidelines) to conclusively determine that the patient is free of signs of active tuberculosis. Patients with active TB must be excluded. If the presence of latent tuberculosis is determined, treatment should be initiated and maintained according to local national guidelines. For patients screened at the same time as outbreaks (inclusion criteria 1b or 1 c), if TB test results cannot be used in time for randomization, these patients can receive randomization therapy (provided they meet all other inclusion/exclusion criteria), provided that the investigator has excluded active disease (i.e., active TB negative) based on the recorded medical history available 3 months prior to the 2 nd visit.

15. There is a history of allergy/hypersensitivity to systemically administered test medications or excipients thereof.

16. Any noted active or suspected malignancy or history of malignancy within 5 years prior to screening, except basal or squamous cell carcinoma of the appropriately treated skin or carcinoma in situ of the cervix.

17. Another investigational device or drug test is currently enrolled or is ending less than 30 days from the other investigational device or drug test or is receiving other investigational therapy.

18. Pregnant, lactating or women scheduled to become pregnant simultaneously in the test. Women who stopped lactation prior to administration of the trial drug need not be excluded from participation; it should avoid breast-feeding up to 16 weeks after administration of the test drug.

19. As assessed by the investigator, major surgery (major surgery assessed by the investigator), e.g., hip replacement, aneurysm removal, gastric ligation, was performed within 12 weeks prior to receiving the first dose of trial drug or was planned during the trial.

20. Current or previous signs of diseases other than GPP, medical conditions (including chronic alcohol or drug abuse or any condition), surgical procedures, mental or social problems, medical examination findings (including vital signs and electrocardiography), or laboratory values outside of the reference range at screening appear clinically significant to researchers and will allow test participants to follow a regimen, follow all test visits/procedures or be unreliable in completing a test, compromise patient safety or compromise quality of data.

Supplement Table S3. Efficacy results and description

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CGI, clinical global impression; DLQI, dermatological quality of life index; EQ-5D-5l, level 5 EuroQol-5 dimension; functional assessment of FACIT, chronic pain therapy; GPP, generalized pustular psoriasis; GPPASI, area and severity index of generalized pustular psoriasis; GPPGA, overall evaluation by the pan-pustular psoriasis physician; IV, intravenous; JDA, japan dermatology department; OL, open label; PRO, patient report results; PSS, psoriasis disorder scale; VAS, visual analog scale.

Make-up Table S4 absence or presence of potentially pathogenic variations of genotyping-based CARD14 and AP1S3 mutations

On the date of database locking (day 18 of 1 month 2021), DNA sequencing (targeted re-sequencing Illumina Miseq, illumina corporation, san Diego, CA) was not completed in three patients and samples from seven patients were absent. * Positive patients had heterozygous mutations (two p.ser200asn; one p.arg682trp; one p.pro506leu; one p.ser5399arg). One patient in the peacable Li Shan anti-team carried double CARD14 and IL36RN mutations (p.ser200asn and p.ser113leu, respectively).A single positive patient had a heterozygous mutation (p.phe4cys). One patient in the peacable Li Shan anti-team carried double AP1S3 and IL36RN mutations (p.phe4cys and p.leu27pro, respectively).

Supplementary Table S5 post hoc sensitivity analysis of primary endpoint of linear regression modulation for gender, race and baseline GPPASI

* Based on a linear regression model using the primary endpoint as the dependent variable and the treatment assignment plus the respective covariates as independent variables. 95% CI and P values are based on stable SE.The treatment P-value differences are based on a linear regression model. CI, confidence interval; psoriasis area of GPPSI, generalized pustular psoriasisSeverity index; SE, standard error.

Supplementary Table S6 post hoc sensitivity analysis of key secondary endpoints with linear regression modulation for gender, race and baseline GPPASI

* Based on a linear regression model using the primary endpoint as the dependent variable and the treatment assignment plus the respective covariates as independent variables. 95% CI and P values are based on stable SE.The treatment P-value differences are based on a linear regression model. CI, confidence interval; GPPSI, psoriasis area and severity index of generalized pustular psoriasis; SE, standard error.

Day 1 randomized group treatment and day 8 open label pendant Li Shan anti-treatment post day 8 exploratory efficacy endpoint. Descriptive analysis of four groups for GPPGA pustule score of 0 or GPPGA total score of 0 or 1:

Of patients (n=35) initially randomized to eupatorium Li Shan, receiving day 1 eupatorium Li Shan, receiving or not receiving day 8 open label eupatorium Li Shan, 19 patients (54%) achieved a GPPGA pustule score of 0 at the end of week 1 and 15 patients (43%) achieved a GPPGA total score of 0 or 1; at week 12, 21 patients (60%) had a GPPGA pustule score of 0 and a GPPGA total score of 0 or 1 (fig. 5 and 6). Random grouping to eupatorium Li Shan antibody, out of 23 patients who did not receive day 8 open label eupatorium Li Shan antibody, 19 (83%) achieved a GPPGA pustule score of 0 and 15 (65%) achieved a GPPGA total score of 0 or 1 at the end of week 1; at week 12, these scores were reported in 15 (65%) and 16 (70%) patients, respectively (fig. 5 and 6). Of the patients (n=12) who received the open label pexol Li Shan antibody on day 8, who were initially randomized to the pexol Li Shan antibody, five patients (42%) achieved a GPPGA pustule score of 0 and two patients (17%) achieved a GPPGA total score of 0 or 1 at the end of week 2; at week 12, six patients (50%) and seven patients (58%) had a GPPGA pustule score of 0 and a GPPGA total score of 0 or 1 (fig. 5 and 6). Of the 15 patients receiving the open-label pexole Li Shan antibody on day 8 in the placebo group, 11 (73%) achieved a GPPGA pustule score of 0 and eight (53%) achieved a GPPGA total score of 0 or 1 at the end of week 2 (seven days after the open-label pexole Li Shan antibody); at week 12, these scores were reported in six (40%) and eight (53%) patients, respectively (fig. 5 and 6).

Descriptive analysis of planned hierarchical secondary endpoint GPPASI 75 and following changes from baseline: pain VAS at week 4 of four groups; PSS; FACIT-fatigue

For week 4 GPPASI 75, GPPASI 75 was achieved by 18/35 (51%) in patients initially randomized to the resistance to pexole Li Shan, receiving the resistance to pexole Li Shan on day 1, and receiving or not receiving the resistance to open label pexole Li Shan on day 8. Random groupings to peacable Li Shan antibody 16 (70%) of 23 patients who did not receive day 8 open label peacable Li Shan antibody achieved week 4 GPPASI 75 (supplementary table S7). Of the 12 pexol Li Shan and 15 placebo patients receiving an open label dose of pexol Li Shan at the end of week 1, two (17%) and six (40%) patients achieved week 4 GPPASI 75 (supplementary table S7), respectively.

For week 4 pain VAS, the median value (quartile range; IQR) relative to baseline was varied to-53.4 (-77.8, -20.2) in patients initially randomized to the eupatorium Li Shan antibody, receiving day 1 eupatorium Li Shan antibody, and receiving or not receiving day 8 open label eupatorium Li Shan antibody (supplementary Table S7). The median (IQR) change from baseline was-63.1 (-79.8, -22.5) in 23 patients randomized to the peacable Li Shan antibody, who did not receive the open label peacable Li Shan antibody on day 8. The median (IQR) change from baseline was-44.6 (-71.2, -17.3) and-54.3 (-79.0, 33.3) in the 12 pexo Li Shan resistant and 15 placebo group patients receiving the open label dose, respectively (supplementary table S7).

For week 4 PSS, the median (IQR) change from baseline was-7.0 (-10.0, -3.0) in patients initially randomized to the eupatorium Li Shan antibody, receiving day 1 eupatorium Li Shan antibody, receiving or not receiving day 8 open label eupatorium Li Shan antibody (supplementary table S7). The median (IQR) change from baseline was-7.0 (-11.0, -2.0) in 23 patients randomized to the peacable Li Shan antibody, who did not receive the day 8 open label peacable Li Shan antibody. The median (IQR) change from baseline was-6.0 (-7.0, -3.5) and-5.0 (-9.0, -2.0) in the 12 pexo Li Shan resistant and 15 placebo group patients receiving the open label dose of pexo3779 resistant, respectively (supplementary table S7).

For week 4 FACIT-fatigue, the median (IQR) change from baseline was 22.0 (1.0, 31.0) in patients initially randomized to the eupatorium Li Shan antibody, receiving day 1 eupatorium Li Shan antibody, and receiving or not receiving day 8 open label eupatorium Li Shan antibody (supplementary Table S7). The median (IQR) change from baseline was 22.0 (3.0, 35.0) in 23 patients randomized to the eupatorium Li Shan antibody, who did not receive the open label eupatorium Li Shan antibody on day 8 (supplementary table S7). The median (IQR) change from baseline was 15.0 (5.5, 28.5) and 16.0 (-19.0, 26.0) in the 12 pexol Li Shan resistant and 15 placebo group patients receiving the open label dose of pexol Li Shan, respectively (supplementary table S7).

Supplement table s7, day 1 random grouping therapy, day 8 open label pendant Li Shan anti-treatment, week 1 and week 4 GPPASI 75, pain VAS, PSS, and FACIT-fatigue

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This exploratory dataset was included in a statistical analysis plan that initially planned an analysis of hierarchical tests for all secondary endpoints at week 4 (GPPASI 75 and following changes from baseline: pain VAS; PSS; and FACIT-fatigue); however, the randomized group was no longer relevant after week 1 of the trial group, as 15/18 patients allocated placebo received day 8 open label petunidin Li Shan antibody. For this analysis, any value after the day 8 open label pendant Li Shan resistance was used, but any value after treatment with the pest-avoidance drug, or pendant Li Shan anti-rescue drug, was not used and was estimated as the worst result in the calculation of median and quartiles. CI, confidence interval; GPPASI 75, psoriasis area and severity index of generalized pustular psoriasis 75% or greater improvement; FACIT-fatigue, functional assessment of chronic pain therapy-fatigue; IQR, quartile range; pain VAS, pain visual analog scale; PSS, psoriasis disorder scale.

Random grouping to peacable Li Shan antibody, receiving one (day 1) or two doses (day 1 plus day 8); descriptive analysis of n=35) pessary Li Shan resistant patient group for GPPASI, GPPASI, pain VAS, DLQI, neutrophil count, and C-reactive protein content:

The median percent improvement from baseline for GPPASI scores was 43% at week 1 and gradually increased to 82% at week 12 (fig. 7A). GPPASI 75 was achieved in 13 patients (37%) at week 2, 18 patients (51%) at week 4, 21 patients (60%) at week 8, and 20 patients (57%) at week 12 (fig. 7B). Rapid decrease in pain VAS scores and improvement in DLQI scores were achieved in week 4 and in week 12 (fig. 7C and 7D). In patients with higher baseline neutrophils, counts were normalized within 1 week of receiving pessary Li Shan antibody (fig. 7E). In patients with higher baseline CRP (. Gtoreq.10 mg/L) receiving one or two doses of peacable Li Shan antibody, median C-reactive protein (CRP) was normalized within 2 weeks (FIG. 7F).

Supplementary Table S8 overview of adverse events according to System organ categories

All AEs that occurred between the start of treatment and the end of the residual action phase (16 weeks after the last dose tested) were considered "treatment elicited". AE was encoded using the pharmaceutical regulatory active medical dictionary version 23.1. AE severity was rated according to the rheumatology common toxicity guidelines version 2.0 safety analysis group. Pustular psoriasis is excluded from this safety analysis as an adverse event. * The dataset included patients receiving up to three doses of peacable Li Shan antibody randomized to peacable Li Shan antibody at week 12, and initially randomized to placebo, patients receiving open label peacable Li Shan antibody at day 8. Including all adverse events from the first time of use of the pendant Li Shan to the residual stage of use of the last time of the pendant Li Shan. Adverse AEs according to the category of organs of the system were reported in > 10% of patients in any treatment group.

Example 2

Pessary Li Shan anti-treatment improves pain, psoriasis symptoms, fatigue, and quality of life in patients with generalized pustular psoriasis: patient report results generated by the effisail 1 study

Introduction and goal: generalized Pustular Psoriasis (GPP) is a rare and potentially life threatening skin disease characterized by extensive sterile pustules and recurrent outbreaks. Signs and symptoms associated with GPP include pain, fever, and fatigue, which can affect activities of daily living and quality of overall life (QoL). Peacable Li Shan resistance has been reported to rapidly improve the clearance of pustules and skin in patients exhibiting GPP outbreaks. The goal of this analysis was to evaluate patient report results (PRO) for metrics on pain, psoriasis symptoms, fatigue and overall QoL impact in patients treated with pessary Li Shan from the effisail 1 study.

Materials and methods: effisayil1 (NCT 03782792) is a multicenter, randomized group, double-blind, placebo-controlled study of patients with GPP outbreaks. Eligible patients (n=53) were randomly assigned (2:1) to receive a single Intravenous (IV) dose of open label 900mg pessary Li Shan antibody or placebo on day 1 for 12 weeks of follow-up. At week 1, if the patient GPP physician global assessment (GPPGA) score was > 2 and did not receive a pest-avoidance drug prior to day 8, the patient was eligible to receive an open label single intravenous dose of 900mg pessary Li Shan antibody. Secondary and further endpoints were assessed by: psoriasis symptoms scale over time to the end of the study (PSS; 0-16, higher scores indicate more severe symptoms), pain vision analog scale (pain VAS;0[ no pain ] to 100[ severe pain ]), chronic pain therapy functional assessment-fatigue (FACIT-fatigue; 0-52, lower scores indicate greater impact) dermatological quality of life index (DLQI; 0[ no impact ] to 30[ great impact ]). For subsequent time points in the analysis, patients receiving either a pest-avoidance therapy (optional standard of care therapy administered to the patient within 1 week of the first dose) or a rescue medication (optional pessary Li Shan antibody at a 900mg IV dose administered at any time beginning on day 8) were considered non-responders.

Results: patients were randomized to receive 900mg of pessary Li Shan antibody (n=35) or placebo (n=18). At baseline, patients had high clinical burden and impaired QoL, as indicated by median PSS (11.0), pain VAS (79.8), facility-fatigue (14.0), and DLQI (19.5) scores (table 9). Improvement in PSS, pain VAS, facility-fatigue and DLQI scores were observed from baseline to week 12 (table). Pain improves as early as week 1, improves further at week 4, and persists to week 12. For other PRO (PSS, FACTI-fatigue and DLQI), improvement was also seen as early as week 1 but continued to improve to week 12.

Conclusion: patients receiving intravenous 900mg of pessary Li Shan antibody and optionally a second dose on day 8 exhibited significant improvement in PRO of pain, psoriasis symptoms, fatigue and overall QoL. These improvements were seen earlier and maintained for up to 12 weeks. These findings indicate that up to 2 doses of pexol Li Shan are resistant to rapid pustule clearance that can lead to GPP outbreaks, which correlates with improvement in patient reported results.

Table 9. Absolute change from baseline for the peacable Li Shan antibody group PRO baseline (n=35)

All data sets included patients randomized to the peacable Li Shan antibody, receiving up to two doses of peacable Li Shan antibody, including 12 patients receiving an open-label single intravenous dose of 900mg peacable Li Shan antibody (second dose) at week 1.

Any value after the application of the week 1 open label peacable Li Shan resistance, but any pest-resistant drug application or peacable Li Shan anti-rescue drug treatment represents no response.

iQR, quartile range

Example 3

Pessary Li Shan anti-treatment improves pain, psoriasis symptoms, fatigue, and quality of life in patients with generalized pustular psoriasis: patient reporting results from the Effisayil 1 study

The purpose is as follows: evaluation of Effiliayil ^TM PRO, a measure of pain, psoriasis symptoms, fatigue and quality of overall life (QoL) impact in patients treated with pessary Li Shan in study 1.

Introduction: GPP is a rare potentially life threatening neutrophilic skin disease characterized by a broad burst of sterile visible pustules, and can occur in the presence or absence of systemic inflammation. Multicenter, randomized, double-blind, placebo-controlled Effisayil ^TM In study 1 (NCT 03782792), in patients exhibiting GPP outbreaks, pexol Li Shan anti-treatment caused rapid pustules and skin clearance within 1 week. The GPP outbreaks in PRO are associated with high clinical burdens, including symptoms such as pain, itching, and fatigue, all of which affect the overall QoL of the patient. Here we explored PRO in patients with GPP outbreaks who received pessary Li Shan anti-treatment.

The method comprises the following steps: patients (n=53) were randomized (2:1) to receive placebo or 900mg of pessary Li Shan antibody on day 1 and were followed for 12 weeks. Before day 1 and 8, patients were able to receive standard of care (SoC) treatment at any time after receiving their first dose of pexored Li Shan antibody or placebo. Patients not receiving SoC treatment during week 1 were eligible to receive an Open Label (OL) eupatorium Li Shan antibody on day 8 and a rescue dose of OL eupatorium Li Shan antibody between day 8 and week 12.

Pendant Li Shan antibody group (n=35): one dose of peacable Li Shan anti (n=23) on day 1; a second dose of OL-pendant Li Shan antibody (n=12) optional on day 8; a third dose of OL-pendant Li Shan antibody (n=2) is optionally selected between week 1 and week 12.

Placebo group (n=18): a first dose of OL-pendant Li Shan antibody (n=15) optional on day 8; a second dose of OL pexol Li Shan anti (n=1) is optionally selected between week 1 and week 12.

Patients who have received a rescue dose of peacable Li Shan resistance are treated with pest-avoidance therapy (SoC) to treat any subsequent outbreaks. All randomized group patients were included in this analysis. Observations of any use of the OL pendant Li Shan antibody on day 8 or post rescue pendant Li Shan antibody therapy on day 8 (representing the intended therapeutic principle) that are not relevant to the pest-avoidance therapy are summarized in a descriptive manner. To monitor any changes in results, the patient completed the following PRO questionnaire throughout the study: psoriasis condition status scale [ PSS ], pain visual analog scale (pain VAS), chronic pain therapy functional assessment-fatigue (FACIT-fatigue) and dermatological quality of life index (DLQI; FIG. 10). All four PRO were measured on day 1, day 8 and weeks 2 to 4, week 8 and week 12. PSS scores were also measured daily during cycle 1 (4 to 7 day data not shown).

Conclusion: in this study, patients receiving 900mg of intravenous peacable Li Shan resistance exhibited clinically significant improvement in pain, psoriasis symptoms, fatigue, and overall quality of life PRO over baseline. Significant segregation of the pealine Li Shan anti-and placebo-profiles occurred earlier during the placebo-controlled phase (week 1) (fig. 11). This indicates that the resistance of the pendant Li Shan causes rapid improvement of PRO with considerable improvement in fatigue and pain. PRO scores continued to improve until week 4 and remained until week 12 (fig. 11).

Example 4

Anti-persistence therapeutic effect against pessary Li Shan in 12 weeks of outbreak of the impetigo; results from the Effiliayil-1 study

The goal of this study was to analyze the effect of pessary Li Shan on the treatment of patients who displayed outbreaks of generalized pustular psoriasis within 12 weeks.

In Effiliayil ^TM In a double blind, randomized, placebo-controlled study, anti-IL-36 receptor antibody pessary Li Shan was resistant to rapid clearance (within 1 week) of causing pustules and skin lesions in patients exhibiting outbreaks of generalized pustular psoriasis (GPP, a rare, life threatening autologous inflammatory disease). Here we explored the effect of pessary Li Shan against the duration of 12 weeks of the study (intended therapeutic analysis).

On day 1, patients (n=53) were randomized to receive a single intravenous dose of 900mg pessary Li Shan antibody (n=35) or placebo (n=18). On day 8, if the patient exhibits persistent symptoms, the patient is eligible to receive an open label dose of pessary Li Shan antibody; contains 12 eupatorium Li Shan resistant groups (34.3%) and 15 (83.3%) placebo patients. In patients randomized to peaked Li Shan antibody, receiving up to two doses (n=35), GPPGA pustule score of 0 was achieved at 61.8% and 84.4% at week 1 and week 12, respectively, and the total score of 0/1 was 50.0% and 81.3% GPPGA. Initially randomized to placebo, patients receiving open-label pexol Li Shan antibody on day 8 had a GPPGA pustule score of 0 at week 2 (1 week after pexol Li Shan antibody) and a GPPGA score of 0 at week 12 of 83.3% and 80.0% and a GPPGA total score of 0/1 of 72.2% and 93.3%, respectively. After day 8, 32 and 17 patients randomized to the peacable Li Shan antibody and placebo, respectively, completed a 12 week follow-up period during which four and two patients needed a new outbreak rescue treatment with the peacable Li Shan antibody.

The peacable Li Shan resistance exhibited rapid and sustained clinical improvement over 12 weeks. These data further support pessary Li Shan as a potential treatment option for patients with GPP outbreaks.

Example 5

Clinical immunogenicity evaluation results-test 1368-0013: pessary Li Shan resistance (BI 655130) was tested in patients with an onset of skin disease called generalized pustular psoriasis

The analysis method comprises the following steps: blood samples for evaluation of ADA/NAb were collected from individuals (patients) before the start and during the course of the peaked Li Shan anti-treatment, and at the end/break of the study. All samples were first analyzed in an ADA screening assay, and only those samples found to be putative positive were subsequently evaluated in an ADA validation assay. Only positive sample titration was confirmed to obtain the value. In addition, the development of NAb was evaluated only in individuals with ADA positive samples.

Evaluation of the resistance to the immunogenicity of peacable Li Shan was performed using data from all evaluable individuals, defined as individuals with baseline immunogenicity evaluation and at least 1 post-baseline value. For Jing Peisuo Li Shan anti-treated individuals, the baseline sample was considered the last sample obtained prior to the initiation of active treatment. For patients not treated with pessary Li Shan, the baseline sample was the last sample prior to receiving placebo treatment.

Test background: this was a randomized group with 2 treatment groups, placebo control, double blind, parallel, single dose trial (900 mg intravenous peacable Li Shan antibody and placebo on day 1). Depending on its GPPGA total score and GPPGA pustule score, the patient may be eligible to receive 900mg intravenous peacable Li Shan anti-Open Label (OL) treatment on day 8, and peacable Li Shan anti-rescue treatment after day 8. If the patient meets the inclusion criteria of the Open Label Extension (OLE) trial 1368-0025, the patient is proposed to follow into this OLE trial. The follow-up period for trial 1368-0013 was 12 to 28 weeks depending on the timing of the last dose of peacable Li Shan in trial 1368-0013 and whether the patient continued the OLE trial.

A total of 53 male and female patients with GPP were randomized to receive a single dose of intravenous 900mg pessary Li Shan (35 patients) or placebo (18 patients) on day 1 at a 2:1 ratio. Pessary Li Shan antibody was administered to a total of 27 patients as an open label dose on day 8 and to a total of 6 patients as a rescue medication after day 8.

Female (n=36) patients were randomized to more male (n=17) patients. All patients were asians (n=29) or caucasians (n=24). The average (StD) age was 43.0 (10.9) years and the average (StD) weight was 72.0 (24.7) kg.

PK and ADA/NAb samples were collected prior to dosing, day 4, week 1, week 2, week 3, week 4, week 8 and end of study. For patients not entering the OLE 1368-0025 trial, the study end visit was considered 16 weeks after the last dose of peaked Li Shan antibody. For patients who entered the OLE trial, the study end visit was week 12 or 6 weeks after the last dose if the patient received a rescue dose indirectly between weeks 7-12.

Anti-drug antibody/neutralizing antibody (ADA/Nab) reaction: in trial 1368-0013, 2 of the 53 randomized patients, randomized to placebo on day 1, did not receive any pessary Li Shan anti-treatment during the trial. All ADA samples from these 2 patients were negative. Of the 51 patient with peacable Li Shan resistance treatment, 50 patients were pre-baseline and post-baseline were assessed for ADA by available ADA assessment, including 1 patient receiving placebo on day 1 and OL rescue peacable Li Shan resistance after day 8. All 50 ADA evaluable patients were ADA negative at baseline.

The incidence of ADA+ patients observed in 1368-0013 was comparable to that observed in the proof of concept experiments 1368-0011. Overall, of the 50 ADA rated and petiole Li Shan resistant treated patients 23 (46%) were positive for ADA and 27 patients (54%) were negative for ADA for the duration of the trial. Twelve patients (24%) had a maximum titer of greater than 4000. Most (87%) ADA positive patients (40% of total treated patients) were also NAb positive and NAb status appears to be related to efficacy value. All ADA samples with potency values greater than 4000 were NAb positive. For ADA samples with potency values less than 4000, some were neutralized, while others were not. The lower the potency, the more likely the ADA sample is NAb negative. In ADA positive patients, ADA appeared earlier, with a median start time of 2.3 weeks and maximum titers reached at a median time of 11.7 weeks. In approximately 75% of patients, the maximum titer occurs at the last sample collected. The time to reach the maximum ADA titer and the titer itself can be influenced by the duration of the assay and the time of collection. In NAb positive patients, NAb was detected at a median start time of 6.7 weeks. At the end of the trial (12 to 17 weeks after the first active dose), ADA resolved in 4 out of 23 ADA positive patients (resolve). Nineteen (38% total ADA rated) patients remained ADA positive, 18 (36%) patients remained NAb positive, and 12 (24%) patients had titers greater than 4000.

ADA incidence was similar between patients treated with 1 dose of pessary Li Shan and patients receiving 2 doses. However, lower maximum ADA titers were observed for patients receiving 2 doses of intravenous pexored Li Shan antibody over the first 8 days (days 1 and 8) compared to patients receiving only 1 intravenous dose (table 10, fig. 12).

TABLE 10 trials 1368-0013: intravenous peacable Li Shan anti-treatment peacable Li Shan anti-ADA incidence and kinetics

¹ Patients who did not receive any pessary Li Shan resistance on day 1 or day 8 but received intravenous pessary Li Shan anti-rescue therapy at week 6 are also included.

² Irrespective of whether the patient received intravenous peace line Li Shan anti-rescue therapy after day 8

³ Last sample obtained before onset of active pendant Li Shan anti-treatment

^4,5,6,7,8,9 As defined in part 5.2.1 of BLA

In addition, females appear to have a higher immunogenic response. ADA occurrence rates in females and males were 58% and 24%, respectively. The percentage of patients with a maximum titer of greater than 4000 was 30% in women relative to 12% in men (table 11). Considering that the number of ADA positive male patients is small, there appears to be no significant difference in maximum titers between sexes.

TABLE 11 test 1368-0013: ADA incidence in female and male GPP patients after intravenous administration of pessary Li Shan resistance

Relationship of treatment initiation ADA/NAb to efficacy

For analysis, an ADA titer group is defined based on percentile points of maximum ADA titers in the patients. The maximum ADA titers observed in the experiments were used to differentiate 3 groups ([.ltoreq.33.3% percentile, 1440], [ >33.3% percentile and ltoreq.66.6% percentile ] and [ >66.6% percentile, 43200 ]) based on the maximum ADA titers. In addition, ADA distinguishes between NAb-negative and NAb-positive patients relative to efficacy analysis. For patients included in the NAb-negative group, all samples were either NAb-negative or ADA-negative. Patients included in the NAb positive group have at least 1 sample that is NAb positive.

Generally, in experiments 1368-0013, the proportion of patients with GPPGA pustule score of 0 or GPPGA total score of 0 or 1 was similar over time for ADA negative and ADA positive patients. When patients are grouped according to percentiles as defined above, the response rates over time for all 3 titer groups are generally similar. Thus, in general, this is also true when patients are classified by an effective value below 4000 and above 4000. At week 12, the response rate appears to decrease for patients with an efficacy value greater than 43200. Of 8 patients with an efficacy value greater than 43200, 4 individual scores decreased, while the other 4 did not. The decrease in response rate was less intense relative to the score itself, as 3 of the 4 patients had a 1 point increase.

Example 6

Peacable Li Shan anti-treatment improves CGI score via JDA severity index in GPP patients

In the effisayilm 1 test, patients with a generalized impetigo psoriasis (GPP) outbreak achieved pustule and skin clearance after receiving pessary Li Shan resistance. We report the change in JDA severity index Clinical Global Impression (CGI) score from baseline at week 1. Patients (n=53) were randomly assigned (2:1) to receive intravenous peacable Li Shan anti 900mg or placebo on day 1 and follow up for 12 weeks. In the peacable Li Shan resistant group (n=31), 67.7% of patients found improvement (scores 1 to 3), and 32.3% did not find improvement (scores 4 to 5). In the placebo group (n=15), 53.3% of patients found improvement, and 46.7% did not. A score of 1 (most improvement) was achieved by 76.2% of pessary Li Shan anti-improvement subjects. In summary, pexol Li Shan anti-treatment improved JDACGI scores for patients with GPP outbreaks compared to placebo.

While certain aspects and implementations of the present invention have been described, these aspects and implementations are presented by way of example only and are not intended to limit the scope of the invention. Indeed, the novel methods and systems described herein may be embodied in a variety of other forms without departing from the spirit thereof. The accompanying claims and their equivalents are intended to cover such forms or modifications as would fall within the scope and spirit of the invention.

All patents and/or publications including journal articles cited in this disclosure are expressly incorporated herein by reference.

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Glu Ser Val Thr Phe Ser Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg

100 105

<210> 11

<211> 119

<212> PRT

<213> Mus sp.

<400> 11

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Leu Pro Ser Thr Gly Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

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

65 70 75 80

Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

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

100 105 110

Thr Leu Val Thr Val Ser Ala

115

<210> 12

<211> 125

<212> PRT

<213> Mus sp.

<400> 12

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

1 5 10 15

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

20 25 30

Tyr Met Asn Trp Val Arg Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Gly Arg Thr Lys Asn Phe Tyr Ser Ser Tyr Ser Tyr Asp Asp Ala Met

100 105 110

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

115 120 125

<210> 13

<211> 124

<212> PRT

<213> Mus sp.

<400> 13

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

1 5 10 15

Ser Val Lys Phe Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Asp

20 25 30

Tyr Ile His Trp Val Arg Gln Arg Pro Glu Gln Gly Leu Glu Trp Val

35 40 45

Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Ala Pro Lys Phe

50 55 60

Gln Asp Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr

65 70 75 80

Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Ser Phe Pro Asn Asn Tyr Tyr Ser Tyr Asp Asp Ala Phe Ala

100 105 110

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

115 120

<210> 14

<211> 118

<212> PRT

<213> Mus sp.

<400> 14

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

1 5 10 15

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

20 25 30

Gly Val His Trp Ile Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Ala Gly Gly Pro Thr Asn Tyr Asn Ser Ala Leu Met

50 55 60

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

65 70 75 80

Arg Ile Asp Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala

85 90 95

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

100 105 110

Ser Val Thr Val Ser Ser

115

<210> 15

<211> 120

<212> PRT

<213> Mus sp.

<400> 15

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Gly Thr Gly Thr Gly Phe Tyr Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 16

<211> 119

<212> PRT

<213> Mus sp.

<400> 16

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

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

65 70 75 80

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

85 90 95

Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ala

115

<210> 17

<211> 119

<212> PRT

<213> Mus sp.

<400> 17

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Phe Asn Ala Pro Phe Lys

50 55 60

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

65 70 75 80

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

85 90 95

Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ala

115

<210> 18

<211> 119

<212> PRT

<213> Mus sp.

<400> 18

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

1 5 10 15

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

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ala

115

<210> 19

<211> 117

<212> PRT

<213> Mus sp.

<400> 19

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Val Ile Trp Pro Val Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met

50 55 60

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

65 70 75 80

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

85 90 95

Lys Met Asp Trp Asp Asp Phe Phe Asp Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Leu Thr Val Ser Ser

115

<210> 20

<211> 124

<212> PRT

<213> Mus sp.

<400> 20

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Pro Arg Phe

50 55 60

Gln Asp Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr

65 70 75 80

Leu His Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Ser Phe Pro Asp Asn Tyr Tyr Ser Tyr Asp Asp Ala Phe Ala

100 105 110

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

115 120

<210> 21

<211> 12

<212> PRT

<213> Mus sp.

<400> 21

Thr Ala Ser Ser Ser Val Ser Ser Ser Tyr Leu His

1 5 10

<210> 22

<211> 11

<212> PRT

<213> Mus sp.

<400> 22

Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Ala

1 5 10

<210> 23

<211> 11

<212> PRT

<213> Mus sp.

<400> 23

Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Gly

1 5 10

<210> 24

<211> 16

<212> PRT

<213> Mus sp.

<400> 24

Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu Gln

1 5 10 15

<210> 25

<211> 11

<212> PRT

<213> Mus sp.

<400> 25

Arg Ala Ser Gln Asp Ile Tyr Lys Tyr Leu Asn

1 5 10

<210> 26

<211> 12

<212> PRT

<213> Mus sp.

<400> 26

Thr Ala Ser Ser Ser Val Ser Ser Ser Tyr Phe His

1 5 10

<210> 27

<211> 11

<212> PRT

<213> Mus sp.

<400> 27

Lys Ala Ser Gln Asp Val Gly Thr Asn Val Leu

1 5 10

<210> 28

<211> 11

<212> PRT

<213> Mus sp.

<400> 28

Lys Ala Ser Gln Asn Val Gly Arg Ala Val Ala

1 5 10

<210> 29

<211> 11

<212> PRT

<213> Mus sp.

<400> 29

Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Gly

1 5 10

<210> 30

<211> 7

<212> PRT

<213> Mus sp.

<400> 30

Ser Thr Ser Asn Leu Ala Ser

1 5

<210> 31

<211> 7

<212> PRT

<213> Mus sp.

<400> 31

Ala Ala Thr Ser Leu Ala Asp

1 5

<210> 32

<211> 7

<212> PRT

<213> Mus sp.

<400> 32

Arg Ser Thr Thr Leu Ala Asp

1 5

<210> 33

<211> 7

<212> PRT

<213> Mus sp.

<400> 33

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 34

<211> 7

<212> PRT

<213> Mus sp.

<400> 34

Tyr Thr Ser Gly Leu His Ser

1 5

<210> 35

<211> 7

<212> PRT

<213> Mus sp.

<400> 35

Arg Thr Ser Asn Leu Ala Ser

1 5

<210> 36

<211> 7

<212> PRT

<213> Mus sp.

<400> 36

Ser Ala Ser Tyr Arg His Ser

1 5

<210> 37

<211> 7

<212> PRT

<213> Mus sp.

<400> 37

Ser Ala Ser Asn Arg Tyr Thr

1 5

<210> 38

<211> 7

<212> PRT

<213> Mus sp.

<400> 38

Arg Ala Thr Ser Leu Ala Asp

1 5

<210> 39

<211> 9

<212> PRT

<213> Mus sp.

<400> 39

His Gln His His Arg Ser Pro Val Thr

1 5

<210> 40

<211> 9

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 40

Gln Gln Val Tyr Thr Thr Pro Leu Thr

1 5

<210> 41

<211> 9

<212> PRT

<213> Mus sp.

<400> 41

Gln Gln Leu Tyr Ser Ala Pro Tyr Thr

1 5

<210> 42

<211> 9

<212> PRT

<213> Mus sp.

<400> 42

Phe Gln Gly Ser His Val Pro Phe Thr

1 5

<210> 43

<211> 9

<212> PRT

<213> Mus sp.

<400> 43

Gln Gln Asp Ser Lys Phe Pro Trp Thr

1 5

<210> 44

<211> 9

<212> PRT

<213> Mus sp.

<400> 44

His Gln Phe His Arg Ser Pro Leu Thr

1 5

<210> 45

<211> 9

<212> PRT

<213> Mus sp.

<400> 45

Gln Gln Tyr Ser Arg Tyr Pro Leu Thr

1 5

<210> 46

<211> 9

<212> PRT

<213> Mus sp.

<400> 46

Gln Gln Tyr Ser Ser Tyr Pro Leu Thr

1 5

<210> 47

<211> 9

<212> PRT

<213> Mus sp.

<400> 47

Gln Gln Leu Tyr Ser Gly Pro Tyr Thr

1 5

<210> 48

<211> 10

<212> PRT

<213> Mus sp.

<400> 48

Gly Asn Thr Val Thr Ser Tyr Trp Met His

1 5 10

<210> 49

<211> 10

<212> PRT

<213> Mus sp.

<400> 49

Gly Tyr Thr Phe Thr Asp Asn Tyr Met Asn

1 5 10

<210> 50

<211> 10

<212> PRT

<213> Mus sp.

<400> 50

Gly Phe Asn Ile Lys Asp Asp Tyr Ile His

1 5 10

<210> 51

<211> 10

<212> PRT

<213> Mus sp.

<400> 51

Gly Phe Ser Leu Thr Lys Phe Gly Val His

1 5 10

<210> 52

<211> 10

<212> PRT

<213> Mus sp.

<400> 52

Gly Phe Ser Leu Ser Ser Tyr Glu Ile Asn

1 5 10

<210> 53

<211> 10

<212> PRT

<213> Mus sp.

<400> 53

Gly Tyr Ser Phe Thr Ser Ser Trp Ile His

1 5 10

<210> 54

<211> 10

<212> PRT

<213> Mus sp.

<400> 54

Gly Phe Ser Leu Thr Asn Tyr Ala Val His

1 5 10

<210> 55

<211> 10

<212> PRT

<213> Mus sp.

<400> 55

Gly Phe Ser Leu Thr Asn Tyr Gly Val His

1 5 10

<210> 56

<211> 10

<212> PRT

<213> Mus sp.

<400> 56

Gly Phe Asn Ile Lys Asp Asp Tyr Ile His

1 5 10

<210> 57

<211> 17

<212> PRT

<213> Mus sp.

<400> 57

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

1 5 10 15

Gly

<210> 58

<211> 17

<212> PRT

<213> Mus sp.

<400> 58

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

1 5 10 15

Gly

<210> 59

<211> 17

<212> PRT

<213> Mus sp.

<400> 59

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

1 5 10 15

Asp

<210> 60

<211> 16

<212> PRT

<213> Mus sp.

<400> 60

Val Ile Trp Ala Gly Gly Pro Thr Asn Tyr Asn Ser Ala Leu Met Ser

1 5 10 15

<210> 61

<211> 16

<212> PRT

<213> Mus sp.

<400> 61

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

1 5 10 15

<210> 62

<211> 15

<212> PRT

<213> Mus sp.

<400> 62

Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe

1 5 10 15

<210> 63

<211> 16

<212> PRT

<213> Mus sp.

<400> 63

Val Ile Trp Ser Asp Gly Ser Thr Asp Phe Asn Ala Pro Phe Lys Ser

1 5 10 15

<210> 64

<211> 16

<212> PRT

<213> Mus sp.

<400> 64

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

1 5 10 15

<210> 65

<211> 16

<212> PRT

<213> Mus sp.

<400> 65

Val Ile Trp Pro Val Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met Ser

1 5 10 15

<210> 66

<211> 17

<212> PRT

<213> Mus sp.

<400> 66

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

1 5 10 15

Asp

<210> 67

<211> 10

<212> PRT

<213> Mus sp.

<400> 67

Val Tyr Phe Gly Asn Pro Trp Phe Ala Tyr

1 5 10

<210> 68

<211> 16

<212> PRT

<213> Mus sp.

<400> 68

Thr Lys Asn Phe Tyr Ser Ser Tyr Ser Tyr Asp Asp Ala Met Asp Tyr

1 5 10 15

<210> 69

<211> 15

<212> PRT

<213> Mus sp.

<400> 69

Ser Phe Pro Asn Asn Tyr Tyr Ser Tyr Asp Asp Ala Phe Ala Tyr

1 5 10 15

<210> 70

<211> 10

<212> PRT

<213> Mus sp.

<400> 70

Gln Ile Tyr Tyr Ser Thr Leu Val Asp Tyr

1 5 10

<210> 71

<211> 12

<212> PRT

<213> Mus sp.

<400> 71

Gly Thr Gly Thr Gly Phe Tyr Tyr Ala Met Asp Tyr

1 5 10

<210> 72

<211> 10

<212> PRT

<213> Mus sp.

<400> 72

Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr

1 5 10

<210> 73

<211> 11

<212> PRT

<213> Mus sp.

<400> 73

Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr

1 5 10

<210> 74

<211> 9

<212> PRT

<213> Mus sp.

<400> 74

Met Asp Trp Asp Asp Phe Phe Asp Tyr

1 5

<210> 75

<211> 15

<212> PRT

<213> Mus sp.

<400> 75

Ser Phe Pro Asp Asn Tyr Tyr Ser Tyr Asp Asp Ala Phe Ala Tyr

1 5 10 15

<210> 76

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 76

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

1 5 10 15

Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 77

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 77

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

1 5 10 15

Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 78

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 78

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

1 5 10 15

Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 79

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 79

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

1 5 10 15

Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 80

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 80

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

1 5 10 15

Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 81

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 81

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

1 5 10 15

Glu Arg Val Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 82

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 82

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

1 5 10 15

Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 83

<211> 108

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 83

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

1 5 10 15

Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 84

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 84

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

1 5 10 15

Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn

20 25 30

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

35 40 45

Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile Pro Asp 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 Glu Tyr Phe Cys Gln Gln Tyr Ser Arg Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 85

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 85

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

1 5 10 15

Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn

20 25 30

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

35 40 45

Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile Pro Asp 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 Ser Arg Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 86

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 86

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

1 5 10 15

Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn

20 25 30

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

35 40 45

Tyr Ser Ala Ser Tyr Arg His Ser 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 Glu Tyr Tyr Cys Gln Gln Tyr Ser Arg Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 87

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 87

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Lys Ala Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 88

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 88

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

1 5 10 15

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

20 25 30

Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Arg Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 89

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 89

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 90

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 90

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Arg Ala Thr Leu Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 91

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 91

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Leu Pro Gly Val Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 92

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 92

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

1 5 10 15

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

20 25 30

Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Arg Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 93

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 93

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Asn Pro Gly Leu Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 94

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 94

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 95

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 95

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Asn Pro Gly Ser Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Lys Ala Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 96

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 96

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

1 5 10 15

Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Lys Met Ser Ser Val Gln Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 97

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 97

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

1 5 10 15

Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 98

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 98

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

1 5 10 15

Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Lys Met Asn Ser Val Thr Val Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 99

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 99

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

1 5 10 15

Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 100

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 100

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Phe Asn Ala Pro Phe Lys

50 55 60

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

65 70 75 80

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

85 90 95

Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 101

<211> 119

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 101

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

1 5 10 15

Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 102

<211> 7

<212> PRT

<213> Mus sp.

<400> 102

Arg Thr Ser Thr Leu Ala Ser

1 5

<210> 103

<211> 7

<212> PRT

<213> Mus sp.

<400> 103

Arg Thr Ser Ile Leu Ala Ser

1 5

<210> 104

<211> 7

<212> PRT

<213> Mus sp.

<400> 104

Arg Thr Ser Arg Leu Ala Ser

1 5

<210> 105

<211> 7

<212> PRT

<213> Mus sp.

<400> 105

Arg Thr Ser Gln Leu Ala Ser

1 5

<210> 106

<211> 7

<212> PRT

<213> Mus sp.

<400> 106

Arg Thr Ser Lys Leu Ala Ser

1 5

<210> 107

<211> 10

<212> PRT

<213> Mus sp.

<400> 107

Gly Phe Ser Leu Thr Asp Tyr Ala Val His

1 5 10

<210> 108

<211> 15

<212> PRT

<213> Mus sp.

<400> 108

Glu Ile Leu Pro Gly Val Val Arg Thr Asn Tyr Asn Glu Asn Phe

1 5 10 15

<210> 109

<211> 15

<212> PRT

<213> Mus sp.

<400> 109

Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe

1 5 10 15

<210> 110

<211> 15

<212> PRT

<213> Mus sp.

<400> 110

Glu Ile Asn Pro Gly Leu Val Arg Thr Asn Tyr Asn Glu Asn Phe

1 5 10 15

<210> 111

<211> 15

<212> PRT

<213> Mus sp.

<400> 111

Glu Ile Asn Pro Gly Ser Val Arg Thr Asn Tyr Asn Glu Asn Phe

1 5 10 15

<210> 112

<211> 330

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 112

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

Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Ala Ala 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 Glu Glu

225 230 235 240

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

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

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 113

<211> 107

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 113

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

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

20 25 30

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

35 40 45

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

50 55 60

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

65 70 75 80

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

85 90 95

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

100 105

<210> 114

<211> 215

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 114

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

1 5 10 15

Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

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

130 135 140

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

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

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

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 115

<211> 215

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 115

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

1 5 10 15

Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

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

130 135 140

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

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

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

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 116

<211> 215

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 116

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

1 5 10 15

Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

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

130 135 140

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

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

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

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 117

<211> 215

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 117

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

1 5 10 15

Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

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

130 135 140

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

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

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

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 118

<211> 215

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 118

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

1 5 10 15

Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

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

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

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

130 135 140

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

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

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

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 119

<211> 215

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 119

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

1 5 10 15

Glu Arg Val Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

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

130 135 140

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

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

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

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 120

<211> 215

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 120

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

1 5 10 15

Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

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

130 135 140

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

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

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

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 121

<211> 215

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 121

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

1 5 10 15

Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

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

130 135 140

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

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

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

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 122

<211> 214

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 122

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

1 5 10 15

Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn

20 25 30

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

35 40 45

Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile Pro Asp 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 Glu Tyr Phe Cys Gln Gln Tyr Ser Arg Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 123

<211> 214

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 123

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

1 5 10 15

Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn

20 25 30

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

35 40 45

Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile Pro Asp 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 Ser Arg Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 124

<211> 214

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 124

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

1 5 10 15

Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn

20 25 30

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

35 40 45

Tyr Ser Ala Ser Tyr Arg His Ser 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 Glu Tyr Tyr Cys Gln Gln Tyr Ser Arg Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

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

115 120 125

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

130 135 140

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

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

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

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 125

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 125

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Lys Ala Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 126

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 126

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

1 5 10 15

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

20 25 30

Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Arg Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 127

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 127

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 128

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 128

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Arg Ala Thr Leu Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 129

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 129

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Leu Pro Gly Val Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 130

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 130

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

1 5 10 15

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

20 25 30

Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Arg Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 131

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 131

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Asn Pro Gly Leu Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 132

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 132

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 133

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 133

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Glu Ile Asn Pro Gly Ser Val Arg Thr Asn Tyr Asn Glu Asn Phe

50 55 60

Arg Asn Lys Ala Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

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

85 90 95

Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 134

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 134

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

1 5 10 15

Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Lys Met Ser Ser Val Gln Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 135

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 135

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

1 5 10 15

Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 136

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 136

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

1 5 10 15

Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

Lys Met Asn Ser Val Thr Val Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 137

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 137

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

1 5 10 15

Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 138

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 138

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

1 5 10 15

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

20 25 30

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

35 40 45

Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Phe Asn Ala Pro Phe Lys

50 55 60

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

65 70 75 80

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

85 90 95

Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 139

<211> 449

<212> PRT

<213> artificial sequence

<220>

<223> description of artificial sequence synthetic polypeptide

<400> 139

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

1 5 10 15

Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr

20 25 30

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

35 40 45

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

50 55 60

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

65 70 75 80

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

85 90 95

Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe

115 120 125

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

130 135 140

Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp

145 150 155 160

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

165 170 175

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

180 185 190

Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro

195 200 205

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

210 215 220

Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro

225 230 235 240

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

245 250 255

Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp

260 265 270

Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn

275 280 285

Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val

290 295 300

Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu

305 310 315 320

Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys

325 330 335

Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr

340 345 350

Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr

355 360 365

Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu

370 375 380

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

385 390 395 400

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

405 410 415

Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu

420 425 430

Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly

435 440 445

Lys

<210> 140

<211> 7

<212> PRT

<213> Mus sp.

<400> 140

Arg Thr Ser His Leu Ala Ser

1 5

Claims

1. A method of treating an outbreak of Generalized Pustular Psoriasis (GPP) in a patient, the method comprising administering to the subject two 900mg intravenous (i.v.) doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

2. A method of treating GPP in a patient, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

3. A method of reducing or alleviating signs and symptoms of acute phase disease initiation of GPP in a patient, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

4. A method of reducing the severity and duration of a GPP symptom, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

5. A method of treating a skin disorder associated with GPP, said treatment comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

6. A method of preventing a relapse of a GPP outbreak in a patient, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

7. A method of reducing pain by at least 10% in a patient having GPP, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

8. A method of improving the quality of life of at least 10% in a patient suffering from moderate to severe GPP symptoms, the method comprising administering to the patient two 900mg intravenous doses of an anti-IL-36R antibody; wherein the second dose is administered less than 2 weeks after the first dose.

9. The method of any of the preceding claims, wherein the patient's GPP physician global assessment (GPPGA) total score is ≡2.

10. The method of any one of the preceding claims, wherein the patient's GPP physician overall assessment (GPPGA) total score is ≡2 and GPPGA pustule score is ≡2.

11. The method of any one of the preceding claims, wherein the patient's GPP physician overall evaluation (GPPGA) total score ∈2 and GPPGA pustule score ∈2 prior to administration of the first i.v. dose.

12. The method of any one of the preceding claims, wherein after administration of the first i.v. dose, the patient's GPP physician overall evaluation (GPPGA) total score ∈2 and GPPGA pustule score ∈2.

13. The method of any one of the preceding claims, wherein the patient's GPP physician overall evaluation (GPPGA) total score ∈2 and GPPGA pustule score ∈2, before and after administration of the first i.v. dose.

14. The method of any one of the preceding claims, wherein the second dose is administered 1 week but less than 2 weeks after the first dose.

15. A method of treating a GPP patient having a GPPGA pustule score of ∈2, the method comprising the steps of: (a) Administering to the patient a first 900mg intravenous (i.v.) dose of an anti-IL-36R antibody; (b) The patient's GPPGA pustule score is evaluated, and if the GPPGA pustule score of the patient ∈2 persists after 1 week after the first dose, the patient is administered a second 900mg (i.v.) dose of peacable Li Shan anti (spiolimia) less than 2 weeks after the first dose.

16. A method of treating a GPP patient having a general rating of GPPGA equal to or greater than 2 for a global assessment by a GPP physician, the method comprising the steps of: (a) Administering to the patient a first 900mg intravenous (i.v.) dose of an anti-IL-36R antibody; (b) The patient's total GPPGA score is assessed, and if the patient's total GPPGA score of ∈2 persists after 1 week after the first dose, a second 900mg (i.v.) dose of pessary Li Shan antibody is administered to the patient less than 2 weeks after the first dose.

17. A method of treating a GPP patient having a general GPPGA score of > 2 and a GPPGA pustule score of > 2, the method comprising the steps of: (a) Administering to the patient a first 900mg intravenous (i.v.) dose of an anti-IL-36R antibody; (b) The patient's GPPGA score is evaluated, and if the patient's GPPGA total score of ∈2 and the GPPGA pustular score of ∈2 persist after 1 week after the first dose, a second 900mg (i.v.) dose of pessary Li Shan antibody is administered to the patient less than 2 weeks after the first dose.

18. The method of any one of the preceding claims, wherein an optional third 900mg i.v. dose of the anti-IL-36R antibody is administered 2 to 12 weeks after the second intravenous dose.

19. The method of any one of the preceding claims, wherein two dose administrations achieve one or more of the following results:

(a) A Generalized Pustular Psoriasis Global Assessment (GPPGA) pustular score of 0 shown within one week after administration of the second intravenous dose;

(b) Within one week after administration of the second intravenous dose, the GPPGA total score is 0 or 1; and/or

(c) The maximum ADA titers at 2, 4, 6, 8, 10 or 12 weeks after administration of the second intravenous dose are lower.

20. The method of claim 19, wherein said results are maintained for up to and at least 12 weeks after administration of the second i.v. dose.

21. The method of any one of the preceding claims, wherein the method further comprises administering a prophylactically effective amount of the anti-IL-36R antibody to the patient in one or more subcutaneous doses after administration of the last i.v. dose.

22. The method of claim 21, wherein each of the one or more subcutaneous doses comprises 150mg, 225mg, 300mg, 450mg, or 600mg of the anti-IL-36R antibody.

23. The method of claim 22, wherein 1, 2, 3 or more subcutaneous doses are administered to the patient, and wherein a first subcutaneous dose is administered after the last intravenous dose.

24. The method of claim 23, wherein a first subcutaneous dose is administered 2 to 8 weeks, 4 to 6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks, 12 weeks, 16 weeks, 20 weeks after the last intravenous dose, and a subsequent subcutaneous dose is administered at 2, 4, 6, 8, 10, or 12 week intervals after the first subcutaneous dose.

25. The method of any one of the preceding claims, wherein the patient maintains clinical relief for at least 12, 24, 36, 48, 60, or 72 weeks after the last i.v. or subcutaneous dose, as measured by GPPGA total score of 0 or 1.

26. The method of any one of the preceding claims, wherein the anti-IL-36R antibody comprises: a) A light chain variable region comprising the amino acid sequence SEQ ID NO. 26 (L-CDR 1); amino acid sequence SEQ ID NO:35, 102, 103, 104, 105, 106 or 140 (L-CDR 2); the amino acid sequence SEQ ID NO. 44 (L-CDR 3); and b) a heavy chain variable region comprising the amino acid sequence SEQ ID NO:53 (H-CDR 1); the amino acid sequence SEQ ID NO. 62, 108, 109, 110 or 111 (H-CDR 2); the amino acid sequence SEQ ID NO:72 (H-CDR 3).

27. The method of any one of the preceding claims, wherein the anti-IL-36R antibody comprises:

30. The method of any one of the preceding claims, wherein the anti-IL-36R antibody is a pessary Li Shan antibody.