Use Of Anti-il-36r Antibodies For Treatment Of Generalized Pustular Psoriasis

Abstract

The present invention relates to the treatment of or alleviation of signs and symptoms of an acute phase flare-up of generalized pustular psoriasis (GPP) with anti-IL36R antibodies.

Description

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Nos. 62/642,641 (filed Mar. 14, 2018), 62/683,720 (filed Jun. 12, 2018), 62/699,274 (filed Jul. 17, 2018) and 62/729,518 (filed Sep. 11, 2018), the entire content of each of which is hereby incorporated herein by reference as though fully set forth herein.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Mar. 5, 2019, is named 09-0683-US-4-2019-03-08-SL.txt and is 146,018 bytes in size.

TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates to methods and compositions for treatment of generalized pustular psoriasis (GPP). More specifically, the invention relates to administration of an interleukin-36 receptor (IL-36R) antibody to a subject with GPP.

BACKGROUND

[0004] GPP is a severe skin disease characterized by the repeated occurrence of acute flares caused by systemic inflammation affecting the skin and internal organs. The classic presentation of acute GPP was first described as a recurrent pustular form of psoriasis by von Zumbusch in 1909. While GPP and plaque psoriasis can occur at the same time in an individual patient, GPP is distinct from plaque psoriasis in clinical presentation, pathophysiology, histopathology, response to therapies, epidemiology and genetics.

[0005] Therefore, it is very critical to differentiate GPP from plaque or erythrodermic psoriasis with secondary pustulation. The clinical presentation of GPP is quite different from psoriasis vulgaris (PV) in its' episodic nature, often with normal appearing skin between very acute and severe disease flares. GPP is clinically characterized by the preponderance of pustules as the primary lesion on an erythematous base rather than red plaques covered with silvery scales representing the primary lesion of typical plaque psoriasis. In addition, the histopathological hallmarks of GPP are distinct spongiform pustules of Kogoj located in the subcorneal portion of the epidermis. GPP may be associated with systemic symptoms (fever, increased CRP and neutrophilia) and severe extra-cutaneous organ manifestations (liver, kidney failure, CV shock). While patients with GPP may have pre-existing or co-existing PV, it is possible to clinically distinguish patients with primary plaque disease (PV) who have a secondary pustular component from patients who have primary pustular disease (GPP) with a concomitant plaque component, based on the sequence of manifestations (primary lesion pustule rather than plaque) and the localization of a GPP pustule on an erythematous base rather than a PsO plaque.

[0006] As descriptions for GPP are discordant among standard dermatology textbooks, the European Rare And Severe Psoriasis Expert Network (ERASPEN) has defined consensus criteria that include as key diagnosis criteria for acute GPP the presence of primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulation is restricted to psoriatic plaques), with or without systemic inflammation, with or without plaque-type psoriasis, either relapsing (>1 episode) or persistent (>3 months).

[0007] Chronic GPP describes the state in between disease flares that may be characterized by the complete absence of symptoms or the persistence of residual skin symptoms such as erythema and scaling and minor pustulation.

[0008] Current treatment options for controlling acute GPP and subcutaneous of response are limited and do not provide sustained efficacy. No treatments are currently approved for GPP in the US and EU, though retinoids, cyclosporine or methotrexate are being recommended. Although these treatments are described to be "remarkably effective or effective" in 70-84% of patients (J Am Acad Dermatol. 2012; 67(2):279-88) these data are based on a retrospective cohort study from Japan without clearly defined endpoints (Japanese Journal of Dermatology. 2010; 120(4):815-39). Furthermore, these treatments cannot be used long-term due to side effects and contraindications (retinoids: teratogenicity, hair loss; cyclosporine: excessive hair growth, renal toxicity; MTX: liver toxicity).

[0009] Biologics (mostly TNF inhibitors, occasionally IL-1 or IL-17 inhibitors) are increasingly used to treat more severe, extensive or treatment resistant patients with GPP, based on small published case series. However, these drugs are also associated with limitations in efficacy (incomplete and delayed responses are frequent) and safety as well as contraindications (infusion reactions, tuberculosis, cardiovascular disease). Thus, a need exists in the art for novel targeted therapies for the treatment and/or prevention of GPP.

SUMMARY OF THE INVENTION

[0010] The present invention addresses the above need by providing biotherapeutics, in particular antibodies, which bind to IL-36R and provide therapeutic or prophylactic therapy for acute and/or chronic GPP and the associated signs and symptoms such as GPP flares.

[0011] In a first aspect, the present invention relates to a method of treating generalized pustular psoriasis (GPP) in a patient, said method including administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody.

[0012] In a second aspect, the present invention relates to a method of treating moderate to severe GPP in a patient, including administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody.

[0013] In a third aspect, the present invention relates to a method of reducing or alleviating signs and symptoms of an acute phase flare-up of GPP in a patient, said method including administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody.

[0014] In a forth aspect, the present invention relates to a method of reducing the severity and duration of GPP flares, said method comprising including administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody.

[0015] In a fifth aspect, the present invention relates to a method of treating a skin disorder associated with acute GPP, said method including administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody.

[0016] In one embodiment related to any of aspects first to fifth, the anti-IL-36R antibody includes: a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105 106 or 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0017] In one embodiment related to any of aspects first to fifth, the anti-IL-36R antibody includes:

[0018] I. a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 102 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0019] II. a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 103 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0020] III. a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 104 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0021] IV. a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 105 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0022] V. a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 106 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0023] VI. a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0024] In one embodiment related to any of aspects first to fifth, the anti-IL-36R antibody includes:

[0025] (i) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or

[0026] (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or

[0027] (iii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or

[0028] (iv) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or

[0029] (v) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or

[0030] (vi) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or

[0031] (vii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or

[0032] (viii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101; or

[0033] (ix) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or

[0034] (x) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101.

[0035] In one embodiment related to any of aspects first to fifth, the anti-IL-36R antibody includes:

[0036] i. a light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125; or

[0037] ii. a light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126; or

[0038] iii. a light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or

[0039] iv. a light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125; or

[0040] v. a light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126; or

[0041] vi. a light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or

[0042] vii. a light chain comprising the amino acid sequence of SEQ ID NO: 123; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138; or

[0043] viii. a light chain comprising the amino acid sequence of SEQ ID NO: 123; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 139; or

[0044] ix. a light chain comprising the amino acid sequence of SEQ ID NO: 124; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138.

[0045] In one embodiment related to any of aspects first to fifth, the anti-IL-36R antibody is administered in one or more intravenous dose(s). In a related embodiment, each of the one or more intravenous dose(s) includes 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg of said anti-IL-36R antibody.

[0046] In another embodiment related to any of aspects first to fifth, the anti-IL-36R antibody is administered in one intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R is administered in one intravenous dose of about 10 mg per kilogram of body weight of the patient. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 210 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 300 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 350 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 450 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 600 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 700 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 750 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 800 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 850 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 900 mg.

[0047] In another embodiment related to any of aspects first to fifth, 1, 2 or 3 intravenous dose(s) is/are administered. In another embodiment related to any of the above aspects, 2 or 3 intravenous doses are administered at 2, 4, 6, 8, 10 or 12 weeks intervals.

[0048] In another embodiment related to any of the above embodiments or aspects first to fifth, the administration results in one or more of the following efficacy endpoints:

[0049] (a) Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 or 1 at Week 1;

[0050] (b) GPPGA pustulation subscore of 0 indicating no visible pustules at Week 1;

[0051] (c) Psoriasis Area and Severity Index for Generalized Pustular Psoriasis (GPPASI) 75 at Week 4;

[0052] (d) Change from baseline in Pain Visual Analog Scale (VAS) score at Week 4;

[0053] (e) Change from baseline in Psoriasis Symptom Scale (PSS) score at Week 4;

[0054] (f) Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue score at Week 4;

[0055] (g) GPPGA 0 or 1 at Week 4;

[0056] (h) GPPGA pustulation subscore of 0 indicating no visible pustules at Week 4;

[0057] (i) GPPASI 50 at Week 1 and 4; or

[0058] (j) Change in GPPASI pustule, erythema or scaling severity subscore from baseline at Week 1 and 4.

[0059] In another embodiment related to the above embodiment, proportion of patients with a response to the administration is statistically significantly higher as compared to patients on placebo for one or more of end points (a)-(j).

[0060] In a sixth aspect, the present invention relates to a method of preventing the recurrence of GPP flares in a patient treated with one or more intravenous dose(s) of the anti-IL-36R antibody according to any of aspects first to fifth or the above embodiments, said method including administering to the patient a prophylactically effective amount of the anti-IL-36R antibody in one or more subcutaneous doses.

[0061] In a seventh aspect, the present invention relates to a method of achieving a Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 in a patient treated with one or more intravenous dose(s) of the anti-IL-36R antibody according to any of aspects first to fifth or the above embodiments, said method including administering to the patient an effective amount of the anti-IL-36R antibody in one or more subcutaneous doses.

[0062] In an eight aspect, the present invention relates to a method of achieving a complete resolution of GPP symptoms in a patient treated with one or more intravenous dose(s) of the anti-IL-36R antibody according to any of aspects first to fifth or the above embodiments, said method comprising administering to the patient an effective amount of the anti-IL-36R antibody in one or more subcutaneous doses; wherein the GPP symptoms comprise postule, erythema, or scaling and the complete resolution comprises a GPPGA score of 0.

[0063] In one embodiment related to any of aspects sixth to eight, each of the one or more subcutaneous doses includes 150 mg, 225 mg, 300 mg, 450 mg or 600 mg of said anti-IL-36R antibody.

[0064] In one embodiment related to any of aspects sixth to eight or the related embodiment(s), 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.

[0065] In one embodiment related to any of aspects sixth to eight or the related embodiment(s), the first subcutaneous dose is administered 2 to 8 weeks, 4 to 6 weeks, 2 weeks, 4 weeks, 6 weeks or 8 weeks, after the last intravenous dose is administered and the second subcutaneous dose is administered 4, 6, 8, 10 or 12 weeks after said first subcutaneous dose is administered.

[0066] In one embodiment related to any of aspects sixth to eight or the related embodiment(s), at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a GPPGA score of 0 or 1 at Week 12, 24, 36, 48, 60 or 72 of the treatment.

[0067] In one embodiment related to any of aspects sixth to eight or the related embodiment(s), at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a change in GPPASI from baseline at Week 12, 24, 36, 48, 60 or 72 of the treatment.

[0068] In one embodiment related to any of aspects sixth to eight or the related embodiment(s), at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a change in GPPASI pustule, erythema or scaling severity subscore from baseline at Week 12, 24, 36, 48, 60 or 72 of the treatment. In a related embodiment, proportion of patients with a response to the administration is statistically significantly higher as compared to patients on placebo for any of the end points recited.

[0069] In a ninth aspect, the present invention relates to a method of treating GPP in a patient, including administering to the patient a therapeutically effective amount of one or more intravenous dose(s) of the anti-IL-36R antibody, according to aspects first to fifth and their related embodiments, followed by one or more subcutaneous dose(s) of the anti-IL-36R antibody.

[0070] In one embodiment relating to aspect ninth, 1 or 2 or 3 intravenous dose(s) of the anti-IL-36R antibody is/are followed by 1 or 2 or 3 subcutaneous dose(s) of the anti-IL-36R antibody.

[0071] In one embodiment relating to aspect ninth, 1 intravenous dose of the anti-IL-36R antibody is followed by 1 or 2 or 3 subcutaneous doss(s) of the anti-IL-36R antibody.

[0072] In one embodiment relating to aspect ninth, 2 intravenous doses of the anti-IL-36R antibody are followed by 1 or 2 or 3 subcutaneous doss(s) of the anti-IL-36R antibody.

[0073] In one embodiment relating to aspect ninth, 3 intravenous doses of the anti-IL-36R antibody are followed by 1 or 2 or 3 subcutaneous doss(s) of the anti-IL-36R antibody.

[0074] In one embodiment relating to aspect ninth and its related embodiment, each of the one or more intravenous dose(s) includes 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg, 850 mg or 900 mg of the anti-IL-36R antibody and each of the one or more subcutaneous dose(s) includes 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of the anti-IL-36R antibody. In a related embodiment, the intravenous doses are administered at 2, 4, 6, 8, 10 or 12 weeks intervals, the subcutaneous doses are administered at 4, 6, 8, 10 or 12 weeks intervals, and the first subcutaneous dose is administered 2 to 8 weeks, 4 to 6 weeks, 2 weeks, 4 weeks, 6 weeks or 8 weeks after the last intravenous dose is administered.

[0075] In an embodiment relating to any of the above aspects, the intravenous dose(s) may be followed by one or more subcutaneous dose(s).

[0076] In an embodiment relating to any of the above aspects, the anti-IL-36R antibody or an antigen binding fragment thereof (disclosed herein) is present in a stable pharmaceutical formulation (as described in co-pending U.S. provisional application No. 62/815,405, filed Mar. 8, 2019, the entire content of which is hereby incorporated herein by reference in its entirety) for administration to a mammal or patient according to any one of the aspects of the present invention.

[0077] In one embodiment, the method of treatment according to any of the aspects described herein, includes administering to the mammal or patient a therapeutic amount of a stable pharmaceutical formulation comprising from about 20 mg/mL to about 150 mg/mL of an anti-IL-36R antibody (disclosed herein), about 20 mM to about 80 mM of a pharmaceutically acceptable buffer (e.g., acetate buffer), about 100 mM to about 250 mM of a pharmaceutically acceptable tonicifying agent (e.g., sucrose), about 0 mM to about 80 mM of a pharmaceutically acceptable stabilizing agent (e.g., arginine) or a pharmaceutically acceptable salt thereof, about 0 to about 150 mM of a pharmaceutically acceptable salt (e.g., sodium chloride), and a pharmaceutically acceptable surfactant (e.g., polysorbate 20) in an amount about 0 g/L to about 1.5 g/L, wherein the generalized pustular psoriasis (GPP) in the patient is treated, or the moderate to severe GPP in the patient is treated, or the signs and symptoms of an acute phase flare-up of GPP in the patient is reduced or alleviated, or the severity and duration of GPP flares in the patient is reduced, or the skin disorder associated with acute GPP in the patient is treated, or the GPP flares in a patient is prevented or inhibited, or the Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 in the patient is achieved, or the complete resolution of GPP symptoms in the patient is achieved, In a related embodiment, the stable pharmaceutical formulation is an aqueous pharmaceutical formulation. In a related embodiment, the pH of the aqueous pharmaceutical formulation is about 5 to about 7. In a related embodiment, the pharmaceutical formulation is for an intravenous administration to the mammal or patient. In a related embodiment, the pharmaceutical formulation is for a subcutaneous administration to the mammal or patient. In a related embodiment, the pharmaceutical formulation for an intravenous administration comprises an anti-IL-36R antibody in an amount of about 60 mg/mL. In a related embodiment, the pharmaceutical formulation for a subcutaneous administration comprises an anti-IL-36R antibody in an amount of about 150 mg/mL.

[0078] In a tenth aspect, the present invention relates to a method of treating GPP in a patient, including

[0079] (a) obtaining a biological sample from said patient, wherein the biological sample is obtained from source including lesional skin or whole blood;

[0080] (b) determining the gene express profile of one or more of genes;

[0081] (c) administering to the patient an effective amount of the anti-IL-36R antibody according to any embodiments relating to aspects first to fifth.

[0082] In one embodiment relating to aspect tenth, the one or more of genes are IL12B, IL1B, IL6, CXCL1, IL23A, TNF, IL17C, IL24 or IL1B in lesional skin, and IL1B, S100A9, S100A12, S100A8, MMP25, MMP9 or CD177 in whole blood.

[0083] Additional features and advantages of the present invention will be set forth in the description below, and in part will be apparent from the description, or may be learned by practice of the subject 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 present invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

[0084] The accompanying drawings, which are included to provide further understanding of the present invention and are incorporated in and constitute a part of this specification, illustrate aspects of the subject technology and together with the description serve to explain the principles of the present invention.

[0085] FIG. 1 shows changes in clinical responses with an anti-IL-36R antibody of the present invention treatment through Week 20; Panel A shows the percentage of patients in whom a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 (clear) or 1 (almost clear) was achieved; Panel B shows the percent change from baseline in Generalized Pustular Psoriasis Area and Severity Index (GPPASI); and Panel C shows the percentage of patients in whom pustule clearance (based upon the GPPASI pustule component severity score) was achieved. Analysis includes all patients with at least one available post-baseline value. One patient received methotrexate post Week 4 for treatment of "pain" and therefore data for Weeks 12 and 20 have been excluded (set to non-response for GPPGA and pustule clearance). By Week 1, two of the three patients with an IL36RN mutation achieved GPPGA 0 or 1; by Week 4, all three patients achieved GPPGA 0 or 1. * At Week 2, GPPGA score for one patient was missing.

[0086] FIG. 2 shows GPPASI 50/75/90 response rates through Week 20. In this figure, the proportion of patients who achieved a decrease of more than 50%, 75%, or 90% in the Generalized Pustular Psoriasis Area and Severity Index (GPPASI 50, 75, or 90) is shown over time. Analysis includes all patients with at least one available post-baseline value. One patient received methotrexate post Week 4 for treatment of "pain" and therefore data for Weeks 12 and 20 have are set to non-response.

[0087] FIG. 3 shows GPPASI subscores through Week 20. In this figure, individual and mean percent change in Generalized Pustular Psoriasis Area and Severity Index (GPPASI) severity subscores for Pustules (panel A), erythema (panel B), and scaling (panel C) are shown. Analysis includes all patients with at least one available post-baseline value. One patient received methotrexate post Week 4 for treatment of "pain" and therefore data for Weeks 12 and 20 have been excluded.

[0088] FIG. 4 shows change from baseline in FACIT-F through Week 4. Mean (SD) change from baseline in FACIT-F score over time is shown. Analysis includes all patients with at least one available post-baseline value. FACIT-F=Functional Assessment of Chronic Illness Therapy-Fatigue; SD=Standard deviation.

[0089] FIG. 5 shows change from baseline in Pain-VAS through Week 4. Mean (SD) change from baseline in Pain-VAS over time is shown. Analysis includes all patients with at least one available post-baseline value. SD=Standard deviation; VAS=Visual analogue scale. *N=6.

[0090] FIG. 6 shows change from baseline in PSS through Week 4. Mean (SD) change from baseline in PSS over time is shown. Analysis includes all patients with at least one available post-baseline value. PSS=Psoriasis symptom scale; SD=Standard deviation.

[0091] FIG. 7 shows change from baseline in CRP through Week 4. Mean (SD) change from baseline in CRP over time is shown. CRP=C-reactive protein; SD=Standard deviation.

[0092] FIG. 8 shows absolute neutrophil count through Week 4. Absolute neutrophil count over time is shown. Analysis includes all patients with at least one available post-baseline value. SD=Standard deviation.

[0093] FIG. 9 shows the study design as discussed in Example 2.

DETAILED DESCRIPTION OF THE INVENTION

[0094] In the following detailed description, numerous specific details are set forth to provide a full understanding of the present invention. It will be apparent, however, to one ordinarily skilled in the art that the subject technology may be practiced without some of these specific details. In other instances, well-known structures and techniques have not been shown in detail so as not to obscure the present invention.

[0095] A phrase such as "an aspect" does not imply that such aspect is essential to the present invention or that such aspect applies to all configurations of the subject technology. A disclosure relating to an aspect may apply to all configurations, or one or more configurations. An aspect may provide one or more examples of the disclosure. A phrase such as "an aspect" may refer to one or more aspects and vice versa. A phrase such as "an embodiment" does not imply that such embodiment is essential to the subject technology or that such embodiment applies to all configurations of the subject technology. A disclosure relating to an embodiment may apply to all embodiments, or one or more embodiments. An embodiment may provide one or more examples of the disclosure.

[0096] The inventors have surprisingly discovered inter alia that the interleukin-36 pathway inhibition with a single dose of a humanized anti-interleukin-36R (anti-IL-36R) monoclonal antibody of the present invention resulted in the rapid and sustained remission of clinical symptoms in patients with acute generalized pustular psoriasis and that no recurrence of GPP flares were observed in 20 weeks after the single dose administration.

[0097] The invention therefore relates to compositions and methods for treating and/or prophylaxis of GPP and its signs and symptoms. More specifically, the invention relates to compositions and methods for treating and/or prophylaxis of moderate to severe GPP, acute GPP, chronic GPP, and/or GPP flares in a mammal with an anti-IL36R antibody or an antigen-binding fragment thereof of the present invention. The compositions and methods include administering to the mammal a therapeutically effective amount of an anti-IL-36R antibody or an antigen-binding fragment thereof, wherein the anti-IL-36R antibody is administered in one intravenous dose. In an embodiment, the anti-IL-36R antibody is administered in one or more intravenous doses which is/are optionally followed by one or more subcutaneous doses.

[0098] Without wishing to be bound by this theory it is believed that anti-IL-36R antibodies or antigen-binding fragments thereof bind to human anti-IL-36R and thus interfere with the binding of IL-36 agonists, and in doing so block at least partially the signaling cascade from the IL-36R to inflammatory mediators. The anti-IL36R antibodies of the present invention are disclosed in U.S. Pat. No. 9,023,995 or WO2013/074569, the entire content of each of which is incorporated herein by reference.

[0099] Acute GPP flares 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 flares cause significant morbidity and mortality due to tender, painful skin lesions, extreme fatigue, high fever, peripheral blood neutrophilia and acute phase response and sepsis. The acute phase is associated with a mean duration of hospitalization of 10 days (range 3-44 days). The observed mortality rate of 7% reported in a retrospective study with 102 GPP cases seen in a tertiary hospital in Johor, Malaysia is likely an underestimate as not all GPP patients were included in the study. Mortality rates are also likely underestimated due to lack of identifying the cause of death as GPP and are largely driven by infectious complications and extra-cutaneous organ manifestations such as renal, hepatic, respiratory and cardiac failure. After responding to treatment or spontaneous flare cessation, it is estimated that up to 50% of patients may suffer from chronic GPP characterized by persistent erythema and scaling that may also include joint symptoms.

[0100] Based on the limitations described above, current therapeutic options are not suitable for life-long treatment and do not provide sustained responses in most patients. Therefore, there is a high need to develop (i) a highly effective treatment with rapid onset of action for patients presenting with an acute GPP flare; and (ii) to develop an effective treatment of chronic GPP, which reliably prevents the occurrence of flares and is safe and tolerable for lifelong treatment.

[0101] The classic presentation of GPP flares as described by von Zumbusch is strongly correlated with polymorphisms in the IL36-R signaling pathway. Individuals with loss-of-function mutations of the IL36RN gene which encodes an endogenous IL36R antagonist (IL-36RN) have dramatically higher incidence of GPP, indicating that uncontrolled upregulation of IL36 signaling due to defective IL36RN antagonism leads to the inflammatory episodes observed in GPP. Genetic human studies have demonstrated the occurrence of GPP clusters in families with a loss of function mutation in IL36RN, which results in uncontrolled IL36R signaling. Mutations in other genes linked to the IL36 pathway such as CARD14 also lead to GPP. A recently published gene expression study indicates sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil chemokine expression, infiltration, and pustule formation, suggesting that the IL-1/IL-36 inflammatory axis is a potent driver of disease pathology in GPP. Moreover, a recent meta-analysis investigated 233 published GPP cases. They found that 49 (21.0%) of 233 cases carried recessive IL36RN alleles. Those 49 recessive IL36RN alleles defined a GPP phenotype characterized by early onset and high risk of systemic inflammation.

[0102] IL36R is a cell surface receptor involved in inflammatory responses in skin and gut. It is a novel member of the IL1R family that forms a heterodimeric complex with the IL1R accessory protein. The heterodimeric IL36R system with stimulating (IL36.alpha., IL36.beta., IL36.gamma.) and inhibitory ligands (IL36Ra) shares a number of structural and functional similarities to other members of the IL1/IL1R family, such as IL1, IL18 and IL33 (R17-3602). All IL1 family members (IL1.alpha., IL1.beta., IL18, IL36.alpha., IL36.beta., IL36.gamma., and IL38) signal through a unique, cognate receptor protein which, upon ligand binding, recruits the common IL1 RacP subunit and activates NFkB and MAP kinase pathways in receptor-positive cell types. In human skin tissues, IL36R is expressed in keratinocytes, dermal fibroblasts and infiltrating myeloid cells. IL36R activation in skin tissue drives the production of inflammatory mediators (e.g. CCL20, MIP-1.beta., TNF-.alpha., IL12, IL17, IL23, TGF-.beta.) and modulates the expression of tissue remodeling genes (e.g. MMPs, TGF-.beta.). Therefore, the link between GPP and mutations in the IL36RN is somewhat analogous to the well-established neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis caused by absence of interleukin-1-receptor antagonist. In this case, absence of the receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. These clinical features responded to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra.

I. Definitions

[0103] The term "about" shall generally mean an acceptable degree of error or variation for the quantity measured given the nature or precision of the measurements. Typical, exemplary degrees of error or variation are within 5% or within 3% or within 1% of a given value or range of values. For example, the expression of "about 100" includes 105 and 95 or 103 and 97 or 101 and 99, and all values in between (e.g., 95.1, 95.2, etc. for range of 95-105; or 97.1, 97.2, etc. for the range of 97-103; 99.1, 99.2, etc. for the range of 99-101). Numerical quantities given herein are approximates unless stated otherwise, meaning that the term "about" can be inferred when not expressly stated.

[0104] A "pharmaceutical formulation" or "formulation" refers to the process but also the product of a process in which an active drug or agent is combined with chemical substances to produce a final medicinal or drug product, the final formulation therefore refers to medicinal products such as liquids, powders or compositions. Therefore, in one embodiment, a pharmaceutical formulation is a pharmaceutical composition.

[0105] A "pharmaceutical composition" refers in this context to a liquid or powder preparation which is in such form as to permit the biological activity of the active ingredient(s) to be unequivocally effective, and which contains no additional components which are significantly toxic to the subjects to which the composition would be administered. Such compositions are sterile. A "powder" refers to a freeze-dried or lyophilized or a spray-dried pharmaceutical composition for parenteral use. The powder is reconstituted or dissolved typically in water. Lyophilisation is a low temperature dehydration process which involves freezing the product, lowering pressure, then removing the ice by sublimation. Freeze drying results in a high quality product because of the low temperature used in processing. For a well-developed lyophilized formulation, the shape and appearance of the product is maintained over time and the quality of the rehydrated product is excellent. Spray drying is another method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas and with the goal of achieving a consistent particle size distribution.

[0106] As used herein, the terms "intravenous dose", "subcutaneous dose" refer to the temporal sequence of administration of the anti-IL-36R antibody. Thus, the "intravenous dose" is the dose which is administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); it may also be referred to as an "initial dose" or "induction dose." The "subcutaneous dose" is the dose which is administered after the intravenous dose, which may also be referred to as a "subsequent dose" or "maintenance dose." The intravenous, subcutaneous doses may all contain the same amount of anti-IL-36R antibody or an antigen binding fragment thereof, but generally may differ from one another in terms of the amount of the antibody administered or the frequency of administration. In an embodiment, the intravenous dose is equal or larger than the subcutaneous dose. An "intravenous dose" which may be interchangeably referred to as an "initial dose" or "induction dose" can be a single dose or, alternatively, a set of doses. The subcutaneous dose which may also be referred to as a "subsequent dose" or "maintenance dose" can be a single dose or, alternatively, a set of doses for administration.

[0107] In certain embodiments, the amount of the anti-IL-36R antibody contained in the induction/initial/intravenous and maintenance/subsequent/subcutaneous doses varies from one another 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.times., 2.times., 2.5.times., 3.times., 3.5.times., 4.times., or 5.times. the second or subsequent amount of the 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 at the beginning of the treatment regimen as "loading doses" or "leading doses" followed by subsequent doses that are administered on a less frequent basis (e.g., "maintenance doses"). In one embodiment, the intravenous dose, the induction dose or the initial dose is about 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg, 850 mg or 900 mg of the anti-IL-36R antibody. In one embodiment, the subcutaneous dose, the maintenance dose or the subsequent dose is about 150, 225 mg or 300 mg. In another embodiment, the subcutaneous dose or maintenance or subsequent dose is administered at least two weeks following the intravenous, induction or initial dose.

[0108] As used herein "buffer" refers to a buffered solution that resists changes in pH by the action of its acid-base conjugate components. The "pH" herein refers to the acidity or basicity of the composition at room temperature. Standard methods to measure the pH of a composition are known to the skilled in the art. Typically, measuring pH consists of calibrating the instrument, placing the electrodes in a well-mixed sample, and then reading the pH directly from the pH meter. The exemplary buffers of the present invention include acetate, citrate, histidine, succinate, phosphate and Tris.

[0109] As used herein, the term "tonicifying agent" or "tonicity agent" or "tonicifyer" refers to substances providing an osmotic pressure equivalent to that of serum in the body including salts (e.g. sodium chloride, potassium chloride, magnesium chloride) or sugars (e.g. sucrose, trehalose, sorbitol, magnesium sulfate (MgSO.sub.4), glycerol, mannitol or dextrose). In addition, sugars present in the solution act as a cryoprotectant for the protein which allows the drug substance to be frozen without damage. This permits shipment in the frozen form and long-term storage of the drug substance prior to the filling of drug product. The exemplary tonicifying agents of the present invention include sodium chloride, potassium chloride, magnesium chloride (salts) and/or sucrose, trehalose, sorbitol, magnesium sulfate (MgSO.sub.4), glycerol, mannitol or dextrose (sugars).

[0110] As used herein, the term "stabilizer" or "stabilizing agent" refers to substances contributing to the stability of the active ingredient in a pharmaceutical formulation. The exemplary stabilizing agents of the present invention include arginine, histidine, glycine, cysteine, proline, methionine, lysine, or pharmaceutically acceptable salts thereof.

[0111] As used herein, the term "surfactant" refers to substances which tend to reduce the surface tension of a liquid in which they are dissolved. The exemplary surfactants of the present invention include poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80.

[0112] The terms, "antibody", "anti-IL-36R antibody", "humanized 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 truncation, and antibody fragments such as variable domains and other portions of antibodies that exhibit a desired biological activity, e.g., IL-36R binding.

[0113] The term "monoclonal antibody" (mAb) refers to an antibody that is highly specific, being directed against a single antigenic determinant, an "epitope". Therefore, the modifier "monoclonal" is indicative of antibodies directed to the identical epitope and is not to be construed as requiring production of the antibody by any particular method. It should be understood that monoclonal antibodies can be made by any technique or methodology known in the art; including e.g., 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 of isolation of 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.

[0114] The term "monomer" refers to a homogenous form of an antibody. For example, for a full-length antibody, monomer means a monomeric antibody having two identical heavy chains and two identical light chains.

[0115] Chimeric antibodies consist of the heavy and light chain variable regions of an antibody from one species (e.g., a non-human mammal such as a mouse) and the heavy and light chain constant regions of another species (e.g., human) antibody and can be obtained by linking the DNA sequences encoding the variable regions of the antibody from the first species (e.g., mouse) to the DNA sequences for the constant regions of the antibody from the second (e.g. human) species and transforming a host with an expression vector containing the linked sequences to allow it to produce a chimeric antibody. Alternatively, the chimeric antibody also could be one in which one or more regions or domains of the heavy and/or light chain is identical with, homologous to, or a variant of the corresponding sequence in a monoclonal antibody from another immunoglobulin class or isotype, or from a consensus or germline sequence. Chimeric antibodies can include fragments of such antibodies, provided that the antibody fragment exhibits the desired biological activity of its parent antibody, for example binding 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).

[0116] The terms, "antibody fragment", "anti-IL-36R antibody fragment", "anti-IL-36R epitope antibody fragment", "humanized anti-IL-36R antibody fragment", "humanized anti-IL-36R epitope antibody fragment", "variant humanized anti-IL-36R epitope antibody fragment" refer to a portion of a full length anti-IL-36R antibody, in which a variable region or a functional capability is retained, for example, specific IL-36R epitope binding. Examples of antibody fragments include, but are not limited to, a Fab, Fab', F(ab').sub.2, Fd, Fv, scFv and scFv-Fc fragment, a diabody, a linear antibody, a single-chain antibody, a minibody, a diabody formed from antibody fragments, and multispecific antibodies formed from antibody fragments.

[0117] The term "intravenous infusion" refers to introduction of an agent into the vein of an animal or human patient over a period of time greater than approximately 15 minutes, generally between approximately 30 to 90 minutes.

[0118] The term "intravenous bolus" or "intravenous push" refers to drug administration into a vein of an animal or human such that the body receives the drug in approximately 15 minutes or less, generally 5 minutes or less.

[0119] The term "subcutaneous administration" refers to introduction of an agent under the skin of an animal or human patient, preferable within a pocket between the skin and underlying tissue, by relatively slow, sustained delivery from a drug receptacle. Pinching or drawing the skin up and away from underlying tissue may create the pocket.

[0120] The term "subcutaneous infusion" refers to introduction of a drug under the skin of an animal or human patient, preferably within a pocket between the skin and underlying tissue, by relatively slow, sustained delivery from a drug receptacle for a period of time including, but not limited to, 30 minutes or less, or 90 minutes or less. Optionally, the infusion may be made by subcutaneous implantation of a drug delivery pump implanted under the skin of the animal or human patient, wherein the pump delivers a predetermined amount of drug for a predetermined period of time, such as 30 minutes, 90 minutes, or a time period spanning the length of the treatment regimen.

[0121] The term "subcutaneous bolus" refers to drug administration beneath the skin of an animal or human patient, where bolus drug delivery is less than approximately 15 minutes; in another aspect, less than 5 minutes, and in still another aspect, less than 60 seconds. In yet even another aspect, administration is within a pocket between the skin and underlying tissue, where the pocket may be created by pinching or drawing the skin up and away from underlying tissue.

[0122] The term "mammal" for purposes of treatment refers to any animal classified as a mammal, including humans, domesticated and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, and the like. Preferably, the mammal is human.

[0123] The terms "treatment" and "therapy" and the like, as used herein, are meant to include therapeutic as well as prophylactic, or suppressive measures for a disease or disorder leading to any clinically desirable or beneficial effect, including but not limited to alleviation or relief of one or more symptoms, regression, slowing or cessation of progression of the disease or disorder. Thus, for example, the term treatment includes the administration of an agent prior to or following the onset of a symptom of a disease or disorder thereby preventing or removing one or more signs of the disease or disorder. As another example, the term includes the administration of an agent after clinical manifestation of the disease to combat the symptoms of the disease. Further, administration of an agent after onset and after clinical symptoms have developed where administration affects clinical parameters of the disease or disorder, such as the degree of tissue injury or the amount or extent of metastasis, whether or not the treatment leads to amelioration of the disease, comprises "treatment" or "therapy" as used herein. Moreover, as long as the compositions of the invention either alone or in combination with another therapeutic agent alleviate or ameliorate at least one symptom of a disorder being treated as compared to that symptom in the absence of use of the humanized anti-IL-36R antibody composition, the result should be considered an effective treatment of the underlying disorder regardless of whether all the symptoms of the disorder are alleviated or not.

[0124] The term "therapeutically effective amount" is used to refer to an amount of an active agent that relieves or ameliorates one or more of the symptoms of the disorder being treated. In another aspect, the therapeutically effective amount refers to a target serum concentration that has been shown to be effective in, for example, slowing disease progression. Efficacy can be measured in conventional ways, depending on the condition to be treated.

[0125] The term "prophylactically effective amount" is used to refer to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, a prophylactic dose is used in subjects prior to the onset of a GPP flare and/or prior to the onset of symptoms of GPP such as to prevent or inhibit the occurrence of acute flares. In an embodiment, a subcutaneous dose as contemplated herein is a prophylactic dose that is used in a patient with acute GPP, after the intravenous dose, to prevent a possible recurrence of the GPP flares in the patient.

[0126] The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, administration, contraindications and/or warnings concerning the use of such therapeutic products.

II. Antibodies

[0127] The anti-IL36R antibodies of the present invention are disclosed in U.S. Pat. No. 9,023,995 or WO2013/074569, the entire content of each of which is incorporated herein by reference.

[0128] In one aspect, described and disclosed herein are anti-IL-36R antibodies, in particular humanized anti-IL-36R antibodies, and compositions and articles of manufacture comprising one or more anti-IL-36R antibody, in particular one or more humanized anti-IL-36R antibody of the present invention. Also described are binding agents that include an antigen-binding fragment of an anti-IL-36 antibody, in particular a humanized anti-IL-36R antibody.

[0129] Mode of Action

[0130] an anti-IL-36R antibody of the present invention is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL36R signaling. Binding of an anti-IL-36R antibody of the present invention to IL36R is anticipated to prevent the subsequent activation of IL36R by cognate ligands (IL36 .alpha., .beta. and .gamma.) and downstream activation of pro-inflammatory and pro-fibrotic pathways with the aim to reduce epithelial cell/fibroblast/immune cell-mediated inflammation and interrupt the inflammatory response that drives pathogenic cytokine production in generalized pustular psoriasis (GPP). As provided herein, an anti-IL-36R antibody of the present invention has been tested and proved to be effective in treating patients with acute Generalized Pustular Psoriasis (GPP), a severe inflammatory skin disease driven by uncontrolled IL36 activity.

[0131] IL-36R is also known as IL-1RL2 and IL-1Rrp2. It has been reported that agonistic IL-36 ligands (.alpha., .beta., or .gamma.) initiate the signaling cascade by engaging the IL-36 receptor which then forms a heterodimer with the IL-1 receptor accessory protein (IL-1RAcP). IL-36 antagonist ligands (IL-36RA/IL1F5, IL-38/ILF10) inhibit the signaling cascade.

[0132] Variable regions and CDRs of representative antibodies of the present invention are disclosed below:

Anti-IL-36R Mouse Antibody Sequences

[0133] Variable regions and CDRs of representative mouse lead antibodies of the present invention (mouse leads) are shown below:

TABLE-US-00001 Light Chain Variable Region (VK) Amino Acid Sequences >33D10B12vK Protein (antibody 33D10) (SEQ ID NO: 1) QIVLTQSPAIMSASLGERVTMTCTASSSVSSSYLHWYQKKPGSSPKLWVYSTSNLASGVPVRF SGSGSGTSYSLTISSMEAEDAATYYCHQHHRSPVTFGSGTKLEMK >172C8B12 vK protein (antibody 172C8) (SEQ ID NO: 2) DIQMTQSPASQSASLGESVTFTCLASQTIGTWLAWYQQRPGKSPQLLIYAATSLADGVPSRFS GSGSGTQFSFNIRSLQAEDFASYYCQQVYTTPLTFGGGTKLEIK >67E7E8 vK protein (antibody 67E7) (SEQ ID NO: 3) DIQMTQSPASQSASLGESVTFTCLASQTIGTWLGWYQQKPGKSPQLLIYRSTTLADGVPSRFS GSGSGTKFSFKISSLQAADFASYYCQQLYSAPYTFGGGTKLEIR >78C8D1 vK Protein (antibody 78C8) (SEQ ID NO: 4) DVLLTQTPLSLPVSLGDQASISCRSSQNIVHSNGNTYLQWYLQKPGQSPKLLIYKVSNRFSGVP DRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPFTFGAGTKLELK >81A1D1 vK Protein (antibody 81A1) (SEQ ID NO: 5) DIQMTQTTSSLSASLGDRVTISCRASQDIYKYLNWYQQKPDGTLKLLIYYTSGLHSGVPSRFSG SGSGTDFSLTISNLEPEDIATYFCQQDSKFPWTFGGDTKLEIK >81B4E11 vK Protein (antibody 81B4) (SEQ ID NO: 6) QIVLTQSPAIMSASLGERVTMTCTASSSVSSSYFHWYQQKPGSSPKLWIYRTSNLASGVPGRF SGSGSGTSYSLTISSMEAEDAATYYCHQFHRSPLTFGAGTKLELK >73C5C10 vK protein (antibody 73C5) (SEQ ID NO: 7) DIVMTQSQKFLSTSVGVRVSVTCKASQDVGTNVLWYQQKIGQSPKPLIYSASYRHSGVPDRFT GSGSGTDFTLIISNVQSEDLAEYFCQQYSRYPLTFGPGTKLELK >73F6F8 vK protein (antibody 73F6) (SEQ ID NO: 8) DIVMTQSQKFLSTSVGVRVSVTCKASQDVGTNVLWYQQKIGQSPKALIYSASYRHSGVPDRFT GSGSGTDFTLIITNVQSEDLAEYFCQQYSRYPLTFGPGTKLELK >76E10E8 vK protein (antibody 76E10) (SEQ ID NO: 9) DIVMTQSQKFMSATVGGRVNITCKASQNVGRAVAWYQQKPGQSPKLLTHSASNRYTGVPDRF TGSGSGTDFTLTITNMQSEDLADYFCQQYSSYPLTFGAGTKLDLK >89A12B8 vK protein (antibody 89A12) (SEQ ID NO: 10) DIQMTQSPASQSASLGESVTFSCLASQTIGTWLGWYQQKPGKSPQLLIYRATSLADGVPSRFS GSGSGTNFSFKISSLQAEDLASYYCQQLYSGPYTFGGGTKLEIR Heavy Chain Variable Region (VH) Amino Acid Sequences >33D10B12vH Protein (antibody 33D10) (SEQ ID NO: 11) QVQLQQSGTELLKPGASVKLSCKASGNTVTSYWMHWVKQRPGQGLEWIGEILPSTGRTNYNE NFKGKAMLTVDKSSSTAYMQLSSLASEDSAVYYCTIVYFGNPWFAYWGQGTLVTVSA >172C8B12 vH protein (antibody 172C8) (SEQ ID NO: 12) EVQLQQSGPELVKPGASVKLSCKASGYTFTDNYMNWVRQSHGKSLEWIGRVNPSNGDTKYN QNFKGKATLTVDKSLSTAYMQLNGLTSEDSAVYYCGRTKNFYSSYSYDDAMDYWGQGTSVTV SS >67E7E8 vH protein (antibody 67E7) (SEQ ID NO: 13) EVQLQQSGAEFVRPGASVKFSCTASGFNIKDDYIHWVRQRPEQGLEWVGRIDPANGNTKYAP KFQDKATITADTSSNTAYLQLSSLTSEDTAVYYCAKSFPNNYYSYDDAFAYWGQGTLVTVSA >78C8D1 vH Protein (antibody 78C8) (SEQ ID NO: 14) QVQLKESGPVLVAPSQSLSITCTVSGFSLTKFGVHWIRQTPGKGLEWLGVIWAGGPTNYNSAL MSRLTISKDISQSQVFLRIDSLQTDDTAMYYCAKQIYYSTLVDYWGQGTSVTVSS >81A1D1 vH Protein (antibody 81A1) (SEQ ID NO: 15) QVQLKESGPGLVAPSQSLFITCTVSGFSLSSYEINWVRQVPGKGLEWLGVIWTGITTNYNSALI SRLSISKDNSKSLVFLKMNSLQTDDTAIYYCARGTGTGFYYAMDYWGQGTSVTVSS >81B4E11 vH Protein (antibody 81B4) (SEQ ID NO: 16) QVQLQQPGADFVRPGASMRLSCKASGYSFTSSWIHWVKQRPGQGLEWIGEINPGNVRTNYN ENFRNKATLTVDKSSTTAYMQLRSLTSADSAVYYCTVVFYGEPYFPYWGQGTLVTVSA >73C5C10 vH Protein (antibody 73C5) (SEQ ID NO: 17) QVQLKESGPGLVAPSQSLSITCTVSGFSLTNYAVHWVRQFPGKGLEWLGVIWSDGSTDFNAP FKSRLSINKDNSKSQVFFKMNSLQIDDTAIYYCARKGGYSGSWFAYWGQGTLVTVSA >73F6F8 vH protein (antibody 73F6) (SEQ ID NO: 18) QVQLKESGPGLVAPSQSLSITCTVSGFSLTNYAVHWVRQFPGKGLEWLGVIWSDGSTDYNAP FKSRLSINKDNSKSQVFFKMNSLQTDDTAIYYCARKGGYSGSWFAYWGQGTLVTVSA >76E10E8 vH protein (antibody 76E10) (SEQ ID NO: 19) QVQLKESGPVLVAPSQSLSITCTVSGFSLTNYGVHWVRQPPGKGLEWLGVIWPVGSTNYNSA LMSRLSIHKDNSKSQVFLRMNSLQTDDTAIYYCAKMDWDDFFDYWGQGTTLTVSS >89A12B8 vH Protein (antibody 89A12) (SEQ ID NO: 20) EVQLQQSGAELVRPGASVRLSCTASGFNIKDDYIHWVRQRPKQGLEWLGRIDPANGNTKYDP RFQDKATITADTSSNTAYLHLSSLTSEDTAVYYCAKSFPDNYYSYDDAFAYWGQGTLVTVSA Light chain CDR-1 (L-CDR1) Amino Acid Sequences >33D10G1 L-CDR1 (SEQ ID NO: 21) TASSSVSSSYLH >172C8B12 L-CDR1 (SEQ ID NO: 22) LASQTIGTWLA >67E7E8 L-CDR1 (SEQ ID NO: 23) LASQTIGTWLG >78C8D1 L-CDR1 (SEQ ID NO: 24) RSSQNIVHSNGNTYLQ >81A1D1 L-CDR1 (SEQ ID NO: 25) RASQDIYKYLN >81B4E11 L-CDR1 (SEQ ID NO: 26) TASSSVSSSYFH >73C5C10 L-CDR1 (SEQ ID NO: 27) KASQDVGTNVL >73F6F8 L-CDR1 (SEQ ID NO: 27) KASQDVGTNVL >76E10E8 L-CDR1 (SEQ ID NO: 28) KASQNVGRAVA >89A12B8 L-CDR1 (SEQ ID NO: 29) LASQTIGTWLG Light chain CDR-2 (L-CDR2) Amino Acid Sequences >33D10B12 L-CDR2 (SEQ ID NO: 30) STSNLAS >172C8B12 L-CDR2 (SEQ ID NO: 31) AATSLAD >67E7E8 L-CDR2 (SEQ ID NO: 32) RSTTLAD >78C8D1 L-CDR2 (SEQ ID NO: 33) KVSNRFS >81A1D1 L-CDR2 (SEQ ID NO: 34) YTSGLHS >81B4E11 L-CDR2 (SEQ ID NO: 35) RTSNLAS >73C5C10 L-CDR2 (SEQ ID NO: 36) SASYRHS >73F6F8 L-CDR2 (SEQ ID NO: 36) SASYRHS >76E10E8 L-CDR2 (SEQ ID NO: 37) SASNRYT >89A12B8 L-CDR2 (SEQ ID NO: 38) RATSLAD Light chain CDR-3 (L-CDR3) Amino Acid Sequences >33D10B12 L-CDR3 (SEQ ID NO: 39) HQHHRSPVT >172C8B12 L-CDR3 (SEQ ID NO: 40) QQVYTTPLT >67E7E8 L-CDR3 (SEQ ID NO: 41) QQLYSAPYT >78C8D1 L-CDR3 (SEQ ID NO: 42) FQGSHVPFT >81A1D1 L-CDR3 (SEQ ID NO: 43) QQDSKFPWT >81B4E11 L-CDR3 (SEQ ID NO: 44) HQFHRSPLT >73C5C10 L-CDR3 (SEQ ID NO: 45) QQYSRYPLT >73F6F8 L-CDR3 (SEQ ID NO: 45) QQYSRYPLT >76E10E8 L-CDR3 (SEQ ID NO: 46) QQYSSYPLT >89A12B8 L-CDR3 (SEQ ID NO: 47) QQLYSGPYT Heavy chain CDR-1 (H-CDR1) Amino Acid Sequences >33D10B12 H-CDR1 (SEQ ID NO: 48)

GNTVTSYWMH >172C8B12 H-CDR1 (SEQ ID NO: 49) GYTFTDNYMN >67E7E8 H-CDR1 (SEQ ID NO: 50) GFNIKDDYIH >78C8D1 H-CDR1 (SEQ ID NO: 51) GFSLTKFGVH >81A1D1 H-CDR1 (SEQ ID NO: 52) GFSLSSYEIN >81B4E11 H-CDR1 (SEQ ID NO: 53) GYSFTSSWIH >73C5C10 H-CDR1 (SEQ ID NO: 54) GFSLTNYAVH >73F6F8 H-CDR1 (SEQ ID NO: 54) GFSLTNYAVH >76E10E8 H-CDR1 (SEQ ID NO: 55) GFSLTNYGVH >89A12B8 H-CDR1 (SEQ ID NO: 56) GFNIKDDYIH Heavy chain CDR-2 (H-CDR2) Amino Acid Sequences >33D10B12 H-CDR2 (SEQ ID NO: 57) EILPSTGRTNYNENFKG >172C8B12 H-CDR2 (SEQ ID NO: 58) RVNPSNGDTKYNQNFKG >67E7E8 H-CDR2 (SEQ ID NO: 59) RIDPANGNTKYAPKFQD >78C8D1 H-CDR2 (SEQ ID NO: 60) VIWAGGPTNYNSALMS >81A1D1 H-CDR2 (SEQ ID NO: 61) VIWTGITTNYNSALIS >81B4E11 H-CDR2 (SEQ ID NO: 62) EINPGNVRTNYNENF >73C5C10 H-CDR2 (SEQ ID NO: 63) VIWSDGSTDFNAPFKS >73F6F8 H-CDR2 (SEQ ID NO: 64) VIWSDGSTDYNAPFKS >76E10E8 H-CDR2 (SEQ ID NO: 65) VIWPVGSTNYNSALMS >89A12B8 H-CDR2 (SEQ ID NO: 66) RIDPANGNTKYDPRFQD Heavy chain CDR-3 (H-CDR3) Amino Acid Sequences >33D10B12 H-CDR3 (SEQ ID NO: 67) VYFGNPWFAY >172C8B12 H-CDR3 (SEQ ID NO: 68) TKNFYSSYSYDDAMDY >67E7E8 H-CDR3 (SEQ ID NO: 69) SFPNNYYSYDDAFAY >78C8D1 H-CDR3 (SEQ ID NO: 70) QIYYSTLVDY >81A1D1 H-CDR3 (SEQ ID NO: 71) GTGTGFYYAMDY >81B4E11 H-CDR3 (SEQ ID NO: 72) VFYGEPYFPY >73C5C10 H-CDR3 (SEQ ID NO: 73) KGGYSGSWFAY >73F6F8 H-CDR3 (SEQ ID NO: 73) KGGYSGSWFAY >76E10E8 H-CDR3 (SEQ ID NO: 74) MDWDDFFDY >89A12B8 H-CDR3 (SEQ ID NO: 75) SFPDNYYSYDDAFAY

Anti-IL-36R Mouse CDR Sequences

A Summary of the CDR Sequences of the Lead Mouse Antibodies is Shown Below:

TABLE-US-00002 [0134] H-CDR L-CDR Antibody Sequences Sequences 33D10 GNTVTSYWMH TASSSVSSSYLH (H-CDR1) (L-CDR1) SEQ ID No: 48 SEQ ID No: 21 EILPSTGRTNYNENFKG STSNLAS (H-CDR2) (L-CDR2) SEQ ID No: 57 SEQ ID No: 30 VYFGNPWFAY HQHHRSPVT (H-CDR3) (L-CDR3) SEQ ID No: 67 SEQ ID No: 39 172C8 GYTFTDNYMN LASQTIGTWLA (H-CDR1) (L-CDR1) SEQ ID No: 49 SEQ ID No: 22 RVNPSNGDTKYNQNFKG AATSLAD (H-CDR2) (L-CDR2) SEQ ID No: 58 SEQ ID No: 31 TKNFYSSYSYDDAMDY QQVYTTPLT (H-CDR3) (L-CDR3) SEQ ID No: 68 SEQ ID No: 40 67E7 GFNIKDDYIH LASQTIGTWLG (H-CDR1) (L-CDR1) SEQ ID No: 50 SEQ ID No: 23 RIDPANGNTKYAPKFQD RSTTLAD (H-CDR2) (L-CDR2) SEQ ID No: 59 SEQ ID No: 32 SFPNNYYSYDDAFAY QQLYSAPYT (H-CDR3) (L-CDR3) SEQ ID No: 69 SEQ ID No: 41 78C8 GFSLTKFGVH RSSQNIVHSNGNTYLQ (H-CDR1) (L-CDR1) SEQ ID No: 51 SEQ ID No: 24 VIWAGGPTNYNSALMS KVSNRFS (H-CDR2) (L-CDR2) SEQ ID No: 60 SEQ ID No: 33 QIYYSTLVDY FQGSHVPFT (H-CDR3) (L-CDR3) SEQ ID No: 70 SEQ ID No: 42 81A1 GFSLSSYEIN RASQDIYKYLN (H-CDR1) (L-CDR1) SEQ ID No: 52 SEQ ID No: 25 VIWTGITTNYNSALIS YTSGLHS (H-CDR2) (L-CDR2) SEQ ID No: 61 SEQ ID No: 34 GTGTGFYYAMDY QQDSKFPWT (H-CDR3) (L-CDR3) SEQ ID No: 71 SEQ ID No: 43 81B4 GYSFTSSWIH TASSSVSSSYFH (H-CDR1) (L-CDR1) SEQ ID No: 53 SEQ ID No: 26 EINPGNVRTNYNENF RTSNLAS (H-CDR2) (L-CDR2) SEQ ID No: 62 SEQ ID No: 35 VFYGEPYFPY HQFHRSPLT (H-CDR3) (L-CDR3) SEQ ID No: 72 SEQ ID No: 44 73C5 GFSLTNYAVH KASQDVGTNVL (H-CDR1) (L-CDR1) SEQ ID No: 54 SEQ ID No: 27 VIWSDGSTDFNAPFKS SASYRHS (H-CDR2) (L-CDR2) SEQ ID No: 63 SEQ ID No: 36 KGGYSGSWFAY QQYSRYPLT (H-CDR3) (L-CDR3) SEQ ID No: 73 SEQ ID No: 45 73F6 GFSLTNYAVH KASQDVGTNVL (H-CDR1) (L-CDR1) SEQ ID No: 54 SEQ ID No: 27 VIWSDGSTDYNAPFKS SASYRHS (H-CDR2) (L-CDR2) SEQ ID No: 64 SEQ ID No: 36 KGGYSGSWFAY QQYSRYPLT (H-CDR3) (L-CDR3) SEQ ID No: 73 SEQ ID No: 45 76E10 GFSLTNYGVH KASQNVGRAVA (H-CDR1) (L-CDR1) SEQ ID No: 55 SEQ ID No: 28 VIWPVGSTNYNSALMS SASNRYT (H-CDR2) (L-CDR2) SEQ ID No: 65 SEQ ID No: 37 MDWDDFFDY QQYSSYPLT (H-CDR3) (L-CDR3) SEQ ID No: 74 SEQ ID No: 46 89A12 GFNIKDDYIH LASQTIGTWLG (H-CDR1) (L-CDR1) SEQ ID No: 56 SEQ ID No: 29 RIDPANGNTKYDPRFQD RATSLAD (H-CDR2) (L-CDR2) SEQ ID No: 66 SEQ ID No: 38 SFPDNYYSYDDAFAY QQLYSGPYT (H-CDR3) (L-CDR3) SEQ ID No: 75 SEQ ID No: 47

Anti-IL-36R Humanized Antibody Sequences

[0135] Human framework sequences were selected for the mouse leads based on the framework homology, CDR structure, conserved canonical residues, conserved interface packing residues and other parameters to produce humanized variable regions (see Example 5).

[0136] Representative humanized variable regions derived from antibodies 81B4 and 73C5 are shown below.

TABLE-US-00003 Light Chain Variable Region (VK) Amino Acid Sequences >81B4vK32_3 vK protein EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSTLASGI PDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 76) >81B4vK32_105 vK protein EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSILASGV PDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 77) >81B4vK32_116 vK protein EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASG VPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 78) >81B4vK32_127 vK protein EIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSRLASG VPDRFSGSGSGTDFTLTISRLEPEDFAVYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 79) >81B4vK32_138 vK protein QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLAS GVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGAGTKLEIK (SEQ ID NO: 80) >81B4vK32_140 vK protein QIVLTQSPGTLSLSPGERVTMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSQLASG IPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 81) >81B4vK32_141 vK protein QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSKLASG VPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 82) >81B4vK32_147 vK protein EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSHLASGI PGRFSGSGSGTDFTLTISRLEPEDAAVYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 83) >73C5vK39_2 vK protein EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGI PDRFSGSGSGTEFTLTISSLQSEDFAEYFCQQYSRYPLTFGQGTKLEIK (SEQ ID NO: 84) >73C5vK39_7 vK protein EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGI PDRFSGSGSGTEFTLTISSLQSEDFAVYYCQQYSRYPLTFGQGTKLEIK (SEQ ID NO: 85) >73C5vK39_15 vK protein EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGI PARFSGSGSGTEFTLTISSLQSEDFAEYYCQQYSRYPLTFGQGTKLEIK (SEQ ID NO: 86) Heavy Chain Variable Region (VH) Amino Acid Sequences >81B4vH33_49 vH Protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGNV RTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGT LVTVSS (SEQ ID NO: 87) >81B4vH33_85T vH Protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGNV RTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGT LVTVSS (SEQ ID NO: 88) >81B4vH33_90 vH Protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVKQAPGQGLEWMGEINPGNV RTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGT LVTVSS (SEQ ID NO: 89) >81B4vH33_93 vH Protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEINPGNV RTNYNENFRNRATLTRDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTL VTVSS (SEQ ID NO: 90) >81B4vH50_22 vH Protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEILPGVV RTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGT LVTVSS (SEQ ID NO: 91) >81B4vH50_30 vH Protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGAV RTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGT LVTVSS (SEQ ID NO: 92) >81B4vH51_13 vH Protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGLVR TNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTL VTVSS (SEQ ID NO: 93) >81B4vH51_15 vH Protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGAVR TNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTL VTVSS (SEQ ID NO: 94) >81B4vH52_83 vH Protein QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGSVR TNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTL VTVSS (SEQ ID NO: 95) >73C5vH46_4 vH Protein QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTD YNAPFKSRVTINKDTSKSQVSFKMSSVQAADTAVYYCARKGGYSGSWFAYWGQGTL VTVSS (SEQ ID NO: 96) >73C5vH46_19 vH Protein QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTD YNAPFKSRVTISKDTSKNQVSLKMNSLTTDDTAVYYCARKGGYSGSWFAYWGQGTLV TVSS (SEQ ID NO: 97) >73C5vH46_40 vH Protein QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTD YNAPFKSRVTISKDNSKSQVSLKMNSVTVADTAVYYCARKGGYSGSWFAYWGQGTL VTVSS (SEQ ID NO: 98) >73C5vH47_65 vH Protein QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWVRQPPGKGLEWIGVIWSDGST DYNAPFKSRVTISKDTSKNQVSFKLSSVTVDDTAVYYCARKGGYSGSWFAYWGQGTL VTVSS (SEQ ID NO: 99) >73C5vH47_77 vH Protein QVQLQESGPGLVAPSETLSLTCTVSGFSLTDYAVHWIRQFPGKGLEWIGVIWSDGSTD FNAPFKSRVTISKDTSKNQVSFKLSSVTTDDTAVYYCARKGGYSGSWFAYWGQGTLV TVSS (SEQ ID NO: 100) >73C5vH58_91 vH Protein QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTD YNAPFKSRVTISKDNSKSQVSFKMSSVTADDTAVYYCARKGGYSGSWFAYWGQGTL VTVSS (SEQ ID NO: 101)

[0137] The CDR sequences from the humanized variable regions derived from antibodies 81B4 and 73C5 shown above are depicted below.

TABLE-US-00004 L-CDR1 Amino Acid Sequences >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) >81 B4vK32_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 Sequences >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 Sequences >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 Sequences >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) H-CDR2 Amino Acid Sequences >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) H-CDR3 Amino Acid Sequences >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)

[0138] In one aspect, a variable region of the present invention is linked to a constant region. For example, a variable region of the present invention is linked to a constant region shown below to form a heavy chain or a light chain of an antibody.

TABLE-US-00005 Heavy Chain Constant region linked downstream of a humanized variable heavy region: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEP KSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGK EYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 112) Light Chain Constant region linked downstream of a humanized variable light region: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSG NSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC (SEQ ID NO: 113)

[0139] Representative light chain and heavy chain sequences of the present invention are shown below (humanized variable regions derived from antibodies 81B4 and 73C5 linked to constant regions).

TABLE-US-00006 Light Chain Amino Acid Sequences >81B4vK32_3 Light Chain EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSTLASGI PDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 114) >81B4vK32_105 Light Chain EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSILASGV PDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 115) >81B4vK32_116 Light Chain EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLASG VPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 116) >81B4vK32_127 Light Chain EIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSRLASG VPDRFSGSGSGTDFTLTISRLEPEDFAVYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 117) >81B4vK32_138 Light Chain QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRLAS GVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGAGTKLEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 118) >81B4vK32_140 Light Chain QIVLTQSPGTLSLSPGERVTMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSQLASG IPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 119) >81B4vK32_141 Light Chain QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSKLASG VPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTY SLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 120) >81B4vK32_147 Light Chain EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSHLASGI PGRFSGSGSGTDFTLTISRLEPEDAAVYYCHQFHRSPLTFGQGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 121) >73C5vK39_2 Light Chain EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGI PDRFSGSGSGTEFTLTISSLQSEDFAEYFCQQYSRYPLTFGQGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 122) >73C5vK39_7 Light Chain EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGI PDRFSGSGSGTEFTLTISSLOSEDFAVYYCQQYSRYPLTFGQGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 123) >73C5vK39_15 Light Chain EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYRHSGI PARFSGSGSGTEFTLTISSLQSEDFAEYYCQQYSRYPLTFGQGTKLEIKRTVAAPSVFI FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 124) Heavy Chain Amino Acid Sequences >81B4vH33_49 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGNV RTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 125) >81B4vH33_85T Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGNV RTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 126) >81B4vH33_90 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVKQAPGQGLEWMGEINPGNV RTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 127) >81B4vH33_93 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEINPGNV RTNYNENFRNRATLTRDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 128) >81B4vH50_22 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEILPGVV RTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 129) >81B4vH50_30 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINPGAV RTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYFPYWGQGT LVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCP PCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 130) >81B4vH51_13 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGLVR TNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 131) >81B4vH51_15 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGAVR TNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 132) >81B4vH52_83 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINPGSVR TNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFPYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 133) >73C5vH46_4 Heavy Chain QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTD YNAPFKSRVTINKDTSKSQVSFKMSSVQAADTAVYYCARKGGYSGSWFAYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 134) >73C5vH46_19 Heavy Chain QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTD YNAPFKSRVTISKDTSKNQVSLKMNSLTTDDTAVYYCARKGGYSGSWFAYWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 135) >73C5vH46_40 Heavy Chain QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTD YNAPFKSRVTISKDNSKSQVSLKMNSVTVADTAVYYCARKGGYSGSWFAYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 136) >73C5vH47_65 Heavy Chain QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWVRQPPGKGLEWIGVIWSDGST DYNAPFKSRVTISKDTSKNQVSFKLSSVTVDDTAVYYCARKGGYSGSWFAYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 137) >73C5vH47_77 Heavy Chain QVQLQESGPGLVAPSETLSLTCTVSGFSLTDYAVHWIRQFPGKGLEWIGVIWSDGSTD FNAPFKSRVTISKDTSKNQVSFKLSSVTTDDTAVYYCARKGGYSGSWFAYWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPC PAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPR EPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 138) >73C5vH58_91 Heavy Chain QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDGSTD YNAPFKSRVTISKDNSKSQVSFKMSSVTADDTAVYYCARKGGYSGSWFAYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPP CPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 139)

[0140] The CDRs listed above are defined using the Chothia numbering system (Al-Lazikani et al., (1997) JMB 273, 927-948).

[0141] In one aspect, an antibody of the present invention comprises 3 light chain CDRs and 3 heavy chain CDRs, for example as set forth above.

[0142] In one aspect, an antibody of the present invention comprises a light chain and a heavy chain variable region as set forth above. In one aspect, a light chain variable region of the invention is fused to a light chain constant region, for example a kappa or lambda constant region. In one aspect, a heavy chain variable region of the invention is fused to a heavy chain constant region, for example IgA, IgD, IgE, IgG or IgM, in particular, IgG.sub.1, IgG.sub.2, IgG.sub.3 or IgG.sub.4.

[0143] The present invention provides an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125 (Antibody B1).

[0144] The present invention provides an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126 (Antibody B2).

[0145] The present invention provides an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127 (Antibody B3).

[0146] The present invention provides an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125 (Antibody B4).

[0147] The present invention provides an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126 (Antibody B5).

[0148] The present invention provides an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127 Antibody B6).

[0149] The present invention provides an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO: 123; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138 (Antibody C3).

[0150] The present invention provides an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO: 123; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 139 (Antibody C2).

[0151] The present invention provides an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO: 124; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138 (Antibody C1)

Representative antibodies of the present invention are shown below.

TABLE-US-00007 TABLE B Antibody Light Chain Sequences Heavy Chain Sequences B1 EIVLTQSPGTLSLSPGERATMSCT QVQLVQSGAEVKKPGASVKVSCKASGY ASSSVSSSYFHWYQQKPGQAPR SFTSSWIHWVRQAPGQGLEWIGEINPGN LLIYRTSILASGVPDRFSGSGSGT VRTNYNENFRNKATMTVDTSISTAYMEL DFTLTISRLEPEDFATYYCHQFHR SRLRSDDTAVYYCAVVFYGEPYFPYWG SPLTFGQGTKLEIKRTVAAPSVFIF QGTLVTVSSASTKGPSVFPLAPSSKSTS PPSDEQLKSGTASVVCLLNNFYP GGTAALGCLVKDYFPEPVTVSWNSGALT REAKVQWKVDNALQSGNSQESV SGVHTFPAVLQSSGLYSLSSVVTVPSSS TEQDSKDSTYSLSSTLTLSKADYE LGTQTYICNVNHKPSNTKVDKRVEPKSC KHKVYACEVTHQGLSSPVTKSFN DKTHTCPPCPAPEAAGGPSVFLFPPKPK RGEC (SEQ ID NO: 115) DTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (SEQ ID NO: 125) B2 EIVLTQSPGTLSLSPGERATMSCT QVQLVQSGAEVKKPGASVKVSCKASGY ASSSVSSSYFHWYQQKPGQAPR SFTSSWIHWVRQRPGQGLEWIGEINPG LLIYRTSILASGVPDRFSGSGSGT NVRTNYNENFRNRVTMTVDTSISTAYME DFTLTISRLEPEDFATYYCHQFHR LSRLRSDDTAVYYCTVVFYGEPYFPYWG SPLTFGQGTKLEIKRTVAAPSVFIF QGTLVTVSSASTKGPSVFPLAPSSKSTS PPSDEQLKSGTASVVCLLNNFYP GGTAALGCLVKDYFPEPVTVSWNSGALT REAKVQWKVDNALQSGNSQESV SGVHTFPAVLQSSGLYSLSSVVTVPSSS TEQDSKDSTYSLSSTLTLSKADYE LGTQTYICNVNHKPSNTKVDKRVEPKSC KHKVYACEVTHQGLSSPVTKSFN DKTHTCPPCPAPEAAGGPSVFLFPPKPK RGEC (SEQ ID NO: 115) DTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (SEQ ID NO: 126) B3 EIVLTQSPGTLSLSPGERATMSCT QVQLVQSGAEVKKPGASVKVSCKASGY ASSSVSSSYFHWYQQKPGQAPR SFTSSWIHWVKQAPGQGLEWMGEINPG LLIYRTSILASGVPDRFSGSGSGT NVRTNYNENFRNKVTMTVDTSISTAYME DFTLTISRLEPEDFATYYCHQFHR LSRLRSDDTAVYYCTVVFYGEPYFPYWG SPLTFGQGTKLEIKRTVAAPSVFIF QGTLVTVSSASTKGPSVFPLAPSSKSTS PPSDEQLKSGTASVVCLLNNFYP GGTAALGCLVKDYFPEPVTVSWNSGALT REAKVQWKVDNALQSGNSQESV SGVHTFPAVLQSSGLYSLSSVVTVPSSS TEQDSKDSTYSLSSTLTLSKADYE LGTQTYICNVNHKPSNTKVDKRVEPKSC KHKVYACEVTHQGLSSPVTKSFN DKTHTCPPCPAPEAAGGPSVFLFPPKPK RGEC (SEQ ID NO: 115) DTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (SEQ ID NO: 127) B4 QIVLTQSPGTLSLSPGERATMTCT QVQLVQSGAEVKKPGASVKVSCKASGY ASSSVSSSYFHWYQQKPGQAPR SFTSSWIHWVRQAPGQGLEWIGEINPGN LWIYRTSRLASGVPDRFSGSGSG VRTNYNENFRNKATMTVDTSISTAYMEL TDFTLTISRLEPEDAATYYCHQFH SRLRSDDTAVYYCAVVFYGEPYFPYWG RSPLTFGAGTKLEIKRTVAAPSVFI QGTLVTVSSASTKGPSVFPLAPSSKSTS FPPSDEQLKSGTASVVCLLNNFYP GGTAALGCLVKDYFPEPVTVSWNSGALT REAKVQWKVDNALQSGNSQESV SGVHTFPAVLQSSGLYSLSSVVTVPSSS TEQDSKDSTYSLSSTLTLSKADYE LGTQTYICNVNHKPSNTKVDKRVEPKSC KHKVYACEVTHQGLSSPVTKSFN DKTHTCPPCPAPEAAGGPSVFLFPPKPK RGEC (SEQ ID NO: 118) DTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (SEQ ID NO: 125) B5 QIVLTQSPGTLSLSPGERATMTCT QVQLVQSGAEVKKPGASVKVSCKASGY ASSSVSSSYFHWYQQKPGQAPR SFTSSWIHWVRQRPGQGLEWIGEINPG LWIYRTSRLASGVPDRFSGSGSG NVRTNYNENFRNRVTMTVDTSISTAYME TDFTLTISRLEPEDAATYYCHQFH LSRLRSDDTAVYYCTVVFYGEPYFPYWG RSPLTFGAGTKLEIKRTVAAPSVFI QGTLVTVSSASTKGPSVFPLAPSSKSTS FPPSDEQLKSGTASVVCLLNNFYP GGTAALGCLVKDYFPEPVTVSWNSGALT REAKVQWKVDNALQSGNSQESV SGVHTFPAVLQSSGLYSLSSVVTVPSSS TEQDSKDSTYSLSSTLTLSKADYE LGTQTYICNVNHKPSNTKVDKRVEPKSC KHKVYACEVTHQGLSSPVTKSFN DKTHTCPPCPAPEAAGGPSVFLFPPKPK RGEC (SEQ ID NO: 118) DTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (SEQ ID NO: 126) B6 QIVLTQSPGTLSLSPGERATMTCT QVQLVQSGAEVKKPGASVKVSCKASGY ASSSVSSSYFHWYQQKPGQAPR SFTSSWIHWVKQAPGQGLEWMGEINPG LWIYRTSRLASGVPDRFSGSGSG NVRTNYNENFRNKVTMTVDTSISTAYME TDFTLTISRLEPEDAATYYCHQFH LSRLRSDDTAVYYCTVVFYGEPYFPYWG RSPLTFGAGTKLEIKRTVAAPSVFI QGTLVTVSSASTKGPSVFPLAPSSKSTS FPPSDEQLKSGTASVVCLLNNFYP GGTAALGCLVKDYFPEPVTVSWNSGALT REAKVQWKVDNALQSGNSQESV SGVHTFPAVLQSSGLYSLSSVVTVPSSS TEQDSKDSTYSLSSTLTLSKADYE LGTQTYICNVNHKPSNTKVDKRVEPKSC KHKVYACEVTHQGLSSPVTKSFN DKTHTCPPCPAPEAAGGPSVFLFPPKPK RGEC (SEQ ID NO: 118) DTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVV SVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (SEQ ID NO: 127)

TABLE-US-00008 TABLE C Antibody Light Chain Sequences Heavy Chain Sequences C1 EIVMTQSPATLSVSPGVRATLSCK QVQLQESGPGLVAPSETLSLTCTVSGFS ASQDVGTNVLWYQQKPGQAPRP LTDYAVHWIRQFPGKGLEWIGVIWSDGS LIYSASYRHSGIPARFSGSGSGTE TDFNAPFKSRVTISKDTSKNQVSFKLSSV FTLTISSLQSEDFAEYYCQQYSRY TTDDTAVYYCARKGGYSGSWFAYWGQ PLTFGQGTKLEIKRTVAAPSVFIFP GTLVTVSSASTKGPSVFPLAPSSKSTSG PSDEQLKSGTASVVCLLNNFYPR GTAALGCLVKDYFPEPVTVSWNSGALTS EAKVQWKVDNALQSGNSQESVT GVHTFPAVLQSSGLYSLSSVVTVPSSSL EQDSKDSTYSLSSTLTLSKADYEK GTQTYICNVNHKPSNTKVDKRVEPKSCD HKVYACEVTHQGLSSPVTKSFNR KTHTCPPCPAPEAAGGPSVFLFPPKPKD GEC (SEQ ID NO: 124) TLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (SEQ ID NO: 138) C2 EIVMTQSPATLSVSPGVRATLSCK QVQLQESGPGLVKPSETLSITCTVSGFSL ASQDVGTNVLWYQQKPGQAPRP TDYAVHWIRQPPGKGLEWIGVIWSDGST LIYSASYRHSGIPDRFSGSGSGTE DYNAPFKSRVTISKDNSKSQVSFKMSSV FTLTISSLQSEDFAVYYCQQYSRY TADDTAVYYCARKGGYSGSWFAYWGQ PLTFGQGTKLEIKRTVAAPSVFIFP GTLVTVSSASTKGPSVFPLAPSSKSTSG PSDEQLKSGTASVVCLLNNFYPR GTAALGCLVKDYFPEPVTVSWNSGALTS EAKVQWKVDNALQSGNSQESVT GVHTFPAVLQSSGLYSLSSVVTVPSSSL EQDSKDSTYSLSSTLTLSKADYEK GTQTYICNVNHKPSNTKVDKRVEPKSCD HKVYACEVTHQGLSSPVTKSFNR KTHTCPPCPAPEAAGGPSVFLFPPKPKD GEC (SEQ ID NO: 123) TLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (SEQ ID NO: 139) C3 EIVMTQSPATLSVSPGVRATLSCK QVQLQESGPGLVAPSETLSLTCTVSGFS ASQDVGTNVLWYQQKPGQAPRP LTDYAVHWIRQFPGKGLEWIGVIWSDGS LIYSASYRHSGIPDRFSGSGSGTE TDFNAPFKSRVTISKDTSKNQVSFKLSSV FTLTISSLQSEDFAVYYCQQYSRY TTDDTAVYYCARKGGYSGSWFAYWGQ PLTFGQGTKLEIKRTVAAPSVFIFP GTLVTVSSASTKGPSVFPLAPSSKSTSG PSDEQLKSGTASVVCLLNNFYPR GTAALGCLVKDYFPEPVTVSWNSGALTS EAKVQWKVDNALQSGNSQESVT GVHTFPAVLQSSGLYSLSSVVTVPSSSL EQDSKDSTYSLSSTLTLSKADYEK GTQTYICNVNHKPSNTKVDKRVEPKSCD HKVYACEVTHQGLSSPVTKSFNR KTHTCPPCPAPEAAGGPSVFLFPPKPKD GEC (SEQ ID NO: 123) TLMISRTPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPE NNYKTTPPVLDSDGSFFLYSKLTVDKSR WQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (SEQ ID NO: 138)

[0152] In some aspects, the humanized antibody displays blocking activity, whereby it decreases the binding of IL-36 ligand to IL-36 receptor by at least 45%, by at least 50%, by at least 55%, by at least 60%, by at least 65%, by at least 70%, by at least 75%, by at least 80%, by at least 85%, by at least 90%, or by at least 95%. The ability of an antibody to block binding of IL-36 ligand to the 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 the production of IL-8, IL-6, and GM-CSF to determine if signaling mediated by the IL-36 receptor is inhibited.

[0153] In a further aspect, the present invention provides a humanized anti-IL-36R antibody having favorable biophysical properties. In one aspect, a humanized anti-IL-36R antibody of the present invention is present in at least 90% monomer form, or in at least 92% monomer form, or in at least 95% monomer form in a buffer. In a further aspect, a humanized anti-IL-36R antibody of the present invention remains in at least 90% monomer form, or in at least 92% monomer form, or in at least 95% monomer form in a buffer for one month or for four months.

[0154] In one aspect, a humanized antibody of the present invention is Antibody B1, Antibody B2, Antibody B3, Antibody B4, Antibody B5, Antibody B6, Antibody C1, Antibody C2, or Antibody C3. Accordingly, in one embodiment, a humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO:115 and the heavy chain sequence of SEQ ID NO:125 (Antibody B1). In another embodiment, a humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO:115 and the heavy chain sequence of SEQ ID NO:126 (Antibody B2). In another embodiment, a humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO:115 and the heavy chain sequence of SEQ ID NO:127 (Antibody B3). In another embodiment, a humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO:118 and the heavy chain sequence of SEQ ID NO:125 (Antibody B4). In another embodiment, a humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO:118 and the heavy chain sequence of SEQ ID NO:126 (Antibody B5). In another embodiment, a humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO:118 and the heavy chain sequence of SEQ ID NO:127 (Antibody B6). In another embodiment, a humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO:124 and the heavy chain sequence of SEQ ID NO:138 (Antibody C1). In another embodiment, a humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO:123 and the heavy chain sequence of SEQ ID NO:139 (Antibody C2). In another embodiment, a humanized antibody of the present invention comprises the light chain sequence of SEQ ID NO:123 and the heavy chain sequence of SEQ ID NO:138 (Antibody C3).

[0155] In a further embodiment, a humanized antibody of the present invention consists of the light chain sequence of SEQ ID NO:115 and the heavy chain sequence of SEQ ID NO:125 (Antibody B1). In another embodiment, a humanized antibody of the present invention consists of the light chain sequence of SEQ ID NO:115 and the heavy chain sequence of SEQ ID NO:126 (Antibody B2). In another embodiment, a humanized antibody of the present invention consists of the light chain sequence of SEQ ID NO:115 and the heavy chain sequence of SEQ ID NO:127 (Antibody B3). In another embodiment, a humanized antibody of the present invention consists of the light chain sequence of SEQ ID NO:118 and the heavy chain sequence of SEQ ID NO:125 (Antibody B4). In another embodiment, a humanized antibody of the present invention consists of the light chain sequence of SEQ ID NO:118 and the heavy chain sequence of SEQ ID NO:126 (Antibody B5). In another embodiment, a humanized antibody of the present invention consists of the light chain sequence of SEQ ID NO:118 and the heavy chain sequence of SEQ ID NO:127 (Antibody B6). In another embodiment, a humanized antibody of the present invention consists of the light chain sequence of SEQ ID NO:124 and the heavy chain sequence of SEQ ID NO:138 (Antibody C1). In another embodiment, a humanized antibody of the present invention consists of the light chain sequence of SEQ ID NO:123 and the heavy chain sequence of SEQ ID NO:139 (Antibody C2). In another embodiment, a humanized antibody of the present invention consists of the light chain sequence of SEQ ID NO:123 and the heavy chain sequence of SEQ ID NO:138 (Antibody C3).

[0156] In some embodiments, the humanized anti-IL-36R antibodies, including antigen-binding fragments thereof, such as heavy and light chain variable regions, comprise an amino acid sequence of the residues derived from Antibody B1, Antibody B2, Antibody B3, Antibody B4, Antibody B5, Antibody B6, Antibody C1, Antibody C2, or Antibody C3.

[0157] In a further embodiment, the present 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 present invention, for example 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.

[0158] The humanized anti-IL-36R antibodies optionally include specific amino acid substitutions in the consensus or germline framework regions. The specific substitution of amino acid residues in these framework positions can improve various aspects of antibody performance including binding affinity and/or stability, over that demonstrated in humanized antibodies formed by "direct swap" of CDRs or HVLs into the human germline framework regions.

[0159] In some embodiments, the present invention describes other monoclonal antibodies with a light chain variable region having the amino acid sequence set forth in any one of SEQ ID NO:1-10. In some embodiments, the present invention describes other monoclonal antibodies with a heavy chain variable region having the amino acid sequence set forth in any one of SEQ ID NO:11-20. Placing such CDRs into FRs of the human consensus heavy and light chain variable domains will yield useful humanized antibodies of the present invention.

[0160] In particular, the present invention provides monoclonal antibodies with the combinations of light chain variable and heavy chain variable regions of SEQ ID NO:1/11, 2/12, 3/13, 4/14, 5/15, 6/16, 7/17, 8/18, 9/19, 10/20. Such variable regions can be combined with human constant regions.

[0161] In some embodiments, the present invention describes other humanized antibodies with light chain variable region sequences having the amino acid sequence set forth in any one of SEQ ID NO:76-86. In some embodiments, the present invention describes other humanized antibodies with heavy chain variable region sequences having the amino acid sequence set forth in any one of SEQ ID NO:87-101. In particular, the present invention provides monoclonal antibodies with the combinations of light chain variable and heavy chain variable regions of SEQ ID NO: 77/89, 80/88, 80/89, 77/87, 77/88, 80/87, 86/100, 85/101, 85/100. Such variable regions can be combined with human constant regions.

[0162] In a further embodiment, the present 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:77 and framework regions 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 regions 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 framework regions 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 regions 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.

[0163] In a further embodiment, the present 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 framework regions 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 regions 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:88 and framework regions 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 regions 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.

[0164] In a further embodiment, the present 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 framework regions 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 regions 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 framework regions 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 regions 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.

[0165] In a further embodiment, the present 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:77 and framework regions 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 regions 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:87 and framework regions 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 regions 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.

[0166] In a further embodiment, the present 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:77 and framework regions 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 regions 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:88 and framework regions 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 regions 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.

[0167] In a further embodiment, the present 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 framework regions 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 regions 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:87 and framework regions 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 regions 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.

[0168] In a further embodiment, the present 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:86 and framework regions 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 regions 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 framework regions 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 regions 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.

[0169] In a further embodiment, the present 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 framework regions 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 regions 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 framework regions 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 regions 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.

[0170] In a further embodiment, the present 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 framework regions 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 regions 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 framework regions 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 regions 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.

[0171] In some specific embodiments, the humanized anti-IL-36R antibodies disclosed herein comprise at least a heavy or a light chain variable domain comprising the CDRs or HVLs of the murine monoclonal antibodies or humanized antibodies as disclosed herein and the FRs of the human germline heavy and light chain variable domains.

[0172] In one further aspect, the present invention provides an anti-IL-36R antibody or antigen-binding fragment thereof comprising a light chain CDR1 (L-CDR1) sequence of any one of SEQ ID NO:21-29; a light chain CDR2 (L-CDR2) sequence of any one of SEQ ID NO:30-38; a light chain CDR3 (L-CDR3) sequence of any one of SEQ ID NO:39-47; a heavy chain CDR1 (H-CDR1) sequence of any one of SEQ ID NO:48-56; a heavy chain CDR2 (H-CDR2) sequence of any one of SEQ ID NO:57-66; and a heavy chain CDR3 (H-CDR3) sequence of any one of SEQ ID NO:67-75. In one aspect, the anti-IL-36R antibody or antigen-binding fragment thereof comprises a light chain variable region comprising a L-CDR1 listed above, a L-CDR2 listed above and a L-CDR3 listed above, and a heavy chain variable region comprising a H-CDR1 listed above, a H-CDR2 listed above and a H-CDR3 listed above.

[0173] In a further aspect, the present invention provides an anti-IL-36R antibody or antigen-binding fragment thereof comprising: [0174] a) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:21, 30, 39, 48, 57 and 67, respectively; or [0175] b) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:22, 31, 40, 49, 58 and 68, respectively; or [0176] c) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:23, 32, 41, 50, 59 and 69, respectively; or [0177] d) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:24, 33, 42, 51, 60 and 70, respectively; or [0178] e) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:25, 34, 43, 52, 61 and 71, respectively; or [0179] f) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:26, 35, 44, 53, 62 and 72, respectively; or [0180] g) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:27, 36, 45, 54, 63 and 73, respectively; or [0181] h) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:27, 36, 45, 54, 64 and 74, respectively; or [0182] i) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:27, 36, 45, 54, 64 and 73, respectively; or [0183] j) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:28, 37, 46, 55, 65 and 74, respectively; or [0184] k) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:29, 38, 47, 56, 66 and 75, respectively.

[0185] In a further aspect, the present invention provides an anti-IL-36R antibody or antigen-binding fragment thereof comprising: [0186] a) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:26, 103, 44, 53, 62 and 72, respectively; or [0187] b) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:26, 104, 44, 53, 62 and 72, respectively; or [0188] c) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:27, 36, 45, 107, 63 and 73, respectively; or [0189] d) a L-CDR1, a L-CDR2, a L-CDR3, a H-CDR1, a H-CDR2 and a H-CDR3 sequence of SEQ ID NO:27, 36, 45, 107, 64 or 73, respectively.

[0190] In one aspect, the anti-IL-36R antibody or antigen-binding fragment thereof comprises a light chain variable region comprising a L-CDR1, L-CDR2 and L-CDR3 combination listed above, and a heavy chain variable region comprising a H-CDR1, H-CDR2 and H-CDR3 combination listed above.

[0191] In specific embodiments, it is contemplated that chimeric antibodies with switched CDR regions (i.e., for example switching one or two CDRs of one of the mouse antibodies or humanized antibody derived therefrom with the analogous CDR from another mouse antibody or humanized antibody derived therefrom) between these exemplary immunoglobulins may yield useful antibodies.

[0192] 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 the production of antibody fragments. Fragments can be derived via proteolytic digestion of intact antibodies (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 fragments can be produced directly in recombinant host cells. For example, Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab').sub.2 fragments (see, e.g., Carter et al., 1992, Bio/Technology 10:163-167). By another approach, F(ab').sub.2 fragments can be isolated directly from recombinant host cell culture. Other techniques for the production of antibody fragments will be apparent to the skilled practitioner. Accordingly, in one aspect, the present invention provides antibody fragments comprising the CDRs described herein, in particular one of the combinations of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 described herein. In a further aspect, the present invention provides antibody fragments comprising the variable regions described herein, for example one of the combinations of light chain variable regions and heavy chain variable regions described herein.

[0193] Certain embodiments include an F(ab').sub.2 fragment of a humanized anti-IL-36R antibody comprise a light chain sequence of any of SEQ ID NO: 115 or 118 in combination with a heavy chain sequence of SEQ ID NO: 125, 126 or 127. Such embodiments can include an intact antibody comprising such an F(ab')2.

[0194] Certain embodiments include an F(ab').sub.2 fragment of a humanized anti-IL-36R antibody comprise a light chain sequence of any of SEQ ID NO: 123 or 124 in combination with a heavy chain sequence of SEQ ID NO: 138 or 139. Such embodiments can include an intact antibody comprising such an F(ab').sub.2.

[0195] In some embodiments, the antibody or antibody fragment includes a constant region that mediates effector function. The constant region can provide antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and/or complement-dependent cytotoxicity (CDC) responses against an anti-IL-36R expressing target cell. The effector domain(s) can be, for example, an Fc region of an Ig molecule.

[0196] The effector domain of an antibody can be from any suitable vertebrate animal species and isotypes. The isotypes from different animal species differ in the abilities to mediate effector functions. For example, the ability of human immunoglobulin to mediate CDC and ADCC/ADCP is generally in the order of IgM.apprxeq.IgG.sub.1.apprxeq.IgG.sub.3>IgG.sub.2>IgG.sub.4 and IgG.sub.1.apprxeq.IgG.sub.3>IgG.sub.2/IgM/IgG.sub.4, respectively. Murine immunoglobulins mediate CDC and ADCC/ADCP generally in the order of murine IgM.apprxeq.IgG.sub.3>>IgG.sub.2b>IgG.sub.2a>>Ig- G.sub.1 and IgG.sub.2b>IgG.sub.2a>IgG.sub.1>>IgG.sub.3, respectively. In another example, murine IgG.sub.2a mediates ADCC while both murine IgG.sub.2a and IgM mediate CDC.

III. Pharmaceutical Doses and Administration

[0197] Anti-IL-36R antibodies of the present invention are typically administered to a patient as 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 composition 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. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, N.Y.). Suitable routes of administration include intravenous injection (including intraarterial injection) and subcutaneous injection.

[0198] In a first aspect, the present invention relates to a method of treating generalized pustular psoriasis (GPP) in a patient, said method including administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody.

[0199] In a second aspect, the present invention relates to a method of treating moderate to severe GPP in a patient, including administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody.

[0200] In a third aspect, the present invention relates to a method of reducing or alleviating signs and symptoms of an acute phase flare-up of GPP in a patient, said method including administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody.

[0201] In a forth aspect, the present invention relates to a method of reducing the severity and duration of GPP flares, said method comprising including administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody.

[0202] In a fifth aspect, the present invention relates to a method of treating a skin disorder associated with acute GPP, said method including administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody.

[0203] In one embodiment related to any of aspects first to fifth, the anti-IL-36R antibody includes: a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105 106 or 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0204] In one embodiment related to any of aspects first to fifth, the anti-IL-36R antibody includes:

[0205] I. a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 102 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0206] II. a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 103 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0207] III. a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 104 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0208] IV. a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 105 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0209] V. a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 106 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0210] VI. a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0211] In one embodiment related to any of aspects first to fifth, the anti-IL-36R antibody includes:

[0212] (i) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or

[0213] (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or

[0214] (iii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or

[0215] (iv) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or

[0216] (v) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or

[0217] (vi) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or

[0218] (vii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or

[0219] (viii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101; or

[0220] (ix) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or

[0221] (x) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101.

[0222] In one embodiment related to any of aspects first to fifth, the anti-IL-36R antibody includes:

[0223] i. a light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125; or

[0224] ii. a light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126; or

[0225] iii. a light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or

[0226] iv. a light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125; or

[0227] v. a light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126; or

[0228] vi. a light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or

[0229] vii. a light chain comprising the amino acid sequence of SEQ ID NO: 123; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138; or

[0230] viii. a light chain comprising the amino acid sequence of SEQ ID NO: 123; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 139; or

[0231] ix. a light chain comprising the amino acid sequence of SEQ ID NO: 124; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 138.

[0232] In one embodiment related to any of aspects first to fifth, the anti-IL-36R antibody is administered in one or more intravenous dose(s). In a related embodiment, each of the one or more intravenous dose(s) includes 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg of said anti-IL-36R antibody.

[0233] In another embodiment related to any of aspects first to fifth, the anti-IL-36R antibody is administered in one intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R is administered in one intravenous dose of about 10 mg per kilogram of body weight of the patient. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 210 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 300 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 350 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 450 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 600 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 700 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 750 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 800 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 850 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in one intravenous dose of 900 mg.

[0234] Representative examples of doses and dose regimens according to the present invention are disclosed in Table 1. Although, doses 900 mg and 750 mg have been exemplified, similar dose regimens equally apply to doses 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg and 800 mg.

TABLE-US-00009 TABLE 1 Doses and Dose Regimens Optional Intravenous Frequency of Frequency of Subcutaneous Frequency of Frequency of dose intravenous intravenous dose subcutaneous subcutaneous (mg) doses administration (mg) doses administration 900 1 Single 150 0 -- 900 1 Single 150 1 -- 900 1 Single 150 2 At 4, 6, 8, 10 or 12 weeks intervals 900 1 Single 150 3 At 4, 6, 8, 10 or 12 weeks intervals 900 1 Single 225 0 -- 900 1 Single 225 1 -- 900 1 Single 225 2 At 4, 6, 8, 10 or 12 weeks intervals 900 1 Single 225 3 At 4, 6, 8, 10 or 12 weeks intervals 900 1 Single 300 0 -- 900 1 Single 300 1 -- 900 1 Single 300 2 At 4, 6, 8, 10 or 12 weeks intervals 900 1 Single 300 3 At 4, 6, 8, 10 or 12 weeks intervals 900 2 At 2, 4, 6, 8, 10 or 12 150 0 -- weeks intervals 900 2 At 2, 4, 6, 8, 10 or 12 150 1 -- weeks intervals 900 2 At 2, 4, 6, 8, 10 or 12 150 2 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 900 2 At 2, 4, 6, 8, 10 or 12 150 3 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 900 2 At 2, 4, 6, 8, 10 or 12 225 0 -- weeks intervals 900 2 At 2, 4, 6, 8, 10 or 12 225 1 -- weeks intervals 900 2 At 2, 4, 6, 8, 10 or 12 225 2 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 900 2 At 2, 4, 6, 8, 10 or 12 225 3 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 900 2 At 2, 4, 6, 8, 10 or 12 300 0 -- weeks intervals 900 2 At 2, 4, 6, 8, 10 or 12 300 1 -- weeks intervals 900 2 At 2, 4, 6, 8, 10 or 12 300 2 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 900 2 At 2, 4, 6, 8, 10 or 12 300 3 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 900 3 At 2, 4, 6, 8, 10 or 12 150 0 -- weeks intervals 900 3 At 2, 4, 6, 8, 10 or 12 150 1 -- weeks intervals 900 3 At 2, 4, 6, 8, 10 or 12 150 2 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 900 3 At 2, 4, 6, 8, 10 or 12 150 3 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 900 3 At 2, 4, 6, 8, 10 or 12 225 0 -- weeks intervals 900 3 At 2, 4, 6, 8, 10 or 12 225 1 -- weeks intervals 900 3 At 2, 4, 6, 8, 10 or 12 225 2 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 900 3 At 2, 4, 6, 8, 10 or 12 225 3 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 900 3 At 2, 4, 6, 8, 10 or 12 300 0 -- weeks intervals 900 3 At 2, 4, 6, 8, 10 or 12 300 1 -- weeks intervals 900 3 At 2, 4, 6, 8, 10 or 12 300 2 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 900 3 At 2, 4, 6, 8, 10 or 12 300 3 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 750 1 Single 150 0 -- 750 1 Single 150 1 -- 750 1 Single 150 2 At 4, 6, 8, 10 or 12 weeks intervals 750 1 Single 150 3 At 4, 6, 8, 10 or 12 weeks intervals 750 1 Single 225 0 -- 750 1 Single 225 1 -- 750 1 Single 225 2 At 4, 6, 8, 10 or 12 weeks intervals 750 1 Single 225 3 At 4, 6, 8, 10 or 12 weeks intervals 750 1 Single 300 0 -- 750 1 Single 300 1 -- 750 1 Single 300 2 At 4, 6, 8, 10 or 12 weeks intervals 750 1 Single 300 3 At 4, 6, 8, 10 or 12 weeks intervals 750 2 At 2, 4, 6, 8, 10 or 12 150 0 -- weeks intervals 750 2 At 2, 4, 6, 8, 10 or 12 150 1 -- weeks intervals 750 2 At 2, 4, 6, 8, 10 or 12 150 2 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 750 2 At 2, 4, 6, 8, 10 or 12 150 3 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 750 2 At 2, 4, 6, 8, 10 or 12 225 0 -- weeks intervals 750 2 At 2, 4, 6, 8, 10 or 12 225 1 -- weeks intervals 750 2 At 2, 4, 6, 8, 10 or 12 225 2 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 750 2 At 2, 4, 6, 8, 10 or 12 225 3 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 750 2 At 2, 4, 6, 8, 10 or 12 300 0 -- weeks intervals 750 2 At 2, 4, 6, 8, 10 or 12 300 1 -- weeks intervals 750 2 At 2, 4, 6, 8, 10 or 12 300 2 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 750 2 At 2, 4, 6, 8, 10 or 12 300 3 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 750 3 At 2, 4, 6, 8, 10 or 12 150 0 -- weeks intervals 750 3 At 2, 4, 6, 8, 10 or 12 150 1 -- weeks intervals 750 3 At 2, 4, 6, 8, 10 or 12 150 2 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 750 3 At 2, 4, 6, 8, 10 or 12 150 3 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 750 3 At 2, 4, 6, 8, 10 or 12 225 0 -- weeks intervals 750 3 At 2, 4, 6, 8, 10 or 12 225 1 -- weeks intervals 750 3 At 2, 4, 6, 8, 10 or 12 225 2 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 750 3 At 2, 4, 6, 8, 10 or 12 225 3 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 750 3 At 2, 4, 6, 8, 10 or 12 300 0 -- weeks intervals 750 3 At 2, 4, 6, 8, 10 or 12 300 1 -- weeks intervals 750 3 At 2, 4, 6, 8, 10 or 12 300 2 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals 750 3 At 2, 4, 6, 8, 10 or 12 300 3 At 4, 6, 8, 10 or weeks intervals 12 weeks intervals

[0235] In one embodiment, 1, 2 or 3 intravenous dose(s) is/are administered to the patient in a dose regimen listed in Table 1.

[0236] In an embodiment relating to any of the above aspects, the mammal or the patient is evaluated for improved Clinical Remission as defined by: (a) Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 or 1 at Week 1; (b) GPPGA pustulation subscore of 0 indicating no visible pustules at Week 1; (c) Psoriasis Area and Severity Index for Generalized Pustular Psoriasis (GPPASI) 75 at Week 4; (d) Change from baseline in Pain Visual Analog Scale (VAS) score at Week 4; (e) Change from baseline in Psoriasis Symptom Scale (PSS) score at Week 4; (f) Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue score at Week 4; (g) GPPGA 0 or 1 at Week 4; (h) GPPGA pustulation subscore of 0 indicating no visible pustules at Week 4; (i) GPPASI 50 at Week 1 and 4; or (j) Change in GPPASI pustule, erythema or scaling severity subscore from baseline at Week 1 and 4. In a related embodiment, proportion of patients with a response to the administration is statistically significantly higher as compared to patients on placebo for any of the end points recited.

[0237] In one embodiment, the present invention relates to a method of treating generalized pustular psoriasis (GPP), a method of treating moderate to severe GPP, a method of reducing or alleviating signs and symptoms of an acute phase flare-up of GPP, a method of reducing the severity and duration of GPP flares, or a method of treating a skin disorder associated with acute GPP in a patient, said method(s) including administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody of the present invention in one or more intravenous dose(s) of 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg or 900 mg each, wherein more than one intravenous doses are administered at 2, 4, 6, 8, 10 or 12 weeks intervals.

[0238] In one embodiment, the present invention relates to a method of treating generalized pustular psoriasis (GPP), a method of treating moderate to severe GPP, a method of reducing or alleviating signs and symptoms of an acute phase flare-up of GPP, a method of reducing the severity and duration of GPP flares, or a method of treating a skin disorder associated with acute GPP in a patient, said method(s) including administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody of the present invention in one intravenous dose of 900 mg.

[0239] the present invention relates to a method of treating generalized pustular psoriasis (GPP), a method of treating moderate to severe GPP, a method of reducing or alleviating signs and symptoms of an acute phase flare-up of GPP, a method of reducing the severity and duration of GPP flares, or a method of treating a skin disorder associated with acute GPP in a patient, said method(s) including administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody of the present invention in 1, 2 or 3 intravenous dose(s) of 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg or 900 mg each, wherein 2 or 3 intravenous doses are administered at 2, 4, 6, 8, 10 or 12 weeks intervals.

[0240] In a sixth aspect, the present invention relates to a method of preventing the recurrence of GPP flares in a patient treated with one or more intravenous dose(s) of the anti-IL-36R antibody according to any of aspects first to fifth or the above embodiments, said method including administering to the patient a prophylactically effective amount of the anti-IL-36R antibody in one or more subcutaneous doses.

[0241] In a seventh aspect, the present invention relates to a method of achieving a Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 in a patient treated with one or more intravenous dose(s) of the anti-IL-36R antibody according to any of aspects first to fifth or the above embodiments, said method including administering to the patient an effective amount of the anti-IL-36R antibody in one or more subcutaneous doses.

[0242] In an eight aspect, the present invention relates to a method of achieving a complete resolution of GPP symptoms in a patient treated with one or more intravenous dose(s) of the anti-IL-36R antibody according to any of aspects first to fifth or the above embodiments, said method comprising administering to the patient an effective amount of the anti-IL-36R antibody in one or more subcutaneous doses; wherein the GPP symptoms comprise postule, erythema, or scaling and the complete resolution comprises a GPPGA score of 0.

[0243] In one embodiment related to any of aspects sixth to eight, each of the one or more subcutaneous doses includes 150 mg, 225 mg, 300 mg, 450 mg or 600 mg of said anti-IL-36R antibody.

[0244] In one embodiment related to any of aspects sixth to eight or the related embodiment(s), 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.

[0245] In one embodiment related to any of aspects sixth to eight or the related embodiment(s), the first subcutaneous dose is administered 2 to 8 weeks, 4 to 6 weeks, 2 weeks, 4 weeks, 6 weeks or 8 weeks, after the last intravenous dose is administered and the second subcutaneous dose is administered 4, 6, 8, 10 or 12 weeks after said first subcutaneous dose is administered.

[0246] In one embodiment, the present invention relates to a method of preventing the recurrence of GPP flares in a patient treated with one or more intravenous dose(s) of the anti-IL-36R antibody of the present invention, said method including administering to the patient a prophylactically effective amount of the anti-IL-36R antibody in one or more subcutaneous doses of 225 mg, 300 mg, 450 mg or 600 mg each of said anti-IL-36R antibody, wherein more than one subcutaneous doses are administered at 4, 6, 8 10 or 12 weeks intervals.

[0247] In one embodiment, the present invention relates to a method of achieving a Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 or a method of achieving a complete resolution of GPP symptoms in a patient treated with one or more intravenous dose(s) of the anti-IL-36R antibody of the present invention, said method including administering to the patient an effective amount of the anti-IL-36R antibody in one or more subcutaneous doses of 225 mg, 300 mg, 450 mg or 600 mg each of said anti-IL-36R antibody, wherein more than one subcutaneous doses are administered at 4, 6, 8 10 or 12 weeks intervals, and wherein the GPP symptoms comprise postule, erythema, or scaling and the complete resolution comprises a GPPGA score of 0.

[0248] In one embodiment, the present invention relates to a method of achieving a Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 or a method of achieving a complete resolution of GPP symptoms in a patient treated with one or more intravenous dose(s) of the anti-IL-36R antibody of the present invention, said method including administering to the patient an effective amount of the anti-IL-36R antibody in 1, 2, 3 subcutaneous doses of 225 mg, 300 mg, 450 mg or 600 mg each of the anti-IL-36R antibody, wherein 2 or 3 subcutaneous doses are administered at 4, 6, 8 10 or 12 weeks intervals, and wherein the GPP symptoms comprise postule, erythema, or scaling and the complete resolution comprises a GPPGA score of 0.

[0249] In one embodiment related to any of aspects sixth to eight or the related embodiment(s), at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a GPPGA score of 0 or 1 at Week 12, 24, 36, 48, 60 or 72 of the treatment.

[0250] In one embodiment related to any of aspects sixth to eight or the related embodiment(s), at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a change in GPPASI from baseline at Week 12, 24, 36, 48, 60 or 72 of the treatment.

[0251] In one embodiment related to any of aspects sixth to eight or the related embodiment(s), at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a change in GPPASI pustule, erythema or scaling severity subscore from baseline at Week 12, 24, 36, 48, 60 or 72 of the treatment. In a related embodiment, proportion of patients with a response to the administration is statistically significantly higher as compared to patients on placebo for any of the end points recited.

[0252] In an embodiment related to any of aspects sixth to eight, at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a GPPGA score of 0 or 1 at Week 12, 24, 36, 48, 60 or 72 of the treatment. In an embodiment related to any of aspects sixth to eight, at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a change in GPPASI from baseline at Week 12, 24, 36, 48, 60 or 72 of the treatment. In an embodiment related to any of aspects sixth to eight, at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a change in GPPASI pustule, erythema or scaling severity subscore from baseline at Week 12, 24, 36, 48, 60 or 72 of the treatment. In a related embodiment, proportion of patients with a response to the administration is statistically significantly higher as compared to patients on placebo for any of the end points recited.

[0253] In an embodiment related to any of aspects sixth to eight, at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a GPPGA score of 0 or 1 at Week 12, 24, 36, 48, 60 or 72 of the treatment. In a related embodiment, the improved effects are maintained at higher percentage with an anti-IL-36R antibody of the present invention than with placebo. In a related embodiment, at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of the mammals or patients maintain improved effects at Week 12, 24, 36, 48, 60 or 72 of the treatment with an anti-IL-36R antibody of the present invention than with placebo.

[0254] In an embodiment related to any of aspects sixth to eight, at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a change in GPPASI from baseline at Week 12, 24, 36, 48, 60 or 72 of the treatment. In a related embodiment, the improved effects are maintained at higher percentage with an anti-IL-36R antibody of the present invention than with placebo. In a related embodiment, at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 0.48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of the mammals or patients maintain improved effects at Week 12, 24, 36, 48, 60 or 72 of the treatment with an anti-IL-36R antibody of the present invention than with placebo.

[0255] In an embodiment related to any of aspects sixth to eight, at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a change in GPPASI pustule, erythema or scaling severity subscore from baseline at Week 12, 24, 36, 48, 60 or 72 of the treatment. In a related embodiment, the improved effects are maintained at higher percentage with an anti-IL-36R antibody of the present invention than with placebo. In a related embodiment, at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of the mammals or patients maintain improved effects at Week 12, 24, 36, 48, 60 or 72 of the treatment with an anti-IL-36R antibody of the present invention than with placebo.

[0256] In a ninth aspect, the present invention relates to a method of treating GPP in a patient, including administering to the patient a therapeutically effective amount of one or more intravenous dose(s) of the anti-IL-36R antibody, according to aspects first to fifth and their related embodiments, followed by one or more subcutaneous dose(s) of the anti-IL-36R antibody.

[0257] In one embodiment relating to aspect ninth, 1 or 2 or 3 intravenous dose(s) of the anti-IL-36R antibody is/are followed by 1 or 2 or 3 subcutaneous doss(s) of the anti-IL-36R antibody.

[0258] In one embodiment relating to aspect ninth, 1 intravenous dose of the anti-IL-36R antibody is followed by 1 or 2 or 3 subcutaneous doss(s) of the anti-IL-36R antibody.

[0259] In one embodiment relating to aspect ninth, 2 intravenous doses of the anti-IL-36R antibody are followed by 1 or 2 or 3 subcutaneous doss(s) of the anti-IL-36R antibody.

[0260] In one embodiment relating to aspect ninth, 3 intravenous doses of the anti-IL-36R antibody are followed by 1 or 2 or 3 subcutaneous doss(s) of the anti-IL-36R antibody.

[0261] In one embodiment relating to aspect ninth and its related embodiment, each of the one or more intravenous dose(s) includes 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg, 850 mg or 900 mg of the anti-IL-36R antibody and each of the one or more subcutaneous dose(s) includes 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of the anti-IL-36R antibody. In a related embodiment, the intravenous doses are administered at 2, 4, 6, 8, 10 or 12 weeks intervals, the subcutaneous doses are administered at 4, 6, 8, 10 or 12 weeks intervals, and the first subcutaneous dose is administered 2 to 8 weeks, 4 to 6 weeks, 2 weeks, 4 weeks, 6 weeks or 8 weeks after the last intravenous dose is administered.

[0262] In an embodiment relating to any of the above aspects, the intravenous dose(s) may be followed by one or more subcutaneous dose(s).

[0263] In an embodiment relating to any of the above aspects, the anti-IL-36R antibody or an antigen binding fragment thereof (disclosed herein) is present in a stable pharmaceutical formulation (as described in co-pending U.S. provisional application No. 62/815,405, filed Mar. 8, 2019, the entire content of which is hereby incorporated herein by reference in its entirety) for administration to a mammal or patient according to any one of the aspects of the present invention.

[0264] In another embodiment, the formulation comprises a therapeutic amount of an anti-IL-36R antibody (disclosed herein) and [0265] i) a pharmaceutically acceptable buffer; or [0266] ii) a pharmaceutically acceptable tonicifying agent; or [0267] iii) a pharmaceutically acceptable stabilizing agent; or [0268] iv) a pharmaceutically acceptable salt; or [0269] v) a pharmaceutically acceptable surfactant; or [0270] vi) a pharmaceutically acceptable buffer and a pharmaceutically acceptable tonicifying agent; or [0271] vii) a pharmaceutically acceptable buffer, a pharmaceutically acceptable tonicifying agent and a pharmaceutically acceptable stabilizing agent; or [0272] viii) a pharmaceutically acceptable buffer, a pharmaceutically acceptable tonicifying agent, a pharmaceutically acceptable stabilizing agent and a pharmaceutically acceptable salt; or [0273] ix) a pharmaceutically acceptable buffer, a pharmaceutically acceptable tonicifying agent, a pharmaceutically acceptable stabilizing agent, a pharmaceutically acceptable salt and a pharmaceutically acceptable surfactant; [0274] each in pharmaceutically acceptable quantities and at a pharmaceutically acceptable pH.

[0275] In another embodiment, the anti-IL-36R antibody or antigen binding fragment thereof is present in the formulation at a concentration of about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 60 mg/mL, about 75 mg/mL, about 80 mg/mL, about 100 mg/mL or about 150 mg/mL. In another related embodiment, the pharmaceutically acceptable buffer is present in the formulation at a concentration within the range from about 20 mM to about 80 mM, or at a concentration of about 20 mM, about 25 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 60 mM. In another related embodiment, the pharmaceutically acceptable tonicifying agent is present in the formulation at a concentration within the range from about 100 mM to about 250 mM, or at a concentration of about 100 mM, about 120 mM, about 150 mM, about 180 mM, about 200 mM. In another related embodiment, the pharmaceutically acceptable stabilizing agent is present in the formulation at a concentration within the range from about 0 mM to about 80 mM, or at a concentration of about 25 mM or about 50 mM. In another related embodiment, the pharmaceutically acceptable salt is present in the formulation at a concentration of within the range from about 0 to about 150 mM, or at a concentration of about 3 mM, 5 mM, 10 mM, 25 mM or 50 mM. In another related embodiment, the pharmaceutically acceptable surfactant is present in the formulation at a concentration within the range from about 0 g/L to about 1.5 g/L, or at a concentration of about 0.1 g/L, 0.2 g/L, 0.4 g/L, 0.5 g/L or 1 g/L. In an embodiment related to the first aspect, the formulation is characterized by a pH within the range from about 5 to about 8. In another related embodiment, the pH is about 5, about 5.5, about 6, about 6.5, about 7, about 7.5 or about 8.

[0276] In another embodiment, the buffer comprises histidine, phosphate, succinate, citrate, acetate or TRIS; the tonicifying agent is one or more sugar and/or polyol including sucrose, trehalose, sorbitol, magnesium sulfate (MgSO4), glycerol, mannitol or dextrose; the stabilizer comprises an amino acid including arginine, histidine, glycine, cysteine, proline, methionine, lysine, aspartate, glutamate or pharmaceutically acceptable salts thereof; the salt comprises sodium chloride (NaCl), magnesium chloride (MgCl2), potassium chloride (KCl), lithium chloride (LiCl), calcium chloride (CaCl2)), boric acid salts or zinc chloride (ZnCl2); and the surfactant comprises poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80.

[0277] In one embodiment, the method of treatment according to any of the aspects described herein, includes administering to the mammal or patient a therapeutic amount of a stable pharmaceutical formulation comprising from about 20 mg/mL to about 150 mg/mL of an anti-IL-36R antibody, about 20 mM to about 80 mM of a pharmaceutically acceptable buffer (e.g., acetate buffer), about 100 mM to about 250 mM of a pharmaceutically acceptable tonicifying agent (e.g., sucrose), about 0 mM to about 80 mM of a pharmaceutically acceptable stabilizing agent (e.g., arginine) or a pharmaceutically acceptable salt thereof, about 0 to about 150 mM of a pharmaceutically acceptable salt (e.g., sodium chloride), and a pharmaceutically acceptable surfactant (e.g., polysorbate 20) in an amount about 0 g/L to about 1.5 g/L, wherein the generalized pustular psoriasis (GPP) in the patient is treated, or the moderate to severe GPP in the patient is treated, or the signs and symptoms of an acute phase flare-up of GPP in the patient is reduced or alleviated, or the severity and duration of GPP flares in the patient is reduced, or the skin disorder associated with acute GPP in the patient is treated, or the GPP flares in a patient is prevented or inhibited, or the Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 in the patient is achieved, or the complete resolution of GPP symptoms in the patient is achieved. In a related embodiment, the stable pharmaceutical formulation is an aqueous pharmaceutical formulation. In a related embodiment, the pH of the aqueous pharmaceutical formulation is about 5 to about 7. In a related embodiment, the pharmaceutical formulation is for an intravenous administration to the mammal or patient. In a related embodiment, the pharmaceutical formulation is for a subcutaneous administration to the mammal or patient. In a related embodiment, the pharmaceutical formulation for the intravenous administration comprises an anti-IL-36R antibody in an amount of about 60 mg/mL. In a related embodiment, the pharmaceutical formulation for a subcutaneous administration comprises an anti-IL-36R antibody in an amount of about 150 mg/mL. In a related embodiment, the anti-IL-36R antibody comprising: (i) a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or (ii) a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or (iii) a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127. In a related embodiment, the anti-IL-36R antibody comprising: a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89.

[0278] In one embodiment, the method of treatment according to any of the preceding aspects, comprises administering to the mammal or patient a therapeutic amount of a stable pharmaceutical formulation selected from the group consisting of consisting of: [0279] I. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM L-Arginine, about 5 mM NaCl and about 1.0 g/L Polysorbate 20, with a pH of about 6.0; [0280] II. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5; [0281] III. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM Glycine, about 0.4 g/L Polysorbate 80, with a pH of about 5.5; [0282] IV. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 150 mM trehalose, about 25 mM methionine, about 0.2 g/L Polysorbate 20, with a pH of about 6.0; [0283] V. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, about 0.2 g/L Polysorbate 20, with a pH of about 6.5; [0284] VI. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, about 0.4 g/L Polysorbate 80, with a pH of about 6.5; [0285] VII. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5; [0286] VIII. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 35 mM histidine, about 180 mM trehalose, about 25 mM L-Arginine, about 3 mM NaCl, about 0.4 g/L Polysorbate 80, with a pH of about 6.0; [0287] IX. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM acetate, about 100 mM mannitol, about 50 mM NaCl, about 0.2 g/L Polysorbate 20, with a pH of about 5.5; [0288] X. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 20 mM succinate, about 220 mM sucrose, about 0.1 g/L Polysorbate 80, with a pH of about 6.0; and [0289] XI. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 0.4 g/L Polysorbate 20, with a pH of about 6.5,

[0290] wherein the generalized pustular psoriasis (GPP) in the patient is treated, or the moderate to severe GPP in the patient is treated, or the signs and symptoms of an acute phase flare-up of GPP in the patient is reduced or alleviated, or the severity and duration of GPP flares in the patient is reduced, or the skin disorder associated with acute GPP in the patient is treated, or the GPP flares in a patient is prevented or inhibited, or the Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 in the patient is achieved, or the complete resolution of GPP symptoms in the patient is achieved. In a related embodiment, the stable pharmaceutical formulation is an aqueous pharmaceutical formulation. In a related embodiment, the pharmaceutical formulation is for an intravenous administration to the mammal or patient. In a related embodiment, the pharmaceutical formulation is for a subcutaneous administration to the mammal or patient. In a related embodiment, the pharmaceutical formulation for an intravenous administration comprises an anti-IL-36R antibody in an amount of about 60 mg/mL. In a related embodiment, the pharmaceutical formulation for a subcutaneous administration comprises an anti-IL-36R antibody in an amount of about 150 mg/mL. In a related embodiment, the anti-IL-36R antibody comprising: (i) a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or (ii) a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or (iii) a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127. In a related embodiment, the anti-IL-36R antibody comprising: a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89.

[0291] In one embodiment, the method of treatment according to any of the preceding aspects, comprises administering to the mammal or patient a therapeutic amount of a stable pharmaceutical formulation selected from the group consisting of consisting of: [0292] I. formulation including about 20 mg/mL of the anti-IL-36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM L-Arginine, about 5 mM NaCl and about 1.0 g/L Polysorbate 20, with a pH of about 6.0; [0293] II. formulation including about 60 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5; [0294] III. formulation including about 20 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM Glycine, about 0.4 g/L Polysorbate 80, with a pH of about 5.5; [0295] IV. formulation including about 150 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 150 mM trehalose, about 25 mM methionine, about 0.2 g/L Polysorbate 20, with a pH of about 6.0; [0296] V. formulation including about 150 mg/mL of the anti-IL-36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, about 0.2 g/L Polysorbate 20, with a pH of about 6.5; [0297] VI. formulation including about 20 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, about 0.4 g/L Polysorbate 80, with a pH of about 6.5; [0298] VII. formulation including about 150 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5; [0299] VIII. formulation including about 15 mg/mL of the anti-IL-36R antibody, about 35 mM histidine, about 180 mM trehalose, about 25 mM L-Arginine, about 3 mM NaCl, about 0.4 g/L Polysorbate 80, with a pH of about 6.0; [0300] IX. formulation including about 80 mg/mL of the anti-IL-36R antibody, about 25 mM acetate, about 100 mM mannitol, about 50 mM NaCl, about 0.2 g/L Polysorbate 20, with a pH of about 5.5; [0301] X. formulation including about 100 mg/mL of the anti-IL-36R antibody, about 20 mM succinate, about 220 mM sucrose, about 0.1 g/L Polysorbate 80, with a pH of about 6.0; and [0302] XI. formulation including about 60 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 0.4 g/L Polysorbate 20, with a pH of about 6.5,

[0303] wherein the generalized pustular psoriasis (GPP) in the patient is treated, or the moderate to severe GPP in the patient is treated, or the signs and symptoms of an acute phase flare-up of GPP in the patient is reduced or alleviated, or the severity and duration of GPP flares in the patient is reduced, or the skin disorder associated with acute GPP in the patient is treated, or the GPP flares in a patient is prevented or inhibited, or a Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 in the patient is achieved, or the complete resolution of GPP symptoms in the patient is achieved. In a related embodiment, the stable pharmaceutical formulation is an aqueous pharmaceutical formulation. In a related embodiment, the pharmaceutical formulation is for an intravenous administration to the mammal or patient. In a related embodiment, the pharmaceutical formulation is for a subcutaneous administration to the mammal or patient. In a related embodiment, the pharmaceutical formulation for an intravenous administration comprises an anti-IL-36R antibody in an amount of about 60 mg/mL. In a related embodiment, the pharmaceutical formulation for a subcutaneous administration comprises an anti-IL-36R antibody in an amount of about 150 mg/mL. In a related embodiment, the anti-IL-36R antibody comprising: (i) a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or (ii) a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or (iii) a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127. In a related embodiment, the anti-IL-36R antibody comprising: a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89. In a tenth aspect, the present invention relates to a method of treating GPP in a patient, including

[0304] (a) obtaining a biological sample from said patient, wherein the biological sample is obtained from source including lesional skin or whole blood;

[0305] (b) determining the gene express profile of one or more of genes;

[0306] (c) administering to the patient an effective amount of the anti-IL-36R antibody according to any embodiments relating to aspects first to fifth.

[0307] In one embodiment relating to aspect tenth, the one or more of genes are IL12B, IL1B, IL6, CXCL1, IL23A, TNF, IL17C, IL24 or IL1B in lesional skin, and IL1B, S100A9, S100A12, S100A8, MMP25, MMP9 or CD177 in whole blood.

[0308] In an embodiment relating to any of the above aspects, the anti-IL-36R antibody includes: a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105 106 or 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0309] In an embodiment relating to any of the above aspects, the anti-IL36R antibody is an anti-IL-36R antibody of the present invention. In one embodiment, the anti-IL36R antibody is disclosed in U.S. Pat. No. 9,023,995 or WO2013/074569. In an embodiment relating to any of the above aspects, the improved effects (including the remission or improved symptoms) last for 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks following the administration of a single dose of an anti-IL-36R antibody of the present invention.

Pharmaceutical Compositions and Administration Thereof

[0310] The antibodies of the present invention can be administered either alone or in combination with other agents. Examples of antibodies for use in such pharmaceutical compositions are those that comprise an antibody or antibody fragment having the light chain variable region amino acid sequence of any of SEQ ID NO: 1-10. Examples of antibodies for use in such pharmaceutical compositions are also those that comprise a humanized antibody or antibody fragment having the heavy chain variable region amino acid sequence of any of SEQ ID NO: 11-20.

[0311] Further examples of antibodies for use in such pharmaceutical compositions are also those that comprise a humanized antibody or antibody fragment having the light chain variable region amino acid sequence of any of SEQ ID NO:76-86. Preferred antibodies for use in such pharmaceutical compositions are also those that comprise a humanized antibody or antibody fragment having the heavy chain variable region amino acid sequence of any of SEQ ID NO:87-101.

[0312] Further examples of antibodies for use in such pharmaceutical compositions are also those that comprise a humanized antibody or antibody fragment having the light chain variable region and heavy chain variable region of any of SEQ ID NO: 77 and 89, SEQ ID NO: 80 and 88, SEQ ID NO: 80 and 89, SEQ ID NO: 77 and 87, SEQ ID NO: 77 and 88, SEQ ID NO: 80 and 87, SEQ ID NO: 86 and 100, SEQ ID NO: 85 and 101, or SEQ ID NO: 85 and 10.

[0313] Further examples of antibodies for use in such pharmaceutical compositions are also those that comprise a humanized antibody having the light chain region amino acid sequence of any of SEQ ID NO:115, 118, 123 or 124. Preferred antibodies for use in such pharmaceutical compositions are also those that comprise humanized antibody having the heavy chain variable region amino acid sequence of any of SEQ ID NO:125, 126, 127, 138 or 139.

[0314] Further examples of antibodies for use in such pharmaceutical compositions are also those that comprise Antibody B1, Antibody B2, Antibody B3, Antibody B4, Antibody B5, Antibody B6, Antibody C1, Antibody C2 or Antibody C3.

[0315] Various delivery systems are known and can 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 can be administered, for example by infusion, bolus or injection, and can be administered together with other biologically active agents such as chemotherapeutic agents. Administration can be systemic or local. In preferred embodiments, the administration is by subcutaneous injection. Formulations for such injections may be prepared in for example prefilled syringes that may be administered once every other week.

[0316] In one aspect, the invention provides an article of manufacture comprising a subcutaneous administration device, which delivers to a patient a fixed dose of an antibody of the present invention. In some embodiments, the subcutaneous administration device is a pre-filled syringe, an autoinjector, or a large volume infusion device. For example, MyDose.TM. product from Roche, a single use infusion device that enables the subcutaneous administration of large quantities of liquid medication, may be used as the administration device. Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition of the present invention. Examples include, but are not limited to AUTOPEN.TM. (Owen Mumford, Inc., 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 and 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., and OPTICLIK.TM. (Sanofi-Aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present invention include, but are not limited to the SOLOSTAR.TM. pen (Sanofi-Aventis), the FLEXPEN.TM. (Novo Nordisk), and the KWIKPEN.TM. (Eli Lilly), the SURECLICK.TM. Autoinjector (Amgen, Thousand Oaks, Calif.), the PENLET.TM. (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HUMIRA.TM. Pen (Abbott Labs, Abbott Park Ill.), YPSOMATE.TM., YPSOMATE 2.25.TM., VAIROJECT.TM. (Ypsomed AG, Burgdorf, Switzerland) to name only a few. Additional information relating to example delivery devices that could be used with an antibody of the present invention may be found, for example, in CH705992A2, WO2009/040602, WO2016/169748, WO2016/179713.

[0317] In specific embodiments, the IL-36R binding agent composition is administered by injection, by means of a catheter, by means of a suppository, or by means of an implant, the implant being of a porous, non-porous, or gelatinous material, including a membrane, such as a sialastic membrane, or a fiber. Typically, when administering the composition, materials to which the anti-IL-36R antibody or agent does not absorb are used.

[0318] 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, polymeric materials can be used. (See, e.g., Medical Applications of Controlled Release (Langer and Wise eds., CRC Press, Boca Raton, Fla., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 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, for example, in Langer, supra.

[0319] An IL-36R binding agent (e.g., an anti-IL-36R antibody) can be administered as pharmaceutical compositions comprising a therapeutically effective amount of the binding agent and one or more pharmaceutically compatible ingredients.

[0320] In one embodiment, the anti-IL-36R antibody or an antigen binding fragment thereof (disclosed herein) is present in a pharmaceutical formulation (as described in co-pending U.S. provisional application No. 62/815,405, filed Mar. 8, 2019, the entire content of which is hereby incorporated herein by reference in its entirety) suitable for administration to a mammal or patient according to any one of the aspects described herein. Various examples to this embodiment are described as numbered clauses (1, 2, 3, etc.) below for convenience. These are provided as examples and do not limit the subject technology. It is noted that any of the dependent clauses may be combined in any combination, and placed into a respective independent clause, e.g., clause 1. The other clauses can be presented in a similar manner. [0321] 1. A pharmaceutical formulation including: [0322] a. An anti-IL-36R antibody or an antigen binding fragment thereof, as disclosed herein, present at a concentration within the range from about 0.5 mg/mL to about 220 mg/mL; and [0323] b. A pharmaceutically acceptable buffer present at a concentration within the range from about 20 mM to about 80 mM; [0324] wherein the formulation is characterized by a pH within the range from about 5 to about 8 when in aqueous form. [0325] 2. The formulation of clause 1, wherein the formulation is in liquid or powder form. [0326] 3. The formulation of clause 1, wherein the anti-IL-36R antibody is present at a concentration of within the range from about 10 mg/mL to about 200 mg/mL. [0327] 4. The formulation of clause 1, wherein the anti-IL-36R antibody is present at a concentration of about 20 mg/mL. [0328] 5. The formulation of clause 1, wherein the anti-IL-36R antibody is present at a concentration of about 60 mg/mL. [0329] 6. The formulation of clause 1, wherein the anti-IL-36R antibody is present at a concentration of about 150 mg/mL. [0330] 7. The formulation of clause 1, wherein the buffer comprises histidine, phosphate, succinate, citrate, acetate or TRIS. [0331] 8. The formulation of clause 1, wherein the buffer comprises citrate or acetate. [0332] 9. The formulation of clause 1, wherein the buffer comprises histidine. [0333] 10. The formulation of clause 1, wherein the buffer comprises acetate. [0334] 11. The formulation of clause 1, wherein the formulation further comprises a pharmaceutically acceptable tonicifying agent present at a concentration within the range from about 100 mM to about 250 mM. [0335] 12. The formulation of clause 11, wherein the tonicifying agent is one or more sugar and/or polyol. [0336] 13. The formulation of clause 11, wherein the tonicifying agent is one or more sugar and/or polyol including sucrose, trehalose, sorbitol, magnesium sulfate (MgSO.sub.4), glycerol, mannitol or dextrose. [0337] 14. The formulation of clause 11, wherein the tonicifying agent comprises sucrose or trehalose. [0338] 15. The formulation of clause 11, wherein the tonicifying agent comprises sucrose. [0339] 16. The formulation of clause 11, wherein the tonicifying agent comprises trehalose. [0340] 17. The formulation of clause 1, wherein the formulation further comprises a pharmaceutically acceptable stabilizer present at a concentration within the range from about 0 mM to about 80 mM. [0341] 18. The formulation of clause 17, wherein the stabilizer comprises an amino acid including arginine, histidine, glycine, cysteine, proline, methionine, lysine, aspartate, glutamate or pharmaceutically acceptable salts thereof. [0342] 19. The formulation of clause 17, wherein the stabilizer comprises L-arginine or pharmaceutically acceptable salts thereof. [0343] 20. The formulation of clause 1, wherein the formulation further comprises a pharmaceutically acceptable salt present at a concentration of within the range from about 0 to about 150 mM. [0344] 21. The formulation of clause 20, wherein the salt comprises sodium chloride (NaCl), magnesium chloride (MgCl.sub.2), potassium chloride (KCl), lithium chloride (LiCl), calcium chloride (CaCl.sub.2)), boric acid salts or zinc chloride (ZnCl.sub.2). [0345] 22. The formulation of clause 20, wherein the salt comprises sodium chloride (NaCl). [0346] 23. The formulation of clause 1, wherein the formulation further comprises a pharmaceutically acceptable surfactant present at a concentration within the range from about 0 g/L to about 1.5 g/L. [0347] 24. The formulation of clause 23, wherein the surfactant comprises poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80. [0348] 25. The formulation of clause 23, wherein the surfactant comprises polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80. [0349] 26. The formulation of clause 23, wherein the surfactant comprises polysorbate 20. [0350] 27. The formulation of clause 23, wherein the surfactant comprises polysorbate 80. [0351] 28. A pharmaceutical formulation including: [0352] a. an anti-IL-36R antibody or an antigen binding fragment thereof, as disclosed herein, present at a concentration within the range from about 10 mg/mL to about 200 mg/mL; [0353] b. an acetate and/or histidine buffer present at a concentration within the range from about 20 mM to about 80 mM; [0354] c. sucrose and-/-or trehalose present at a concentration within the range from about 100 mM to about 250 mM; [0355] d. L-arginine and-/-or pharmaceutically acceptable salts thereof present at a concentration within the range from about 0 mM to about 80 mM; [0356] e. sodium chloride (NaCl) present at a concentration of within the range from about 0 to about 150 mM; and [0357] f. polysorbate 20 and/or polysorbate 80 present at a concentration within the range from about 0 g/L to about 1.5 g/L; [0358] wherein the formulation is characterized by a pH within the range from about 5 to about 7 when in aqueous form. [0359] 29. A pharmaceutical formulation including: [0360] a. an anti-IL-36R antibody or an antigen binding fragment thereof, as disclosed herein, present at a concentration of about 20 mg/mL; [0361] b. an citrate buffer present at a concentration at a concentration of about 25 mM; [0362] c. sucrose and/or trehalose present at a concentration of about 200 mM; [0363] d. polysorbate 80 present at a concentration of about 0.4 g/L; [0364] wherein the formulation is characterized by a pH within the range from about 6 to about 7 when in aqueous form. [0365] 30. A pharmaceutical formulation including: [0366] a. an anti-IL-36R antibody or an antigen binding fragment thereof, as disclosed herein, present at a concentration of about 60 mg/mL; [0367] b. an acetate buffer present at a concentration at a concentration of about 45 mM; [0368] c. sucrose and/or trehalose present at a concentration of about 150 mM; [0369] d. L-arginine or pharmaceutically acceptable salts thereof present at a concentration of about 25 mM; and [0370] e. polysorbate 20 present at a concentration of about 0.4 g/L; [0371] wherein the formulation is characterized by a pH within the range from about 5 to about 6 when in aqueous form. [0372] 31. A pharmaceutical formulation including: [0373] a. an anti-IL-36R antibody or an antigen binding fragment thereof, as disclosed herein, present at a concentration of about 150 mg/mL; [0374] b. an acetate buffer present at a concentration at a concentration of about 45 mM; [0375] c. sucrose or trehalose present at a concentration of about 150 mM; [0376] d. L-arginine or pharmaceutically acceptable salts thereof present at a concentration of about 25 mM; and [0377] e. polysorbate 20 present at a concentration of about 0.4 g/L; [0378] wherein the formulation is characterized by a pH within the range from about 5 to about 6 when in aqueous form. [0379] 32. The pharmaceutical formulation of any one of clauses 1-31, wherein the formulation is characterized by an osmolality within the range from about 210 mOsmol/kg to about 390 mOsm/kg. [0380] 33. The pharmaceutical formulation of any one of clauses 1-32, wherein less than about 5% of the antibody is present in an aggregate form in the formulation. [0381] 34. The pharmaceutical formulation of any one of clauses 1-33, wherein the formulation is sterile. [0382] 35. The pharmaceutical formulation of any one of clauses 1-34, wherein the formulation is stable upon freezing and thawing. [0383] 36. The pharmaceutical formulation of any of clauses 1-35, wherein the formulation comprises water or is reconstituted with water. [0384] 37. The pharmaceutical formulation of any of clauses 1-36, wherein the formulation has a pH of between about 5 to about 6 in liquid form or when reconstituted with water. [0385] 38. The pharmaceutical formulation of any of clauses 1-37, wherein the formulation has a pH of about 6 in liquid or when reconstituted with water. [0386] 39. The pharmaceutical formulation of any of clauses 1-37, wherein the formulation has at least one feature selected from the group consisting of: [0387] (i) Increased shelf life [0388] (ii) better temperature stability, [0389] (iii) decreased formation of aggregates, [0390] (iv) better chemical stability, [0391] (v) decreased viscosity, and [0392] as compared to a reference formulation. [0393] 40. The pharmaceutical formulation of any of clauses 1-37, wherein the formulation having at least one feature selected from the group consisting of: [0394] (a) decreased percentage of aggregates as measured by High Performance Size Exclusion Chromatography (HP-SEC), [0395] (b) higher percentage of monomers as measured by HP-SEC, [0396] (c) higher percentage of main peak (less degradation of charge variants) measured by CEX, [0397] (d) lower percentage of subvisual particles such as .gtoreq.10 .mu.m and .gtoreq.25 .mu.m, and [0398] (e) lower turbidity value in Formazin Nephelometry Units (FNU), after storage at about 40.degree. C. as compared to the reference formulation. [0399] 41. A pharmaceutical formulation including: [0400] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0401] i. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or [0402] ii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or [0403] iii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127; [0404] wherein the formulation is selected from the group consisting of: [0405] I. formulation including about 20 mg/mL of the anti-IL-36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM L-Arginine, about 5 mM NaCl and about 1.0 g/L Polysorbate 20, with a pH of about 6.0; [0406] II. formulation including about 60 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5; [0407] III. formulation including about 20 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM Glycine, about 0.4 g/L Polysorbate 80, with a pH of about 5.5; [0408] IV. formulation including about 150 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 150 mM trehalose, about 25 mM methionine, about 0.2 g/L Polysorbate 20, with a pH of about 6.0; [0409] V. formulation including about 150 mg/mL of the anti-IL-36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, about 0.2 g/L Polysorbate 20, with a pH of about 6.5; [0410] VI. formulation including about 20 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, about 0.4 g/L Polysorbate 80, with a pH of about 6.5; [0411] VII. formulation including about 150 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5; [0412] VIII. formulation including about 15 mg/mL of the anti-IL-36R antibody, about 35 mM histidine, about 180 mM trehalose, about 25 mM L-Arginine, about 3 mM NaCl, about 0.4 g/L Polysorbate 80, with a pH of about 6.0; [0413] IX. formulation including about 80 mg/mL of the anti-IL-36R antibody, about 25 mM acetate, about 100 mM mannitol, about 50 mM NaCl, about 0.2 g/L Polysorbate 20, with a pH of about 5.5; [0414] X. formulation including about 100 mg/mL of the anti-IL-36R antibody, about 20 mM succinate, about 220 mM sucrose, about 0.1 g/L Polysorbate 80, with a pH of about 6.0; and [0415] XI. formulation including about 60 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 0.4 g/L Polysorbate 20, with a pH of about 6.5. [0416] 42. A pharmaceutical formulation including: [0417] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0418] i. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or [0419] ii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or [0420] iii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127; [0421] wherein the formulation includes about 20 mg/mL of the anti-IL-36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM L-Arginine, about 5 mM NaCl and about 1.0 g/L Polysorbate 20, with a pH of about 6.0. [0422] 43. A pharmaceutical formulation including: [0423] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0424] i. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or [0425] ii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or [0426] iii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127; [0427] wherein the formulation includes about 60 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5. [0428] 44. A pharmaceutical formulation including: [0429] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0430] i. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or [0431] ii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or [0432] iii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127;

[0433] wherein the formulation includes about 20 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM Glycine, about 0.4 g/L Polysorbate 80, with a pH of about 5.5. [0434] 45. A pharmaceutical formulation including: [0435] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0436] i. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or [0437] ii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or [0438] iii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127; [0439] wherein the formulation includes about 150 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 150 mM trehalose, about 25 mM methionine, about 0.2 g/L Polysorbate 20, with a pH of about 6.0. [0440] 46. A pharmaceutical formulation including: [0441] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0442] i. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or [0443] ii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or [0444] iii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127; [0445] wherein the formulation includes about 150 mg/mL of the anti-IL-36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, about 0.2 g/L Polysorbate 20, with a pH of about 6.5. [0446] 47. A pharmaceutical formulation including: [0447] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0448] i. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or [0449] ii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or [0450] iii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127; [0451] wherein the formulation includes about 20 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, about 0.4 g/L Polysorbate 80, with a pH of about 6.5. [0452] 48. A pharmaceutical formulation including: [0453] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0454] i. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or [0455] ii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or [0456] iii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127; [0457] wherein the formulation includes about 150 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5. [0458] 49. A pharmaceutical formulation including: [0459] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0460] i. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or [0461] ii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or [0462] iii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127; [0463] wherein the formulation includes about 15 mg/mL of the anti-IL-36R antibody, about 35 mM histidine, about 180 mM trehalose, about 25 mM L-Arginine, about 3 mM NaCl, about 0.4 g/L Polysorbate 80, with a pH of about 6.0. [0464] 50. A pharmaceutical formulation including: [0465] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0466] i. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or [0467] ii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or [0468] iii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127; [0469] wherein the formulation includes about 80 mg/mL of the anti-IL-36R antibody, about 25 mM acetate, about 100 mM mannitol, about 50 mM NaCl, about 0.2 g/L Polysorbate 20, with a pH of about 5.5. [0470] 51. A pharmaceutical formulation including: [0471] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0472] i. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or [0473] ii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or [0474] iii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127; [0475] wherein the formulation includes about 100 mg/mL of the anti-IL-36R antibody, about 20 mM succinate, about 220 mM sucrose, about 0.1 g/L Polysorbate 80, with a pH of about 6.0. [0476] 52. A pharmaceutical formulation including: [0477] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0478] i. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or [0479] ii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or [0480] iii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127; [0481] wherein the formulation includes about 60 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 0.4 g/L Polysorbate 20, with a pH of about 6.5. [0482] 53. A pharmaceutical formulation including: [0483] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0484] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0485] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0486] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or [0487] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0488] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0489] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; [0490] wherein the formulation includes: about 20 mg/mL of the anti-IL-36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM L-Arginine, about 5 mM NaCl and about 1.0 g/L Polysorbate 20, with a pH of about 6.0. [0491] 54. A pharmaceutical formulation including: [0492] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0493] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0494] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0495] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or [0496] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0497] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0498] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; [0499] wherein the formulation includes: about 60 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5. [0500] 55. A pharmaceutical formulation including: [0501] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0502] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0503] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0504] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or [0505] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0506] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0507] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; [0508] wherein the formulation includes: about 20 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM Glycine, about 0.4 g/L Polysorbate 80, with a pH of about 5.5. [0509] 56. A pharmaceutical formulation including: [0510] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0511] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0512] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0513] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or [0514] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0515] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0516] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; [0517] wherein the formulation includes: about 150 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 150 mM trehalose, about 25 mM methionine, about 0.2 g/L Polysorbate 20, with a pH of about 6.0. [0518] 57. A pharmaceutical formulation including: [0519] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0520] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0521] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0522] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or [0523] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0524] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0525] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; [0526] wherein the formulation includes: about 150 mg/mL of the anti-IL-36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, about 0.2 g/L Polysorbate 20, with a pH of about 6.5. [0527] 58. A pharmaceutical formulation including: [0528] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0529] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0530] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0531] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or [0532] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0533] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or

[0534] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; [0535] wherein the formulation includes: about 20 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, about 0.4 g/L Polysorbate 80, with a pH of about 6.5. [0536] 59. A pharmaceutical formulation including: [0537] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0538] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0539] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0540] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or [0541] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0542] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0543] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; [0544] wherein the formulation includes: about 150 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5. [0545] 60. A pharmaceutical formulation including: [0546] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0547] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0548] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0549] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or [0550] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0551] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0552] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; [0553] wherein the formulation includes: about 15 mg/mL of the anti-IL-36R antibody, about 35 mM histidine, about 180 mM trehalose, about 25 mM L-Arginine, about 3 mM NaCl, about 0.4 g/L Polysorbate 80, with a pH of about 6.0. [0554] 61. A pharmaceutical formulation including: [0555] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0556] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0557] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0558] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or [0559] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0560] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0561] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; [0562] wherein the formulation includes: about 80 mg/mL of the anti-IL-36R antibody, about 25 mM acetate, about 100 mM mannitol, about 50 mM NaCl, about 0.2 g/L Polysorbate 20, with a pH of about 5.5. [0563] 62. A pharmaceutical formulation including: [0564] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0565] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0566] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0567] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or [0568] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0569] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0570] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; [0571] wherein the formulation includes: about 100 mg/mL of the anti-IL-36R antibody, about 20 mM succinate, about 220 mM sucrose, about 0.1 g/L Polysorbate 80, with a pH of about 6.0. [0572] 63. A pharmaceutical formulation including: [0573] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0574] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0575] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0576] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or [0577] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0578] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0579] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; [0580] wherein the formulation includes: about 60 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 0.4 g/L Polysorbate 20, with a pH of about 6.5. [0581] 64. A pharmaceutical formulation including: [0582] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0583] i. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or [0584] ii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or [0585] iii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127; [0586] wherein the formulation is selected from the group consisting of: [0587] I. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM L-Arginine, about 5 mM NaCl and about 1.0 g/L Polysorbate 20, with a pH of about 6.0; [0588] II. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5; [0589] III. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM Glycine, about 0.4 g/L Polysorbate 80, with a pH of about 5.5; [0590] IV. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 150 mM trehalose, about 25 mM methionine, about 0.2 g/L Polysorbate 20, with a pH of about 6.0; [0591] V. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, about 0.2 g/L Polysorbate 20, with a pH of about 6.5; [0592] VI. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, about 0.4 g/L Polysorbate 80, with a pH of about 6.5; [0593] VII. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5; [0594] VIII. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 35 mM histidine, about 180 mM trehalose, about 25 mM L-Arginine, about 3 mM NaCl, about 0.4 g/L Polysorbate 80, with a pH of about 6.0; [0595] IX. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM acetate, about 100 mM mannitol, about 50 mM NaCl, about 0.2 g/L Polysorbate 20, with a pH of about 5.5; [0596] X. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 20 mM succinate, about 220 mM sucrose, about 0.1 g/L Polysorbate 80, with a pH of about 6.0; and [0597] XI. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 0.4 g/L Polysorbate 20, with a pH of about 6.5. [0598] 65. A pharmaceutical formulation including: [0599] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0600] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0601] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0602] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or [0603] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or [0604] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or [0605] a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; [0606] wherein the formulation is selected from the group consisting of: [0607] I. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM L-Arginine, about 5 mM NaCl and about 1.0 g/L Polysorbate 20, with a pH of about 6.0; [0608] II. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5; [0609] III. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM Glycine, about 0.4 g/L Polysorbate 80, with a pH of about 5.5; [0610] IV. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 150 mM trehalose, about 25 mM methionine, about 0.2 g/L Polysorbate 20, with a pH of about 6.0; [0611] V. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, about 0.2 g/L Polysorbate 20, with a pH of about 6.5; [0612] VI. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, about 0.4 g/L Polysorbate 80, with a pH of about 6.5; [0613] VII. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5; [0614] VIII. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 35 mM histidine, about 180 mM trehalose, about 25 mM L-Arginine, about 3 mM NaCl, about 0.4 g/L Polysorbate 80, with a pH of about 6.0; [0615] IX. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM acetate, about 100 mM mannitol, about 50 mM NaCl, about 0.2 g/L Polysorbate 20, with a pH of about 5.5; [0616] X. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 20 mM succinate, about 220 mM sucrose, about 0.1 g/L Polysorbate 80, with a pH of about 6.0; and [0617] XI. formulation including about 20 mg/mL to about 150 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 0.4 g/L Polysorbate 20, with a pH of about 6.5. [0618] 66. A pharmaceutical product including a vial or syringe including the pharmaceutical formulation according to any of the preceding clauses for use in any one of the aspects of the present invention. [0619] 67. The pharmaceutical product according to clause 66 further including a pre-assembled injection device. [0620] 68. The pharmaceutical product of clause 67 wherein the pre-assembled injection device is an autoinjector or a syringe with or without a needle safety device. [0621] 69. A pre-assembled injection device including a pharmaceutical formulation according to any of the preceding clauses for use in any one of the aspects of the present invention. [0622] 70. The pre-assembled injection device according to clause 69, wherein said device is an autoinjector or a syringe with or without a needle safety device. [0623] 71. The pre-assembled injection device according to clause 69, wherein said formulation is suitable for intravenous, subcutaneous or intramuscular administration.

[0624] 72. The pre-assembled injection device according to clause 70, wherein the autoinjector or the syringe with or without needle safety device includes a pharmaceutical formulation including: [0625] an anti-IL-36R antibody or antigen-binding fragment thereof, including: [0626] i. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:125; or [0627] ii. a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:126; or [0628] a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as SEQ ID NO:127; wherein the formulation is selected from the group consisting of: [0629] I. formulation including about 20 mg/ml of the anti-IL-36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM L-Arginine, about 5 mM NaCl and about 1.0 g/L Polysorbate 20, with a pH of about 6.0; [0630] II. formulation including about 60 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5; [0631] III. formulation including about 20 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM Glycine, about 0.4 g/L Polysorbate 80, with a pH of about 5.5; [0632] IV. formulation including about 150 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 150 mM trehalose, about 25 mM methionine, about 0.2 g/L Polysorbate 20, with a pH of about 6.0; [0633] V. formulation including about 150 mg/mL of the anti-IL-36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, about 0.2 g/L Polysorbate 20, with a pH of about 6.5; [0634] VI. formulation including about 20 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, about 0.4 g/L Polysorbate 80, with a pH of about 6.5; [0635] VII. formulation including about 150 mg/mL of the anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-Arginine, about 0.4 g/L Polysorbate 20, with a pH of about 5.5; [0636] VIII. formulation including about 15 mg/mL of the anti-IL-36R antibody, about 35 mM histidine, about 180 mM trehalose, about 25 mM L-Arginine, about 3 mM NaCl, about 0.4 g/L Polysorbate 80, with a pH of about 6.0; [0637] IX. formulation including about 80 mg/mL of the anti-IL-36R antibody, about 25 mM acetate, about 100 mM mannitol, about 50 mM NaCl, about 0.2 g/L Polysorbate 20, with a pH of about 5.5; [0638] X. formulation including about 100 mg/mL of the anti-IL-36R antibody, about 20 mM succinate, about 220 mM sucrose, about 0.1 g/L Polysorbate 80, with a pH of about 6.0; and [0639] XI. formulation including about 60 mg/mL of the anti-IL-36R antibody, about 25 mM citrate, about 0.4 g/L Polysorbate 20, with a pH of about 6.5. [0640] 73. The pre-assembled injection device according to clause 70, wherein the autoinjector or the syringe with a needle safety device includes: [0641] a. about 300 mg of the antibody in about 2 mL formulation volume; or [0642] b. about 225 mg of the antibody in about 1.5 mL formulation volume; or [0643] c. about 150 mg of the antibody in about 1 mL formulation volume; or [0644] d. about 75 mg of the antibody in about 0.5 mL formulation volume; or [0645] e. about 60 mg of the antibody in about 0.4 mL formulation volume. [0646] 74. The vial according to clause 66, wherein the vial includes: [0647] a. about 1200 mg of the antibody in about 20 mL formulation volume; or [0648] b. about 900 mg of the antibody in about 15 mL formulation volume; or [0649] c. about 600 mg of the antibody in about 10 mL formulation volume; or [0650] d. about 300 mg of the antibody in about 150 mL formulation volume; or [0651] e. about 1500 mg of the antibody in about 2.5 mL formulation volume. [0652] 75. A pharmaceutical product, including: a vial including about 100 mg to 1500 mg of an anti-IL-36R antibody in powder form; instructions for reconstitution of the anti-IL-36R antibody; and instructions for preparing the reconstituted antibody for infusion, wherein the anti-IL-36R antibody comprises a light chain including an amino acid sequence set forth as SEQ ID NO:118 and a heavy chain including an amino acid sequence set forth as any one of SEQ ID Nos: 125, 126 or 127; and the reconstitution instructions require reconstitution with water for injection to an extractable volume from 1 to 50 mL.

[0653] Further, the pharmaceutical composition can be provided as a pharmaceutical kit comprising (a) a container containing a 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. The pharmaceutically acceptable diluent can be used for reconstitution or dilution of the lyophilized anti-IL-36R antibody or agent. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

[0654] Such combination therapy administration can have an additive or synergistic effect on disease parameters (e.g., severity of a symptom, the number of symptoms, or frequency of relapse).

[0655] With respect to therapeutic regimens for combinatorial administration, in a specific embodiment, an anti-IL-36R antibody or IL-36R binding agent is administered concurrently with a therapeutic agent. In another specific embodiment, the therapeutic agent is administered prior or subsequent to administration of the anti-IL-36R antibody or IL-36R binding agent, by at least an hour and up to several months, for example at least an hour, five hours, 12 hours, a day, a week, a month, or three months, prior or subsequent to administration of the anti-IL-36R antibody or IL-36R binding agent.

[0656] The invention is further described in the following examples, which are not intended to limit the scope of the invention.

EXAMPLES

Example 1: IL-36 Receptor Inhibition for Treatment of Generalized Pustular Psoriasis

[0657] An antibody of the present invention, i.e., an anti-IL-36R antibody of the present invention (disclosed herein and also in U.S. Pat. No. 9,023,995), is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL36R signaling. Binding of an anti-IL-36R antibody of the present invention to IL36R is anticipated to prevent the subsequent activation of IL36R by cognate ligands (IL36 .alpha., .beta. and .gamma.) and downstream activation of proinflammatory and pro-fibrotic pathways with the aim to reduce epithelial cell/fibroblast/immune cell-mediated inflammation and interrupt the inflammatory response that drives pathogenic cytokine production in generalized pustular psoriasis (GPP).

[0658] Preclinical profiles of an anti-IL-36R antibody of the present invention and clinical data from healthy volunteer trials suggest that an anti-IL-36R antibody of the present invention is safe, tolerable and may address an unmet medical need in GPP patients.

Background

[0659] Mutations in IL36RN are strongly implicated in the pathogenesis of generalized pustular psoriasis. The efficacy and safety of an anti-IL-36R antibody of the present invention, a humanized monoclonal antibody inhibiting interleukin-36R signaling, was assessed in this single dose, open-label, proof-of-concept, phase I study in patients with acute generalized pustular psoriasis.

Methods

[0660] Seven patients, three of whom were IL36RN mutation-positive, received a single intravenous dose of 10 mg/kg an anti-IL-36R antibody of the present invention, and were monitored for 20 weeks. The primary endpoint was safety; efficacy endpoints included the proportion of patients with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 (clear) or 1 (almost clear), and percent change from baseline in Generalized Pustular Psoriasis Area and Severity Index (GPPASI) score at Week 2.

Results

[0661] An anti-IL-36R antibody of the present invention was well tolerated with no drug-related serious adverse events or safety signals. At Week 1, GPPGA score of 0 or 1 was achieved in five patients, and in all patients by Week 4. Within 48 hours, pustules were cleared in three patients, and in six patients by Week 2. A major improvement in GPPASI was observed in all patients with a mean (SD) percent change from baseline of 73.2% (16.2) at Week 2; by Week 4, this was further reduced to 82.0%. Efficacy was generally maintained up to 20 weeks.

Conclusions

[0662] Interleukin-36 pathway inhibition with a single dose of an anti-IL-36R antibody of the present invention resulted in the rapid and sustained remission of clinical symptoms in patients with acute generalized pustular psoriasis. Alternatively, a single dose of an anti-IL-36R antibody of the present invention resulted in the rapid and sustained remission of clinical symptoms, with no adverse safety signals in patients with acute generalized pustular psoriasis, regardless of IL36RN mutation status.

Introduction

[0663] Generalized pustular psoriasis is a rare, severe multisystemic disease first described by von Zumbusch in 1909, characterized by intermittent acute flares consisting of a disseminated erythematous and pustular skin rash associated with general symptoms including fever, and often extracutaneous organ involvement; in some cases, life-threatening complications may occur. Biologically, high C-reactive protein (CRP) serum levels and leukocytosis with neutrophilia are the most common features, together with liver test abnormalities. Epidemiological studies report prevalence as low as 1.76/million, highlighting the rarity of the disease.

[0664] Therapeutic intervention in generalized pustular psoriasis is a major challenge with no treatments currently approved in the US or Europe. A wide range of anti-psoriatic strategies have been proposed based on the psoriasis vulgaris model, with the efficacy of apheresis, and inhibitors of tumor necrosis factor, interleukin-17 and interleukin-23 reported in open-label trials and case reports forming the basis of approval for generalized pustular psoriasis in Japan. However, apheresis is restricted to specialized centers, while the contribution of these key inflammatory cytokines in psoriasis vulgaris, to the pathogenesis of generalized pustular psoriasis remains unclear.

[0665] Recently, major advances in our understanding of the mechanisms underlying pustular psoriasis have been gained from genetic studies that identified loss-of-function homozygous or compound heterozygous IL36RN gene mutations in some patients with generalized pustular psoriasis. These mutations severely alter the function of the IL36RN product, the interleukin-36 receptor antagonist (interleukin-36Ra), resulting in the dysregulation of the proinflammatory interleukin-36 (IL-36.alpha., IL-36.beta. and IL-36.gamma.) pathway, and lead to generalized pustular psoriasis according to a monogenic model. While these mutations have been found in other pustular psoriasis subtypes, they have not been detected in patients with plaque psoriasis alone, unveiling the autoinflammatory nature of pustular psoriasis and establishing generalized pustular psoriasis as a distinct entity from plaque psoriasis.

[0666] These immunogenetic insights established the rationale to therapeutically target interleukin-36R in generalized pustular psoriasis. The results of this first study conducted in a human disease with an anti-IL-36R antibody of the present invention, a human monoclonal antibody targeted against the interleukin-36R, assessing the safety and efficacy in patients with an acute flare of generalized pustular psoriasis are reported. To our knowledge, this is the first study to assess treatment in patients with acute generalized pustular psoriasis.

Methods

[0667] Study Design

[0668] This 20-week, multicenter, single-arm, open-label, phase I, proof-of-concept trial enrolled patients from five sites (France, Malaysia, Republic of Korea, Taiwan, and Tunisia). Eligible patients received a single intravenous (IV) dose of 10 mg/kg an anti-IL-36R antibody of the present invention and were monitored for 20 weeks.

[0669] Patients

[0670] Patients aged 18-75 years were eligible if they had a known and documented history of generalized pustular psoriasis, regardless of IL36RN mutation status, with previous evidence of fever, and/or asthenia, and/or myalgia, and/or elevated CRP, and/or leukocytosis with neutrophilia, presenting with an acute flare involving 10% or more of their body surface area (BSA) with erythema and the presence of pustules, and a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 3 or higher (clinician assessment of GPP severity based on a modified PGA [see Supplementary Appendix]; scores range from 0 [clear skin] to 4 [severe disease]) at the time of treatment. Patients could continue to receive subcutaneous treatment with retinoids and/or methotrexate.

[0671] Patients were excluded if they had an immediate life-threatening generalized pustular psoriasis flare or acute generalized exanthematous pustulosis (see Table 2 for the full inclusion/exclusion criteria). Patients providing consent were enrolled in the trial in the absence of a flare. Screening (visit 1) was initiated several days or weeks before a patient was admitted for treatment for a flare of generalized pustular psoriasis (visit 2). For patients satisfying the inclusion/exclusion criteria, treatment with BI 655130 was initiated the day after visit 2 (visit 3).

TABLE-US-00010 TABLE 2 Inclusion/Exclusion Criteria Inclusion Criteria Patients will only be included into the trial if they meet the following criteria: 1. Male or female patients, aged 18-75 years at screening 2. A known and documented history of generalized pustular psoriasis (GPP) regardless of the IL36RN mutation status, with previous evidence of fever, and/or asthenia, and/or myalgia, and/or elevated C-reactive protein, and/or leukocytosis with peripheral blood neutrophilia (above ULN) 3. Presenting with a flare of GPP with at least 10% of body surface area with erythema and pustules 4. A GPPGA score of at least moderate severity 5. GPP patients receiving subcutaneous treatment with retinoids and/or methotrexate for at least 4 weeks or GPP patients not receiving any subcutaneous therapy, at the screening visit 6. Signed and dated written informed consent prior to admission to the study in accordance with good clinical practice and local legislation 7. Women of childbearing potential* must be ready and able to use highly effective methods of birth control per ICH M3 that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. Male patients must be ready and able to use condoms. Birth control method must be continued up to 20 weeks after an anti-IL-36R antibody of the present invention administration. * A woman is considered of childbearing potential, i.e. fertile, following menarche, and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilization. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. Exclusion Criteria Patients will not be allowed to participate if any of the following general criteria apply: 1. Women who are pregnant, nursing, or who plan to become pregnant while in the trial. Women who stop nursing before the study drug administration do not need to be prevented from participating. They should refrain from breastfeeding up to 20 weeks after the study drug administration 2. Immediate life-threatening flare of GPP or requiring intensive care treatment, according to the investigator's judgement. Life-threatening complications mainly include, but are not limited to, cardiovascular/cytokine driven shock and pulmonary distress 3. Identified, ongoing serious/severe infection 4. Acute generalized exanthematous pustulosis 5. Patient's clinical presentation being considered due to the differential diagnosis of toxic epidermal necrosis or Stevens-Johnson syndrome 6. Currently involved in or intending to participate in another investigational study during the course of this trial 7. Previous enrolment in this trial 8. Use of any restricted medication as specified in Table 3, or any drug considered likely to interfere with the safe conduct of the study 9. Patients with dose escalation of their subcutaneous therapy with methotrexate and/or retinoids within the 4 weeks preceding the screening visit 10. Background therapy with cyclosporine within the last 30 days preceding the screening visit 11. Previous exposure to an interleukin-36R inhibitor 12. Severe, progressive, or uncontrolled renal, hepatic, hematological, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms thereof, as judged by the investigator. Patients with a less than 3-fold ULN increase in aspartate aminotransferase and/or alanine aminotransferase and/or alkaline phosphatase and/or with a less than 2-fold ULN increase in total bilirubin at infusion day may be included, provided that no cause of liver damage other than GPP has been identified 13. Known chronic or relevant acute infections including active tuberculosis (TB), HIV or viral hepatitis; QuantiFERON .RTM. TB test will be performed at screening. If the result is positive, patients may participate in the study if further work-up (according to local practice/guidelines) establishes conclusively that the patient has no evidence of active TB. If the presence of latent TB is established, then treatment should have been initiated and maintained according to local country guidelines 14. Patients with a transplanted organ (with the exception of a corneal transplant >12 weeks prior to the screening visit) or those who have ever received stem cell therapy (e.g. Prochymal .RTM.) 15. Known history of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly 16. Any documented active or suspected malignancy or history of malignancy within 5 years prior to second screening visit, except appropriately treated basal or squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix 17. Evidence of a current or previous disease, medical condition (including chronic alcohol or drug abuse) other than GPP, surgical procedure (i.e. organ transplant), medical examination finding (including vital signs and electrocardiogram), or laboratory value at the second screening visit outside of the reference range, that in the opinion of the investigator, is clinically significant and would make the study participant unreliable to adhere to the protocol or to complete the trial, compromise the safety of the patient, or compromise the quality of the data 18. History of allergy/hypersensitivity to a systemically administered biologic agent or its excipients 19. Patient's refusal to be hospitalized for 4 days following the infusion

TABLE-US-00011 TABLE 3 Restricted Medications Restriction Duration Medication or Class of Medications (Through End of Trial Visit*) Natalizumab, efalizumab, or agents that 6 months prior to screening (visit 2) deplete B or T cells (e.g. rituximab, alemtuzumab, or visilizumab), briakinumab, secukinumab, ustekinumab, guselkumab, tildrakizumab IL-36R inhibitors Not allowed either before nor during trial participation Brodalumab, ixekizumab 4 months prior to screening (visit 2) Adalimumab, infliximab, investigational 12 weeks prior to screening (visit 2) products for psoriasis (non-biologics) Etanercept, live virus vaccinations 6 weeks prior to screening (visit 2) Any investigational device or product 30 days prior to screening (visit 2) (excludes psoriasis products), other systemic immunomodulating treatments except background therapy with methotrexate (e.g. cyclosporine A, corticosteroids.sup..dagger., cyclophosphamide), tofacitinib, apremilast, other systemic psoriasis treatments except background therapy with retinoids (e.g. fumarates, any other drug known to possibly benefit psoriasis), photochemotherapy (e.g. PUVA). Phototherapy (e.g. UVA, UVB), topical 14 days prior to screening (visit 2) treatment for psoriasis or any other skin condition (e.g. corticosteroids.sup..dagger-dbl., vitamin D analogues, vitamin A analogues, pimecrolimus, retinoids, salicylvaseline, salicylic acid, lactic acid, tacrolimus, tar, urea, anthralin, .alpha.-hydroxy, fruit acids) Anakinra 7 days prior to screening (visit 2) *In case of worsening of the flare, the use of a rescue medication is left at the discretion of the investigator; in case of any other acute setting after Day 28, the use of a restricted medication is permitted. .sup..dagger.There is no restriction on corticosteroids with only a topical effect (e.g. inhaled corticosteroids to treat asthma or corticosteroids drops administered in the eye or ear). .sup..dagger-dbl.Exception: Topical steroids of US class 6 (mild, such as desonide) or US class 7 (least potent, such as hydrocortisone) for use on the face, axilla, and/or genitalia with a restriction of use within 24 hours prior to trial visit in which GPPASI is assessed. GPPASI = Generalized Pustular Psoriasis Area and Severity Index.

[0672] All patients underwent genotyping for mutations in IL36RN, CARD14, and AP1S3.

[0673] Genotyping

[0674] To identify mutations in IL36RN, CARD14 and AP1S3, targeted re-sequencing was performed using Illumina MiSeq with Nextera Rapid Capture Custom Enrichment Kit (Illumina Inc., San Diego, Calif.). The sequences were aligned and mapped against human genome version 19 by MiSeq Reporter (Illumina Inc., San Diego, Calif.). A mutation was considered potentially pathogenic if there were correlations with published functional data or risk associations to generalized pustular psoriasis, or if the mutation was a non-synonymous substitution, or located in a known gene regulatory element (e.g. start codon).

[0675] Efficacy and Safety Assessments

[0676] The primary endpoint was the safety and tolerability of an anti-IL-36R antibody of the present invention. Safety assessments included adverse events (coded with the use of the Medical Dictionary for Drug Regulatory Activities, version 20.1), serious adverse events, laboratory assessments, vital signs, injection site reactions, and immunogenicity over the duration of the trial. Immunogenicity assessments are described in the Supplementary Appendix. Secondary endpoints at Week 2 included percent change from baseline in Generalized Pustular Psoriasis Area and Severity Index (GPPASI; a modified composite index based on PASI, (J Dermatolog Treat 2003; 14:158-65) whereby the induration component has been substituted with a pustules component; scores range from 0 to 72, higher scores represent greater disease severity), proportion of patients with GPPGA of 0 (clear) or 1 (almost clear), change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F; instrument, based on 13 questions, for monitoring fatigue and its effects on patients; scores range from 0 to 52, lower scores represent greater fatigue) scale, (J Pain Symptom Manage 1997; 13:63-74) and change from baseline in patients assessment of pain on a visual analog scale (Pain-VAS). See Table 4 for the demographics and disease characteristics of the patients at baseline.

TABLE-US-00012 TABLE 4 Demographics and Disease Characteristics at Baseline Time from Presence of Body initial gene mutations Age Sex weight BMI diagnosis (+/-) Patient (yrs) (M/F) Race* Country (kg) (kg/m.sup.2) (years) IL36RN.sup..dagger. CARD14.sup..dagger-dbl. AP1S3 2100103 47 M White Tunisia 52.0 19.1 46.9 + - - 2100104 31 M White Tunisia 82.0 25.9 5.0 + - - 3301001 26 F N/A France 70.4 26.5 19.9 - - - 6001003 34 F Asian Malyasia 67.9 29.8 9.7 - - - 6001004 52 F Asian Malyasia 57.6 23.7 4.0 - - - 8201002 22 M Asian Republic 56.9 18.2 0.1 - - - of Korea 8801001 58 F Asian Taiwan 52.8 20.1 29.3 + + - Total 38.6 M = 3 White = 2 NA 62.8 23.3 16.4 3 1 0 (N = 7) (13.8) F = 4 Asian = 4 (11.0) (4.3) (16.8) (42.9%) (14.3%) N/A = 1 Time from current flare to Pustule an anti-IL-36R severity Prior antibody of GPPGA GPPASI score CRP systemic Patient (0-4) .sup..sctn. (0-72) .sup. (0-4) ** (mg/l) FACIT-F.sup..dagger..dagger. Pain-VAS PSS.sup..dagger-dbl..dagger-dbl. therapies 2100103 1 3 22.2 1.8 237.0 28 95 10 RET 2100104 1 3 52.5 2.3 276.6 12 90 12 RET 3301001 18 3 20.3 1.5 4.0 46 60 8 CYSP 6001003 2 3 26.2 3.0 152.9 18 80 13 CYSP, MTX, RET 6001004 14 3 21.0 2.8 82.8 40 80 12 MTX 8201002 0 3 33.4 1.8 N/A 32 70 9 CYSP 8801001 1 3 16.7 2.8 0.80 46 30 4 RET Total 5.3 3 27.5 2.3 69.4 31.7 72.1 9.71 CYSP = 3 (42.9) (N = 7) (7.4) (0) (12.3) (0.6) (57.0) (13.3) (22.0) (3.1) MTX = 2 (28.6) RET = 4 (57.1) Values are mean (standard deviaton) unless stated otherwise. *Race was self-reported by the patient. Race was not reported for patient 3301001. .sup..dagger.Homozygous missense variant rs387906914 (patients 1 and 2), and intronic mutation variant rs148755083 (patient 7). .sup..dagger-dbl.Heterozygous variant rs117360605 (patient 7). .sup..sctn. Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) is a clinician assessment of overall GPP severity based on a modified PGA; scores range from 0 (clear skin) to 4 (severe disease). .sup. Generalized Pustular Psoriasis Area and Severity Index (GPPASI) is a modified composite index for patients with GPP, based on the established PASI, whereby the induration component has been substituted with a pustules component; scores range from 0 to 72, and higher scores represent greater disease severity. ** Pustule severity is based on the GPPASI component subscore and ranges from 0 to 4; higher scores represent greater severity. .sup..dagger..dagger.Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores range from 0 to 52; lower scores represent greater fatigue. .sup..dagger-dbl..dagger-dbl.Psoriasis Symptom Scale (PSS) scores range from 0 to 16, with higher scores representing greater severity of symptoms (psoriasis pain, redness, itching, and burning). CI = confidence interval; CRP = C-reactive protein; N/A = not available; NA = not applicable; SD = standard deviation; VAS = Visual Analogue Scale. indicates data missing or illegible when filed

[0677] Other pre-specified efficacy endpoints included change and percent change from baseline in pustule severity (based on the GPPASI component), change and percent change from baseline in GPPASI, proportion of patients with GPPGA score of 0 or 1, proportion of patients with clearance of edema, change from baseline in pustular BSA, change and percent change from baseline in erythema severity (based on GPPASI component); change from baseline in FACIT-F and Pain-VAS at Weeks 1 and 4; change from baseline in Psoriasis Symptom Scale (PSS; a four item patient reported outcome instrument assessing psoriasis pain, redness, itching, and burning. Symptom severity is assessed using a 5-point Likert-type scale ranging from 0 (none) to 4 (very severe) and a total score is calculated by adding all subscore) score, (J Patient-Rep Outcomes 2017; 1:4) proportion of patients with PSS total score of 0, and improvement in Clinical Global Impression (observer-rated scale measuring global illness improvement, based on a 7-point scale, scores range from 1 [very much improved] to 7 [very much worse]) (Jpn J Dermatol 2010; 120:815-39) (at Weeks 1, 2, and 4. Efficacy endpoints that were not pre-specified included the proportion of patients achieving 50, 75, and 90 percent improvement in GPPASI over time and percent change from baseline in scaling severity (GPPASI component).

[0678] Photographic documentation of skin lesions was performed at baseline, and post-treatment. Biochemical, cellular, and pharmacogenomic biomarkers were evaluated in skin and whole blood (see below for biomarker methodologies). Skin biopsies were performed at baseline and Week 1 (an additional optional biopsy was performed at Week 2).

[0679] Generalized Pustular Psoriasis Physician Global Assessment (GPPGA)

[0680] GPPGA relies on the clinical assessment of the patient's skin presentation. It is a modified PGA, a physician's assessment of psoriatic lesions, which has been adapted to the evaluation of patients with generalized pustular psoriasis. (J Dermatolog Treat 2015; 26(1):23-31) The investigator (or qualified site personnel) scores the erythema, pustules, and scaling of all psoriatic lesions from 0-4. Each component is graded separately, the average is calculated, and the final GPPGA is determined from this composite score. A lower score then indicates a lesser severity, with 0 being clear and 1 being almost clear. To receive a score of 0 or 1, the patient should be afebrile, in addition to the skin presentation requirements.

[0681] Generalized Pustular Psoriasis Area and Severity Index (GPPASI)

[0682] The GPPASI is an adaptation of the PASI, an established measure of severity and area of psoriatic lesions in patients with psoriasis, for patients with generalized pustular psoriasis. (Dermatologica 1978; 157(4):238-44) Similar adaptions have been used for palmoplantar psoriasis. (J Eur Acad Dermatol Venereol 2009; 23(4):415-9) In the GPPASI, the induration component has been substituted by a pustules component. It is a tool which provides a numeric scoring for patient's overall generalized pustular psoriasis disease state, ranging from 0 to 72. It is a linear combination of percent of surface area of skin (body region area score) that is affected and the severity (scored on a five-point scale, ranging from 0 [least severe] to 4 [most severe] (See Table 5)) of erythema, pustules, and scaling (desquamation) over four body regions (head, upper limb, trunk, and lower limb).

TABLE-US-00013 TABLE 5 Generalized Pustular Psoriasis Area and Severity Index Score Erythema Pustules Scaling 0 Normal or post- No visible pustules No scaling or crusting inflammatory hyperpigmentation 1 Faint, diffuse pink or Low density occasional Superficial focal scaling slight red small discrete pustules or crusting restricted to (noncoalescent) periphery of lesions 2 Light red Moderate density Predominantly fine grouped discrete small scaling or crusting pustules (noncoalescent) 3 Bright red High density pustules Moderate scaling or with some coalescence crusting covering most or all lesions 4 Deep fiery red Very high density pustules Severe scaling or with pustular crusting covering most lakes or all lesions Individual score per body region = body region factor (head = 0.1, upper limb = 0.2, trunk = 0.3, lower limb = 0.4) .times. body region area score .times. sum of component severity scores in body region Total GPPASI score = sum of individual score from all body regions

[0683] Immunogenicity Assessments

[0684] Plasma samples from all patients for anti-drug antibody assessment were taken at pre-dose and on days 7, 14, 21, 28, 84 and 140 post-dose. The samples were analyzed for anti-an anti-IL-36R antibody of the present invention antibodies using a validated Meso Scale Discovery.RTM. (MSD) drug bridging electrochemiluminescent (ECL) method with acid dissociation at QPS, LLC, Newark, Del., USA. Anti-drug antibody plasma samples and controls were first diluted in 0.3M acetic acid before neutralization with 1.5M tris base and master mix, which included biotin-labeled drug and sulfo-tag-labeled drug, prior to transfer and incubation on a blocked MSD streptavidin plate. In the presence of tripropylamine-containing read buffer, sulfo-tag produces an ECL signal that is triggered when voltage is applied using the MSD Sector Imager 600s. The resulting chemiluminescence is measured in relative light units which is proportional to the amount of anti-drug antibody present in the plasma samples. The immunogenicity of an anti-IL-36R antibody of the present invention was assessed using a three-tiered approach.

[0685] All anti-drug antibody samples were first analyzed in the anti-drug antibody screening assay. A sample was considered positive for anti-an anti-IL-36R antibody of the present invention antibodies if its response in the screening assay was greater than or equal to the screening plate-specific cut point, and if it was confirmed positive in the confirmatory assay (ECL response inhibited by addition of excess an anti-IL-36R antibody of the present invention above the confirmatory cutpoint). Samples that were confirmed positive for anti-an anti-IL-36R antibody of the present invention antibodies were further characterized in the titration assay. Titers were determined by analysis of 2-fold serial dilutions of a sample. The reported titer was the highest dilution that produced a mean ECL value greater than or equal to the plate specific titration cutpoint.

[0686] The anti-drug antibody assay validation demonstrated that the sensitivity of the screening assay in GPP plasma was 2.5 ng/mL using an anti-an anti-IL-36R antibody of the present invention rabbit polyclonal antibody positive control. In addition, 100 and 250 ng/mL levels of the positive control were detected in the presence of at least 2000 .mu.g/mL an anti-IL-36R antibody of the present invention. None of the ADA samples had an anti-IL-36R antibody of the present invention levels greater than 2000 .mu.g/mL. The assay performance data indicated that the method was reliable for screening, confirmation, and determination of titers of anti-an anti-IL-36R antibody of the present invention antibodies in plasma samples from patients in this study.

[0687] Biomarker Assessments

[0688] Assessment of CRP levels (non-high sensitive) and absolute neutrophil count were conducted using standard methodologies by local laboratories. Samples for assessments were collected at baseline before treatment initiation and on days 7, 14, and 28.

[0689] Pharmacogenomics Biomarker Assessments

[0690] Global transcriptome-wide sequencing of RNA from lesion and non-lesional skin biopsy samples and whole blood from all patients was achieved using the Illumina Hi-Seq 3000 (IIlumina Inc., San Diego, Calif.). Data were normalized by TMM using the edgeR package; log 2 fold changes and corresponding FDR-adjusted p-values were analyzed using the limma package (Bioconductor, US). (Genome Biol 2010; 11(3):R25; Nucleic Acids Res 2015; 43(7):e47) Briefly, data were voom-transformed and correlations between paired measurements per patient were estimated by the duplicate Correlation function. A linear model was fitted using the ImFit-f unction and moderated t-statistics were computed for lesional versus non-lesional and pre-versus post-treatment with an anti-IL-36R antibody of the present invention. (Nucleic Acids Res 2015; 43(15):e97; Genome Biol 2014; 15(2):R29) Adjusted P-values of <0.05 were considered significant.

[0691] Statistical Analyses

[0692] This trial, due to its small sample size and the absence of a comparator, did not test any statistical hypotheses. Endpoints are described in their entirety and are evaluated by descriptive statistical methods. Safety analyses included all treated patients (full analysis set; FAS); efficacy analyses were conducted with patients who had a baseline and at least one post-baseline measurement available for either GPPASI or GPPGA; and biomarker analyses were conducted with all treated patients who had provided at least one observation for at least one biomarker matrix. Non-response imputation was used for binary efficacy endpoints following use of rescue medication; for continuous endpoints, only observations collected prior to use of rescue medication were summarized. One patient received rescue treatment during study hence data subsequent to this use (post-Week 4) are handled as described.

Results

[0693] Patients

[0694] Of 16 patients screened, seven patients (three men and four women, aged between 22 and 58 years) at five study sites, who experienced a moderate to severe acute flare, received a single IV dose of 10 mg/kg an anti-IL-36R antibody of the present invention between February and August. Baseline demographic data and disease characteristics are reported in Table 3. Two patients carried a homozygous loss of function IL36RN mutation (rs387906914/p.Leu27Pro) known to cause generalized pustular psoriasis and one patient carried potentially generalized pustular psoriasis-causing mutations, including a homozygous IL36RN mutation (rs148755083) and a heterozygous CARD14 mutation (rs117360605/p.Arg275His). The mean (SD) time from initial diagnosis for all patients was 16.4 (16.8) years. All patients presented with a flare of moderate severity, characterized by a GPPGA of 3 and a pustule subscore of 2-4 (moderate to very high density). The mean (SD) time interval between the onset of the current flare and an anti-IL-36R antibody of the present invention infusion was 5.3 (7.4) days (range: 0-18 days). All patients had previously received prior systemic treatments for generalized pustular psoriasis and were stopped prior to receiving an anti-IL-36R antibody of the present invention; cyclosporine was discontinued 30 days prior to an anti-IL-36R antibody of the present invention administration. All patients completed the trial up to Week 20, however, there were two protocol violations: One patient (patient 8201002) did not satisfy the inclusion criterion for having a known prior history of generalized pustular psoriasis, but did satisfy other inclusion criteria, and a second patient (patient 6001004) received methotrexate at Week 4 for treatment of "pain". Both patients were included in the FAS, however, only efficacy data up to Week 4 is included for patient 6001004.

[0695] Safety

[0696] Through 20 weeks, four patients (57.1%) were deemed to have had a drug-related adverse events (Table 6); all were graded as mild or moderate. No severe or serious adverse events were reported. Laboratory parameters were normal in most patients, two patients (28.6%) had low hemoglobin; two patients (14.3%) had elevated eosinophils, one patient had elevated creatine kinase, two patients had elevated triglycerides, and one patient had low glucose, following treatment with an anti-IL-36R antibody of the present invention. Three patients (42.9%) had positive anti-drug antibodies at Week 2, sustained through Week 20 with maximum titer at Week 12 for two of the patients; no pre-existing anti-drug antibodies were detected.

TABLE-US-00014 TABLE 6 Adverse Events through Week 20* 10 mg/kg an anti-IL-36R antibody of Adverse Event, n (%) the present invention (N = 7) Any adverse event 7 (100) Severe adverse event 0 Drug-related adverse event 4 (57.1) Eosinophilia 2 (28.6) Vomiting 1 (14.3) Chills 1 (14.3) Pain.sup..dagger. 1 (14.3) Upper respiratory tract infection 2 (28.6) Urinary tract infection 1 (14.3) Infusion related reaction 1 (14.3) Arthralgia 1 (14.3) Adverse event leading to 0 discontinuation of trial drug Serious drug-related adverse event 0 *Adverse events were coded with the use of the Medical Dictionary for Drug Regulatory Activities, version 20.1. The intensity of adverse events were categorized as mild, moderate, or severe by investigators. .sup..dagger.Patient reported pain at sites of previous lesions, located on both shins.

[0697] Efficacy

[0698] Clinical Endpoints

[0699] A GPPGA score of 0 or 1 was achieved in five patients (71.4%) as early as Week 1 after a single dose of an anti-IL-36R antibody of the present invention, and in all patients by Week 4 (FIG. 1A).

[0700] A major improvement in GPPASI was observed in all patients very early with a mean (SD) percent change from baseline of 73.2% (16.2) at Week 2 (FIG. 1B); by Week 4, this was further reduced to 79.8%, and was maintained to Week 20 (83.6%). Within 48 hours of treatment, pustules were completely cleared in three patients (42.9%); pustules were cleared in five patients (71.4%) by Week 1, and in six patients (85.7%) by Week 2 (FIG. 1C). By Week 1, 85.7% of patients had achieved a GPPASI 50, by Week 4, 71.4% of patients had achieved a GPPASI 75, and by Week 12, 57.1% of patients had achieved a GPPASI 90 (FIG. 2). The mean GPPASI erythema subscore was reduced from baseline by 27.8%, 48.3%, and 53.5% at Weeks 1, 2, and 4, respectively. Similarly, the mean GPPASI scaling subscore was reduced from baseline by 38.1%, 49.6%, and 57.1% at Weeks 1, 2, and 4 respectively (FIG. 3).

[0701] Patient-Reported Outcomes

[0702] The mean (SD) improvement in FACIT-F from baseline to Week 2 was 12.3 (10.1) and was maintained to Week 4 (FIG. 4). For Pain-VAS, the mean (SD) change from baseline to Week 2 was -45.9 (32.3) and was maintained to Week 4 (FIG. 5). Similarly, there was a mean (SD) change from baseline of -5.14 (3.18) in PSS at Week 2 that was also maintained to Week 4 (FIG. 6).

[0703] Biomarker Analyses

[0704] A rapid reduction in CRP approaching normalization was observed with a mean (SD) change in CRP from baseline to Week 2 of -64.2 (55.1) mg/dl that was maintained to Week 4 (FIG. 7). Absolute neutrophil count was reduced rapidly by Week 2 and was maintained to Week 4 (FIG. 8).

[0705] Global transcriptome analysis of lesional and non-lesional skin biopsies samples found 3276 genes to be differentially expressed (1885 elevated; 1391 decreased) at baseline between lesional and non-lesional skin biopsies (adjusted P.ltoreq.0.05, fold-change .gtoreq.2). After seven days of treatment with an anti-IL-36R antibody of the present invention, expression of 1444 genes in lesional skin was strongly up or downregulated, reaching near non-lesional skin levels; genes differentially expressed were associated with innate (e.g. IL6, TNF, and CXCL1) and Th1/Th17 mediated inflammation (e.g. IL1B, IL12B, and IL23A) and with proinflammatory processes of keratinocyte activation (e.g. IL17C and IL24) (Table 7).

TABLE-US-00015 TABLE 7 Gene Expression Profile in Lesional versus Non-Lesional Skin and Pre and Post-Treatment with an anti-IL-36R antibody of the present invention Lesional skin Pre Versus post an anti-IL-36R Lesional Versus antibody of the Non-Lesional present invention Skin at Baseline treatment at Week 1 Gene Description (Log2FC) (Log2FC) IL36A Interleukin 36 alpha 6.5042** -1.98 IL36B Interleukin 36 beta 1.3974 0.0258 IL36G Interleukin 36 gamma 3.7135** -0.9053 IL12B Interleukin 12B 5.5762** -3.4247* IL1B Interleukin 1 beta 4.4361** -2.2585* IL6 Interleukin 6 3.9185* -3.6732* CXCL1 Chemokine 5.4683*** -2.6705* (C--X--C motif) ligand 1 CXCL8 Interleukin 8 4.8027** -1.1786 IL23A Interleukin 23A 4.5025** -2.8952* TNF Tumor necrosis factor 1.7834*** -1.5952* IL17C Interleukin 17C 5.6359** -3.6090* IL24 Interleukin 24 8.0150* -4.3571* Adjusted P-values: *P < 0.05, **P < 0.01, ***P < 0.001. Data was normalized by TMM using the edgeR package. The limma package was utilized to derive log 2 fold changes and corresponding false discovery rate adjusted P-values. TMM = Trimmed mean of M-values.

[0706] In all patients, IL-36.alpha., IL-36.gamma. and IL-8 were strongly increased in lesional skin biopsies; after seven days of treatment with an anti-IL-36R antibody of the present invention, the expression of IL-36.alpha. and IL-36.gamma. was strongly reduced in four patients, while IL-8 was strongly reduced in three patients (fold change .gtoreq.2). RNA expression from whole blood detected differentially expressed genes (adjusted P.ltoreq.0.05, fold-change .gtoreq.2) after 7, 14 and 28 days (364, 476 and 568 genes, respectively). Genes of proinflammatory mediators involved in neutrophil activation, such as IL1B, CD177, S100A8/9, S100A12, MMP9, and MMP25 were among those most strongly downregulated (Table 8).

TABLE-US-00016 TABLE 8 Gene Expression Profile in Whole Blood Pre- and Post-Treatment with an anti- IL-36R antibody of the present invention Whole blood Differential expression from baseline following an anti-IL-36R antibody of the present invention treatment (Log2FC) Gene Description Day 1 Week 1 Week 2 Week 4 IL1B Interleukin 1 beta -0.0569 -0.8180* -0.9891** -1.1283** S100A9 S100 calcium binding protein A9 -0.3686 -0.9398 -1.2238* -1.5496** S100A12 S100 calcium binding protein A12 -0.5480 -1.3200* -1.8570** -2.1336*** S100A8 S100 calcium binding protein A8 -0.5096 -1.0197 -1.3282* -1.6132** MMP25 Matrix metallopeptidase 25 -0.2015 -0.5665 -1.0276** -0.8226* MMP9 Matrix metallopeptidase 9 -0.2247 -0.5728 -1.5403* -1.6919** CD177 CD177 molecule -0.4945 -2.6019 -4.6062* -4.7470** Adjusted P-values: *P < 0.05, **P < 0.01, ***P < 0.001. Data was normalized by TMM using the edgeR package. The limma package was utilized to derive log 2 fold changes and corresponding false discovery rate adjusted P-values. TMM = Trimmed mean of M-values.

[0707] Discussion

[0708] This first-in-human disease study investigating the safety and efficacy of an anti-IL-36R antibody of the present invention, an anti-interleukin-36R human monoclonal antibody, studied patients with generalized pustular psoriasis due to the significant disease burden, high unmet need, and the robust evidence for the contribution of interleukin-36 dysregulation to skin and systemic inflammation in this syndrome. Indeed, the absence or impairment of interleukin-36Ra due to IL36RN mutations causes generalized pustular psoriasis, although the prevalence of such mutations varies across different cohorts, ranging from 5% to 70%, leading to the identification of a new autoinflammatory syndrome called DITRA (Deficiency of Interleukin-36 Receptor Antagonist). The relevance of the interleukin-36R inhibiting strategy in generalized pustular psoriasis has been reinforced by a genetically-engineered mouse model of DITRA, and by advanced knowledge of the structure and function of the human interleukin-36R that has enabled the production of an anti-IL-36R antibody of the present invention, which inhibits the inflammatory effects of interleukin-36. Results from this proof-of-concept study demonstrate rapid resolution of systemic inflammation and efficacy, with five of seven patients clear or almost clear one week after an anti-IL-36R antibody of the present invention infusion, and all patients achieving this status by Week 4. The assessment of efficacy at these early time points was designed specifically to avoid wrongly attributing the drug intervention (in this single-arm study) with the spontaneously self-remitting course of generalized pustular psoriasis flares which usually occurs over a few weeks to months--a disease characteristic which limits the impact of many therapeutic studies in generalized pustular psoriasis with later timed efficacy end points. (Br J Dermatol 1968; 80:771-93) Likewise, advocated successful treatments with a wide range of targeted biologics such as inhibitors of tumor necrosis factor, interleukin-17 and interleukin-23, should be considered with caution. (J Dermatol 2016; 43:1011-7; Arch Dermatol 2012; 148:1423-5; Ann Intern Med 2010; 153:66-7) This early, striking response pattern of both skin and systemic components suggest that interleukin-36R inhibition with a single dose of an anti-IL-36R antibody of the present invention leads to a rapid and sustained shutdown of the inflammatory cascade in generalized pustular psoriasis. These early responses were also reflected in rapid improvements in patient-reported outcomes (FACIT-F, Pain-VAS, and PSS). Another key observation is the similar efficacy observed in patients with and without IL36RN mutations, supporting the recent hypothesis that interleukin-36 cytokines are engaged in skin inflammation not only across pustular psoriasis subtypes with different genetic backgrounds, but also potentially in psoriasis vulgaris lesions. The rapid improvement in clinical endpoints were reflected by a rapid improvement in the gene expression profile of lesional skin to near normal skin levels within seven days, underlining the central role of the interleukin-36 pathway in this disease. The differentially expressed genes in whole blood up to 28 days support the durable and long lasting clinical effect of a single dose of an anti-IL-36R antibody of the present invention.

[0709] Regarding tolerance, no clear treatment-emergent safety signal was identified, adding to previous safety data in 124 healthy volunteers (unpublished data) and are consistent with the recent characterization of individuals with IL36R knockout mutations, resulting in the complete absence of the interleukin-36R but without any evidence of an increased risk of superinfection, nor of a significant impact on the innate and adaptive immune responses. (Sci Transl Med 2017; 9)

[0710] Given the low number of patients in the trial, no clear association between immunogenicity with a change in either safety or efficacy was detected.

[0711] Taking into consideration the limitations associated with a proof-of-concept study in a rare disease (a small open-label study of short duration), these results of interleukin-36R inhibition with a single dose of an anti-IL-36R antibody of the present invention provide promising perspectives for the treatment of generalized pustular psoriasis. Larger randomized controlled trials to confirm these findings are ongoing. The results of the current study also provide additional support to the hypothesis that inhibiting the interleukin-36 pathway may be beneficial in pustular psoriasis beyond patients with IL36RN mutations.

[0712] In conclusion, inhibition of the interleukin-36 pathway following a single dose of an anti-IL-36R antibody of the present invention, resulted in the rapid and sustained remission of clinical symptoms, with no adverse safety signals in patients with acute generalized pustular psoriasis.

Example 2: Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Phase II Study to Evaluate Efficacy, Safety and Tolerability of an Anti-IL-36R Antibody of the Present Invention in Patients with Generalized Pustular Psoriasis (GPP) Presenting with an Acute Flare of Moderate to Severe Intensity

[0713] Current treatment options for controlling acute GPP, complete resolution of symptoms and prevention of reoccurrence of flares are limited and do not provide sustained efficacy. No treatments are currently approved for GPP in the US and EU, though a combination of retinoids, cyclosporine or methotrexate has been recommended as primary options for controlling worsening of chronic GPP. However, long-term use of these treatments is limited due to side effects and contraindications (retinoids: teratogenicity, hair loss; cyclosporine: excessive hair growth, renal toxicity; MTX: liver toxicity). Side effects, such as hair loss, excessive hair growth and teratogenicity particularly limit the use of these treatments in women. Biologics (mostly TNF inhibitors, occasionally IL-1 or IL-17 inhibitors) are increasingly used to treat more severe, extensive or treatment resistant patients with GPP, based on small published case series. However, these drugs are also associated with limitations in efficacy (incomplete and delayed responses are frequent) and safety (risk of infections and infusion reactions).

[0714] Based on the limitations described above, current therapeutic options are not suitable for life-long treatment and do not provide sustained responses in most patients. Therefore, to address the high unmet needs in GPP there is a critical need to develop (i) a highly effective treatment with rapid onset of action for patients presenting with an acute GPP flare; and (ii) to develop an effective treatment that also reliably reduces the occurrence of flares and leads to complete resolution of manifestations such as widespread erythema and scaling, and is safe and tolerable for lifelong treatment. In addition, a search of the current literature did not yield any published studies focusing on moderate to severe GPP flares. Thus, our PoC approach and subsequent development plan further addresses the need for GPP treatment options.

[0715] The strong genetic link between the IL36 signaling pathway and GPP and experimental data identifying IL-36 as the dominant cytokine driving GPP suggest that inhibition of IL36R signaling with the humanized anti-IL36R antibody an anti-IL-36R antibody of the present invention might be beneficial in treatment of GPP--similar to the strong responses seen in IL1R antagonist deficient patients with sterile multifocal osteomyelitis after treatment with Anakinra. In addition, a recent characterization of individuals with homozygous IL36R KO mutations revealed that normal immune function was broadly preserved suggesting that IL36 signaling pathway inhibition does not compromise host defenses.

[0716] Based on this rationale, an open-label, single arm study trial has been conducted to investigate proof-of-concept of a single dose of an anti-IL-36R antibody of the present invention in patients with GPP. In total, seven patients have been treated with a single IV administration of 10 mg/kg of an anti-IL-36R antibody of the present invention.

[0717] As described above, inhibiting IL36R activity results in a rapid and sustained improvement in GPP clinical skin and systemic symptoms. In the patients studied, an anti-IL-36R antibody of the present invention was well tolerated. Through 20 weeks of the trial duration, only adverse events of mild or moderate intensity were reported. In addition, no severe or serious adverse events were reported.

[0718] Based on these results, the objective of this subsequent GPP trial is to evaluate efficacy, safety, and tolerability of an anti-IL-36R antibody of the present invention compared to placebo in patients with GPP presenting with an acute flare of moderate to severe intensity.

[0719] In order to be able to address future scientific questions, patients will be asked to voluntarily donate biospecimens for banking. If the patient agrees, banked samples may be used for future biomarker research and drug development projects, e.g. to identify patients that are more likely to benefit from a treatment or experience an adverse event (AE), or to gain a mechanistic or genetic understanding of drug effects and thereby better match patients with therapies.

[0720] Trial Objectives and Endpoints

[0721] Main Objectives

[0722] To evaluate efficacy, safety, and tolerability of an anti-IL-36R antibody of the present invention in patients with Generalized Pustular Psoriasis (GPP) presenting with an acute flare of moderate to severe intensity.

[0723] Clinical Trial Protocol Synopsis

TABLE-US-00017 Number of patients At least 27 entered: Number of patients on 18 patients on an anti-IL-36R antibody of the present invention and each treatment: 9 patients on placebo Diagnosis: Patients with Generalized Pustular Psoriasis (GPP) presenting with an acute flare of moderate to severe intensity. Main in- and exclusion Main inclusion criteria: criteria Patients will be enrolled (screened) into the trial, if they meet the following criteria: 1a) Patients with GPPGA of 0 or 1 and a known and documented history of GPP per European Rare And Severe Psoriasis Expert Network (ERASPEN) criteria regardless of IL36RN mutation status, with previous evidence of fever, and/or asthenia, and/ormyalgia, and/or elevated C-reactive protein, and/or leukocytosis with peripheral blood neutrophilia. OR 1b) Patients with an acute flare of moderate to severe intensity meeting the (ERASPEN) criteria of GPP with a known and documented history of GPP (per ERASPEN criteria) regardless of IL36RN mutation status, with previous evidence of fever, and/orasthenia, and/or myalgia, and/or elevated C-reactive protein, and/or leucocytosis with peripheral blood neutrophilia. OR 1c) Patients with first episode of an acute GPP flare of moderate to severe intensity with evidence of fever, and/or asthenia, and/ormyalgia, and/or elevated C-reactive protein, and/or leukocytosis with peripheral blood neutrophilia (above ULN). For these patients the diagnosis will be confirmed retrospectively by a central external expert/committee. Patients may or may not be receiving background treatment with retinoids and/or methotrexate and/or cyclosporine. Patients must discontinue retinoids/methotrexate/cyclosporine prior to receiving the first dose of an anti-IL-36R antibody of the present invention/ placebo. Male or female patients, aged 18 to 75 years at screening. Signed and dated written informed consent prior to admission to the study in accordance with ICH-GCP and local legislation prior to start of any screening procedures. Women of childbearing potential and men able to father a child must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. Note: A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Tubal ligation is not a method of permanent sterilization. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. Main Exclusion Criteria: Patients with SAPHO (Synovitis-acne-pustulosis-hyperostosis- osteitis) syndrome. Patients with primary erythrodermic psoriasis vulgaris. Patients with primary plaque psoriasis vulgaris without presence of pustules or with pustules that are restricted to psoriatic plaques. Drug-triggered Acute Generalized Exanthematous Pustulosis (AGEP). Immediate life-threatening flare of GPP or requiring intensive care treatment, according to the investigator's judgement. Life- threatening complications mainly include, but are not limited to, cardiovascular/cytokine driven shock, pulmonary distress syndrome, or renal failure. [TMM to send TCM threshold] Severe, progressive, or uncontrolled hepatic disease, defined as >3-fold Upper Limit of Normal (ULN) elevation in AST or ALT or alkaline phosphatase, or >2-fold ULN elevation in total bilirubin. Patients with dose escalation of their subcutaneous therapy with cyclosporine and/or methotrexate and/or retinoids within the 2 weeks prior to receiving the first dose of an anti-IL-36R antibody of the present invention/placebo. The initiation of systemic agents such as cyclosporine and/orretinoids and/or methotrexate 2 weeks prior to receiving the first dose of an anti-IL-36R antibody of the present invention/ placebo. Treatment (Visit 2) will be initiated immediately in patients: Who meet the inclusion criteria above Who are presenting with an acute GPP flare of moderate to severe intensity, defined by emergence of: a) Generalized Pustular Psoriasis Physician Global Assessment(GPPGA) score of at least 3 (moderate), and b) presence of fresh pustules (new appearance or worsening of pustules), and c) GPPGA pustulation sub score of at least 2 (mild), and d) at least 5% of Body Surface Area (BSA) covered with erythema and the presence of pustules And who do not meet any of the exclusion criteria above. dose: 900 mg, single dose mode of administration: i.v. Comparator products: Placebo comparator dose: Not applicable mode of administration: i.v. Duration of treatment: Single dose Endpoints Primary Endpoints: The co-Primary Endpoints of the study are: A Generalized Pustular Psoriasis Physician Global Assessment(GPPGA) score of 0 or 1 at Week 1. A GPPGA pustulation subscore of 0 indicating no visible pustules at Week 1. Secondary Endpoints: Secondary Endpoints of the study at week 4 which are included in the statistical testing strategy in a hierarchical manner subsequent to performance of the tests on the co-primary endpoints are: A Psoriasis Area and Severity Index for Generalized Pustular Psoriasis (GPPASI) 75 at Week 4. Change from baseline in Pain Visual Analog Scale (VAS) score at Week 4. Change from baseline in Psoriasis Symptom Scale (PSS) score at Week 4. Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue score at Week 4. Secondary endpoints of the study which are not included in the statistical testing hierarchy are: A GPPGA 0 or 1 at Week 4. A GPPGA pustulation subscore of 0 indicating no visible pustules at Week 4. A GPPASI 50 at Week 1, and 4. The percent reduction in GPPASI from baseline at Week 1, and 4. The following safety endpoint is also defined: The occurrence of Treatment Emergent Adverse Events (TEAEs).

[0724] This study will be a single-dose, placebo-controlled study of patients with acute GPP flares of moderate to severe intensity receiving 900 mg an anti-IL-36R antibody of the present invention and then followed for an additional 12 weeks. Patients who satisfy the inc/exc criteria of subsequent open-label extension trial will receive an option to continue receiving treatment for GPP with s.c. dosing. See FIG. 9 for additional details on the trial design.

Example 3: Treating Patients with Acute GPP Flares

[0725] In this example, an anti-IL36R antibody (e.g., an anti-IL-36R antibody of the present invention) is used to treat patients with acute GPP flares. Initially, each patient has one or more inclusion criteria listed in Example 2. A single 900 mg dose i.v. of an anti-IL36R antibody of the present invention (in solution for infusion at 60 mg/mL) is administered to each patient.

[0726] Following the administration of the anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the present invention), safety and efficacy assessments reveal the followings: At least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of the patients achieve clinical remission as defined by (a) Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 or 1 at Week 1; (b) GPPGA pustulation subscore of 0 indicating no visible pustules at Week 1; (c) Psoriasis Area and Severity Index for Generalized Pustular Psoriasis (GPPASI) 75 at Week 4; (d) Change from baseline in Pain Visual Analog Scale (VAS) score at Week 4; (e) Change from baseline in Psoriasis Symptom Scale (PSS) score at Week 4; (f) Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue score at Week 4; (g) GPPGA 0 or 1 at Week 4; (h) GPPGA pustulation subscore of 0 indicating no visible pustules at Week 4; (i) GPPASI 50 at Week 1 and 4; or (j) Change in GPPASI pustule, erythema or scaling severity subscore from baseline at Week 1 and 4 of the treatment. The proportion of patients with a response to the administration is statistically significantly higher as compared to patients on placebo for one or more of end points (a)-(j).

Example 4: Preventing Flares from Recurring in GPP Patients

[0727] In this example, a single 900 mg dose i.v. of an anti-IL36R antibody of the present invention (in solution for infusion at 60 mg/mL) is used to treat patients with acute GPP flares. Subsequent to the i.v. dose, as shown in Table 1, additional subcutaneous doses of the anti-IL36R antibody are administered to prevent the GPP flares from recurring.

[0728] Following the administration of the last dose of the anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the present invention), at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a GPPGA score of 0 or 1 at Week 12, 24, 36, 48, 60 or 72. The improved effects are maintained at higher percentage with an anti-IL-36R antibody of the present invention than with placebo. At least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of the mammals or patients maintain improved effects at Week 12, 24, 36, 48, 60 or 72 after the last dose of the anti-IL-36R is administered, as compared to placebo.

[0729] Following the administration of the last dose of the anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the present invention), at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a change in GPPASI from baseline at Week 12, 24, 36, 48, 60 or 72. The improved effects are maintained at higher percentage with an anti-IL-36R antibody of the present invention than with placebo. At least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 6.4%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of the mammals or patients maintain improved effects at Week 12, 24, 36, 48, 60 or 72 after the last dose of the anti-IL-36R is administered, as compared to placebo.

[0730] Following the administration of the last dose of the anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the present invention), at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients remain in clinical remission as measured by a change in GPPASI pustule, erythema or scaling severity subscore from baseline at Week 12, 24, 36, 48, 60 or 72. The improved effects are maintained at higher percentage with an anti-IL-36R antibody of the present invention than with placebo. At least 10%, 11%, 12%, 13%, 1.4%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 0.48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of the mammals or patients maintain improved effects at Week 12, 24, 36, 48, 60 or 72 after the last dose of the anti-IL-36R is administered, as compared to placebo.

Example 5: Achieving Complete Resolution of GPP Symptoms in GPP Patients

[0731] In this example, a single 900 mg dose i.v. of an anti-IL36R antibody of the present invention (in solution for infusion at 60 mg/mL) is used to treat patients with acute GPP flares. Subsequent to the i.v. dose, as shown in Table 1, additional subcutaneous doses of the anti-IL36R antibody are administered to achieve complete resolution of GPP symptoms in the patients.

[0732] Following the administration of the last dose of the anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the present invention), at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of the patients complete resolution of GPP symptoms as measured by a GPPGA score of 0 at Week 12, 24, 36, 48, 60 or 72. The improved effects are maintained at higher percentage with an anti-IL-36R antibody of the present invention than with placebo. At least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 0.41%, 42%, 43%, 0.44%, 45%, 0.4.6%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 6.4%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of the mammals or patients maintain improved effects at Week 12, 24, 36, 48, 60 or 72 after the last dose of the anti-IL-36R is administered, as compared to placebo.

[0733] While certain aspects and embodiments of the invention have been described, these have been 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.

[0734] All patents and/or publications including journal articles cited in this disclosure are expressly incorporated herein by reference.

Sequence CWU 1

1

1401108PRTMus sp. 1Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly1 5 10 15Glu Arg Val Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Leu His Trp Tyr Gln Lys Lys Pro Gly Ser Ser Pro Lys Leu Trp 35 40 45Val Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu65 70 75 80Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln His His Arg Ser Pro 85 90 95Val Thr Phe Gly Ser Gly Thr Lys Leu Glu Met Lys 100 1052107PRTMus sp. 2Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Gln Ser Ala Ser Leu Gly1 5 10 15Glu Ser Val Thr Phe Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp 20 25 30Leu Ala Trp Tyr Gln Gln Arg Pro Gly Lys Ser Pro Gln Leu Leu Ile 35 40 45Tyr Ala Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Gln Phe Ser Phe Asn Ile Arg Ser Leu Gln Ala65 70 75 80Glu Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Val Tyr Thr Thr Pro Leu 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 1053107PRTMus sp. 3Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Gln Ser Ala Ser Leu Gly1 5 10 15Glu Ser Val Thr Phe Thr Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile 35 40 45Tyr Arg Ser Thr Thr Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Lys Phe Ser Phe Lys Ile Ser Ser Leu Gln Ala65 70 75 80Ala Asp Phe Ala Ser Tyr Tyr Cys Gln Gln Leu Tyr Ser Ala Pro Tyr 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg 100 1054112PRTMus sp. 4Asp Val Leu Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly1 5 10 15Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser 20 25 30Asn Gly Asn Thr Tyr Leu Gln Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile65 70 75 80Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95Ser His Val Pro Phe Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 1105107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 5Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly1 5 10 15Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Tyr Lys Tyr 20 25 30Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Leu Lys Leu Leu Ile 35 40 45Tyr Tyr Thr Ser Gly Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Ser Leu Thr Ile Ser Asn Leu Glu Pro65 70 75 80Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Ser Lys Phe Pro Trp 85 90 95Thr Phe Gly Gly Asp Thr Lys Leu Glu Ile Lys 100 1056108PRTMus sp. 6Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly1 5 10 15Glu Arg Val Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Trp 35 40 45Ile Tyr Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Gly Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu65 70 75 80Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 1057107PRTMus sp. 7Asp Ile Val Met Thr Gln Ser Gln Lys Phe Leu Ser Thr Ser Val Gly1 5 10 15Val Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Asn 20 25 30Val Leu Trp Tyr Gln Gln Lys Ile Gly Gln Ser Pro Lys Pro Leu Ile 35 40 45Tyr Ser Ala Ser Tyr Arg His Ser Gly Val Pro Asp Arg Phe Thr Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Ile Ile Ser Asn Val Gln Ser65 70 75 80Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Ser Arg Tyr Pro Leu 85 90 95Thr Phe Gly Pro Gly Thr Lys Leu Glu Leu Lys 100 1058107PRTMus sp. 8Asp Ile Val Met Thr Gln Ser Gln Lys Phe Leu Ser Thr Ser Val Gly1 5 10 15Val Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asp Val Gly Thr Asn 20 25 30Val Leu Trp Tyr Gln Gln Lys Ile Gly Gln Ser Pro Lys Ala Leu Ile 35 40 45Tyr Ser Ala Ser Tyr Arg His Ser Gly Val Pro Asp Arg Phe Thr Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Ile Ile Thr Asn Val Gln Ser65 70 75 80Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Ser Arg Tyr Pro Leu 85 90 95Thr Phe Gly Pro Gly Thr Lys Leu Glu Leu Lys 100 1059107PRTMus sp. 9Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Ala Thr Val Gly1 5 10 15Gly Arg Val Asn Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Arg Ala 20 25 30Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Thr 35 40 45His Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Met Gln Ser65 70 75 80Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Leu 85 90 95Thr Phe Gly Ala Gly Thr Lys Leu Asp Leu Lys 100 10510107PRTMus sp. 10Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Gln Ser Ala Ser Leu Gly1 5 10 15Glu Ser Val Thr Phe Ser Cys Leu Ala Ser Gln Thr Ile Gly Thr Trp 20 25 30Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile 35 40 45Tyr Arg Ala Thr Ser Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Asn Phe Ser Phe Lys Ile Ser Ser Leu Gln Ala65 70 75 80Glu Asp Leu Ala Ser Tyr Tyr Cys Gln Gln Leu Tyr Ser Gly Pro Tyr 85 90 95Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg 100 10511119PRTMus sp. 11Gln Val Gln Leu Gln Gln Ser Gly Thr Glu Leu Leu Lys Pro Gly Ala1 5 10 15Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Asn Thr Val Thr Ser Tyr 20 25 30Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Leu Pro Ser Thr Gly Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Lys Gly Lys Ala Met Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr65 70 75 80Met Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95Thr Ile Val Tyr Phe Gly Asn Pro Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ala 11512125PRTMus sp. 12Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala1 5 10 15Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Asn 20 25 30Tyr Met Asn Trp Val Arg Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45Gly Arg Val Asn Pro Ser Asn Gly Asp Thr Lys Tyr Asn Gln Asn Phe 50 55 60Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Leu Ser Thr Ala Tyr65 70 75 80Met Gln Leu Asn Gly Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95Gly Arg Thr Lys Asn Phe Tyr Ser Ser Tyr Ser Tyr Asp Asp Ala Met 100 105 110Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 12513124PRTMus sp. 13Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Phe Val Arg Pro Gly Ala1 5 10 15Ser Val Lys Phe Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Asp 20 25 30Tyr Ile His Trp Val Arg Gln Arg Pro Glu Gln Gly Leu Glu Trp Val 35 40 45Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Ala Pro Lys Phe 50 55 60Gln Asp Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr65 70 75 80Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Ser Phe Pro Asn Asn Tyr Tyr Ser Tyr Asp Asp Ala Phe Ala 100 105 110Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 115 12014118PRTMus sp. 14Gln Val Gln Leu Lys Glu Ser Gly Pro Val Leu Val Ala Pro Ser Gln1 5 10 15Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Lys Phe 20 25 30Gly Val His Trp Ile Arg Gln Thr Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45Gly Val Ile Trp Ala Gly Gly Pro Thr Asn Tyr Asn Ser Ala Leu Met 50 55 60Ser Arg Leu Thr Ile Ser Lys Asp Ile Ser Gln Ser Gln Val Phe Leu65 70 75 80Arg Ile Asp Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala 85 90 95Lys Gln Ile Tyr Tyr Ser Thr Leu Val Asp Tyr Trp Gly Gln Gly Thr 100 105 110Ser Val Thr Val Ser Ser 11515120PRTMus sp. 15Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln1 5 10 15Ser Leu Phe Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Ser Tyr 20 25 30Glu Ile Asn Trp Val Arg Gln Val Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45Gly Val Ile Trp Thr Gly Ile Thr Thr Asn Tyr Asn Ser Ala Leu Ile 50 55 60Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Leu Val Phe Leu65 70 75 80Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95Arg Gly Thr Gly Thr Gly Phe Tyr Tyr Ala Met Asp Tyr Trp Gly Gln 100 105 110Gly Thr Ser Val Thr Val Ser Ser 115 12016119PRTMus sp. 16Gln Val Gln Leu Gln Gln Pro Gly Ala Asp Phe Val Arg Pro Gly Ala1 5 10 15Ser Met Arg Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr65 70 75 80Met Gln Leu Arg Ser Leu Thr Ser Ala Asp Ser Ala Val Tyr Tyr Cys 85 90 95Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ala 11517119PRTMus sp. 17Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln1 5 10 15Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30Ala Val His Trp Val Arg Gln Phe Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Phe Asn Ala Pro Phe Lys 50 55 60Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe65 70 75 80Lys Met Asn Ser Leu Gln Ile Asp Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ala 11518119PRTMus sp. 18Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln1 5 10 15Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30Ala Val His Trp Val Arg Gln Phe Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys 50 55 60Ser Arg Leu Ser Ile Asn Lys Asp Asn Ser Lys Ser Gln Val Phe Phe65 70 75 80Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ala 11519117PRTMus sp. 19Gln Val Gln Leu Lys Glu Ser Gly Pro Val Leu Val Ala Pro Ser Gln1 5 10 15Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asn Tyr 20 25 30Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45Gly Val Ile Trp Pro Val Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met 50 55 60Ser Arg Leu Ser Ile His Lys Asp Asn Ser Lys Ser Gln Val Phe Leu65 70 75 80Arg Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala 85 90 95Lys Met Asp Trp Asp Asp Phe Phe Asp Tyr Trp Gly Gln Gly Thr Thr 100 105 110Leu Thr Val Ser Ser 11520124PRTMus sp. 20Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala1 5 10 15Ser Val Arg Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Asp 20 25 30Tyr Ile His Trp Val Arg Gln Arg Pro Lys Gln Gly Leu Glu Trp Leu 35 40 45Gly Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Pro Arg Phe 50 55 60Gln Asp Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr65 70 75 80Leu His Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Lys Ser Phe Pro Asp Asn Tyr Tyr Ser Tyr Asp Asp Ala Phe Ala 100 105 110Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala 115 1202112PRTMus sp. 21Thr Ala Ser Ser Ser Val Ser Ser Ser Tyr Leu His1 5 102211PRTMus sp. 22Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Ala1 5 102311PRTMus sp. 23Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Gly1 5 102416PRTMus sp. 24Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu Gln1 5 10 152511PRTMus sp. 25Arg Ala Ser Gln Asp Ile Tyr Lys Tyr Leu Asn1 5 102612PRTMus sp. 26Thr Ala Ser Ser Ser Val Ser Ser Ser Tyr Phe His1 5 102711PRTMus sp. 27Lys Ala Ser Gln Asp Val Gly Thr Asn Val Leu1 5 102811PRTMus sp. 28Lys Ala Ser Gln Asn Val Gly Arg Ala Val Ala1 5 102911PRTMus sp. 29Leu Ala Ser Gln Thr Ile Gly Thr Trp Leu Gly1 5 10307PRTMus sp. 30Ser Thr Ser Asn Leu Ala Ser1 5317PRTMus sp. 31Ala Ala Thr Ser Leu Ala Asp1 5327PRTMus sp. 32Arg Ser Thr Thr Leu Ala Asp1 5337PRTMus sp. 33Lys Val Ser Asn Arg Phe Ser1

5347PRTMus sp. 34Tyr Thr Ser Gly Leu His Ser1 5357PRTMus sp. 35Arg Thr Ser Asn Leu Ala Ser1 5367PRTMus sp. 36Ser Ala Ser Tyr Arg His Ser1 5377PRTMus sp. 37Ser Ala Ser Asn Arg Tyr Thr1 5387PRTMus sp. 38Arg Ala Thr Ser Leu Ala Asp1 5399PRTMus sp. 39His Gln His His Arg Ser Pro Val Thr1 5409PRTArtificial SequenceDescription of Artificial Sequence Synthetic peptide 40Gln Gln Val Tyr Thr Thr Pro Leu Thr1 5419PRTMus sp. 41Gln Gln Leu Tyr Ser Ala Pro Tyr Thr1 5429PRTMus sp. 42Phe Gln Gly Ser His Val Pro Phe Thr1 5439PRTMus sp. 43Gln Gln Asp Ser Lys Phe Pro Trp Thr1 5449PRTMus sp. 44His Gln Phe His Arg Ser Pro Leu Thr1 5459PRTMus sp. 45Gln Gln Tyr Ser Arg Tyr Pro Leu Thr1 5469PRTMus sp. 46Gln Gln Tyr Ser Ser Tyr Pro Leu Thr1 5479PRTMus sp. 47Gln Gln Leu Tyr Ser Gly Pro Tyr Thr1 54810PRTMus sp. 48Gly Asn Thr Val Thr Ser Tyr Trp Met His1 5 104910PRTMus sp. 49Gly Tyr Thr Phe Thr Asp Asn Tyr Met Asn1 5 105010PRTMus sp. 50Gly Phe Asn Ile Lys Asp Asp Tyr Ile His1 5 105110PRTMus sp. 51Gly Phe Ser Leu Thr Lys Phe Gly Val His1 5 105210PRTMus sp. 52Gly Phe Ser Leu Ser Ser Tyr Glu Ile Asn1 5 105310PRTMus sp. 53Gly Tyr Ser Phe Thr Ser Ser Trp Ile His1 5 105410PRTMus sp. 54Gly Phe Ser Leu Thr Asn Tyr Ala Val His1 5 105510PRTMus sp. 55Gly Phe Ser Leu Thr Asn Tyr Gly Val His1 5 105610PRTMus sp. 56Gly Phe Asn Ile Lys Asp Asp Tyr Ile His1 5 105717PRTMus sp. 57Glu Ile Leu Pro Ser Thr Gly Arg Thr Asn Tyr Asn Glu Asn Phe Lys1 5 10 15Gly5817PRTMus sp. 58Arg Val Asn Pro Ser Asn Gly Asp Thr Lys Tyr Asn Gln Asn Phe Lys1 5 10 15Gly5917PRTMus sp. 59Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Ala Pro Lys Phe Gln1 5 10 15Asp6016PRTMus sp. 60Val Ile Trp Ala Gly Gly Pro Thr Asn Tyr Asn Ser Ala Leu Met Ser1 5 10 156116PRTMus sp. 61Val Ile Trp Thr Gly Ile Thr Thr Asn Tyr Asn Ser Ala Leu Ile Ser1 5 10 156215PRTMus sp. 62Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe1 5 10 156316PRTMus sp. 63Val Ile Trp Ser Asp Gly Ser Thr Asp Phe Asn Ala Pro Phe Lys Ser1 5 10 156416PRTMus sp. 64Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys Ser1 5 10 156516PRTMus sp. 65Val Ile Trp Pro Val Gly Ser Thr Asn Tyr Asn Ser Ala Leu Met Ser1 5 10 156617PRTMus sp. 66Arg Ile Asp Pro Ala Asn Gly Asn Thr Lys Tyr Asp Pro Arg Phe Gln1 5 10 15Asp6710PRTMus sp. 67Val Tyr Phe Gly Asn Pro Trp Phe Ala Tyr1 5 106816PRTMus sp. 68Thr Lys Asn Phe Tyr Ser Ser Tyr Ser Tyr Asp Asp Ala Met Asp Tyr1 5 10 156915PRTMus sp. 69Ser Phe Pro Asn Asn Tyr Tyr Ser Tyr Asp Asp Ala Phe Ala Tyr1 5 10 157010PRTMus sp. 70Gln Ile Tyr Tyr Ser Thr Leu Val Asp Tyr1 5 107112PRTMus sp. 71Gly Thr Gly Thr Gly Phe Tyr Tyr Ala Met Asp Tyr1 5 107210PRTMus sp. 72Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr1 5 107311PRTMus sp. 73Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr1 5 10749PRTMus sp. 74Met Asp Trp Asp Asp Phe Phe Asp Tyr1 57515PRTMus sp. 75Ser Phe Pro Asp Asn Tyr Tyr Ser Tyr Asp Asp Ala Phe Ala Tyr1 5 10 1576108PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 76Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Arg Thr Ser Thr Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 10577108PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 77Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Arg Thr Ser Ile Leu Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 10578108PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 78Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Trp 35 40 45Ile Tyr Arg Thr Ser Arg Leu Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 10579108PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 79Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Arg Thr Ser Arg Leu Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 10580108PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 80Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Trp 35 40 45Ile Tyr Arg Thr Ser Arg Leu Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys 100 10581108PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 81Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Val Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Arg Thr Ser Gln Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 10582108PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 82Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Arg Thr Ser Lys Leu Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 10583108PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 83Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Arg Thr Ser His Leu Ala Ser Gly Ile Pro Gly Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Ala Ala Val Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 10584107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 84Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn 20 25 30Val Leu Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile 35 40 45Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Glu Tyr Phe Cys Gln Gln Tyr Ser Arg Tyr Pro Leu 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 10585107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 85Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn 20 25 30Val Leu Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile 35 40 45Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Arg Tyr Pro Leu 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 10586107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 86Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn 20 25 30Val Leu Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile 35 40 45Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Glu Tyr Tyr Cys Gln Gln Tyr Ser Arg Tyr Pro Leu 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 10587119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 87Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Lys Ala Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11588119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 88Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Arg Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11589119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 89Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11590119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 90Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Arg Ala Thr Leu Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11591119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 91Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Glu Ile Leu Pro Gly Val Val Arg Thr Asn Tyr Asn Glu Asn

Phe 50 55 60Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11592119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 92Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Arg Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11593119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 93Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn Pro Gly Leu Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11594119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 94Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11595119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 95Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn Pro Gly Ser Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Lys Ala Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11596119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 96Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 20 25 30Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys 50 55 60Ser Arg Val Thr Ile Asn Lys Asp Thr Ser Lys Ser Gln Val Ser Phe65 70 75 80Lys Met Ser Ser Val Gln Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11597119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 97Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 20 25 30Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys 50 55 60Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu65 70 75 80Lys Met Asn Ser Leu Thr Thr Asp Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11598119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 98Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 20 25 30Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys 50 55 60Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Leu65 70 75 80Lys Met Asn Ser Val Thr Val Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 11599119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 99Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 20 25 30Ala Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys 50 55 60Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Phe65 70 75 80Lys Leu Ser Ser Val Thr Val Asp Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115100119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 100Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 20 25 30Ala Val His Trp Ile Arg Gln Phe Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Phe Asn Ala Pro Phe Lys 50 55 60Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Phe65 70 75 80Lys Leu Ser Ser Val Thr Thr Asp Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 115101119PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 101Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 20 25 30Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys 50 55 60Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Phe65 70 75 80Lys Met Ser Ser Val Thr Ala Asp Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser 1151027PRTMus sp. 102Arg Thr Ser Thr Leu Ala Ser1 51037PRTMus sp. 103Arg Thr Ser Ile Leu Ala Ser1 51047PRTMus sp. 104Arg Thr Ser Arg Leu Ala Ser1 51057PRTMus sp. 105Arg Thr Ser Gln Leu Ala Ser1 51067PRTMus sp. 106Arg Thr Ser Lys Leu Ala Ser1 510710PRTMus sp. 107Gly Phe Ser Leu Thr Asp Tyr Ala Val His1 5 1010815PRTMus sp. 108Glu Ile Leu Pro Gly Val Val Arg Thr Asn Tyr Asn Glu Asn Phe1 5 10 1510915PRTMus sp. 109Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe1 5 10 1511015PRTMus sp. 110Glu Ile Asn Pro Gly Leu Val Arg Thr Asn Tyr Asn Glu Asn Phe1 5 10 1511115PRTMus sp. 111Glu Ile Asn Pro Gly Ser Val Arg Thr Asn Tyr Asn Glu Asn Phe1 5 10 15112330PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 112Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150 155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu225 230 235 240Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265 270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe 275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 325 330113107PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 113Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu1 5 10 15Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 20 25 30Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 35 40 45Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 50 55 60Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu65 70 75 80Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 85 90 95Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 105114215PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 114Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Arg Thr Ser Thr Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215115215PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 115Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Arg Thr Ser Ile Leu Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215116215PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 116Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Trp 35 40

45Ile Tyr Arg Thr Ser Arg Leu Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215117215PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 117Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Arg Thr Ser Arg Leu Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215118215PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 118Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Trp 35 40 45Ile Tyr Arg Thr Ser Arg Leu Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215119215PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 119Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Val Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Arg Thr Ser Gln Leu Ala Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215120215PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 120Gln Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Arg Thr Ser Lys Leu Ala Ser Gly Val Pro Asp Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Phe Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215121215PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 121Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly1 5 10 15Glu Arg Ala Thr Met Ser Cys Thr Ala Ser Ser Ser Val Ser Ser Ser 20 25 30Tyr Phe His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45Ile Tyr Arg Thr Ser His Leu Ala Ser Gly Ile Pro Gly Arg Phe Ser 50 55 60Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu65 70 75 80Pro Glu Asp Ala Ala Val Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala 100 105 110Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser145 150 155 160Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205Ser Phe Asn Arg Gly Glu Cys 210 215122214PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 122Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn 20 25 30Val Leu Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile 35 40 45Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Glu Tyr Phe Cys Gln Gln Tyr Ser Arg Tyr Pro Leu 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210123214PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 123Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn 20 25 30Val Leu Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile 35 40 45Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Arg Tyr Pro Leu 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210124214PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 124Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly1 5 10 15Val Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Val Gly Thr Asn 20 25 30Val Leu Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Pro Leu Ile 35 40 45Tyr Ser Ala Ser Tyr Arg His Ser Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser65 70 75 80Glu Asp Phe Ala Glu Tyr Tyr Cys Gln Gln Tyr Ser Arg Tyr Pro Leu 85 90 95Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln145 150 155 160Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205Phe Asn Arg Gly Glu Cys 210125449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 125Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Lys Ala Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys126449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 126Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser

20 25 30Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Arg Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys127449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 127Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys128449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 128Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Glu Ile Asn Pro Gly Asn Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Arg Ala Thr Leu Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys129449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 129Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Glu Ile Leu Pro Gly Val Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys130449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 130Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Arg Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Thr Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys131449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 131Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn Pro Gly Leu Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser

180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys132449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 132Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn Pro Gly Ala Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Lys Val Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys133449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 133Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Ser Ser 20 25 30Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45Gly Glu Ile Asn Pro Gly Ser Val Arg Thr Asn Tyr Asn Glu Asn Phe 50 55 60Arg Asn Lys Ala Thr Met Thr Val Asp Thr Ser Ile Ser Thr Ala Tyr65 70 75 80Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95Ala Val Val Phe Tyr Gly Glu Pro Tyr Phe Pro Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys134449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 134Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 20 25 30Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys 50 55 60Ser Arg Val Thr Ile Asn Lys Asp Thr Ser Lys Ser Gln Val Ser Phe65 70 75 80Lys Met Ser Ser Val Gln Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys135449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 135Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 20 25 30Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys 50 55 60Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Leu65 70 75 80Lys Met Asn Ser Leu Thr Thr Asp Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys136449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 136Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 20 25 30Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys 50 55 60Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Leu65 70 75 80Lys Met Asn Ser Val Thr Val Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys137449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 137Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 20 25 30Ala Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys 50 55 60Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Phe65 70 75 80Lys Leu Ser Ser Val Thr Val Asp Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys138449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 138Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 20 25 30Ala Val His Trp Ile Arg Gln Phe Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Phe Asn Ala Pro Phe Lys 50 55 60Ser Arg Val Thr Ile Ser Lys Asp Thr Ser Lys Asn Gln Val Ser Phe65 70 75 80Lys Leu Ser Ser Val Thr Thr Asp Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys139449PRTArtificial SequenceDescription of Artificial Sequence Synthetic polypeptide 139Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Asp Tyr 20 25 30Ala Val His Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Val Ile Trp Ser Asp Gly Ser Thr Asp Tyr Asn Ala Pro Phe Lys 50 55 60Ser Arg Val Thr Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Ser Phe65 70 75 80Lys Met Ser Ser Val Thr Ala Asp Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Lys Gly Gly Tyr Ser Gly Ser Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 115 120 125Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu 130 135 140Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp145 150 155 160Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 165 170 175Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 180 185 190Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro 195 200 205Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys 210 215 220Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro225 230 235 240Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 245 250 255Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 260 265 270Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 275 280 285Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 290 295 300Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu305 310 315 320Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 325 330 335Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 340 345 350Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 355 360 365Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 370 375 380Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu385 390 395 400Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 405 410 415Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 420 425 430Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 435 440 445Lys1407PRTMus sp. 140Arg Thr Ser His Leu Ala Ser1 5

Claims

1-38. (canceled)

39. A method of treating generalized pustular psoriasis (GPP) in a patient, said method comprising administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody, wherein the anti-IL-36R antibody is administered in one or more intravenous doses comprising 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg, 850 mg or 900 mg of the anti-IL-36R antibody, wherein the anti-IL-36R antibody comprises: (i) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or (iii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or (iv) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or (v) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or (vi) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or (vii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or (viii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101; or (ix) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or (x) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101.

40. The method of claim 39, wherein the anti-IL-36R antibody is administered in one intravenous dose of 700 mg.

41. The method of claim 39, wherein the anti-IL-36R antibody is administered in one intravenous dose of 750 mg.

42. The method of claim 39, wherein the anti-IL-36R antibody is administered in one intravenous dose of 800 mg.

43. The method of claim 39, wherein the anti-IL-36R antibody is administered in one intravenous dose of 850 mg.

44. The method of claim 39, wherein the anti-IL-36R antibody is administered in one intravenous dose of 900 mg.

45. The method of claim 39, wherein 1, 2 or 3 intravenous doses is/are administered.

46. The method of claim 45, wherein 2 or 3 intravenous doses are administered at 4 to 12 weeks intervals.

47. A method of treating generalized pustular psoriasis (GPP) in a patient, said method comprising administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody, wherein the anti-IL-36R antibody is administered in one intravenous dose of about 10 mg per kilogram of body weight of the patient, wherein the anti-IL-36R antibody comprises: (i) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or (ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or (iii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or (iv) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or (v) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or (vi) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or (vii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or (viii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101; or (ix) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or (x) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:101.

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