Use of anti-IL-36R antibodies for the treatment of generalized pustular psoriasis

Abstract

To provide methods for the treatment of generalized pustular psoriasis (GPP).SOLUTION: A method of treating generalized pustular psoriasis in a patient comprises administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application Nos. 62 / 642,641 (filed March 14, 2018), 62 / 683,720 (filed June 12, 2018), 62 / 699,274 (filed July 17, 2018), and 62 / 729,518 (filed September 11, 2018), the entire contents of each of which are hereby incorporated by reference herein as if fully set forth herein.

[0002] Sequence Listing This application contains a Sequence Listing that was submitted in ASCII format via EFS-Web and is incorporated herein by reference in its entirety. The ASCII copy created on March 5, 2019 is named 09-0683-US-4-2019-03-08-SL.txt and is 146,018 bytes in size.

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

[0004] background Generalized pustular psoriasis is a severe skin disease characterized by repeated occurrence of acute flares caused by systemic inflammation affecting the skin and internal organs.The classical symptoms of acute generalized pustular psoriasis were first described by von Zumbusch in 1909 as recurrent pustular psoriasis.Generalized pustular psoriasis and plaque psoriasis may occur simultaneously in individual patients, but generalized pustular psoriasis is distinct from plaque psoriasis in clinical symptoms, pathophysiology, histopathology, response to treatment, epidemiology, and genetics.

[0005] Therefore, it is very important to distinguish generalized pustular psoriasis from plaque psoriasis or erythrodermic psoriasis with secondary pustules. The clinical manifestations of generalized pustular psoriasis are quite different from psoriasis vulgaris (PV) in the nature of its manifestations, often with normal-appearing skin between very acute and severe disease flares. Generalized pustular psoriasis is clinically characterized by a predominance of primary pustules on a bed of erythroderma, rather than the red rash covered with silvery scales that typify the primary lesions of typical plaque psoriasis. Furthermore, the histopathological hallmark of generalized pustular psoriasis is the well-defined spongiform pustules located in the substratum corneum of the epidermis. Generalized pustular psoriasis may be accompanied by systemic symptoms (fever, elevated CRP, and neutrophilia) and severe extradermal organ manifestations (liver failure, renal failure, circulatory shock). Because patients with generalized pustular psoriasis may have a history of or concomitant plaque psoriasis, it is possible to clinically distinguish patients with a primary plaque skin disease with a secondary pustular component (psoriasis vulgaris) from those with a concomitant primary pustular skin disease with a plaque component (generalized pustular psoriasis) based on the constellation of signs (the primary lesion is a pustule rather than a plaque) and the location of the pustules of generalized pustular psoriasis on a base of erythema rather than plaque psoriasis.

[0006] Although descriptions of generalized pustular psoriasis are inconsistent among standard dermatology textbooks, the European Rare and Severe Psoriasis Expert Network (ERASPEN) has defined consensus criteria as key diagnostic criteria for acute generalized pustular psoriasis, including the presence of primary, sterile, microscopically visible pustules on nonacral skin (unless pustules are localized to plaque psoriasis) with or without systemic inflammation, with or without plaque psoriasis, and either relapsing (more than one episode) or persistent (>3 months).

[0007] Chronic generalized pustular psoriasis describes a state between disease flares that may be characterized by a complete absence of symptoms or by the persistence of residual skin symptoms such as erythema and scaling and small pustules.

[0008] Current treatment options for controlling acute generalized pustular psoriasis and skin responses are limited and do not provide sustained efficacy. There are no treatments currently approved for generalized pustular psoriasis in the United States and Europe, but retinoids, cyclosporine, or methotrexate are recommended. Although these treatments have been described as "effective or effective" in 70-84% of patients (J Am Acad Dermatol. 2012;67(2):279-88), these data are based on a Japanese retrospective cohort study that did not include 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, nephrotoxicity; methotrexate: hepatotoxicity).

[0009] Based on a small number of published case series, biologics (mainly TNF inhibitors, occasionally IL-1 or IL-17 inhibitors) are increasingly used to treat patients with generalized pustular psoriasis that is more severe, widespread, or resistant to treatment.However, these drugs also have limitations in efficacy (frequently incomplete and delayed response) and safety, as well as contraindications (infusion reaction, tuberculosis, cardiovascular disease).Therefore, there is a need in the art for new targeted therapies for the treatment and / or prevention of generalized pustular psoriasis.

[0010] Summary of the Invention The present invention addresses the above needs by providing biopharmaceuticals, particularly antibodies, that bind to IL-36R, providing therapeutic or prophylactic therapy for acute and / or chronic generalized pustular psoriasis, and associated signs and symptoms, such as generalized pustular psoriasis flares.

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

[0014] In a fourth aspect, the present invention relates to a method of reducing the severity and duration of a generalized pustular psoriasis flare, the method comprising administering or having administered to a 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 skin disorders associated with acute generalized pustular psoriasis, the method comprising administering or having administered to a patient a therapeutically effective amount of an anti-IL-36R antibody.

[0016] In one embodiment related to any of the first to fifth aspects, the anti-IL-36R antibody comprises: 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 the first to fifth aspects, the anti-IL-36R antibody comprises: Ia) 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). 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). 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). 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). Va) 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), 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). Includes.

[0018] In one embodiment related to any of the first to fifth aspects, 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. Includes.

[0019] In one embodiment related to any of the first to fifth aspects, the anti-IL-36R antibody comprises: 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 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 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 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 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 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 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 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 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. Includes.

[0020] In one embodiment related to any of the first through fifth aspects, 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) comprises 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg, or 900 mg of the anti-IL-36R antibody.

[0021] In another embodiment related to any of the first to fifth aspects, the anti-IL-36R antibody is administered in a single intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of about 10 mg per kg of patient body weight. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 210 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 300 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 350 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 450 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 600 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 700 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 750 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 800 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 850 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 900 mg.

[0022] In another embodiment related to any of the first through fifth aspects, one, two or three intravenous dose(s) are administered. In another embodiment related to any of the above aspects, two or three intravenous dose(s) are administered 2, 4, 6, 8, 10 or 12 weeks apart.

[0023] In another embodiment related to any of the first to fifth above embodiments or aspects, administration provides: (a) Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 or 1 at week 1; (b) GPPGA pustule formation subscore of 0 at week 1 (indicating no visible pustules); (c) Generalized Pustular Psoriasis Psoriasis Area and Severity Index (GPPASI) of 75 at week 4; (d) change from baseline in pain visual analog scale (VAS) scores 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-Fatigue (FACIT) score at week 4; (g) GPPGA at week 4 was 0 or 1; (h) GPPGA pustule formation subscore of 0 at week 4 (indicating no visible pustules); (i) GPPASI at weeks 1 and 4 of 50; or (j) Change from baseline in GPPASI pustule, erythema, or scaling severity subscores at Weeks 1 and 4 One or more of the following efficacy endpoints will be obtained:

[0024] In another embodiment related to the above embodiment, the proportion of patients who respond to treatment is statistically significantly higher for one or more of the endpoints (a)-(j) compared to placebo patients.

[0025] In a sixth aspect, the present invention relates to a method for preventing recurrence of a generalized pustular psoriasis flare in a patient who has been treated with one or more intravenous dose(s) of an anti-IL-36R antibody according to any of the first to fifth aspects or embodiments above, the method comprising administering to the patient a prophylactically effective amount of an anti-IL-36R antibody in one or more subcutaneous doses.

[0026] 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 an anti-IL-36R antibody according to any of the first to fifth aspects or embodiments above, the method comprising administering to the patient an effective amount of an anti-IL-36R antibody in one or more subcutaneous doses.

[0027] In an eighth aspect, the present invention relates to a method of achieving complete remission of generalized pustular psoriasis symptoms in a patient treated with one or more intravenous dose(s) of an anti-IL-36R antibody according to any of the first to fifth aspects or embodiments above, the method comprising administering to the patient an effective amount of an anti-IL-36R antibody in one or more subcutaneous doses, wherein the generalized pustular psoriasis symptoms comprise pustules, erythema, or scales, and wherein complete remission comprises a GPPGA score of 0.

[0028] In one embodiment related to any of the sixth to eighth aspects, each of the one or more subcutaneous doses comprises 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of the anti-IL-36R antibody.

[0029] In one embodiment or related embodiment(s) related to any of the sixth to eighth aspects, one, two, three or more subcutaneous doses are administered to the patient, wherein a first subcutaneous dose is administered after a final intravenous dose.

[0030] In one embodiment or related embodiment(s) related to any of the sixth to eighth aspects, 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.

[0031] In one embodiment or related embodiment(s) related to any of the sixth to eighth aspects, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission as judged by a GPPGA score of 0 or 1 at 12, 24, 36, 48, 60, or 72 weeks of treatment.

[0032] In one embodiment or related embodiment(s) related to any of the sixth to eighth aspects, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission as measured by change from baseline in GPPASI at 12, 24, 36, 48, 60, or 72 weeks of treatment.

[0033] In one embodiment or related embodiment(s) related to any of the sixth through eighth aspects, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission as measured by change in GPPASI pustule, erythema, or scaling severity subscores from baseline at 12, 24, 36, 48, 60, or 72 weeks of treatment. In related embodiments, the proportion of patients responding to treatment is statistically significantly higher for any of the listed endpoints compared to placebo patients.

[0034] In a ninth aspect, the present invention relates to a method of treating generalized pustular psoriasis in a patient, comprising administering to the patient a therapeutically effective amount of one or more intravenous dose(s) of an anti-IL-36R antibody according to the first to fifth aspects and their associated embodiments.

[0035] In one embodiment related to the ninth aspect, one or two or three intravenous dose(s) of an anti-IL-36R antibody are followed by one or two or three subcutaneous dose(s) of an anti-IL-36R antibody.

[0036] In one embodiment related to the ninth aspect, one intravenous dose(s) of anti-IL-36R antibody is followed by one or two or three subcutaneous dose(s) of anti-IL-36R antibody.

[0037] In one embodiment related to the ninth aspect, two intravenous dose(s) of anti-IL-36R antibody are followed by one or two or three subcutaneous dose(s) of anti-IL-36R antibody.

[0038] In one embodiment related to the ninth aspect, three intravenous dose(s) of anti-IL-36R antibody are followed by one or two or three subcutaneous dose(s) of anti-IL-36R antibody.

[0039] In one embodiment related to the ninth aspect and related embodiments thereof, the one or more intravenous dose(s) each comprise 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg, 850 mg, or 900 mg of anti-IL-36R antibody and the one or more subcutaneous dose(s) each comprise 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of anti-IL-36R antibody. In related embodiments, the intravenous doses are administered at 2, 4, 6, 8, 10, or 12 week intervals and the subcutaneous doses are administered at 4, 6, 8, 10, or 12 week intervals, with the first subcutaneous dose being administered 2-8 weeks, 4-6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks after the last intravenous dose was administered.

[0040] In one embodiment related to any of the above aspects, the intravenous dose(s) may be followed by one or more subcutaneous dose(s).

[0041] In one embodiment related to any of the above aspects, the anti-IL-36R antibody or antigen-binding fragment thereof (disclosed herein) is stably present in a stable pharmaceutical formulation (as described in co-pending U.S. Provisional Patent Application No. 62 / 815,405, filed March 8, 2019, the entire contents of which are hereby incorporated by reference in their entirety) for administration to a mammal or patient according to any one of the aspects of the invention.

[0042] In one embodiment, the method of treatment according to any of the aspects described herein comprises administering to a mammal a therapeutic amount of a stable pharmaceutical formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody (as disclosed herein), about 20 mM to about 80 mM of a pharma- ceutically acceptable buffer (e.g., acetate buffer), about 100 mM to about 250 mM of a pharma- ceutically acceptable tonicity agent (e.g., sucrose), about 0 mM to about 80 mM of a pharma- ceutically acceptable stabilizer (e.g., arginine) or a pharma- ceutically acceptable salt thereof, about 0 to about 150 mM of a pharma- ceutically acceptable salt (e.g., sodium chloride), and a pharma- ceutically acceptable surfactant (e.g., polysorbate 20) in an amount of about 0 g / L to about 1.5 g / L. or administering to a patient, wherein the patient is treated with generalized pustular psoriasis (GPP), or the patient is treated with moderate to severe generalized pustular psoriasis, or the signs and symptoms of acute generalized pustular psoriasis flare are reduced or alleviated in the patient, or the severity and duration of generalized pustular psoriasis flares are reduced in the patient, or the patient is treated with skin disorders associated with acute generalized pustular psoriasis, or the patient is prevented or inhibited from having a generalized pustular psoriasis flare, or the patient achieves a Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0, or the patient achieves complete remission of generalized pustular psoriasis symptoms. 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 intravenous administration to a mammal or a patient. In a related embodiment, the pharmaceutical formulation is for subcutaneous administration to a mammal or patient. In a related embodiment, the pharmaceutical formulation for intravenous administration comprises an anti-IL-36R antibody in an amount of about 60 mg / mL. In a related embodiment, the pharmaceutical formulation for subcutaneous administration comprises an anti-IL-36R antibody in an amount of about 150 mg / mL.

[0043] In a tenth aspect, the present invention provides a method for producing a composition comprising the steps of: (a) obtaining a biological sample from a patient, where the biological sample is obtained from a source including a skin lesion or whole blood; (b) determining a gene expression profile for one or more genes; (c) administering to the patient an effective amount of an anti-IL-36R antibody according to any of the embodiments related to the first to fifth aspects. Includes.

[0044] In one embodiment related to the tenth aspect, the one or more 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.

[0045] Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the present techniques. 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 invention as claimed. [Brief description of the drawings]

[0046] The accompanying drawings, which are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate aspects of the technology of the present application and, together with the description, serve to explain the principles of the invention. [Figure 1A]FIG. 1 shows the change in clinical response with treatment with anti-IL-36R antibodies of the present invention by week 20; Panel A shows the proportion of patients who achieved a Physician's Global Assessment for Generalized Pustular Psoriasis (GPPGA) score of 0 (clear) or 1 (almost clear); Panel B shows the percentage change from baseline in the Generalized Pustular Psoriasis Area and Severity Index (GPPASI); Panel C shows the proportion of patients who achieved pustule clearance (based on the severity score of the pustule component of the GPPASI). The analysis includes all patients with at least one available post-baseline value. One patient received methotrexate after week 4 for the treatment of "pain", and therefore data at weeks 12 and 20 are excluded (set to no response for GPPGA and pustule clearance). By week 1, two of three patients with IL36RN mutations achieved GPPGA 0 or 1; by week 4, all three patients achieved GPPGA 0 or 1. *At week 2, GPPGA scores were missing for one patient. [Figure 1B] FIG. 1 shows the change in clinical response with treatment with anti-IL-36R antibodies of the present invention by week 20; Panel A shows the proportion of patients who achieved a Physician's Global Assessment for Generalized Pustular Psoriasis (GPPGA) score of 0 (clear) or 1 (almost clear); Panel B shows the percentage change from baseline in the Generalized Pustular Psoriasis Area and Severity Index (GPPASI); Panel C shows the proportion of patients who achieved pustule clearance (based on the severity score of the pustule component of the GPPASI). The analysis includes all patients with at least one available post-baseline value. One patient received methotrexate after week 4 for the treatment of "pain", and therefore data at weeks 12 and 20 are excluded (set to no response for GPPGA and pustule clearance). By week 1, two of three patients with IL36RN mutations achieved GPPGA 0 or 1; by week 4, all three patients achieved GPPGA 0 or 1. *At week 2, GPPGA scores were missing for one patient. [Figure 1C]FIG. 1 shows the change in clinical response with treatment with anti-IL-36R antibodies of the present invention by week 20; Panel A shows the proportion of patients who achieved a Physician's Global Assessment for Generalized Pustular Psoriasis (GPPGA) score of 0 (clear) or 1 (almost clear); Panel B shows the percentage change from baseline in the Generalized Pustular Psoriasis Area and Severity Index (GPPASI); Panel C shows the proportion of patients who achieved pustule clearance (based on the severity score of the pustule component of the GPPASI). The analysis includes all patients with at least one available post-baseline value. One patient received methotrexate after week 4 for the treatment of "pain", and therefore data at weeks 12 and 20 are excluded (set to no response for GPPGA and pustule clearance). By week 1, two of three patients with IL36RN mutations achieved GPPGA 0 or 1; by week 4, all three patients achieved GPPGA 0 or 1. *At week 2, GPPGA scores were missing for one patient. [Diagram 2] Figure 2 shows GPPASI 50 / 75 / 90 response rates through week 20. In this figure, the proportion of patients who achieved greater than 50%, 75% or 90% reduction in Generalized Pustular Psoriasis Area and Severity Index (GPPASI 50, 75 or 90) over time is shown. The analysis includes all patients with at least one available post-baseline value. One patient received methotrexate after week 4 for the treatment of "pain", therefore the data at weeks 12 and 20 are set to non-response. [Figure 3A] Figure 3 shows GPPASI subscores through week 20. In this figure, individual and mean percent changes in Generalized Pustular Psoriasis Area and Severity Index (GPPASI) severity subscores for pustules (panel A), erythema (panel B) and scales (panel C) are shown. The analysis includes all patients with at least one available post-baseline value. One patient received methotrexate after week 4 for the treatment of "pain" and therefore data at weeks 12 and 20 are excluded. [Figure 3B]Figure 3 shows GPPASI subscores through week 20. In this figure, individual and mean percent changes in Generalized Pustular Psoriasis Area and Severity Index (GPPASI) severity subscores for pustules (panel A), erythema (panel B) and scales (panel C) are shown. The analysis includes all patients with at least one available post-baseline value. One patient received methotrexate after week 4 for the treatment of "pain" and therefore data at weeks 12 and 20 are excluded. [Figure 3C] Figure 3 shows GPPASI subscores through week 20. In this figure, individual and mean percent changes in Generalized Pustular Psoriasis Area and Severity Index (GPPASI) severity subscores for pustules (panel A), erythema (panel B) and scales (panel C) are shown. The analysis includes all patients with at least one available post-baseline value. One patient received methotrexate after week 4 for the treatment of "pain" and therefore data at weeks 12 and 20 are excluded. [Figure 4] Figure 4 shows the change from baseline in FACIT-F by week 4. The mean (SD) change from baseline in FACIT-F scores over time is shown. Analyses include all patients with at least one available post-baseline value. FACIT-F=Functional Assessment of Chronic Illness Therapy-Fatigue; SD=standard deviation. [Diagram 5] Figure 5 shows the change from baseline in Pain-VAS by 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 analog scale. *N=6. [Figure 6] Figure 6 shows the change from baseline in PSS by week 4. The mean (SD) change from baseline in PSS over time is shown. The analysis included all patients with at least one available post-baseline value. PSS = Psoriasis Symptom Scale; SD = Standard Deviation. [Figure 7]Figure 7 shows the change from baseline in CRP by week 4. Shown are the mean (SD) changes from baseline in CRP over time. CRP = C-reactive protein; SD = standard deviation. [Figure 8] Figure 8 shows absolute neutrophil counts through week 4. Absolute neutrophil counts over time are shown. Analysis includes all patients with at least one available post-baseline value. SD = standard deviation. [Figure 9-1] FIG. 9 shows the study design as discussed in Example 2. [Figure 9-2] FIG. 9 shows the study design as discussed in Example 2.

[0047] Detailed Description of the Invention In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, it will be apparent to those skilled in the art that the technology of the present application can be practiced without the use of some of these specific details. In other instances, well-known structures and techniques are not shown in detail in order to clarify the present invention.

[0048] A phrase such as "aspect" does not mean that such aspect is essential to the invention or that such aspect applies to all configurations of the technology of the present application. Disclosure related 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 "aspect" may refer to one or more aspects, and vice versa. A phrase such as "embodiment" does not mean that such an embodiment is essential to the technology of the present application or that such an embodiment applies to all configurations of the technology of the present application. Disclosure related to an embodiment may apply to all embodiments or one or more embodiments. An embodiment may provide one or more examples of the disclosure.

[0049] The inventors have surprisingly discovered, inter alia, that inhibition of the interleukin-36 pathway with a single dose of a humanized anti-interleukin-36R (anti-IL-36R) monoclonal antibody of the invention resulted in rapid and sustained clinical remission in patients with acute generalized pustular psoriasis, with no recurrence of GPP flares observed 20 weeks after administration of a single dose.

[0050] Therefore, the present invention relates to compositions and methods for the treatment and / or prevention of generalized pustular psoriasis (GPP) and its signs and symptoms. More specifically, the present invention relates to compositions and methods for treating and / or preventing moderate to severe GPP, acute GPP, chronic GPP, and / or GPP flare in a mammal using an anti-IL36R antibody or antigen-binding fragment thereof of the present invention. The compositions and methods comprise administering a therapeutically effective amount of an anti-IL-36R antibody or antigen-binding fragment thereof to a mammal, wherein the anti-IL-36R antibody is administered in a single intravenous dose. In one embodiment, the anti-IL-36R antibody is administered in one or more intravenous doses, optionally followed by one or more subcutaneous doses.

[0051] Without wishing to be bound by this theory, it is believed that the anti-IL-36R antibody or antigen-binding fragment thereof binds to human anti-IL-36R and thus interferes with the binding of IL-36 agonists, thereby at least partially blocking the signaling cascade from IL-36R to inflammatory mediators. The anti-IL-36R antibodies of the present invention are disclosed in U.S. Pat. No. 9,023,995 or WO 2013 / 074569, the entire contents of each of which are incorporated herein by reference.

[0052] Acute GPP flares of various 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 to severe GPP flares cause significant morbidity and mortality due to tender skin lesions, extreme fatigue, high fever, peripheral blood neutrophilia, and acute phase response and sepsis. The acute phase is associated with a mean hospital stay of 10 days (range 3-44 days). The mortality rate reported in a retrospective study of 102 GPP cases seen in a tertiary care hospital in Johor, Malaysia, and observed to be 7% is likely an underestimate because not all GPP patients were included in the study. Mortality is also likely to be underestimated due to failure to identify the cause of death as GPP, which is mainly caused by infectious complications and extradermal organ manifestations such as renal, hepatic, respiratory, and cardiac failure. After responding to treatment or after a flare subsides naturally, it is estimated that up to 50% of patients may suffer from chronic GPP, characterized by persistent erythema and scaling, which may also include joint symptoms.

[0053] Based on the above limitations, current therapeutic options are not suitable for lifelong treatment and do not provide a durable response in the majority of patients. Therefore, there is a high need to (i) develop highly effective treatments with rapid onset of action for patients experiencing acute GPP flares, and (ii) develop effective treatments for chronic GPP that reliably prevent the occurrence of flares and are safe and tolerable for lifelong treatment.

[0054] Classical symptoms of GPP flares as described by von Zumbusch are strongly correlated with polymorphisms in the IL-36R signaling pathway. Individuals with loss-of-function mutations in the IL36RN gene, which encodes an endogenous IL36R antagonist (IL-36RN), show a dramatically higher incidence of GPP, indicating that uncontrolled upregulation of IL36 signaling due to defective IL36RN antagonism leads to the expression of inflammatory symptoms observed in GPP. Human genetic studies have demonstrated the occurrence of GPP clusters in families with loss-of-function mutations in IL36RN and, as a result, uncontrolled IL36R signaling. Mutations in other genes linked to the IL36 pathway, such as CARD14, also lead to GPP. Recently published gene expression studies have shown sustained activation of IL-1 and IL-36 in GPP, inducing chemokine expression, infiltration, and pustule formation by neutrophils, suggesting that the IL-1 / IL-36 inflammatory system is a potent driver of disease pathology in GPP. Furthermore, a recent meta-analysis examined 233 published GPP cases. 49 of the 233 (21.0%) cases were found to carry the recessive IL36RN allele. These 49 recessive IL36RN alleles defined a GPP phenotype characterized by early onset and high risk of systemic inflammation.

[0055] IL36R is a cell surface receptor involved in inflammatory responses in the skin and intestine. It is a novel member of the IL1R family that forms a heterodimeric complex with IL1R accessory proteins. The heterodimeric IL36R system, which includes stimulatory (IL36α, IL36β, IL36γ) and inhibitory (IL36Ra) ligands, shares many structural and functional similarities with other members of the IL1 / IL1R family, such as IL1, IL18, and IL33 (R17-3602). All IL1 family members (IL1α, IL1β, IL18, IL36α, IL36β, IL36γ, and IL38) signal through a unique cognate receptor protein, which upon ligand binding recruits a common IL1RacP subunit and activates NFκB and MAP kinase pathways in receptor-positive cell types. In human skin tissue, IL36R is expressed in keratinocytes, dermal fibroblasts, and infiltrating myeloid cells. IL36R activation in skin tissue drives the production of inflammatory mediators (e.g., CCL20, MIP-1β, TNF-α, IL12, IL17, IL23, TGF-β) and regulates the expression of tissue remodeling genes (e.g., matrix metalloproteinases, TGF-β). The link between GPP and IL36RN mutations is therefore somewhat similar to the well-established neonatal-onset aseptic multifocal osteomyelitis, periostitis, and pustulosis caused by the absence of interleukin-1 receptor antagonists. In this case, the absence of receptor antagonists results in an inability to antagonize the action of interleukin-1, resulting in life-threatening systemic inflammation along with development in the skin and bone. These clinical features responded to empirical treatment with the recombinant interleukin-1 receptor antagonist anakinra.

[0056] I. Definition The term "about" generally refers to an acceptable degree of error or variation for the quantity measured, given the nature or precision of the measurement. Typically, exemplary degrees of error or variation are within 5% or within 3% or within 1% of a given numerical value or range of a given numerical value. For example, the expression "about 100" includes 105 and 95, or 103 and 97, or 101 and 99, and all values ​​therebetween (e.g., 95.1, 95.2, etc. in the range of 95-105; or 97.1 or 97.2, etc. in the range of 97-103; 99.1, 99.2, etc. in the range of 99-101). Quantities provided herein are approximate unless otherwise specified, meaning that the term "about" can be inferred when not explicitly stated.

[0057] A "pharmaceutical formulation" or "formulation" refers not only to the process of combining an active drug or agent with chemicals to produce a final drug or medical product, but also to the product of the process, and thus the final formulation also refers to a pharmaceutical product such as a liquid, powder, or composition. Thus, in one embodiment, the pharmaceutical formulation is a pharmaceutical composition.

[0058] "Pharmaceutical composition" in the present context refers to a solution or powder in such a form that allows the biological activity of the active ingredient(s) to be undoubtedly effective and does not contain any additional ingredients that are significantly toxic to the subject to whom it will be administered. Such compositions are sterile. "Powder" refers to a freeze-dried, i.e. lyophilized or spray-dried pharmaceutical composition for parenteral use. Powders are typically reconstituted or dissolved in water. Freeze-drying is a low-temperature dehydration process that involves freezing the product, reducing the air pressure, and then removing the ice by sublimation. Freeze-drying results in a high-quality product due to the low temperatures used in processing. In a well-developed freeze-dried formulation, the shape and appearance of the product are 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 using hot gas to rapidly dry with the goal of achieving a consistent particle size distribution.

[0059] The terms "intravenous dose" and "subcutaneous dose" as used herein refer to the time sequence of administration of anti-IL-36R antibody. Thus, an "intravenous dose" is the dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose"); it may also be referred to as an "initial dose" or an "induction dose". A "subcutaneous dose" is the dose administered after an intravenous dose, which may also be referred to as a "subsequent dose" or a "maintenance dose". An intravenous dose, a subcutaneous dose may contain the same amount of anti-IL-36R antibody or an antigen-binding fragment thereof, but generally may differ from each other in terms of the amount of antibody administered or the frequency of administration. In one embodiment, an intravenous dose is equal to or greater than a subcutaneous dose. An "intravenous dose" may be interchangeably referred to as an "initial dose" or an "induction dose", which may be a single dose or, alternatively, a set of doses. A subcutaneous dose may be referred to as a "subsequent dose" or a "maintenance dose", which may be a single dose or, alternatively, a set of doses.

[0060] In certain embodiments, the amount of anti-IL-36R antibody contained in the induction dose / initial dose / intravenous dose and the maintenance dose / subsequent dose / subcutaneous dose differs from each other during the course of treatment. In certain embodiments, one or more initial doses / induction doses / intravenous doses each contain a first amount of the antibody or antigen-binding fragment thereof, and one or more maintenance doses / subsequent doses / subcutaneous doses each contain a second amount of the antibody or antigen-binding fragment thereof. In some embodiments, the first amount of the antibody or fragment thereof is 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, or 5 times the amount of the second or subsequent antibody or antigen-binding fragment thereof. In certain embodiments, one or more (e.g., 1, 2, 3, 4 or 5 or more) initial doses are administered as a "loading dose" or "lead dose" at the beginning of the treatment regimen, followed by subsequent doses (e.g., "maintenance doses") administered less frequently. In one embodiment, the intravenous dose, induction dose or 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 anti-IL-36R antibody. In one embodiment, the subcutaneous dose, maintenance dose or subsequent dose is about 150 mg, 225 mg, or 300 mg. In another embodiment, the subcutaneous dose or maintenance dose or subsequent dose is administered at least 2 weeks after the intravenous dose, induction dose or initial dose.

[0061] As used herein, "buffer" refers to a buffered solution that resists changes in pH by the action of its acid-base conjugate components. "pH" herein refers to the acidity or basicity of a composition at room temperature. Standard methods for measuring the pH of a composition are known to those skilled in the art. Typically, measuring pH consists of calibrating the instrument, placing an electrode in a well-mixed sample, and then reading the pH directly from the pH meter. Exemplary buffers of the present invention include acetate, citrate, histidine, succinate, phosphate, and tris.

[0062] The term "tonicifying agent" or "isotonic agent" or "tonicifier" as used herein refers to a substance that provides an osmotic pressure equivalent to that of serum in vivo, including salts (e.g., sodium chloride, potassium chloride, magnesium chloride) or sugars (e.g., sucrose, trehalose, sorbitol, magnesium sulfate (MgSO4), glycerol, mannitol, or dextrose). Additionally, sugars present in the solution act as cryoprotectants for proteins, which allow the drug to be frozen without being damaged. This allows for delivery in frozen form and long-term storage of the drug prior to filling of the medical product. Exemplary tonicifying agents of the present invention include sodium chloride, potassium chloride, magnesium chloride (salts) and / or sucrose, trehalose, sorbitol, magnesium sulfate (MgSO4), glycerol, mannitol, or dextrose (sugars).

[0063] The term "stabilizer" or "stabilizing agent" as used herein refers to a substance that contributes to the stability of an active ingredient in a pharmaceutical formulation. Exemplary stabilizers of the present invention include arginine, histidine, glycine, cysteine, proline, methionine, lysine, or a pharma- ceutically acceptable salt thereof.

[0064] As used herein, the term "surfactant" refers to a substance that tends to reduce the surface tension of the liquid they are dissolved in. Exemplary surfactants of the present invention include poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0065] The terms "antibody," "anti-IL-36R antibody," "humanized anti-IL-36R antibody," "humanized anti-IL-36R epitope antibody," and "mutated 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-terminal and / or C-terminal truncations, and antibody fragments, e.g., variable domains, and other antibody portions that exhibit the desired biological activity (e.g., binding to IL-36R).

[0066] The term "monoclonal antibody" (mAb) refers to an antibody that is highly specific and directed against a single antigenic determinant, an "epitope." Thus, the modifier "monoclonal" indicates antibodies directed against the same epitope, and is not to be construed as requiring production of the antibody by any particular method. It should be understood that monoclonal antibodies may be made by any technique or method known in the art, including, for example, isolation of recombinantly produced monoclonal antibodies using phage antibody libraries, using 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 the techniques described in Clackson et al., 1991, Nature 352: 624-628 and Marks et al., 1991, J. Mol. Biol. 222: 581-597.

[0067] The term "monomeric" refers to a homogeneous 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.

[0068] A chimeric antibody consists of the variable regions of the heavy and light chains of an antibody from one species (e.g., a non-human mammal, e.g., a mouse) and the constant regions of the heavy and light chains of an antibody from another species (e.g., a human), which can be obtained by linking a DNA sequence encoding the variable region of an antibody from a first species (e.g., a mouse) to a DNA sequence of the constant region of an antibody from a second species (e.g., a human) and transforming a host with an expression vector containing the linked sequences, thereby allowing the host to produce the chimeric antibody. Alternatively, a chimeric antibody can also be one in which one or more regions or domains of the heavy and / or light chains are identical to, homologous to, or variants of corresponding sequences in a monoclonal antibody from another immunoglobulin class or isotype, or from a consensus or germline sequence. A chimeric antibody can include fragments of such antibodies. However, such antibody fragments retain the desired biological activity of the parent antibody, e.g., 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).

[0069] 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," and "mutated humanized anti-IL-36R epitope antibody fragment" refer to a portion of a full-length anti-IL-36R antibody that retains a variable region or a function, such as specific binding to an IL-36R epitope.

[0070] Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fd, Fv, scFv, and scFv-Fc fragments, diabodies, linear antibodies, single-chain antibodies, minibodies, diabodies formed from antibody fragments, and multispecific antibodies formed from antibody fragments.

[0071] The term "intravenous infusion" refers to the introduction of a drug into an animal or human patient's vein over a period of at least about 15 minutes, typically about 30-90 minutes.

[0072] The term "intravenous bolus" or "intravenous push" refers to the administration of a drug into a vein of an animal or human such that the organism receives the drug within about 15 minutes, typically within 5 minutes.

[0073] The term "subcutaneous administration" refers to the introduction of an agent by relatively slow and sustained delivery from a drug reservoir under the skin of an animal or human patient, preferably into a pocket between the skin and the underlying tissue. The pocket can be created by pinching the skin or by pulling the skin up and away from the underlying tissue.

[0074] The term "subcutaneous infusion" refers to the introduction of a drug under the skin of an animal or human patient, preferably into a pocket between the skin and the underlying tissue, by relatively slow and sustained delivery from a drug reservoir, over a period of time, including but not limited to, 30 minutes or less, or 90 minutes or less. Optionally, the infusion can be performed by subcutaneous implantation of a drug delivery pump implanted under the skin of the animal or human patient, where the pump delivers a predetermined amount of drug over a predetermined period of time, for example, 30 minutes, 90 minutes, or over the length of the treatment regimen.

[0075] The term "subcutaneous bolus" refers to administration of a drug under the skin of an animal or human patient, where the bolus drug delivery is within about 15 minutes; in another embodiment, within 5 minutes, and in yet another embodiment, within 60 seconds. In still yet another embodiment, administration is within a pocket between the skin and the underlying tissue, where the pocket can be created by pinching or pulling the skin up and away from the underlying tissue.

[0076] 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, etc. Preferably, the mammal is a human.

[0077] As used herein, the terms "treatment" and "therapy" and the like are meant to include therapeutic measures as well as preventive or suppressive measures for a disease or disorder that produce any clinically desirable or beneficial effect, including, but not limited to, alleviation or mitigation of one or more symptoms, regression, slowing, or cessation of a disease or disorder. Thus, for example, the term treatment includes administration of an agent before or after the onset of a disease or disorder symptom, thereby preventing or eliminating one or more signs of a disease or disorder. As another example, the term includes combating a disease symptom by administering an agent after clinical signs of the disease. In addition, administration of an agent after onset and after clinical signs have occurred (where administration affects a clinical parameter of a disease or disorder, such as the degree of tissue damage, or the amount or extent of metastasis, regardless of whether the treatment results in disease remission) includes "treatment" or "therapy" as used herein. Furthermore, so long as a composition of the invention, alone or in combination with another therapeutic agent, reduces or ameliorates at least one symptom of the disorder being treated compared to the symptom in the absence of the humanized anti-IL-36R antibody composition, the result should be deemed to be an effective treatment of the underlying disorder, regardless of whether all symptoms of the disorder are alleviated.

[0078] The term "therapeutically effective amount" is used to refer to an amount of an active agent that relieves or ameliorates one or more symptoms of the disorder being treated. In another embodiment, a therapeutically effective amount refers to a serum concentration of a target that has been shown to be effective in slowing the progression of the disease. Efficacy can be measured by conventional methods, depending on the condition to be treated.

[0079] The term "prophylactically effective amount" is used to refer to an amount effective, at a dosage and for a period of time required to achieve a desired prophylactic result. Typically, a prophylactic dose is used in a subject prior to the onset of a GPP flare and / or prior to the onset of symptoms of GPP, thereby preventing or inhibiting the occurrence of an acute flare. In one embodiment, the subcutaneous dose contemplated herein is a prophylactic dose used in an acute GPP patient to prevent the possible recurrence of a GPP flare in the patient after an intravenous dose.

[0080] The term "package insert" is used to refer to instructions customarily included in the commercial packaging of therapeutic products that contain information regarding the indications, uses, administration, contraindications, and / or warnings concerning the use of such therapeutic products.

[0081] II. Antibodies The anti-IL-36R antibodies of the present invention are disclosed in U.S. Pat. No. 9,023,995 or WO 2013 / 074569, the entire contents of each of which are incorporated herein by reference.

[0082] In one aspect, described and disclosed herein are anti-IL-36R antibodies, particularly humanized anti-IL-36R antibodies, as well as compositions and articles of manufacture comprising one or more anti-IL-36R antibodies, particularly one or more humanized anti-IL-36R antibodies of the invention. Also described are binding agents comprising antigen-binding fragments of anti-IL-36R antibodies, particularly humanized anti-IL-36R antibodies.

[0083] Mechanism of action The anti-IL-36R antibody of the present invention is a humanized antagonistic monoclonal IgG1 antibody that blocks the signal transduction of human IL36R. The binding of the anti-IL-36R antibody of the present invention to IL36R is expected to prevent the subsequent activation of IL36R by its cognate ligands (IL36α, β and γ) and the downstream activation of proinflammatory and profibrotic pathways, with the aim of reducing inflammation mediated by epithelial cells / fibroblasts / immune cells and interrupting the inflammatory response that drives pathological cytokine production in generalized pustular psoriasis (GPP). As provided herein, the anti-IL-36R antibody of the present invention has been tested and found to be effective in treating patients with acute generalized pustular psoriasis (GPP), a severe inflammatory skin disease driven by uncontrolled IL36 activity.

[0084] IL-36R is also known as IL-1RL2 and IL-1Rrp2. Antagonistic IL-36 ligands (α, β, or γ) are reported to engage the IL-36 receptor and subsequently initiate a signaling cascade by forming a heterodimer with the IL-1 receptor accessory protein (IL-1RAcP). IL-36 antagonistic ligands (IL-36RA / IL1F5, IL-38 / ILF10) suppress the signaling cascade.

[0085] The variable regions and CDRs of each antibody of the invention are disclosed below:

[0086] Anti-IL-36R mouse antibody sequence The variable regions and CDRs of a representative murine lead antibody (murine lead) of the invention are shown below:

[0087] [Table 1] TIFF0007673168000002.tif211169

[0088] [Table 2] TIFF0007673168000004.tif140169

[0089] [Table 3] TIFF0007673168000006.tif230169 TIFF0007673168000007.tif220169 TIFF0007673168000008.tif229169 TIFF0007673168000009.tif205169

[0090] [Table 4] TIFF0007673168000011.tif230169 TIFF0007673168000012.tif88169

[0091] Anti-IL-36R humanized antibody sequence Human framework sequences for the mouse leads were selected based on framework homology, CDR structure, conserved canonical residues, conserved interface filling residues, and other parameters resulting in humanized variable regions (see Example 5).

[0092] Representative humanized variable regions derived from antibodies 81B4 and 73C5 are shown below.

[0093] [Table 5] TIFF0007673168000014.tif251169

[0094] [Table 6] TIFF0007673168000016.tif217169

[0095] The CDR sequences from the humanized variable regions derived from antibodies 81B4 and 73C5 shown above are shown below.

[0096] [Table 7] TIFF0007673168000018.tif232169 TIFF0007673168000019.tif216169 TIFF0007673168000020.tif232169 TIFF0007673168000021.tif231169 TIFF0007673168000022.tif131169

[0097] In one embodiment, the variable region of the present invention is linked to a constant region. For example, the variable region of the present invention is linked to the constant region shown below to form an antibody heavy or light chain.

[0098] [Table 8]

[0099] [Table 9]

[0100] Representative light and heavy chain sequences of the invention are shown below (humanized variable regions derived from antibodies 81B4 and 73C5 linked to constant regions).

[0101] [Table 10] TIFF0007673168000026.tif208169

[0102] [Table 11] TIFF0007673168000028.tif228169 TIFF0007673168000029.tif232169 TIFF0007673168000030.tif167169

[0103] The CDRs listed above are defined using the Chothia numbering system (Al-Lazikani et al., (1997) JMB 273, 927-948).

[0104] In one embodiment, an antibody of the invention comprises three light chain CDRs and three heavy chain CDRs, eg, as set out above.

[0105] In one embodiment, an antibody of the invention comprises one light chain variable region and one heavy chain variable region as shown above. In one embodiment, the light chain variable region of the invention is fused to a light chain constant region, such as a kappa or lambda constant region. In one embodiment, the heavy chain variable region of the invention is fused to a heavy chain constant region, such as an IgA, IgD, IgE, IgG or IgM, in particular an IgG1, IgG2, IgG3 or IgG4.

[0106] The present invention provides an anti-IL-36R antibody (Antibody B1), 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.

[0107] The present invention provides an anti-IL-36R antibody (antibody B2) 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.

[0108] The present invention provides an anti-IL-36R antibody (antibody B3) 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.

[0109] The present invention provides an anti-IL-36R antibody (antibody B4) 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.

[0110] The present invention provides an anti-IL-36R antibody (antibody B5) 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.

[0111] The present invention provides an anti-IL-36R antibody (antibody B6) 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.

[0112] The present invention provides an anti-IL-36R antibody (antibody C3) 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.

[0113] The present invention provides an anti-IL-36R antibody (Antibody C2) 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.

[0114] The present invention provides an anti-IL-36R antibody (antibody C1) 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.

[0115] Representative antibodies of the present invention are shown below.

[0116] [Table 12] TIFF0007673168000032.tif231169 TIFF0007673168000033.tif196169

[0117] [Table 13] TIFF0007673168000035.tif68169

[0118] In some embodiments, the humanized antibody exhibits blocking activity, thereby reducing the binding of IL-36 ligand to the IL-36 receptor by at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%. The ability of an antibody to block the binding of 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 granulocyte-macrophage colony-stimulating factor (GM-CSF), and determining whether signal transduction mediated by the IL-36 receptor is inhibited.

[0119] In a further aspect, the present invention provides a humanized anti-IL-36R antibody having favorable biophysical properties. In one aspect, the humanized anti-IL-36R antibody of the present invention is present in a buffer solution at least 90% in monomeric form, or at least 92% in monomeric form, or at least 95% in monomeric form. In a further aspect, the humanized anti-IL-36R antibody of the present invention remains in a buffer solution at least 90% in monomeric form, or at least 92% in monomeric form, or at least 95% in monomeric form for one month or four months.

[0120] In one embodiment, the humanized antibody of the invention is antibody B1, antibody B2, antibody B3, antibody B4, antibody B5, antibody B6, antibody C1, antibody C2, or antibody C3. Thus, in one embodiment, the humanized antibody of the invention comprises the light chain sequence of SEQ ID NO: 115 and the heavy chain sequence of SEQ ID NO: 125 (antibody B1). In another embodiment, the humanized antibody of the 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, the humanized antibody of the 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, the humanized antibody of the 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, the humanized antibody of the 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 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 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 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 invention comprises the light chain sequence of SEQ ID NO: 123 and the heavy chain sequence of SEQ ID NO: 138 (antibody C3).

[0121] In a further embodiment, the humanized antibody of the 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, the humanized antibody of the 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, the humanized antibody of the 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, the humanized antibody of the 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, the humanized antibody of the 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, the humanized antibody of the 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, the humanized antibody of the 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 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 invention consists of the light chain sequence of SEQ ID NO: 123 and the heavy chain sequence of SEQ ID NO: 138 (Antibody C3).

[0122] In some embodiments, the humanized anti-IL-36R antibody (including an antigen-binding fragment thereof, such as a heavy chain variable region and a light chain variable region) comprises the amino acid sequence of residues derived from Antibody B1, Antibody B2, Antibody B3, Antibody B4, Antibody B5, Antibody B6, Antibody C1, Antibody C2, or Antibody C3.

[0123] In a further embodiment, the present invention provides an anti-IL-36R antibody or antigen-binding fragment thereof that binds to human anti-IL-36R in competition with an antibody of the present invention, e.g., antibody B1, antibody B2, antibody B3, antibody B4, antibody B5, antibody B6, antibody C1, antibody C2, or antibody C3. 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.

[0124] Humanized anti-IL-36R antibodies optionally contain specific amino acid substitutions in the consensus or germline framework regions. Specific substitutions of amino acid residues at these framework positions can improve various aspects of antibody performance, including binding affinity and / or stability, over those demonstrated in humanized antibodies formed by "direct swapping" of complementarity determining regions (CDRs) or hypervariable loops (HVLs) into human germline framework regions.

[0125] In some embodiments, the present invention describes other monoclonal antibodies having a light chain variable region having the amino acid sequence shown in any one of SEQ ID NOs: 1 to 10. In some embodiments, the present invention describes other monoclonal antibodies having a heavy chain variable region having the amino acid sequence shown in any one of SEQ ID NOs: 11 to 20. Such placement of CDRs in the FRs of the human common heavy chain variable domain and light chain variable domain will result in useful humanized antibodies of the present invention.

[0126] In particular, the present invention provides monoclonal antibodies having a combination of light and heavy chain variable regions of SEQ ID NOs: 1 / 11, 2 / 12, 3 / 13, 4 / 14, 5 / 15, 6 / 16, 7 / 17, 8 / 18, 9 / 19, 10 / 20. Such variable regions may be combined with human constant regions.

[0127] In some embodiments, the present invention describes other humanized antibodies having a light chain variable region sequence having an amino acid sequence as set forth in any one of SEQ ID NOs: 76-86. In some embodiments, the present invention describes other humanized antibodies having a heavy chain variable region sequence having an amino acid sequence as set forth in any one of SEQ ID NOs: 87-101. In particular, the present invention provides monoclonal antibodies having a combination of light chain variable region and heavy chain variable region of SEQ ID NOs: 77 / 89, 80 / 88, 80 / 89, 77 / 87, 77 / 88, 80 / 87, 86 / 100, 85 / 101, 85 / 100. Such variable regions can be combined with human constant regions.

[0128] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising the CDRs of SEQ ID NO: 77 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the light chain variable domain 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 that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the heavy chain variable domain amino acid sequence of SEQ ID NO: 89. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0129] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising the CDRs of SEQ ID NO: 80 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the light chain variable domain 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 that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the heavy chain variable domain amino acid sequence of SEQ ID NO: 88. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0130] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising the CDRs of SEQ ID NO: 80 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the light chain variable domain 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 that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the heavy chain variable domain amino acid sequence of SEQ ID NO: 89. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0131] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising the CDRs of SEQ ID NO: 77 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the light chain variable domain 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 that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the heavy chain variable domain amino acid sequence of SEQ ID NO: 87. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0132] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising the CDRs of SEQ ID NO: 77 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the light chain variable domain 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 that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the heavy chain variable domain amino acid sequence of SEQ ID NO: 88. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0133] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising the CDRs of SEQ ID NO: 80 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the light chain variable domain 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 that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the heavy chain variable domain amino acid sequence of SEQ ID NO: 87. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0134] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising the CDRs of SEQ ID NO: 86 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the light chain variable domain 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 that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the heavy chain variable domain amino acid sequence of SEQ ID NO: 100. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0135] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising the CDRs of SEQ ID NO: 85 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the light chain variable domain 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 that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework regions of the heavy chain variable domain amino acid sequence of SEQ ID NO: 101. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0136] In a further embodiment, the invention relates to an anti-IL-36R antibody or antigen-binding fragment thereof comprising a humanized light chain variable domain comprising the CDRs of SEQ ID NO: 85 and framework regions having an amino acid sequence that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework region of the light chain variable domain 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 that is at least 90% identical, at least 93% identical, or at least 95% identical to the amino acid sequence of the framework region of the heavy chain variable domain amino acid sequence of SEQ ID NO: 100. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

[0137] In some specific embodiments, the humanized anti-IL-36R antibodies disclosed herein comprise at least one heavy or light chain variable domain comprising the CDRs or HVLs of a murine monoclonal antibody or a humanized antibody as disclosed herein and human germline heavy and light chain variable domain frameworks.

[0138] In a further aspect, the present invention provides an anti-IL-36R antibody or an antigen-binding fragment thereof comprising a light chain CDR1 (L-CDR1) sequence of any one of SEQ ID NOs: 21 to 29; a light chain CDR2 (L-CDR2) sequence of any one of SEQ ID NOs: 30 to 38; a light chain CDR3 (L-CDR3) sequence of any one of SEQ ID NOs: 39 to 47; a heavy chain CDR1 (H-CDR1) sequence of any one of SEQ ID NOs: 48 to 56; a heavy chain CDR2 (H-CDR2) sequence of any one of SEQ ID NOs: 57 to 66; and a heavy chain CDR3 (H-CDR3) sequence of any one of SEQ ID NOs: 67 to 75. In one embodiment, the anti-IL-36R antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the L-CDR1 listed above, the L-CDR2 listed above, and the L-CDR3 listed above, and a heavy chain variable region comprising the H-CDR1 listed above, the H-CDR2 listed above, and the H-CDR3 listed above.

[0139] In a further aspect, the present invention provides a method for producing a method for treating a cancer cell comprising the steps of: a) the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NOs: 21, 30, 39, 48, 57, and 67, respectively; or b) the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NOs: 22, 31, 40, 49, 58, and 68, respectively; or c) the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NOs: 23, 32, 41, 50, 59, and 69, respectively; or d) the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NOs: 24, 33, 42, 51, 60, and 70, respectively; or e) the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NOs: 25, 34, 43, 52, 61, and 71, respectively; or f) the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NOs: 26, 35, 44, 53, 62, and 72, respectively; or g) the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NOs: 27, 36, 45, 54, 63, and 73, respectively; or h) the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NOs: 27, 36, 45, 54, 64, and 74, respectively; or i) the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NOs: 27, 36, 45, 54, 64, and 73, respectively; or j) the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NOs: 28, 37, 46, 55, 65, and 74, respectively; or k) L-CDR1 sequences, L-CDR2 sequences, L-CDR3 sequences, H-CDR1 sequences, H-CDR2 sequences, and H-CDR3 sequences of SEQ ID NOs: 29, 38, 47, 56, 66, and 75, respectively. The present invention provides an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising:

[0140] In a further aspect, the present invention provides a method for producing a method for treating a cancer cell comprising the steps of: a) the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NOs: 26, 103, 44, 53, 62, and 72, respectively; or b) the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NOs: 26, 104, 44, 53, 62, and 72, respectively; or c) the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NOs: 27, 36, 45, 107, 63, and 73, respectively; or d) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2, and H-CDR3 sequences of SEQ ID NOs: 27, 36, 45, 107, 64, and 73, respectively. The present invention provides an anti-IL-36R antibody or an antigen-binding fragment thereof, comprising:

[0141] In one embodiment, the anti-IL-36R antibody or antigen-binding fragment thereof comprises a light chain variable region comprising a combination of L-CDR1, L-CDR2 and L-CDR3 as listed above, and a heavy chain variable region comprising a combination of H-CDR1, H-CDR2 and H-CDR3 as listed above.

[0142] In specific embodiments, it is believed that useful antibodies may result from chimeric antibodies in which CDR regions have been swapped between these exemplary immunoglobulins (i.e., one or more CDRs from one of, for example, a murine antibody or a humanized antibody derived therefrom, have been swapped with the analogous CDRs from another murine or humanized antibody derived therefrom).

[0143] In certain embodiments, the humanized anti-IL-36R antibody is an antibody fragment. Various antibody fragments are generally discussed above, and there are techniques developed for the production of antibody fragments. Fragments can be obtained 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, 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')2 fragments (see, e.g., Carter et al., 1992, Bio / Technology 10:163-167). According to another approach, F(ab')2 fragments can be directly isolated from recombinant host cell culture medium. Other techniques for the production of antibody fragments will be apparent to those skilled in the art. Thus, in one aspect, the invention provides antibody fragments comprising one of the CDRs described herein, in particular the L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 combinations described herein. In a further aspect, the invention provides antibody fragments comprising one of the variable regions described herein, such as the light chain variable region and heavy chain variable region combinations described herein.

[0144] Certain embodiments include a F(ab')2 fragment of a humanized anti-IL-36R antibody comprising the light chain sequence of either SEQ ID NO: 115 or 118 in combination with the heavy chain sequence of SEQ ID NO: 125, 126 or 127. Such embodiments may also include an intact antibody comprising such a F(ab')2.

[0145] Certain embodiments include a F(ab')2 fragment of a humanized anti-IL-36R antibody comprising the light chain sequence of either SEQ ID NO: 123 or 124 in combination with the heavy chain sequence of SEQ ID NO: 138 or 139. Such embodiments may also include an intact antibody comprising such a F(ab')2.

[0146] In some embodiments, the antibody or antibody fragment comprises a constant region that mediates effector function. The constant region can confer antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and / or complement-dependent cytotoxicity (CDC) responses against anti-IL-36R expressing target cells. The effector domain(s) can be, for example, the Fc region of an Ig molecule.

[0147] The effector domain of the antibody may be derived from any suitable vertebrate species and isotype. Isotypes derived from different animal species differ in their ability to mediate effector functions. For example, the ability of human immunoglobulins to mediate CDC and ADCC / ADCP is generally in the order of IgM≒IgG1≒IgG3>IgG2>IgG4 and IgG1≒IgG3>IgG2 / IgM / IgG4, respectively. Mouse immunoglobulins mediate CDC and ADCC / ADCP generally in the order of mouse IgM≒IgG3>>IgG, respectively. 2b >IgG 2a >>IgG1 and IgG 2b >IgG 2a >IgG1>>IgG3. Another example is mouse IgG 2a mediates ADCC, whereas mouse IgG 2a Both IgM and IgM mediate CDC.

[0148] III. Drug Dosage and Administration The anti-IL-36R antibodies of the present invention are typically administered to patients as pharmaceutical compositions in which the antagonist is mixed with a pharma- ceutically acceptable carrier or excipient. See, for example, Remington's Pharmaceutical Sciences and the United States Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984). Pharmaceutical compositions may be formulated in any manner suitable for the intended route of administration. Examples of pharmaceutical formulations include lyophilized powders, slurries, 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, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, William & Wilkins, New York, NY; Avis et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Decker & Co., NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Decker & Co., NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Decker & Co., NY; Weiner and Kotkoskie (2000) Excipient Toxicity (See, for example, The American Journal of Clinical Chemistry and Safety, Marcel Dekker & Co., New York, NY.) Suitable routes of administration include intravenous injection (including intraarterial injection) and subcutaneous injection.

[0149] In a first aspect, the present invention relates to a method of treating generalized pustular psoriasis (GPP) in a patient, the method comprising administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody.

[0150] In a second aspect, the present invention relates to a method of treating moderate to severe generalized pustular psoriasis in a patient comprising administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody.

[0151] In a third aspect, the present invention relates to a method of reducing or alleviating the signs and symptoms of an acute generalized pustular psoriasis outbreak in a patient, the method comprising administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody.

[0152] In a fourth aspect, the present invention relates to a method of reducing the severity and duration of a generalized pustular psoriasis flare, the method comprising administering or having administered to a patient a therapeutically effective amount of an anti-IL-36R antibody.

[0153] In a fifth aspect, the present invention relates to a method of treating skin disorders associated with acute generalized pustular psoriasis, the method comprising administering or having administered to a patient a therapeutically effective amount of an anti-IL-36R antibody.

[0154] In one embodiment related to any of the first to fifth aspects, the anti-IL-36R antibody comprises: 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).

[0155] In one embodiment related to any of the first to fifth aspects, the anti-IL-36R antibody comprises: Ia) 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). 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). 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). 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). Va) 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), 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). Includes.

[0156] In one embodiment related to any of the first to fifth aspects, 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. Includes.

[0157] In one embodiment related to any of the first to fifth aspects, the anti-IL-36R antibody comprises: 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 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 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 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 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 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 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 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 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. Includes.

[0158] In one embodiment related to any of the first through fifth aspects, 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) comprises 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg of the anti-IL-36R antibody.

[0159] In another embodiment related to any of the first to fifth aspects, the anti-IL-36R antibody is administered in a single intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of about 10 mg per kg of patient body weight. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 210 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 300 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 350 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 450 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 600 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 700 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 750 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 800 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 850 mg. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single intravenous dose of 900 mg.

[0160] Representative examples of doses and dosage regimens according to the present invention are disclosed in Table 1. Although doses of 900 mg and 750 mg are illustrated, similar dosage regimens apply equally to doses of 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, and 800 mg.

[0161] [Table 14] TIFF0007673168000037.tif228169 TIFF0007673168000038.tif254169 TIFF0007673168000039.tif43169

[0162] In one embodiment, one, two or three intravenous dose(s) are administered to a patient in the dose regimen listed in Table 1.

[0163] In one embodiment related to any of the above aspects, the mammal or patient has: (a) a Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 or 1 at week 1; (b) a GPPGA Pustulation Subscore of 0 at week 1, indicating the absence of any visible pustules; (c) a Generalized Pustular Psoriasis Psoriasis Area and Severity Index (GPPASI) of 75 at week 4; (d) a change from baseline in Pain Visual Analog Scale (VAS) score at week 4; (e) a change from baseline in Psoriasis Symptom Scale (PSS) score at week 4; (f) change from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT) score at week 4; (g) GPPGA score of 0 or 1 at week 4; (h) GPPGA pustule formation subscore of 0 at week 4 (indicating no visible pustules); (i) GPPASI score of 50 at weeks 1 and 4; or (j) change from baseline in GPPASI pustule, erythema, or scaling severity subscores at weeks 1 and 4. In a related embodiment, the proportion of patients who respond to dosing is statistically significantly higher compared to placebo patients for any of the listed endpoints.

[0164] In one embodiment, the present invention relates to a method of treating generalized pustular psoriasis (GPP), treating moderate to severe generalized pustular psoriasis, reducing or alleviating the signs and symptoms of acute generalized pustular psoriasis outbreaks, reducing the severity and duration of generalized pustular psoriasis flares, or treating a skin disorder associated with acute generalized pustular psoriasis in a patient, the method comprising administering or having administered to the patient a therapeutically effective amount of 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, respectively, of an anti-IL-36R antibody of the present invention, wherein the more than one intravenous doses are administered at 2, 4, 6, 8, 10, or 12 week intervals.

[0165] In one embodiment, the present invention relates to a method of treating generalized pustular psoriasis (GPP), treating moderate to severe generalized pustular psoriasis, reducing or alleviating the signs and symptoms of acute generalized pustular psoriasis outbreaks, reducing the severity and duration of generalized pustular psoriasis flares, or treating skin disorders associated with acute generalized pustular psoriasis in a patient, the method comprising administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody of the present invention in a single 900 mg intravenous dose.

[0166] The present invention relates to a method of treating generalized pustular psoriasis (GPP), treating moderate to severe generalized pustular psoriasis, reducing or alleviating the signs and symptoms of acute generalized pustular psoriasis outbreaks, reducing the severity and duration of generalized pustular psoriasis flares, or treating a skin disorder associated with acute generalized pustular psoriasis in a patient, the method comprising administering or having administered to the patient a therapeutically effective amount of an anti-IL-36R antibody of the present invention in one, two or three intravenous dose(s) of 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg, or 900 mg, respectively, wherein the two or three intravenous doses are administered 2, 4, 6, 8, 10 or 12 weeks apart.

[0167] In a sixth aspect, the present invention relates to a method for preventing recurrence of a generalized pustular psoriasis flare in a patient treated with one or more intravenous dose(s) of an anti-IL-36R antibody according to any of the first to fifth aspects or embodiments above, the method comprising administering to the patient one or more subcutaneous doses of a prophylactically effective amount of an anti-IL-36R antibody.

[0168] 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 an anti-IL-36R antibody according to any of the first to fifth aspects or embodiments above, the method comprising administering to the patient one or more subcutaneous doses of an effective amount of an anti-IL-36R antibody.

[0169] In an eighth aspect, the present invention relates to a method of achieving complete remission of symptoms of generalized pustular psoriasis in a patient treated with one or more intravenous dose(s) of an anti-IL-36R antibody according to any of the first to fifth aspects or embodiments above, the method comprising administering to the patient one or more subcutaneous doses of an effective amount of an anti-IL-36R antibody; wherein symptoms of generalized pustular psoriasis include pustules, erythema or scaling and complete remission comprises a GPPGA score of 0.

[0170] In one embodiment related to any of the sixth to eighth aspects, each of the one or more subcutaneous doses comprises 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of the anti-IL-36R antibody.

[0171] In one embodiment related to any of the sixth to eighth aspects or a related embodiment, one, two, three or more subcutaneous doses are administered to the patient, where a first subcutaneous dose is administered after a final intravenous dose.

[0172] In one embodiment related to any of the sixth to eighth aspects or related embodiments, 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.

[0173] In one embodiment, the invention relates to a method of preventing recurrence of generalized pustular psoriasis flares in a patient treated with one or more intravenous dose(s) of an anti-IL-36R antibody of the invention, the method comprising 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 the anti-IL-36R antibody, wherein the more than one subcutaneous doses are administered at 4, 6, 8, 10 or 12 week intervals.

[0174] In one embodiment, the invention relates to a method of achieving a Global Programmed Pustular Psoriasis Assessment (GPPGA) score of 0, or achieving complete remission of symptoms of generalized pustular psoriasis, in a patient treated with one or more intravenous dose(s) of an anti-IL-36R antibody of the invention, the method comprising administering to the patient an effective amount of an anti-IL-36R antibody in one or more subcutaneous doses of 225 mg, 300 mg, 450 mg or 600 mg of the anti-IL-36R antibody, respectively, wherein the more than one subcutaneous doses are administered at 4, 6, 8, 10 or 12 week intervals, and wherein the symptoms of generalized pustular psoriasis include pustules, erythema or scaling, and wherein complete remission comprises a GPPGA score of 0.

[0175] In one embodiment, the invention relates to a method of achieving a Global Programmed Pustular Psoriasis Assessment (GPPGA) score of 0, or achieving complete remission of symptoms of generalized pustular psoriasis, in a patient treated with one or more intravenous dose(s) of an anti-IL-36R antibody of the invention, the method comprising administering to the patient an effective amount of an anti-IL-36R antibody in one, two or three subcutaneous doses of 225 mg, 300 mg, 450 mg or 600 mg of anti-IL-36R antibody, respectively, wherein the two or three subcutaneous doses are administered 4, 6, 8, 10 or 12 weeks apart, wherein the symptoms of generalized pustular psoriasis include pustules, erythema or scaling, and wherein complete remission comprises a GPPGA score of 0.

[0176] In one embodiment or related embodiment(s) related to any of the sixth to eighth aspects, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission as judged by a GPPGA score of 0 or 1 at 12, 24, 36, 48, 60, or 72 weeks of treatment.

[0177] In one embodiment or related embodiment(s) related to any of the sixth to eighth aspects, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission as measured by change from baseline in GPPASI at 12, 24, 36, 48, 60, or 72 weeks of treatment.

[0178] In one embodiment or related embodiment(s) related to any of the sixth through eighth aspects, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission as measured by change in GPPASI pustule, erythema, or scaling severity subscores from baseline at 12, 24, 36, 48, 60, or 72 weeks of treatment. In related embodiments, the proportion of patients responding to treatment is statistically significantly higher compared to placebo patients for any of the listed endpoints.

[0179] In one embodiment related to any of the sixth to eighth aspects, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission at 12, 24, 36, 48, 60, or 72 weeks of treatment as judged by a GPPGA score of 0 or 1. In one embodiment related to any of the sixth to eighth aspects, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission at 12, 24, 36, 48, 60, or 72 weeks of treatment as judged by change from baseline in GPPASI. In one embodiment related to any of the sixth through eighth aspects, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission as measured by change in GPPASI pustule, erythema, or scaling severity subscores from baseline at 12, 24, 36, 48, 60, or 72 weeks of treatment. In a related embodiment, the proportion of patients responding to treatment is statistically significantly higher than placebo patients for any of the listed endpoints.

[0180] In one embodiment related to any of the sixth to eighth aspects, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission at 12, 24, 36, 48, 60, or 72 weeks of treatment as judged by a GPPGA score of 0 or 1. In a related embodiment, the improvement is maintained in a higher proportion with the anti-IL-36R antibody of the 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%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 109%, 100%. 6%, 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% maintain improved efficacy after 12, 24, 36, 48, 60, or 72 weeks of treatment with an anti-IL-36R antibody of the invention compared to placebo.

[0181] In one embodiment related to any of the sixth to eighth aspects, at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of patients remain in clinical remission as measured by change in GPPASI from baseline at 12, 24, 36, 48, 60 or 72 weeks of treatment. In a related embodiment, the improvement is maintained in a higher proportion with the anti-IL-36R antibody of the 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%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 109%, 100%. 6%, 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% maintain improved efficacy at 12, 24, 36, 48, 60, or 72 weeks of treatment with an anti-IL-36R antibody of the invention compared to placebo.

[0182] In one embodiment related to any of the sixth to eighth aspects, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission as measured by change in GPPASI pustule, erythema, or scaling severity subscores from baseline at 12, 24, 36, 48, 60, or 72 weeks of treatment. In a related embodiment, the improvement is maintained in a greater proportion with the anti-IL-36R antibody of the 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%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 109%, 100%. 6%, 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% maintain improved efficacy at 12, 24, 36, 48, 60, or 72 weeks of treatment with an anti-IL-36R antibody of the invention compared to placebo.

[0183] In a ninth aspect, the present invention relates to a method of treating generalized pustular psoriasis in a patient, comprising administering to the patient a therapeutically effective amount of one or more intravenous dose(s) of an anti-IL-36R antibody according to the first to fifth aspects and their associated embodiments, followed by administering one or more subcutaneous dose(s) of an anti-IL-36R antibody.

[0184] In one embodiment related to the ninth aspect, one or two or three intravenous dose(s) of an anti-IL-36R antibody are followed by one or two or three subcutaneous dose(s) of an anti-IL-36R antibody.

[0185] In one embodiment related to the ninth aspect, one intravenous dose(s) of anti-IL-36R antibody is followed by one or two or three subcutaneous dose(s) of anti-IL-36R antibody.

[0186] In one embodiment related to the ninth aspect, two intravenous dose(s) of anti-IL-36R antibody are followed by one or two or three subcutaneous dose(s) of anti-IL-36R antibody.

[0187] In one embodiment related to the ninth aspect, three intravenous dose(s) of anti-IL-36R antibody are followed by one or two or three subcutaneous dose(s) of anti-IL-36R antibody.

[0188] In one embodiment related to the ninth aspect and related embodiments thereof, the one or more intravenous dose(s) each comprises 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg, 850 mg, or 900 mg of anti-IL-36R antibody and the one or more subcutaneous dose(s) each comprises 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of anti-IL-36R antibody. In related embodiments, the intravenous doses are administered at 2, 4, 6, 8, 10 or 12 week intervals and the subcutaneous doses are administered at 4, 6, 8, 10 or 12 week intervals, with the first subcutaneous dose being administered 2 to 8 weeks, 4 to 6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks after the last intravenous dose was administered.

[0189] In one embodiment related to any of the above aspects, the intravenous dose(s) may be followed by one or more subcutaneous dose(s).

[0190] In one embodiment related to any of the above aspects, the anti-IL-36R antibody or antigen-binding fragment thereof (disclosed herein) is present in a stable pharmaceutical formulation (as described in co-pending U.S. Provisional Patent Application No. 62 / 815,405, filed March 8, 2019, the entire contents of which are hereby incorporated by reference in their entirety) for administration to a mammal or patient according to any one of the aspects of the invention.

[0191] In another embodiment, the formulation comprises a therapeutic amount of an anti-IL-36R antibody (disclosed herein), and i) a pharma- ceutically acceptable buffer; or ii) a pharma- ceutically acceptable tonicity agent; or iii) a pharma- ceutically acceptable stabilizer; or iv) a pharma- ceutically acceptable salt; or v) a pharma- ceutically acceptable surfactant; or vi) a pharma- ceutically acceptable buffer and a pharma-ceutically acceptable tonicity agent; or vii) a pharma- ceutically acceptable buffer, a pharma-ceutically acceptable tonicity agent, and a pharma-ceutically acceptable stabilizer; or viii) Pharmacologically acceptable buffers, pharmaceutically acceptable isotonicity agents, pharmaceutically acceptable stabilizers and pharmaceutically acceptable salts; or ix) Pharmaceutically acceptable buffers, pharmaceutically acceptable isotonicity agents, pharmaceutically acceptable stabilizers, pharmaceutically acceptable salts and pharmaceutically acceptable surfactants. each in a pharma- ceutically acceptable amount and at a pharma-ceutically acceptable pH.

[0192] 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 pharma- ceutically acceptable buffer is present in the formulation at a concentration in the range of 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 pharma- ceutically acceptable tonicity agent is present in the formulation at a concentration in the range of 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 pharma- ceutically acceptable stabilizer is present in the formulation at a concentration in the range of about 0 mM to about 80 mM, or at a concentration of about 25 mM or about 50 mM. In another related embodiment, the pharma- ceutically acceptable salt is present in the formulation at a concentration in the range of about 0 mM 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 pharma- ceutically acceptable surfactant is present in the formulation at a concentration in the range of 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 in the range of 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.

[0193] In another embodiment, the buffer comprises histidine, phosphate, succinate, citrate, acetate, or Tris; the isotonicity agent is one or more sugars and / or polyols, such as sucrose, trehalose, sorbitol, magnesium sulfate (MgSO4), glycerol, mannitol, or dextrose; the stabilizer comprises an amino acid, such as arginine, histidine, glycine, cysteine, proline, methionine, lysine, aspartic acid, glutamic acid, or a pharma- ceutically acceptable salt thereof; the salt comprises sodium chloride (NaCl), magnesium chloride (MgCl2), potassium chloride (KCl), lithium chloride (LiCl), calcium chloride (CaCl2), borate, or zinc chloride (ZnCl2); the surfactant comprises poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0194] In one embodiment, the method of treatment according to any of the aspects described herein comprises administering to a mammal or patient a therapeutic amount of a stable pharmaceutical formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 20 mM to about 80 mM of a pharma- ceutically acceptable buffer (e.g., acetate buffer), about 100 mM to about 250 mM of a pharma- ceutically acceptable isotonicity agent (e.g., sucrose), about 0 mM to about 80 mM of a pharma- ceutically acceptable stabilizer (e.g., arginine) or a pharma- ceutically acceptable salt thereof, about 0 to about 150 mM of a pharma- ceutically acceptable salt (e.g., sodium chloride), and a pharma- ceutically acceptable surfactant (e.g., polysorbate 20) in an amount of about 0 g / L to about 1.5 g / L. The method includes the steps of: treating generalized pustular psoriasis (GPP) in a patient; treating moderate to severe generalized pustular psoriasis in a patient; reducing or alleviating the signs and symptoms of acute generalized pustular psoriasis flare in a patient; reducing the severity and duration of a generalized pustular psoriasis flare in a patient; treating skin disorders associated with acute generalized pustular psoriasis in a patient; preventing or inhibiting a generalized pustular psoriasis flare in a patient; achieving a Global Patient Profile for Generalized Pustular Psoriasis Assessment (GPPGA) score of 0 in a patient; or achieving complete remission of symptoms of generalized pustular psoriasis in a patient. 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 intravenous administration to a mammal or a patient. In a related embodiment, the pharmaceutical formulation is for subcutaneous administration to a mammal or patient. In a related embodiment, the pharmaceutical formulation for intravenous administration comprises an anti-IL-36R antibody in an amount of about 60 mg / mL. In a related embodiment, the pharmaceutical formulation for 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 comprises (i) a light chain comprising the amino acid sequence set forth as SEQ ID NO:118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:125; or (ii) a light chain comprising the amino acid sequence set forth as SEQ ID NO:118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:126; or (iii) a light chain comprising the amino acid sequence set forth as SEQ ID NO:118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:127. In a related embodiment, the anti-IL-36R antibody comprises 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.

[0195] In one embodiment, the method of treatment according to any of the preceding aspects comprises: I. A formulation comprising about 20 mg / mL to about 150 mg / mL of an 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, having a pH of about 6.0; II. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, and about 0.4 g / L polysorbate 20, having a pH of about 5.5; III. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM glycine, and about 0.4 g / L polysorbate 80, having a pH of about 5.5; IV. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM citrate, about 150 mM trehalose, about 25 mM methionine, and about 0.2 g / L polysorbate 20, having a pH of about 6.0; V. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, and about 0.2 g / L polysorbate 20, having a pH of about 6.5; VI. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, and about 0.4 g / L polysorbate 80, having a pH of about 6.5; VII. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, and about 0.4 g / L polysorbate 20, having a pH of about 5.5; VIII. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 35 mM histidine, about 180 mM trehalose, about 25 mM L-arginine, about 3 mM NaCl, and about 0.4 g / L polysorbate 80, having a pH of about 6.0; IX. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM acetate, about 100 mM mannitol, about 50 mM NaCl, and about 0.2 g / L polysorbate 20, having a pH of about 5.5; X. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 20 mM succinate, about 220 mM sucrose, and about 0.1 g / L polysorbate 80, having a pH of about 6.0; and XI. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM citrate, and about 0.4 g / L polysorbate 20, having a pH of about 6.5 The present invention relates to a method for treating a skin disorder associated with acute generalized pustular psoriasis in a patient, comprising administering to a mammal or patient a therapeutic amount of a stable pharmaceutical formulation selected from the group consisting of: wherein the patient is treated with generalized pustular psoriasis (GPP), or the patient is treated with moderate to severe generalized pustular psoriasis, or the signs and symptoms of acute generalized pustular psoriasis flare are reduced or alleviated in the patient, or the patient is treated with reduced severity and duration of generalized pustular psoriasis flare, or the patient is treated with skin disorder associated with acute generalized pustular psoriasis, or the patient is prevented or inhibited from having a generalized pustular psoriasis flare, or the patient is achieved a Global Psoriasis Generalized Pustular Psoriasis Assessment (GPPGA) score of 0, or the patient is achieved complete remission of symptoms of generalized pustular psoriasis. In a related embodiment, the stable pharmaceutical formulation is an aqueous pharmaceutical formulation. In a related embodiment, the pharmaceutical formulation is for intravenous administration to a mammal or patient. In a related embodiment, the pharmaceutical formulation is for subcutaneous administration to a mammal or patient. In a related embodiment, the pharmaceutical formulation for intravenous administration comprises an anti-IL-36R antibody in an amount of about 60 mg / mL. In a related embodiment, the pharmaceutical formulation for 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 comprises (i) a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or (ii) a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or (iii) a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127.In a related embodiment, the anti-IL-36R antibody comprises 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.

[0196] In one embodiment, the method of treatment according to any of the preceding aspects comprises: I. A formulation comprising about 20 mg / mL 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, having a pH of about 6.0; II. A formulation comprising about 60 mg / mL anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, about 0.4 g / L polysorbate 20, at a pH of about 5.5; III. A formulation comprising about 20 mg / mL anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM glycine, about 0.4 g / L polysorbate 80, at a pH of about 5.5; IV. A formulation comprising about 150 mg / mL anti-IL-36R antibody, about 25 mM citrate, about 150 mM trehalose, about 25 mM methionine, about 0.2 g / L polysorbate 20, at a pH of about 6.0; V. A formulation comprising about 150 mg / mL anti-IL-36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, about 0.2 g / L polysorbate 20, having a pH of about 6.5; VI. A formulation comprising about 20 mg / mL anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, about 0.4 g / L polysorbate 80, having a pH of about 6.5; VII. A formulation comprising about 150 mg / mL anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, about 0.4 g / L polysorbate 20, at a pH of about 5.5; VIII. A formulation comprising about 15 mg / mL 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, having a pH of about 6.0; IX. A formulation comprising about 80 mg / mL anti-IL-36R antibody, about 25 mM acetate, about 100 mM mannitol, about 50 mM NaCl, about 0.2 g / L polysorbate 20, at a pH of about 5.5; X. A formulation comprising about 100 mg / mL anti-IL-36R antibody, about 20 mM succinate, about 220 mM sucrose, about 0.1 g / L polysorbate 80, having a pH of about 6.0; and XI. A formulation comprising about 60 mg / mL anti-IL-36R antibody, about 25 mM citrate, and about 0.4 g / L polysorbate 20, having a pH of about 6.5 The present invention relates to a method for treating a skin disorder associated with acute generalized pustular psoriasis in a patient, comprising administering to a mammal or patient a therapeutic amount of a stable pharmaceutical formulation selected from the group consisting of: wherein the patient is treated with generalized pustular psoriasis (GPP), or the patient is treated with moderate to severe generalized pustular psoriasis, or the signs and symptoms of acute generalized pustular psoriasis flare are reduced or alleviated in the patient, or the patient is treated with reduced severity and duration of generalized pustular psoriasis flare, or the patient is treated with skin disorder associated with acute generalized pustular psoriasis, or the patient is prevented or inhibited from having a generalized pustular psoriasis flare, or the patient is achieved a Global Psoriasis Generalized Pustular Psoriasis Assessment (GPPGA) score of 0, or the patient is achieved complete remission of symptoms of generalized pustular psoriasis. In a related embodiment, the stable pharmaceutical formulation is an aqueous pharmaceutical formulation. In a related embodiment, the pharmaceutical formulation is for intravenous administration to a mammal or patient. In a related embodiment, the pharmaceutical formulation is for subcutaneous administration to a mammal or patient. In a related embodiment, the pharmaceutical formulation for intravenous administration comprises an anti-IL-36R antibody in an amount of about 60 mg / mL. In a related embodiment, the pharmaceutical formulation for 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 comprises (i) a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or (ii) a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or (iii) a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127.In a related embodiment, the anti-IL-36R antibody comprises 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 generalized pustular psoriasis in a patient, comprising the steps of: (a) obtaining a biological sample from the patient, wherein the biological sample is obtained from a source including a skin lesion or whole blood; (b) determining a gene expression profile of one or more genes; and (c) administering to the patient an effective amount of an anti-IL-36R antibody according to any of the embodiments related to the first to fifth aspects.

[0197] In one embodiment related to the tenth aspect, the one or more 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.

[0198] In an embodiment related to any of the above aspects, the anti-IL-36R antibody comprises: 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).

[0199] In an embodiment related to any of the above aspects, the anti-IL-36R antibody is an anti-IL-36R antibody of the invention. In one embodiment, the anti-IL-36R antibody is disclosed in U.S. Pat. No. 9,023,995 or WO 2013 / 074569. In a related embodiment of any of the above aspects, the ameliorative effect (including remission or improved symptoms) lasts 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 after administration of a single dose of an anti-IL-36R antibody of the invention.

[0200] Pharmaceutical Compositions and Their Administration The antibody of the present invention may be administered alone or in combination with other drugs. Examples of antibodies for use in such pharmaceutical compositions include antibodies or antibody fragments having a light chain variable region amino acid sequence of any of SEQ ID NOs: 1 to 10. Examples of antibodies for use in such pharmaceutical compositions include humanized antibodies or antibody fragments having a heavy chain variable region amino acid sequence of any of SEQ ID NOs: 11 to 20.

[0201] Further examples of antibodies for use in such pharmaceutical compositions include humanized antibodies or antibody fragments having the amino acid sequence of the light chain variable region of any of SEQ ID NOs: 76 to 86. Preferred antibodies for use in such pharmaceutical compositions also include humanized antibodies or antibody fragments having the amino acid sequence of the heavy chain variable region of any of SEQ ID NOs: 87 to 101.

[0202] Further examples of antibodies for use in such pharmaceutical compositions include humanized antibodies or antibody fragments having the light chain variable regions and heavy chain variable regions of any of SEQ ID NOs:77 and 89, SEQ ID NOs:80 and 88, SEQ ID NOs:80 and 89, SEQ ID NOs:77 and 87, SEQ ID NOs:77 and 88, SEQ ID NOs:80 and 87, SEQ ID NOs:86 and 100, SEQ ID NOs:85 and 101, or SEQ ID NOs:85 and 10.

[0203] Further examples of antibodies for use in such pharmaceutical compositions also include humanized antibodies having the light chain region amino acid sequence of any of SEQ ID NOs: 115, 118, 123 or 124. Preferred antibodies for use in such pharmaceutical compositions also include humanized antibodies having the heavy chain variable region amino acid sequence of any of SEQ ID NOs: 125, 126, 127, 138 or 139.

[0204] Further examples of antibodies for use in such pharmaceutical compositions also include antibody B1, antibody B2, antibody B3, antibody B4, antibody B5, antibody B6, antibody C1, antibody C2, or antibody C3.

[0205] Various delivery systems are known and can be used to administer anti-IL-36R binding agents. Introduction methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. Anti-IL-36R binding agents can be administered, for example, by infusion, bolus, or injection, and can be administered together with other biologically active agents, for example, chemotherapeutic agents. Administration can be systemic or local. In a preferred embodiment, administration is by subcutaneous injection. Such formulations for injection can be prepared, for example, in prefilled syringes that can be administered once every two weeks.

[0206] In one aspect, the present invention provides a product comprising a subcutaneous administration device that delivers a dose of the antibody of the present invention to a patient. In some embodiments, the subcutaneous administration device is a pre-filled syringe, an autoinjector, or a large volume injection device. For example, the MyDose™ product from Roche, a single-use injection device that allows for subcutaneous administration of large volumes of liquid drugs, may be used as the administration device. Many reusable pen and autoinjector type delivery devices have application for subcutaneous delivery of the pharmaceutical composition of the present invention. Examples include, but are not limited to, AutoPen™ (Owen Mumford, Woodstock, UK), Zycetronic™ Pen (Zycetronic Medical Systems, Burgdorf, Switzerland), Humalog Mix 75 / 25™ Pen, Humalog™ Pen, Humalin 70 / 30™ Pen (Eli Lilly and Company, Indianapolis, IN), Novopen™ I, II and III (Novo Nordisk, Copenhagen, Denmark), Novopen Jr.™ (Novo Nordisk, Copenhagen, Denmark), BD™ Pen (Becton Dickinson and Company, Franklin Lakes, NJ), OptiPen™, OptiPen Pro™, OptiPen Starlet™, and OptiClick™ (Sanofi Aventis, Frankfurt, Germany), to name just a few. Examples of disposable pen delivery devices having application for subcutaneous delivery of the pharmaceutical compositions of the present invention include, but are not limited to, the Solostar™ pen (Sanofi-Aventis), FlexPen™ (Novo Nordisk), and KwikPen™ (Eli Lilly and Company), the SureClick™ autoinjector (Amgen, Thousand Oaks, Calif.), Penlet™ (Haselmeyer, Stuttgart, Germany), EpiPen (Dey, LP), and Humira™ pen (Abbott Laboratories, Abbott Park III), YPSOMATE™, YPSOMATE2.25™, and VAIROJECT™ (Ipsmed, Burgdorf, Switzerland), to name just a few.Additional information regarding exemplary delivery devices that can be used with the antibodies of the invention can be found, for example, in CH705992A2, WO 2009 / 040602, WO 2016 / 169748, WO 2016 / 179713.

[0207] In specific embodiments, the IL-36R binding agent composition is administered by injection, using a catheter, using a suppository, or using an implant, which is a porous, non-porous, or gelatinous material, including membranes such as silicone rubber membranes or fibers. Typically, a material is used that does not absorb the anti-IL-36R antibody or agent when the composition is administered.

[0208] 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 other embodiments, polymeric materials may 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, e.g., in Langer, supra.

[0209] An IL-36R binding agent (eg, an anti-IL-36R antibody) can be administered as a pharmaceutical composition comprising a therapeutically effective amount of the binding agent and one or more pharma- ceutically compatible ingredients.

[0210] In one embodiment, the anti-IL-36R antibody or antigen-binding fragment thereof (disclosed herein) is in a pharmaceutical formulation (as described in co-pending U.S. Provisional Patent Application No. 62 / 815,405, filed March 8, 2019, the entire contents of which are hereby incorporated by reference in their entirety) suitable for administration to a mammal or patient according to any one of the aspects described herein. Various examples of this embodiment are conveniently described as the following numbered paragraphs (1, 2, 3, etc.). These are provided as examples and are not intended to limit the technology of this application. It should be noted that the dependent claims may be combined in any combination and may be placed in their respective independent claims, e.g., paragraph 1. Other paragraphs may be presented similarly.

[0211] 1.a. an anti-IL-36R antibody or antigen-binding fragment thereof as disclosed herein, present at a concentration in the range of about 0.5 mg / mL to about 220 mg / mL; and b. a pharma- ceutically acceptable buffer present at a concentration in the range of about 20 mM to about 80 mM wherein the formulation, when in the form of an aqueous solution, is characterized by a pH in the range of about 5 to about 8.

[0212] 2. The formulation of paragraph 1, wherein the formulation is in liquid or powder form.

[0213] 3. The formulation of paragraph 1, wherein the anti-IL-36R antibody is present at a concentration within the range of about 10 mg / mL to about 200 mg / mL.

[0214] 4. The formulation of paragraph 1, wherein the anti-IL-36R antibody is present in a concentration of about 20 mg / mL.

[0215] 5. The formulation of paragraph 1, wherein the anti-IL-36R antibody is present in a concentration of about 60 mg / mL.

[0216] 6. The formulation of paragraph 1, wherein the anti-IL-36R antibody is present in a concentration of about 150 mg / mL.

[0217] 7. The formulation of paragraph 1, wherein the buffer comprises histidine, phosphate, succinate, citrate, acetate, or Tris.

[0218] 8. The formulation of paragraph 1, wherein the buffer comprises a citrate or acetate salt.

[0219] 9. The formulation of paragraph 1, wherein the buffer contains histidine.

[0220] 10. The formulation of paragraph 1, wherein the buffer comprises acetate.

[0221] 11. The formulation of paragraph 1, wherein the formulation further comprises a pharma- ceutically acceptable tonicity agent present in a concentration in the range of about 100 mM to about 250 mM.

[0222] 12. The formulation of clause 11, wherein the tonicity agent is one or more sugars and / or polyols.

[0223] 13. The formulation of paragraph 11, wherein the isotonicity agent is one or more sugars and / or polyols, such as sucrose, trehalose, sorbitol, magnesium sulfate (MgSO4), glycerol, mannitol or dextrose.

[0224] 14. The formulation of paragraph 11, wherein the tonicity agent comprises sucrose or trehalose.

[0225] 15. The formulation of paragraph 11, wherein the tonicity agent comprises sucrose.

[0226] 16. The formulation of paragraph 11, wherein the tonicity agent comprises trehalose.

[0227] 17. The formulation of paragraph 1, wherein the formulation further comprises a pharma- ceutically acceptable stabilizer present in a concentration in the range of about 0 mM to about 80 mM.

[0228] 18. The formulation of paragraph 17, wherein the stabilizer comprises an amino acid, e.g., arginine, histidine, glycine, cysteine, proline, methionine, lysine, aspartic acid, glutamic acid, or a pharma- ceutically acceptable salt thereof.

[0229] 19. The formulation of paragraph 17, wherein the stabilizing agent comprises L-arginine or a pharma- ceutically acceptable salt thereof.

[0230] 20. The formulation of paragraph 1, wherein the formulation further comprises a pharma- ceutically acceptable salt present in a concentration in the range of about 0 to about 150 mM.

[0231] 21. A formulation of paragraph 20, wherein the salt comprises sodium chloride (NaCl), magnesium chloride (MgCl2), potassium chloride (KCl), lithium chloride (LiCl), calcium chloride (CaCl2), a borate, or zinc chloride (ZnCl2).

[0232] 22. A formulation of paragraph 20, wherein the salt comprises sodium chloride (NaCl).

[0233] 23. The formulation of paragraph 1, wherein the formulation further comprises a pharma- ceutically acceptable surfactant present in a concentration in the range of about 0 g / L to about 1.5 g / L.

[0234] 24. The formulation of paragraph 23, wherein the surfactant comprises poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0235] 25. The formulation of paragraph 23, wherein the surfactant comprises polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0236] 26. The formulation of paragraph 23, wherein the surfactant comprises polysorbate 20.

[0237] 27. A formulation according to paragraph 23, wherein the surfactant comprises polysorbate 80.

[0238] 28.a. an anti-IL-36R antibody or antigen-binding fragment thereof as disclosed herein, present at a concentration in the range of about 10 mg / mL to about 200 mg / mL; b. acetate and / or histidine buffer present at a concentration in the range of about 20 mM to about 80 mM; c. sucrose and / or trehalose present at a concentration in the range of about 100 mM to about 250 mM; d. L-arginine and / or a pharma- ceutically acceptable salt thereof, present at a concentration in the range of about 0 mM to about 80 mM; e. Sodium chloride (NaCl), present at a concentration in the range of about 0 to about 150 mM; f. Polysorbate 20 and / or Polysorbate 80, present in a concentration ranging from about 0 g / L to about 1.5 g / L wherein the formulation, when in aqueous solution, is characterized by a pH in the range of about 5 to about 7.

[0239] 29.a. an anti-IL-36R antibody or antigen-binding fragment thereof as disclosed herein, present in a concentration of about 20 mg / mL; b. a citrate buffer, present at a concentration of about 25 mM; c. sucrose and / or trehalose present at a concentration of about 200 mM; d. Polysorbate 80, present at a concentration of about 0.4 g / L wherein the formulation, when in the form of an aqueous solution, is characterized by a pH in the range of about 6 to about 7.

[0240] 30.a. an anti-IL-36R antibody or antigen-binding fragment thereof as disclosed herein, present in a concentration of about 60 mg / mL; b. acetate buffer, present at a concentration of about 45 mM; c. sucrose and / or trehalose present at a concentration of about 150 mM; d. L-arginine, or a pharma- ceutically acceptable salt thereof, present at a concentration of about 25 mM; e. Polysorbate 20 present at a concentration of approximately 0.4 g / L wherein the formulation, when in the form of an aqueous solution, is characterized by a pH in the range of about 5 to about 6.

[0241] 31.a. an anti-IL-36R antibody or antigen-binding fragment thereof as disclosed herein, present in a concentration of about 150 mg / mL; b. acetate buffer, present at a concentration of about 45 mM; c. sucrose or trehalose, present at a concentration of about 150 mM; d. L-arginine or a pharma- ceutically acceptable salt thereof, present in a concentration of about 25 mM; and e. Polysorbate 20 present at a concentration of approximately 0.4 g / L wherein the formulation, when in the form of an aqueous solution, is characterized by a pH in the range of about 5 to about 6.

[0242] 32. The pharmaceutical formulation of any one of clauses 1 to 31, wherein the formulation is characterized by an osmolality in the range of about 210 mOsm / kg to about 390 mOsm / kg.

[0243] 33. The pharmaceutical formulation of any one of clauses 1-32, wherein less than about 5% of the antibody is present in the formulation in the form of aggregates.

[0244] 34. The pharmaceutical formulation of any one of clauses 1 to 33, wherein the formulation is sterile.

[0245] 35. The pharmaceutical formulation of any one of clauses 1 to 34, wherein the formulation is stable when frozen and thawed.

[0246] 36. A pharmaceutical formulation according to any one of claims 1 to 35, wherein the formulation contains water or is reconstituted with water.

[0247] 37. The pharmaceutical formulation of any of paragraphs 1 to 36, wherein the formulation, in liquid form or when reconstituted with water, has a pH of about 5 to about 6.

[0248] 38. The pharmaceutical formulation of any of paragraphs 1-37, wherein the formulation, in liquid form or when reconstituted with water, has a pH of about 6.

[0249] 39. The formulation, compared to the reference formulation, (i) the extended validity period; (ii) better stability to temperature; (iii) reduced aggregate formation; (iv) better stability against chemicals; (v) reduced viscosity 38. The pharmaceutical formulation of any one of items 1 to 37, having at least one feature selected from the group consisting of:

[0250] 40. The preparation is (a) A reduction in the proportion of aggregates as determined by high performance size exclusion chromatography (HP-SEC); (b) a higher proportion of monomer as determined by HP-SEC; (c) a higher proportion of the main peak (less resolution of the charge variants) as judged by cation exchange; (d) a lower proportion of sub-visible particles, such as particles 10 μm or larger and 25 μm or larger; and (e) Lower turbidity values ​​in formazin scattering nephelometric units (FNU) after storage at approximately 40°C compared to the reference formulation 38. The pharmaceutical formulation of any one of items 1 to 37, having at least one feature selected from the group consisting of:

[0251] 41.i. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or antigen-binding fragment thereof, wherein the formulation comprises: I. A formulation comprising about 20 mg / mL 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, having a pH of about 6.0; II. A formulation comprising about 60 mg / mL anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, about 0.4 g / L polysorbate 20, at a pH of about 5.5; III. A formulation comprising about 20 mg / mL anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM glycine, about 0.4 g / L polysorbate 80, at a pH of about 5.5; IV. A formulation comprising about 150 mg / mL anti-IL-36R antibody, about 25 mM citrate, about 150 mM trehalose, about 25 mM methionine, about 0.2 g / L polysorbate 20, at a pH of about 6.0; V. A formulation comprising about 150 mg / mL anti-IL-36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, about 0.2 g / L polysorbate 20, having a pH of about 6.5; VI. A formulation comprising about 20 mg / mL anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, about 0.4 g / L polysorbate 80, having a pH of about 6.5; VII. A formulation comprising about 150 mg / mL anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, about 0.4 g / L polysorbate 20, at a pH of about 5.5; VIII. A formulation comprising about 15 mg / mL 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, having a pH of about 6.0; IX. A formulation comprising about 80 mg / mL anti-IL-36R antibody, about 25 mM acetate, about 100 mM mannitol, about 50 mM NaCl, about 0.2 g / L polysorbate 20, at a pH of about 5.5; X. A formulation comprising about 100 mg / mL anti-IL-36R antibody, about 20 mM succinate, about 220 mM sucrose, about 0.1 g / L polysorbate 80, having a pH of about 6.0; and XI. A formulation comprising about 60 mg / mL anti-IL-36R antibody, about 25 mM citrate, and about 0.4 g / L polysorbate 20, having a pH of about 6.5 is selected from the group consisting of:

[0252] 42.i. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127. 20 mg / mL of an anti-IL-36R antibody or an antigen-binding fragment thereof, wherein the formulation comprises about 20 mg / mL of an 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, and has a pH of about 6.0.

[0253] 43.i. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising:

[0254] 44.i. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127. 20 mg / mL of an anti-IL-36R antibody or an antigen-binding fragment thereof, wherein the formulation comprises about 20 mg / mL of an anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM glycine, about 0.4 g / L polysorbate 80, and has a pH of about 5.5.

[0255] 45.i. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising:

[0256] 46.i. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising:

[0257] 47.i. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127. 25 mM citrate, about 200 mM sucrose, about 0.4 g / L polysorbate 80, and has a pH of about 6.5.

[0258] 48.i. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising:

[0259] 49.i. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising:

[0260] 50.i. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising:

[0261] 51.i. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising:

[0262] 52.i. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127. wherein the formulation comprises about 60 mg / mL of anti-IL-36R antibody, about 25 mM citrate, about 0.4 g / L polysorbate 20, and has a pH of about 6.5.

[0263] 53. 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. 20 mg / mL of an anti-IL-36R antibody or an antigen-binding fragment thereof, wherein the formulation comprises about 20 mg / mL of an 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, and has a pH of about 6.0.

[0264] 54. 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. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising:

[0265] 55. 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. 20 mg / mL of an anti-IL-36R antibody or an antigen-binding fragment thereof, wherein the formulation comprises about 20 mg / mL of an anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM glycine, about 0.4 g / L polysorbate 80, and has a pH of about 5.5.

[0266] 56. 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. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising:

[0267] 57. 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. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising:

[0268] 58. 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. 25 mM citrate, about 200 mM sucrose, about 0.4 g / L polysorbate 80, and has a pH of about 6.5.

[0269] 59. 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. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising:

[0270] 60. 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. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising:

[0271] 61. 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. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising:

[0272] 62. 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. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising:

[0273] 63. 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. wherein the formulation comprises about 60 mg / mL of anti-IL-36R antibody, about 20 mM citrate, about 0.4 g / L polysorbate 20, and has a pH of about 6.5.

[0274] 64.i. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or antigen-binding fragment thereof, wherein the formulation comprises: I. A formulation comprising about 20 mg / mL to about 150 mg / mL of an 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, having a pH of about 6.0; II. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, and about 0.4 g / L polysorbate 20, having a pH of about 5.5; III. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM glycine, and about 0.4 g / L polysorbate 80, having a pH of about 5.5; IV. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM citrate, about 150 mM trehalose, about 25 mM methionine, and about 0.2 g / L polysorbate 20, having a pH of about 6.0; V. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, and about 0.2 g / L polysorbate 20, having a pH of about 6.5; VI. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, and about 0.4 g / L polysorbate 80, having a pH of about 6.5; VII. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, and about 0.4 g / L polysorbate 20, having a pH of about 5.5; VIII. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 35 mM histidine, about 180 mM trehalose, about 25 mM L-arginine, about 3 mM NaCl, and about 0.4 g / L polysorbate 80, having a pH of about 6.0; IX. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM acetate, about 100 mM mannitol, about 50 mM NaCl, and about 0.2 g / L polysorbate 20, having a pH of about 5.5; X. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 20 mM succinate, about 220 mM sucrose, and about 0.1 g / L polysorbate 80, having a pH of about 6.0; and XI. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM citrate, and about 0.4 g / L polysorbate 20, having a pH of about 6.5 is selected from the group consisting of:

[0275] 65. 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. 1. A pharmaceutical formulation comprising an anti-IL-36R antibody or antigen-binding fragment thereof, wherein the formulation comprises: I. A formulation comprising about 20 mg / mL to about 150 mg / mL of an 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, having a pH of about 6.0; II. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, and about 0.4 g / L polysorbate 20, having a pH of about 5.5; III. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM glycine, and about 0.4 g / L polysorbate 80, having a pH of about 5.5; IV. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM citrate, about 150 mM trehalose, about 25 mM methionine, and about 0.2 g / L polysorbate 20, having a pH of about 6.0; V. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, and about 0.2 g / L polysorbate 20, having a pH of about 6.5; VI. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, and about 0.4 g / L polysorbate 80, having a pH of about 6.5; VII. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, and about 0.4 g / L polysorbate 20, having a pH of about 5.5; VIII. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 35 mM histidine, about 180 mM trehalose, about 25 mM L-arginine, about 3 mM NaCl, and about 0.4 g / L polysorbate 20, having a pH of about 6.0; IX. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM acetate, about 100 mM mannitol, about 50 mM NaCl, and about 0.2 g / L polysorbate 20, having a pH of about 5.5; X. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 20 mM succinate, about 220 mM sucrose, and about 0.1 g / L polysorbate 80, having a pH of about 6.0; and XI. A formulation comprising about 20 mg / mL to about 150 mg / mL of an anti-IL-36R antibody, about 25 mM citrate, and about 0.4 g / L polysorbate 20, having a pH of about 6.5 is selected from the group consisting of:

[0276] 66. A pharmaceutical product comprising a vial or syringe containing the pharmaceutical formulation according to any one of paragraphs 1 to 65 for use in any one of the aspects of the present invention.

[0277] 67. The pharmaceutical product of paragraph 66, further comprising a preassembled injection device.

[0278] 68. A medicinal product of paragraph 67, in which the preassembled injection device is an autoinjector or a syringe, with or without a needle safety device.

[0279] 69. A pre-assembled injection device comprising a pharmaceutical formulation according to any one of paragraphs 1 to 68 for use in any one of the aspects of the present invention.

[0280] 70. A preassembled injection device according to paragraph 69, wherein the device is an autoinjector or a syringe with or without a needle safety device.

[0281] 71. A preassembled injection device according to paragraph 69, wherein the formulation is suitable for intravenous, subcutaneous, or intramuscular administration.

[0282] 72. Autoinjectors or syringes with or without needle safety devices: i. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 125; or ii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 126; or iii. a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127. a pharmaceutical formulation comprising an anti-IL-36R antibody or an antigen-binding fragment thereof comprising: The formulation here is: I. A formulation comprising about 20 mg / ml 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, having a pH of about 6.0; II. A formulation comprising about 60 mg / mL anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, about 0.4 g / L polysorbate 20, at a pH of about 5.5; III. A formulation comprising about 20 mg / mL anti-IL-36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM glycine, about 0.4 g / L polysorbate 80, at a pH of about 5.5; IV. A formulation comprising about 150 mg / mL anti-IL-36R antibody, about 25 mM citrate, about 150 mM trehalose, about 25 mM methionine, about 0.2 g / L polysorbate 20, at a pH of about 6.0; V. A formulation comprising about 150 mg / mL anti-IL-36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, about 0.2 g / L polysorbate 20, having a pH of about 6.5; VI. A formulation comprising about 20 mg / mL anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, about 0.4 g / L polysorbate 80, having a pH of about 6.5; VII. A formulation comprising about 150 mg / mL anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM L-arginine, about 0.4 g / L polysorbate 20, at a pH of about 5.5; VIII. A formulation comprising about 15 mg / mL 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, having a pH of about 6.0; IX. A formulation comprising about 80 mg / mL anti-IL-36R antibody, about 25 mM acetate, about 100 mM mannitol, about 50 mM NaCl, about 0.2 g / L polysorbate 20, at a pH of about 5.5; X. A formulation comprising about 100 mg / mL anti-IL-36R antibody, about 20 mM succinate, about 220 mM sucrose, about 0.1 g / L polysorbate 80, having a pH of about 6.0; and XI. A formulation comprising about 60 mg / mL anti-IL-36R antibody, about 25 mM citrate, and about 0.4 g / L polysorbate 20, having a pH of about 6.5 is selected from the group consisting of:

[0283] 73. Autoinjectors or syringes with needle safety devices a. about 300 mg of antibody in a formulation volume of about 2 mL; or b. about 225 mg of antibody in a formulation volume of about 1.5 mL; or c. about 150 mg of antibody in a formulation volume of about 1 mL; or d. about 75 mg of antibody in a formulation volume of about 0.5 mL; or e. about 60 mg of antibody in a formulation volume of about 0.4 mL 71. The preassembled injection device of claim 70, comprising:

[0284] 74. Vials are a. about 1200 mg of antibody in a formulation volume of about 20 mL; or b. about 900 mg of antibody in a formulation volume of about 15 mL; or c. about 600 mg of antibody in a formulation volume of about 10 mL; or d. about 300 mg of antibody in a formulation volume of about 150 mL; or e. about 1500 mg of antibody in a formulation volume of about 2.5 mL 67. The vial of claim 66, comprising:

[0285] 75. A pharmaceutical product comprising a vial containing 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 injection, wherein the anti-IL-36R antibody comprises a light chain comprising the amino acid sequence set forth as SEQ ID NO:118 and a heavy chain comprising the amino acid sequence set forth as any one of SEQ ID NOs:125, 126 or 127; the reconstitution instructions require reconstitution with water for injection to an extractable volume of 1 to 50 mL.

[0286] Additionally, the pharmaceutical composition may be provided as a pharmaceutical kit comprising (a) a container containing an IL-36R binding agent (e.g., an anti-IL-36R antibody) in lyophilized form and (b) a second container containing a pharma- ceutically acceptable diluent (e.g., sterile water) for injection. The pharma- ceutically acceptable diluent may be used for reconstitution or dilution of the lyophilized anti-IL-36R antibody or agent. Such container(s) may optionally be accompanied by a notice in a format prescribed by a governmental agency regulating the manufacture, use, and sale of pharmaceuticals or biological products, which notice reflects that the product has been approved by the agency for manufacture, use, or sale for administration to humans.

[0287] Administration of such combination therapy may have an additive or synergistic effect on a disease parameter (eg, severity of symptoms, number of symptoms, or frequency of recurrence).

[0288] With respect to therapeutic regimens for combined administration, in a specific embodiment, the anti-IL-36R antibody or IL-36R binding agent is administered simultaneously with the Therapeutic Agent. In another specific embodiment, the Therapeutic Agent is administered at least 1 hour and up to several months before or after administration of the anti-IL-36R antibody or IL-36R binding agent, e.g., at least 1 hour, 5 hours, 12 hours, 1 day, 1 week, 1 month, or 3 months before or after administration of the anti-IL-36R antibody or IL-36R binding agent.

[0289] The present invention is further described in the following examples, which do not limit the scope of the invention.

[0290] Working Example Example 1: Inhibition of IL-36 receptor for the treatment of generalized pustular psoriasis The antibody of the present invention, i.e., the anti-IL-36R antibody of the present invention (disclosed herein and also in US Pat. No. 9,023,995), is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL36R signaling. Binding of the anti-IL-36R antibody of the present invention to IL36R is expected to prevent the subsequent activation of IL36R by its cognate ligands (IL36α, β and γ) and downstream activation of proinflammatory and profibrotic pathways, with the aim of reducing inflammation mediated by epithelial cells / fibroblasts / immune cells and interrupting the inflammatory response that drives pathological cytokine production in generalized pustular psoriasis (GPP).

[0291] The preclinical profile of the anti-IL-36R antibodies of the invention and clinical data from studies in healthy volunteers suggest that the anti-IL-36R antibodies of the invention are safe and tolerable, and may address an unmet medical need in patients with GPP.

[0292] background Mutations in IL36RN are strongly associated with the pathogenesis of generalized pustular psoriasis. The efficacy and safety of the anti-IL-36R antibody of the present invention, a humanized monoclonal antibody that inhibits interleukin-36R signaling, in patients with acute generalized pustular psoriasis was evaluated in this single-dose, open-label, proof-of-concept, Phase I study.

[0293] method Seven patients, three of whom were IL36RN mutation positive, received a single dose of 10 mg / kg of an anti-IL-36R antibody of the present invention intravenously and were monitored for 20 weeks. The primary endpoint was safety; efficacy endpoints included the proportion of patients with a Generalized Pustular Psoriasis Physician's Global Assessment (GPPGA) score of 0 (clear) or 1 (almost clear) and the percentage change from baseline in the Generalized Pustular Psoriasis Area and Severity Index (GPPASI) score at week 2.

[0294] result The anti-IL-36R antibody of the present invention was well tolerated and was not associated with any serious drug-related adverse events or safety signals. At week 1, a GPPGA score of 0 or 1 was achieved in five patients, and by week 4 in all patients. Within 48 hours, pustules had disappeared in three patients, and by week 2, pustules had disappeared in six patients. A large improvement in GPPASI was observed in all patients, with a mean (standard deviation) percent change from baseline at week 2 of 73.2% (16.2); by week 4, this had further decreased to 82.0%. Efficacy was generally maintained up to week 20.

[0295] conclusion Inhibition of the interleukin-36 pathway with a single dose of an anti-IL-36R antibody of the present invention resulted in 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 rapid and sustained remission of clinical symptoms in patients with acute generalized pustular psoriasis, regardless of IL36RN mutation status, without any adverse safety signals.

[0296] Introduction Generalized pustular psoriasis is a rare and severe multi-organ disease, first described in 1909 by von Zumbusch, characterized by intermittent acute flares consisting of a disseminated erythematous and pustular rash, accompanied by systemic symptoms, including fever and often involvement of extradermal organs; in some cases, life-threatening complications may occur. Biologically, high serum C-reactive protein (CRP) levels and leukocytosis with neutrophilia are the most common features, along with abnormal liver tests. Epidemiological studies have reported a low prevalence of 1.76 per million, highlighting the rarity of the disease.

[0297] Therapeutic intervention in generalized pustular psoriasis is a big challenge, and no treatment is currently approved in the United States or Europe.A variety of strategies for psoriasis have been proposed based on the psoriasis vulgaris model, and the efficacy of apheresis and inhibitors of tumor necrosis factor, interleukin-17 and interleukin-23 have been reported in open-label studies and case reports, forming the basis for approval in Japan for generalized pustular psoriasis.However, apheresis is limited to specialized facilities, while the contribution of these important inflammatory cytokines in psoriasis vulgaris to the pathogenesis of generalized pustular psoriasis remains unclear.

[0298] Recently, a great advance in our understanding of the mechanism underlying pustular psoriasis has come from genetic studies that have identified loss-of-function homozygous or compound heterozygous IL36RN gene mutations in some patients with generalized pustular psoriasis. According to a single gene model, these mutations significantly alter the function of the product of IL36RN, namely interleukin-36 receptor antagonist (interleukin-36Ra), resulting in dysregulation of the proinflammatory interleukin-36 (IL-36α, IL-36β, and IL-36γ) pathway, leading to generalized pustular psoriasis. Although these mutations are also found in other pustular psoriasis subtypes, they are not detected in patients with only psoriasis vulgaris, revealing the autoimmune nature of pustular psoriasis and establishing that generalized pustular psoriasis is distinct from plaque psoriasis.

[0299] These immunogenetic insights established the basis for interleukin-36R as a therapeutic target in generalized pustular psoriasis. The results of this first study conducted in human disease with the anti-IL-36R antibody of the present invention, a human monoclonal antibody targeted against interleukin-36R, evaluating safety and efficacy in patients with acute flares of generalized pustular psoriasis are reported. To the best of our knowledge, this is the first study to evaluate treatment in patients with acute generalized pustular psoriasis.

[0300] method Study design This 20-week, multicenter, single-arm, open-label, Phase I, proof-of-concept study enrolled patients from five locations (France, Malaysia, South Korea, Taiwan, and Tunisia). Eligible patients received a single 10 mg / kg dose of an anti-IL-36R antibody of the invention intravenously (IV) and were monitored for 20 weeks.

[0301] patient 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 a previous acute flare complicated by erythema and / or asthma and / or myalgia and / or elevated CRP and / or leukocytosis with neutrophilia, with the presence of pustules and a Physician's Global Assessment for Generalized Pustular Psoriasis (GPPGA) score of 3 or more at the time of treatment (a clinical assessment of the severity of generalized pustular psoriasis based on a modified Physician's Global Assessment [see supplementary material]; a score ranging from 0 [clear skin] to 4 [severe disease]). Patients could continue to receive treatment with subcutaneous retinoids and / or methotrexate.

[0302] Patients were excluded if they had an immediately life-threatening generalized pustular psoriasis flare or acute generalized exanthematous pustulosis (see Table 2 for complete inclusion / exclusion criteria). Consenting patients were enrolled in the study in the absence of a flare. Screening (Visit 1) began days or weeks before admission for treatment of a generalized pustular psoriasis flare (Visit 2). For patients who met the inclusion / exclusion criteria, treatment with BI655130 began the day after Visit 2 (Visit 3).

[0303] [Table 15] TIFF0007673168000041.tif127169

[0304] [Table 16]

[0305] All patients underwent genotyping for IL36RN, CARD14 and AP1S3 mutations.

[0306] Genotyping To identify mutations in IL36RN, CARD14, and AP1S3, targeted resequencing was performed using the Nextera Rapid Capture Custom Enrichment kit (Illumina, San Diego, CA) and an Illumina MiSeq. Sequences were aligned and mapped to the human genome version 19 by MiSeq Reporter (Illumina, San Diego, CA). Mutations were considered likely pathogenic if there was correlation with published functional data or risk associated with generalized pustular psoriasis, or if the mutation was a nonsynonymous substitution or located in a known gene regulatory sequence (e.g., start codon).

[0307] Efficacy and safety evaluation The primary endpoint was the safety and tolerability of the anti-IL-36R antibody of the present invention. Safety assessments included adverse events (coded using the Medical Dictionary for Drug Regulatory Activities, version 20.1), serious adverse events, clinical laboratory assessments, vital signs, infusion reactions, and immunogenicity during the study. The immunogenicity assessment is described in the supplementary material. Secondary outcome measures at week 2 included the percentage change from baseline in the Generalized Pustular Psoriasis Area and Severity Index (GPPASI; a modified composite index based on the Psoriasis Area and Severity Index, (J Dermatolog Treat 2003;14:158-65), whereby the indurated component is replaced by the pustular component; scores range from 0 to 72, with higher scores indicating greater disease severity), the proportion of patients with a GPPGA of 0 (clear) or 1 (almost clear), the change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F; a scale based on 13 questions to monitor fatigue and its effect on the patient; scores range from 0 to 52, with lower scores indicating greater fatigue) scale (J Pain Symptom Manage 1997;13:63-74), and the change from baseline in the Patient Assessment of Pain on a Visual Analog Scale (Pain-VAS). See Table 4 for patient demographics and disease characteristics at baseline.

[0308] [Table 17] TIFF0007673168000044.tif75169

[0309] Other previously specified efficacy endpoints included change from baseline and percent change in pustule severity (based on components of the Generalized Pustular Psoriasis Area and Severity Index), change from baseline and percent change in Generalized Pustular Psoriasis Area and Severity Index, proportion of patients with a Global Assessment Score for Generalized Pustular Psoriasis of 0 or 1, proportion of patients with resolution of edema, change from baseline in body surface area of ​​pustules, and percent change from baseline in severity of erythema (based on components of the Generalized Pustular Psoriasis Area and Severity Index). These included change and percent change from baseline; change from baseline in Functional Assessment of Chronic Disease Therapy-Fatigue and Pain-VAS at weeks 1 and 4; change from baseline in the Psoriasis Symptom Scale (PSS; a four-item patient-reported scale assessing psoriasis pain, redness, itchiness, and burning; symptom severity is rated using a five-point Likert-type scale ranging from 0 (none) to 4 (very severe); a total score is calculated by adding all subscores) score (J Patient-Rep Outcomes 2017;1:4), the proportion of patients with a Psoriasis Symptom Scale total score of 0, and improvement in Clinical Global Impression (an observer-rated scale measuring overall improvement in disease condition based on a seven-point scale; scores range from 1 [much improved] to 7 [much worse]) at weeks 1, 2, and 4 (Jpn J Dermatol 2010;120:815-39). Non-prespecified efficacy outcomes included the proportion of patients achieving ≥50%, ≥75%, and ≥90% improvement in GPPASI over time, and percent change from baseline in scale severity (GPPASI component).

[0310] Photographic documentation of skin lesions was performed at baseline and after treatment. Biochemical, cellular, and pharmacogenomic biomarkers were assessed in skin and whole blood (see below for biomarker methods). Skin biopsies were performed at baseline and week 1 (an additional optional biopsy was performed at week 2).

[0311] Physician Global Assessment (GPPGA) for Generalized Pustular Psoriasis The GPPGA relies on a clinical assessment of the patient's skin symptoms. It is a modified Physician Global Assessment, i.e., a physician's assessment of psoriasis lesions, adapted for the assessment of patients with generalized pustular psoriasis (J Dermatolog Treat 2015;26(1):23-31). The investigator (or qualified site personnel) scores all psoriasis lesions for erythema, pustules, and scaling from 0 to 4. Each component is graded separately, the mean value is calculated, and the final GPPGA is determined from this composite score, where lower scores indicate less severity, 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 symptom requirements.

[0312] Generalized Pustular Psoriasis Area and Severity Index (GPPASI) GPPASI is an adaptation of the PASI (Psoriasis Area and Severity Index), an established measure of the severity and area of ​​psoriatic lesions in patients with psoriasis, for patients with generalized pustular psoriasis (Dermatologica 1978;157(4):238-44). A similar adaptation has been used for palmoplantar pustulosis (J Eur Acad Dermatol Venereol 2009;23(4):415-9). In GPPASI, the induration component is replaced by the pustular component. It is a numerical scoring tool ranging from 0 to 72, relating to the patient's overall generalized pustular psoriasis disease status. It is a linear combination of the % surface area of ​​skin affected (body area score) and the severity of erythema, pustules, and scaling (scoring) on ​​four body regions (head, upper extremities, trunk, and lower extremities) scored on a 5-point scale ranging from 0 [least severe] to 4 [most severe] (see Table 5).

[0313] [Table 18]

[0314] Immunogenicity assessment For the evaluation of anti-drug antibodies, plasma samples of all patients were collected pre-dose and 7, 14, 21, 28, 84 and 140 days after dosing. Samples were analyzed for antibodies against the anti-IL-36R antibodies of the present invention using a validated Mesoscale Discovery® (MSD) drug-bridging electrochemiluminescence (ECL) method with acid dissociation at QPS, LLC (Newark, DE, USA). Anti-drug antibody plasma samples and controls were first diluted with 0.3 M acetic acid, then neutralized with 1.5 M Tris base and a master mix (which contains the biotin-labeled drug and the sulfo-tag-labeled drug), and then transferred and incubated on a blocked MSD streptavidin plate. In the presence of a tripropylamine-containing read buffer, the sulfo-tag generates an electrochemiluminescence signal that is triggered when a voltage is applied using an MSD Sector Imager 600s. The resulting chemiluminescence is measured in relative light units, which are proportional to the amount of anti-drug antibodies present in the plasma sample. The immunogenicity of the anti-IL-36R antibodies of the present invention was evaluated using a three-stage approach.

[0315] All anti-drug antibody samples were first analyzed in an anti-drug antibody screening assay. A sample was determined to be positive for antibodies against the anti-IL-36R antibody of the present invention if its response in the screening assay was higher than or equal to the screening plate specific cut point and if it was confirmed positive in the confirmatory assay (electrochemiluminescence response was inhibited above the confirmatory cut point by addition of excess anti-IL-36R antibody of the present invention). Samples confirmed to be positive for antibodies against the anti-IL-36R antibody of the present invention were further characterized in a titration assay. Titers were determined by analysis of two-fold serial dilutions of the sample. The reported titer was the highest dilution that produced an electrochemiluminescence mean value higher than or equal to the plate specific titration cut point.

[0316] Validation by anti-drug antibody assay demonstrated that the sensitivity of the screening assay in plasma of generalized pustular psoriasis was 2.5ng / ml using rabbit polyclonal antibody positive control against the anti-IL-36R antibody of the present invention. Furthermore, the positive control levels of 100 and 250ng / mL were detected in the presence of at least 2000μg / mL of the anti-IL-36R antibody of the present invention. None of the anti-drug antibody samples had levels of the anti-IL-36R antibody of the present invention exceeding 2000μg / mL. The assay performance data showed that the method was reliable for screening, confirming, and determining the titer of antibodies against the anti-IL-36R antibody of the present invention in plasma samples from patients in this study.

[0317] Biomarker evaluation Assessment of CRP levels (non-high sensitivity) and absolute neutrophil counts was performed using standard methods by local laboratories. Samples for assessment were collected at baseline before treatment initiation and on days 7, 14, and 28.

[0318] Pharmacogenomic Biomarker Evaluation Comprehensive transcriptome-wide sequencing of RNA from lesional and non-lesional skin biopsies and whole blood from all patients was accomplished using an Illumina Hi-Seq3000 (Illumina, San Diego, CA). Data were normalized by TMM using the edgeR package; log2 fold changes and corresponding false discovery rate corrected p-values ​​were analyzed using the limma package (Bioconductor, USA) (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 double correlation function. Linear models were fitted using the ImFit function and adjusted t-statistics for lesioned vs. non-lesioned and pre- vs. post-treatment with an anti-IL-36R antibody of the invention were computed (Nucleic Acids Res 2015;43(15):e97; Genome Biol 2014;15(2):R29). A corrected p-value of <0.05 was considered significant.

[0319] statistical analysis Due to its small sample size and the absence of a comparator, the study did not test any statistical hypotheses. The endpoints are described in their entirety and evaluated by descriptive statistics. Safety analyses included all treated patients (full analysis set; FAS); efficacy analyses were performed using patients with available baseline measurements and at least one post-baseline measurement for either GPPASI or GPPGA; biomarker analyses were performed using all treated patients with at least one observation for at least one biomarker matrix. Imputation of non-response was used for binary efficacy endpoints after the use of rescue medication; for continuous endpoints, only observations collected before the use of rescue medication were summarized. One patient received rescue medication during the study, and therefore data after this use (after week 4) are treated as described.

[0320] result patient Among 16 patients screened in the five study sites, seven patients (three males and four females, age 22-58 years) who experienced moderate to severe acute flares received a single dose of 10 mg / kg of the anti-IL-36R antibody of the present invention intravenously between February and August. Baseline demographic data and disease characteristics are reported in Table 3. Two patients had a homozygous loss-of-function IL36RN mutation (rs387906914 / p.Leu27Pro) known to cause generalized pustular psoriasis, and one patient had a mutation that may cause generalized pustular psoriasis, including a homozygous IL36RN mutation (rs148755083) and a heterozygous CARD14 mutation (rs117360605 / p.Arg275His). The mean (standard deviation) time from first diagnosis for all patients was 16.4 (16.8) years. All patients presented with moderate flares, characterized by a GPPGA score of 3 and a pustular subscore of 2 to 4 (moderate to very high density). The mean (standard deviation) time interval between the onset of the current flare and the infusion of the anti-IL-36R antibody of the present invention was 5.3 (7.4) days (range: 0 to 18 days). All patients received prior systemic treatment for generalized pustular psoriasis, which was discontinued before receiving the anti-IL-36R antibody of the present invention; cyclosporine was discontinued 30 days before administration of the anti-IL-36R antibody of the present invention. All patients completed the study by week 20, but there were two protocol violations: one patient (patient 8201002) did not meet the inclusion criteria for having a known history of generalized pustular psoriasis, but met the other inclusion criteria, and a second patient (patient 6001004) received methotrexate at week 4 for the treatment of "pain." Both patients were included in the full analysis set (FAS), but for patient 6001004, only efficacy data through week 4 are included.

[0321] safety By week 20, four patients (57.1%) were considered to have had drug-related adverse events (Table 6); all were graded as mild or moderate. No severe or serious adverse events were reported. After treatment with the anti-IL-36R antibody of the present invention, clinical laboratory parameters were normal in the majority of patients, with two patients (28.6%) having low hemoglobin values; two patients (14.3%) exhibiting elevated eosinophils, one patient exhibiting elevated creatine kinase, two patients exhibiting elevated triglycerides, and one patient exhibiting low blood glucose levels. Three patients (42.9%) exhibited positive anti-drug antibodies at week 2 that persisted through week 20, with two patients showing maximum titers at week 12; no pre-existing anti-drug antibodies were detected.

[0322] [Table 19]

[0323] Effectiveness Clinical endpoints A GPPGA score of 0 or 1 was achieved in 5 patients (71.4%) as early as week 1 and in all patients by week 4 after administration of a single dose of an anti-IL-36R antibody of the invention (Figure 1A).

[0324] A significant improvement in GPPASI was observed very early in all patients, with a mean (standard deviation) percent change from baseline of 73.2% (16.2) at week 2 (Figure 1B); by week 4, this had further decreased to 79.8% and was maintained until week 20 (83.6%). Within 48 hours of treatment, pustules had completely disappeared in three patients (42.9%); pustules had disappeared in five patients (71.4%) by week 1 and in six patients (85.7%) by week 2 (Figure 1C). By week 1, 85.7% of patients had achieved GPPASI50, by week 4, 71.4% of patients had achieved GPPASI75, and by week 12, 57.1% of patients had achieved GPPASI90 (Figure 2). The mean GPPASI erythema subscore decreased by 27.8%, 48.3%, and 53.5% from baseline at weeks 1, 2, and 4, respectively. Similarly, the mean GPPASI scaling subscore decreased by 38.1%, 49.6%, and 57.1% from baseline at weeks 1, 2, and 4, respectively (Figure 3).

[0325] Patient-reported outcomes The mean (SD) improvement in FACIT-F from baseline to week 2 was 12.3 (10.1) and was maintained through week 4 (Figure 4). For Pain-VAS, the mean (SD) change from baseline to week 2 was -45.9 (32.3) and was maintained through week 4 (Figure 5). Similarly, the mean (SD) change from baseline in PSS at week 2 was -5.14 (3.18) and was also maintained through week 4 (Figure 6).

[0326] Biomarker analysis A rapid decrease in CRP approaching normalization was observed with a mean (standard deviation) CRP change of -64.2 (55.1) mg / dl from baseline to week 2, which was maintained through week 4 (Figure 7). Absolute neutrophil counts rapidly decreased by week 2 and were maintained through week 4 (Figure 8).

[0327] Global transcriptome analysis of lesional and non-lesional skin biopsies revealed that 3276 genes were differentially expressed (1885 increased; 1391 decreased) between lesional and non-lesional skin biopsies at baseline (corrected P value ≦0.05, fold change ≧2). After 7 days of treatment with the anti-IL-36R antibodies of the invention, expression of 1444 genes in lesional skin was strongly up- or down-regulated, reaching nearly non-lesional skin levels; differentially expressed genes were associated with innate inflammation (e.g., IL6, TNF, and CXCL1) and Th1 / Th17-mediated inflammation (e.g., IL1B, IL12B, and IL23A) and inflammation-induced keratinocyte activation processes (e.g., IL17C and IL24) (Table 7).

[0328] [Table 20]

[0329] In all patients, IL-36α, IL-36γ and IL-8 were strongly increased in lesional skin biopsies; 7 days after treatment with the anti-IL-36R antibodies of the invention, IL-36α and IL-36γ expression was strongly decreased in 4 patients, whereas IL-8 was strongly decreased in 3 patients (fold change > 2). Whole blood RNA expression detected differentially expressed genes (corrected P value < 0.05, fold change > 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 the most strongly downregulated genes (Table 8).

[0330] [Table 21]

[0331] Consideration This first-in-human disease study investigating the safety and efficacy of the anti-IL-36R antibody of the present invention, an anti-interleukin-36R human monoclonal antibody, investigated patients with generalized pustular psoriasis due to significant disease burden, high unmet need, and solid evidence that interleukin-36 dysregulation is responsible for skin and systemic inflammation in this syndrome. Indeed, the absence or impairment of interleukin-36Ra due to mutations in IL36RN causes generalized pustular psoriasis, but the incidence of such mutations varies in different populations, ranging from 5% to 70%, which identifies a novel autoinflammatory syndrome called DITRA (Deficiency of Interleukin-36 Receptor Antagonist). The relevance of interleukin-36 inhibition strategies in generalized pustular psoriasis is strengthened by the genetically engineered mouse model of DITRA and by the advanced knowledge of human interleukin-36R structure and function, which allows the production of the anti-IL-36R antibodies of the present invention, which inhibit the inflammatory effects of interleukin-36. The results of this proof-of-concept study demonstrated rapid systemic inflammation resolution and efficacy, with 5 out of 7 patients having no or almost no inflammation one week after infusion of the anti-IL-36R antibodies of the present invention, and all patients achieving this state by the 4th week. The evaluation of efficacy at these early time points was specifically designed to avoid misattributing the naturally self-resolving course of generalized pustular psoriasis flares, which usually occurs over weeks to months, to drug intervention (in this single-arm study), a characteristic of the disease that limits the impact of testing many therapeutic agents for generalized pustular psoriasis with efficacy endpoints at later time points (Br J Dermatol 1968;80:771-93). Similarly, the proposed successful treatment with a variety 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 and striking response pattern of both cutaneous and systemic components suggests that inhibition of interleukin-36R with a single dose of the anti-IL-36R antibody of the present invention results in rapid and sustained quiescence of the inflammatory cascade in generalized pustular psoriasis. These early responses were also reflected in rapid improvements in patient-reported endpoints (FACIT-F, pain-VAS, and PSS). Another important observation was the similar efficacy observed in patients with and without IL36RN mutations, supporting the recent hypothesis that interleukin-36 cytokines are involved in skin inflammation not only among pustular psoriasis subtypes with different genetic backgrounds, but possibly also in plaque psoriasis lesions. Rapid improvement of clinical endpoints was reflected by the rapid improvement of gene expression profile of skin lesions to near-normal skin levels within 7 days, highlighting the central role of the interleukin-36 pathway in this disease. Differentially expressed genes in whole blood by day 28 support a sustainable and long-lasting clinical effect of a single dose of the anti-IL-36R antibody of the invention.

[0332] Regarding tolerability, besides previous safety data in 124 healthy trial volunteers (unpublished data), no obvious safety signals emerged from the treatment were identified, which is consistent with the recent characterization of individuals with an IL36R knockout mutation resulting in a complete absence of interleukin-36R, without evidence of an increased risk of superinfection and without any significant effect on the innate and adaptive immune responses (Sci Transl Med 2017;9).

[0333] Given the small number of patients in the study, no clear association was detected between any changes in safety or efficacy and immunogenicity.

[0334] Considering the limitations associated with proof-of-concept trials (short-term, few open-label trials) in rare diseases, these results of interleukin-36R inhibition with a single dose of the anti-IL-36R antibody of the present invention provide promising prospects for the treatment of generalized pustular psoriasis.A larger randomized controlled trial is underway to confirm these findings.The results of the current trial also provide further support for the hypothesis that inhibition of interleukin-36 pathway may also be beneficial in pustular psoriasis other than patients with IL36RN mutation.

[0335] In conclusion, inhibition of the interleukin-36 pathway following administration of a single dose of an anti-IL-36R antibody of the invention resulted in rapid and sustained remission of clinical symptoms in patients with acute generalized pustular psoriasis without any adverse safety signals.

[0336] Example 2: A multicenter, double-blind, randomized, placebo-controlled, phase II study to evaluate the efficacy, safety, and tolerability of an anti-IL-36R antibody of the present invention in patients with generalized pustular psoriasis (GPP) presenting with acute flares of moderate to severe intensity Current treatment options for controlling acute generalized pustular psoriasis, completely remitting symptoms, and preventing recurrence of flares are limited and do not provide sustained efficacy. There are currently no treatments approved for generalized pustular psoriasis in the United States and Europe, but combinations of retinoids, cyclosporine, or methotrexate are recommended as the main options for controlling exacerbations of chronic generalized pustular psoriasis. However, the long-term use of these treatments is limited by side effects and contraindications (retinoids: teratogenicity, hair loss; cyclosporine: excessive hair growth, nephrotoxicity; methotrexate: hepatotoxicity). Side effects such as hair loss, excessive hair growth, and teratogenicity particularly limit the use of these treatments in women. Biologics (mainly TNF inhibitors, occasionally IL-1 inhibitors or IL-17 inhibitors) are increasingly being used to treat patients with more severe, widespread, or treatment-resistant generalized pustular psoriasis, based on a small number of published case series. However, these drugs also have limitations in efficacy (frequent incomplete and delayed responses) and safety (risk of infection and infusion reactions).

[0337] Based on the above limitations, current treatment options are not suitable for long-term treatment and do not provide sustained responses in the majority of patients. Therefore, to address the high unmet need in generalized pustular psoriasis, there is a critical need to (i) develop a highly effective treatment that shows rapid onset of action for patients presenting with acute GPP flares; and (ii) develop an effective treatment that reliably reduces the occurrence of flares, results in complete remission of symptoms such as widespread erythema and scaling, and is safe and tolerable for lifelong treatment. Furthermore, a search of the current literature did not yield any published studies focused on moderate to severe generalized pustular psoriasis flares. Therefore, our proof-of-concept approach and subsequent development plan will further address the need for treatment options in generalized pustular psoriasis.

[0338] The strong genetic link between the IL36 signaling pathway and generalized pustular psoriasis and experimental data identifying IL-36 as the main cytokine driving generalized pustular psoriasis suggests that inhibition of IL36R signaling with a humanized anti-IL-36R antibody, i.e., the anti-IL-36R antibody of the present invention, may be beneficial in treating generalized pustular psoriasis, which is similar to the strong response seen in IL1R antagonist-deficient patients with aseptic multifocal osteomyelitis after treatment with anakinra. Furthermore, recent characterization of individuals with homozygous IL36R knockout mutations has found widespread preservation of normal immune function, suggesting that inhibition of the IL36 signaling pathway does not impair host defense.

[0339] Based on this rationale, an open-label, single-arm study was conducted to investigate the proof-of-concept of a single dose of the anti-IL-36R antibody of the present invention in patients with generalized pustular psoriasis. A total of seven patients were treated with a single intravenous dose of 10 mg / kg of the anti-IL-36R antibody of the present invention.

[0340] As described above, inhibition of IL36R activity leads to rapid and sustained improvement in the skin and systemic symptoms of generalized pustular psoriasis.In the patients tested, the anti-IL-36R antibody of the present invention was well tolerated.Only mild or moderate adverse events were reported throughout the 20-week test period.Moreover, no severe or serious adverse events were reported.

[0341] Based on these results, the objective of this follow-on generalized pustular psoriasis study is to evaluate the efficacy, safety and tolerability of an anti-IL-36R antibody of the invention compared to placebo in patients with generalized pustular psoriasis presenting with moderate to severe acute flares.

[0342] To allow further scientific questions to be addressed, patients will be asked if they would be willing to donate a biospecimen for deposit. If the patient agrees, the deposited sample can be used for future biomarker research and drug development programs, for example to identify patients more likely to benefit from treatment or more likely to experience adverse events (AEs), or to perform mechanistic or genetic elucidation of the effects of drugs, thereby better matching therapeutic approaches to patients.

[0343] Study objectives and evaluation items Main Objective To evaluate the efficacy, safety and tolerability of anti-IL-36R antibodies of the present invention in patients with generalized pustular psoriasis (GPP) presenting with moderate to severe acute flares.

[0344] Clinical trial protocol overview [Table 22] TIFF0007673168000050.tif229169 TIFF0007673168000051.tif230169 TIFF0007673168000052.tif101169

[0345] This study will be a single-dose placebo-controlled study of patients with moderate to severe acute GPP flares receiving 900 mg of the anti-IL-36R antibody of the present invention followed by an additional 12 weeks of follow-up. Patients who meet the inclusion / exclusion criteria for the subsequent open-label extension study will have the option to continue receiving treatment for GPP with subcutaneous dosing. See Figure 9 for further details on the study design.

[0346] Example 3: Treatment of patients with acute GPP flare In this example, an anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the present invention) is used to treat patients with acute GPP flare. Initially, each patient has one or more of the selection criteria listed in Example 2. A single dose of 900 mg of an anti-IL-36R antibody of the present invention (at 60 mg / mL in solution for infusion) is administered to each patient.

[0347] Following administration of an anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the invention), safety and efficacy evaluation reveals: 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%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 109%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 4%, 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% had (a) generalized abscesses at week 1 (b) a Global Psoriasis Profile Assessment (GPPGA) score of 0 or 1; (b) a GPPGA pustule formation subscore of 0 at week 1 (indicating no visible pustules); (c) a Generalized Pustular Psoriasis Area and Severity Index (GPPASI) of 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 chronic disease at week 4. Achieve clinical remission as defined by: (a) change from baseline in Functional Assessment of Patient Treatment and Fatigue (FACIT) score; (b) GPPGA score of 0 or 1 at week 4; (c) GPPGA pustule formation subscore of 0 at week 4 (indicating no visible pustules); (d) GPPASI score of 50 at weeks 1 and 4; or (e) change from baseline in GPPASI pustule, erythema, or scaling severity subscores at weeks 1 and 4 of treatment. The proportion of patients who respond to treatment is statistically significantly higher compared to placebo patients for one or more of endpoints (a) through (j).

[0348] Example 4: Prevention of recurrent flares in GPP patients In this example, a single dose of 900 mg (intravenous) of an anti-IL-36R antibody of the invention (at 60 mg / mL in solution for infusion) is used to treat a patient with an acute GPP flare. Following the intravenous dose, an additional subcutaneous dose of anti-IL-36R antibody is administered to prevent recurrence of GPP flares, as shown in Table 1.

[0349] Following administration of the last dose of an anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the invention), at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of patients remain in clinical remission as judged by a GPPGA score of 0 or 1 at weeks 12, 24, 36, 48, 60 or 72. The improved response is maintained in a higher proportion with the anti-IL-36R antibody of the 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%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 108%, 109%, 101% %, 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% maintain improved response 12, 24, 36, 48, 60, or 72 weeks after the last dose of anti-IL-36R antibody is administered compared to placebo.

[0350] Following administration of the last dose of an anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the invention), at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of patients remain in clinical remission as judged by change in GPPASI from baseline at weeks 12, 24, 36, 48, 60 or 72. The improved response is maintained in a higher proportion with the anti-IL-36R antibody of the 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%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 108%, 109%, 101% %, 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% maintain improved response 12, 24, 36, 48, 60, or 72 weeks after the last dose of anti-IL-36R antibody is administered compared to placebo.

[0351] Following administration of the last dose of an anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the invention), at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of patients remain in clinical remission as judged by change from baseline in GPPASI pustule, erythema, or scaling severity subscores from baseline at weeks 12, 24, 36, 48, 60 or 72. The improved response is maintained in a higher proportion with the anti-IL-36R antibody of the 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%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 108%, 109%, 101% %, 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% maintain improved response 12, 24, 36, 48, 60, or 72 weeks after the last dose of anti-IL-36R antibody is administered compared to placebo.

[0352] Example 5: Achieving complete remission of GPP symptoms in GPP patients In this example, a single dose of 900 mg (intravenous) of an anti-IL-36R antibody of the invention (at 60 mg / mL in solution for infusion) is used to treat a patient with an acute GPP flare. Following the intravenous dose, additional subcutaneous doses of anti-IL-36R antibody are administered to achieve complete remission of GPP symptoms in the patient, as shown in Table 1.

[0353] Following administration of the last dose of anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the invention), at least 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80% of patients achieve remission of GPP symptoms as judged by a GPPGA score of 0 at weeks 12, 24, 36, 48, 60 or 72. The improved efficacy is maintained at a higher rate with the anti-IL-36R antibody of the 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%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109%, 109%, 108%, 109%, 101% %, 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% maintain improved response 12, 24, 36, 48, 60, or 72 weeks after the last dose of anti-IL-36R antibody is administered compared to placebo.

[0354] Although specific aspects and embodiments of the invention have been described, they are offered 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 wide 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.

[0355] All patents and / or publications (including journal articles) cited in this disclosure are expressly incorporated herein by reference.

Claims

1. A pharmaceutical formulation for reducing or alleviating the signs and symptoms of acute generalized pustular psoriasis (GPP) outbreaks in a patient, or for reducing the severity and duration of GPP flares in a patient, wherein the formulation, when in the form of an aqueous solution or when reconstituted with water, 1. A pharmaceutical formulation comprising an anti-IL-36R antibody present at a concentration in the range of 0.5 mg / mL to 220 mg / mL, and a pharma- ceutically acceptable buffer present at a concentration in the range of 20 mM to 80 mM, characterized by a pH in the range of 5 to 8, wherein said anti-IL-36R antibody comprises 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.

2. 2. The pharmaceutical formulation of claim 1, wherein the anti-IL-36R antibody comprises 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.

3. 3. The pharmaceutical formulation according to claim 1 or 2, wherein the formulation is in liquid or powder form.

4. 3. The pharmaceutical formulation of claim 1 or 2, wherein the anti-IL-36R antibody is present at a concentration in the range of 10 mg / mL to 200 mg / mL.

5. 3. The pharmaceutical formulation of claim 1 or 2, wherein the anti-IL-36R antibody is present at a concentration of 20 mg / mL.

6. 3. The pharmaceutical formulation of claim 1 or 2, wherein the anti-IL-36R antibody is present at a concentration of 60 mg / mL.

7. 3. The pharmaceutical formulation of claim 1 or 2, wherein the anti-IL-36R antibody is present at a concentration of 150 mg / mL.

8. 3. The pharmaceutical formulation of claim 1 or 2, wherein the buffer comprises histidine, phosphate, succinate, citrate, acetate, or Tris.

9. 3. The pharmaceutical formulation of claim 1 or 2, wherein the buffer comprises a citrate or acetate salt.

10. 3. The pharmaceutical formulation of claim 1 or 2, wherein the buffer comprises histidine.

11. 3. The pharmaceutical formulation of claim 1 or 2, wherein the buffer comprises an acetate salt.

12. 3. The pharmaceutical formulation of claim 1 or 2, wherein the formulation further comprises a pharma- ceutically acceptable tonicity agent present in a concentration in the range of 100 mM to 250 mM.

13. 13. The pharmaceutical formulation of claim 12, wherein the isotonicity agent is one or more sugars and / or polyols.

14. The one or more sugars and / or polyols are selected from the group consisting of sucrose, trehalose, sorbitol, magnesium sulfate (MgSO ４ ), glycerol, mannitol or dextrose.

15. 13. The pharmaceutical formulation of claim 12, wherein the tonicity agent comprises sucrose or trehalose.

16. 13. The pharmaceutical formulation of claim 12, wherein the tonicity agent comprises sucrose.

17. 13. The pharmaceutical formulation of claim 12, wherein the tonicity agent comprises trehalose.

18. 3. The pharmaceutical formulation of claim 1 or 2, wherein the formulation further comprises a pharma- ceutically acceptable stabilizer present in a concentration ranging from 0 mM to 80 mM.

19. 20. The pharmaceutical formulation of claim 18, wherein the stabilizer comprises an amino acid, or a pharma- ceutically acceptable salt thereof.

20. 19. The pharmaceutical formulation of claim 18, wherein the stabilizer comprises L-arginine or a pharma- ceutically acceptable salt thereof.

21. 3. The pharmaceutical formulation of claim 1 or 2, wherein the formulation further comprises a pharma- ceutically acceptable salt present in a concentration in the range of 0 to 150 mM.

22. Salts include sodium chloride (NaCl), magnesium chloride (MgCl ２ ), potassium chloride (KCl), lithium chloride (LiCl), calcium chloride (CaCl ２ ), borate or zinc chloride (ZnCl ２ 22. The pharmaceutical formulation of claim 21 , comprising:

23. 22. The pharmaceutical formulation of claim 21, wherein the salt comprises sodium chloride (NaCl).

24. 3. The pharmaceutical formulation of claim 1 or 2, wherein the formulation further comprises a pharma- ceutically acceptable surfactant present in a concentration ranging from 0 g / L to 1.5 g / L.

25. 25. The pharmaceutical formulation of claim 24, wherein the surfactant comprises poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

26. 25. The pharmaceutical formulation of claim 24, wherein the surfactant comprises polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

27. 25. The pharmaceutical formulation of claim 24, wherein the surfactant comprises polysorbate 20.

28. 25. The pharmaceutical formulation of claim 24, wherein the surfactant comprises polysorbate 80.

29. A pharmaceutical formulation for reducing or alleviating the signs and symptoms of acute generalized pustular psoriasis (GPP) outbreaks in a patient, or for reducing the severity and duration of GPP flares in a patient, wherein the formulation, when in the form of an aqueous solution or when reconstituted with water, a. an anti-IL-36R antibody comprising 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, present at a concentration ranging from 10 mg / mL to 200 mg / mL; b. acetate and / or histidine buffer, present at a concentration ranging from 20 mM to 80 mM; c. sucrose and / or trehalose, present at a concentration ranging from 100 mM to 250 mM; d. L-arginine and / or a pharma- ceutically acceptable salt thereof, present at a concentration ranging from 0 mM to 80 mM; e. Sodium chloride (NaCl), present at a concentration ranging from 0 to 150 mM; and f. Polysorbate 20 and / or Polysorbate 80, present in a concentration ranging from 0 g / L to 1.5 g / L and characterized by a pH in the range of 5 to 7.

30. A pharmaceutical formulation for reducing or alleviating the signs and symptoms of an acute generalized pustular psoriasis (GPP) outbreak in a patient, or for reducing the severity and duration of a GPP flare in a patient, wherein the formulation, when in the form of an aqueous solution or when reconstituted with water, a. an anti-IL-36R antibody comprising 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, present at a concentration of 20 mg / mL; b. Citrate buffer, present at a concentration of 25 mM; c. sucrose and / or trehalose, present at a concentration of 200 mM; and d. Polysorbate 80, present at a concentration of 0.4 g / L and characterized by a pH in the range of 6 to 7.

31. A pharmaceutical formulation for reducing or alleviating the signs and symptoms of an acute generalized pustular psoriasis (GPP) outbreak in a patient, or for reducing the severity and duration of a GPP flare in a patient, wherein the formulation, when in the form of an aqueous solution or when reconstituted with water, a. an anti-IL-36R antibody comprising 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, present at a concentration of 60 mg / mL; b. Acetate buffer, present at a concentration of 45 mM; c. sucrose and / or trehalose, present at a concentration of 150 mM; d. L-arginine or a pharma- ceutically acceptable salt thereof, present at a concentration of 25 mM; and e. Polysorbate 20 present at a concentration of 0.4 g / L and characterized by a pH in the range of 5 to 6.

32. A pharmaceutical formulation for reducing or alleviating the signs and symptoms of an acute generalized pustular psoriasis (GPP) outbreak in a patient, or for reducing the severity and duration of a GPP flare in a patient, wherein the formulation, when in the form of an aqueous solution or when reconstituted with water, a. an anti-IL-36R antibody comprising 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, present at a concentration of 150 mg / mL; b. Acetate buffer, present at a concentration of 45 mM; c. sucrose or trehalose, present at a concentration of 150 mM; d. L-arginine or a pharma- ceutically acceptable salt thereof, present at a concentration of 25 mM; and e. Polysorbate 20 present at a concentration of 0.4 g / L and characterized by a pH in the range of 5 to 6.

33. 33. A pharmaceutical formulation according to any one of claims 1 to 32, wherein the formulation is characterised by an osmolarity in the range of 210 mOsmol / kg to 390 mOsmol / kg.

34. The pharmaceutical formulation of any one of claims 1 to 33, wherein less than 5% of the antibody is present in the formulation in the form of aggregates.

35. The pharmaceutical formulation of any one of claims 1 to 34, wherein the formulation is sterile.

36. The pharmaceutical formulation of any one of claims 1 to 35, wherein the formulation is stable when frozen and thawed.

37. A pharmaceutical formulation according to any one of claims 1 to 36, wherein the formulation, in liquid form or when reconstituted with water, has a pH of from 5 to 6.

38. A pharmaceutical formulation according to any one of claims 1 to 37, wherein the formulation has a pH of 6 in liquid form or when reconstituted with water.

39. The formulation, compared to the reference formulation, (i) an extended validity period; (ii) better stability to temperature; (iii) reduced aggregate formation; (iv) better stability to chemicals, and (v) reduced viscosity 39. The pharmaceutical formulation of any one of claims 1 to 38, having at least one feature selected from the group consisting of:

40. The formulation, compared to the reference formulation, (a) a reduction in the proportion of aggregates as determined by high performance size exclusion chromatography (HP-SEC); (b) a higher proportion of monomer as judged by HP-SEC; (c) a higher proportion of the main peak (less resolution of the charge variants) as judged by cation exchange; (d) a lower proportion of sub-visible particles, such as 10 μm or larger and 25 μm or larger; and (e) Lower turbidity values ​​in Formazin Nephelometric Units (FNU) after storage at 40°C 40. The pharmaceutical formulation of any one of claims 1 to 39, having at least one feature selected from the group consisting of:

41. 1. A pharmaceutical formulation for reducing or alleviating signs and symptoms of acute generalized pustular psoriasis (GPP) outbreaks in a patient or for reducing the severity and duration of GPP flares in a patient comprising an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127, wherein the formulation comprises: I. A formulation comprising 20 mg / mL anti-IL-36R antibody, 40 mM histidine, 120 mM sucrose, 50 mM L-arginine, 5 mM NaCl, and 1.0 g / L polysorbate 20, pH 6.0; II. A formulation comprising 60 mg / mL anti-IL-36R antibody, 45 mM acetate, 150 mM sucrose, 25 mM L-arginine, 0.4 g / L polysorbate 20, pH 5.5; III. A formulation containing 20 mg / mL anti-IL-36R antibody, 45 mM acetate, 180 mM sucrose, 25 mM glycine, 0.4 g / L polysorbate 80, pH 5.5; IV. A formulation containing 150 mg / mL anti-IL-36R antibody, 25 mM citrate, 150 mM trehalose, 25 mM methionine, 0.2 g / L polysorbate 20, pH 6.0; V. A formulation comprising 150 mg / mL anti-IL-36R antibody, 25 mM histidine, 180 mM sucrose, 20 mM mannitol, 0.2 g / L polysorbate 20, pH 6.5; VI. A formulation comprising 20 mg / mL anti-IL-36R antibody, 25 mM citrate, 200 mM sucrose, 0.4 g / L polysorbate 80, pH 6.5; VII. A formulation comprising 150 mg / mL anti-IL-36R antibody, 45 mM acetate, 150 mM sucrose, 25 mM L-arginine, 0.4 g / L polysorbate 20, pH 5.5; VIII. A formulation comprising 15 mg / mL anti-IL-36R antibody, 35 mM histidine, 180 mM trehalose, 25 mM L-arginine, 3 mM NaCl, 0.4 g / L polysorbate 80, pH 6.0; IX. A formulation comprising 80 mg / mL anti-IL-36R antibody, 25 mM acetate, 100 mM mannitol, 50 mM NaCl, 0.2 g / L polysorbate 20, pH 5.5; X. A formulation comprising 100 mg / mL anti-IL-36R antibody, 20 mM succinate, 220 mM sucrose, 0.1 g / L polysorbate 80, pH 6.0; and XI. Formulation containing 60 mg / mL anti-IL-36R antibody, 25 mM citrate, 0.4 g / L polysorbate 20, pH 6.5 Selected from the group consisting of: Pharmaceutical preparations.

42. 1. A pharmaceutical formulation for reducing or alleviating signs and symptoms of an acute generalized pustular psoriasis (GPP) outbreak in a patient, or for reducing the severity and duration of a GPP flare in a patient, comprising an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO:118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:127, wherein the formulation comprises 20 mg / mL of the anti-IL-36R antibody, 40 mM histidine, 120 mM sucrose, 50 mM L-arginine, 5 mM NaCl, and 1.0 g / L polysorbate 20, at a pH of 6.

0.

43. 1. A pharmaceutical formulation for reducing or alleviating signs and symptoms of acute generalized pustular psoriasis (GPP) outbreaks in a patient, or for reducing the severity and duration of GPP flares in a patient, comprising an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO:118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:127, wherein the formulation comprises 60 mg / mL anti-IL-36R antibody, 45 mM acetate, 150 mM sucrose, 25 mM L-arginine, 0.4 g / L polysorbate 20, and has a pH of 5.

5.

44. 1. A pharmaceutical formulation for reducing or alleviating signs and symptoms of an acute generalized pustular psoriasis (GPP) outbreak in a patient, or for reducing the severity and duration of a GPP flare in a patient, comprising an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO:118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:127, wherein the formulation comprises 20 mg / mL of the anti-IL-36R antibody, 45 mM acetate, 180 mM sucrose, 25 mM glycine, 0.4 g / L polysorbate 80, and has a pH of 5.

5.

45. 1. A pharmaceutical formulation for reducing or alleviating signs and symptoms of acute generalized pustular psoriasis (GPP) outbreaks in a patient, or for reducing the severity and duration of GPP flares in a patient, comprising an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO:118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:127, wherein the formulation comprises 150 mg / mL anti-IL-36R antibody, 25 mM citrate, 150 mM trehalose, 25 mM methionine, 0.2 g / L polysorbate 20, and pH 6.

0.

46. 1. A pharmaceutical formulation for reducing or alleviating signs and symptoms of acute generalized pustular psoriasis (GPP) outbreaks in a patient, or for reducing the severity and duration of GPP flares in a patient, comprising an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO:118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:127, wherein the formulation comprises 150 mg / mL of the anti-IL-36R antibody, 25 mM histidine, 180 mM sucrose, 20 mM mannitol, 0.2 g / L polysorbate 20, and has a pH of 6.

5.

47. 1. A pharmaceutical formulation for reducing or alleviating signs and symptoms of acute generalized pustular psoriasis (GPP) outbreaks in a patient, or for reducing the severity and duration of GPP flares in a patient, comprising an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO:118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:127, wherein the formulation comprises 20 mg / mL anti-IL-36R antibody, 25 mM citrate, 200 mM sucrose, 0.4 g / L polysorbate 80, and has a pH of 6.

5.

48. 1. A pharmaceutical formulation for reducing or alleviating signs and symptoms of acute generalized pustular psoriasis (GPP) outbreaks in a patient, or for reducing the severity and duration of GPP flares in a patient, comprising an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO:118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:127, wherein the formulation comprises 150 mg / mL anti-IL-36R antibody, 45 mM acetate, 150 mM sucrose, 25 mM L-arginine, 0.4 g / L polysorbate 20, and has a pH of 5.

5.

49. 1. A pharmaceutical formulation for reducing or alleviating signs and symptoms of acute generalized pustular psoriasis (GPP) outbreaks in a patient, or for reducing the severity and duration of GPP flares in a patient, comprising an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO:118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:127, wherein the formulation comprises 15 mg / mL of the anti-IL-36R antibody, 35 mM histidine, 180 mM trehalose, 25 mM L-arginine, 3 mM NaCl, 0.4 g / L polysorbate 80, and has a pH of 6.

0.

50. 1. A pharmaceutical formulation for reducing or alleviating signs and symptoms of acute generalized pustular psoriasis (GPP) outbreaks in a patient, or for reducing the severity and duration of GPP flares in a patient, comprising an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO:118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:127, wherein the formulation comprises 80 mg / mL anti-IL-36R antibody, 25 mM acetate, 100 mM mannitol, 50 mM NaCl, 0.2 g / L polysorbate 20, and has a pH of 5.

5.

51. 1. A pharmaceutical formulation for reducing or alleviating signs and symptoms of an acute generalized pustular psoriasis (GPP) outbreak in a patient, or for reducing the severity and duration of a GPP flare in a patient, comprising an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO:118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:127, wherein the formulation comprises 100 mg / mL anti-IL-36R antibody, 20 mM succinate, 220 mM sucrose, 0.1 g / L polysorbate 80, and has a pH of 6.

0.

52. 1. A pharmaceutical formulation for reducing or alleviating signs and symptoms of acute generalized pustular psoriasis (GPP) outbreaks in a patient, or for reducing the severity and duration of GPP flares in a patient, comprising an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO:118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:127, wherein the formulation comprises 60 mg / mL anti-IL-36R antibody, 25 mM citrate, 0.4 g / L polysorbate 20, and has a pH of 6.

5.

53. 1. A pharmaceutical formulation for reducing or alleviating signs and symptoms of acute generalized pustular psoriasis (GPP) outbreaks in a patient or for reducing the severity and duration of GPP flares in a patient comprising an anti-IL-36R antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 127, wherein the formulation comprises: I. A formulation comprising 20 mg / mL to 150 mg / mL of anti-IL-36R antibody, 40 mM histidine, 120 mM sucrose, 50 mM L-arginine, 5 mM NaCl, and 1.0 g / L polysorbate 20, pH 6.0; II. A formulation comprising 20 mg / mL to 150 mg / mL of anti-IL-36R antibody, 45 mM acetate, 150 mM sucrose, 25 mM L-arginine, 0.4 g / L polysorbate 20, pH 5.5; III. A formulation comprising 20 mg / mL to 150 mg / mL of an anti-IL-36R antibody, 45 mM acetate, 180 mM sucrose, 25 mM glycine, 0.4 g / L polysorbate 80, pH 5.5; IV. A formulation comprising 20 mg / mL to 150 mg / mL of anti-IL-36R antibody, 25 mM citrate, 150 mM trehalose, 25 mM methionine, 0.2 g / L polysorbate 20, pH 6.0; V. A formulation comprising 20 mg / mL to 150 mg / mL of an anti-IL-36R antibody, 25 mM histidine, 180 mM sucrose, 20 mM mannitol, 0.2 g / L polysorbate 20, pH 6.5; VI. A formulation comprising 20 mg / mL to 150 mg / mL of anti-IL-36R antibody, 25 mM citrate, 200 mM sucrose, 0.4 g / L polysorbate 80, pH 6.5; VII. A formulation comprising 20 mg / mL to 150 mg / mL of an anti-IL-36R antibody, 45 mM acetate, 150 mM sucrose, 25 mM L-arginine, 0.4 g / L polysorbate 20, pH 5.5; VIII. A formulation comprising 20 mg / mL to 150 mg / mL of an anti-IL-36R antibody, 35 mM histidine, 180 mM trehalose, 25 mM L-arginine, 3 mM NaCl, 0.4 g / L polysorbate 80, pH 6.0; IX. A formulation comprising 20 mg / mL to 150 mg / mL of an anti-IL-36R antibody, 25 mM acetate, 100 mM mannitol, 50 mM NaCl, 0.2 g / L polysorbate 20, pH 5.5; X. A formulation comprising 20 mg / mL to 150 mg / mL of an anti-IL-36R antibody, 20 mM succinate, 220 mM sucrose, 0.1 g / L polysorbate 80, pH 6.0; and XI. Formulation comprising 20 mg / mL to 150 mg / mL of anti-IL-36R antibody, 25 mM citrate, 0.4 g / L polysorbate 20, pH 6.5 Selected from the group consisting of: Pharmaceutical preparations.

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