EA046186B1 - USE OF ANTIBODIES TO IL-36R FOR THE TREATMENT OF GENERALIZED PUSTULAR PSORIASIS - Google Patents

Description

Related applications

This application claims the benefit of 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 them are hereby incorporated by reference in their entirety as if set forth in their entirety herein.

List of sequences

The present invention contains a sequence listing that has been filed in ASCII format using EFS-Web and is thus incorporated by reference in its entirety. The specified ASCII copy, created on March 5, 2019, is called 09-0683-US-4-2019-03-08-SL.txt and is 146018 bytes in size.

Technical field to which the invention relates

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

Prerequisites for creating the invention

GPP is a severe skin disease characterized by the recurrent appearance of acute hyperemic lesions caused by systemic inflammation affecting the skin and internal organs. The classic presentation of acute GPP was first described as the recurrent pustular form of psoriasis by von Zumbusch in 1909. While GPP and plaque psoriasis may co-occur in an individual patient, GPP differs from plaque psoriasis in clinical presentation, pathophysiology, histopathology, response to treatment, epidemiology and genetics.

Therefore, it is extremely important to differentiate GPP from plaque or erythrodermic psoriasis with secondary pustulization. The clinical presentation of GPP differs significantly from psoriasis vulgaris (PV) in its episodic nature, often with normal skin appearance between extremely acute and severe exacerbations of the disease. GPP is clinically characterized by a predominance of pustules as the primary lesion on an erythematous basis rather than the red plaques covered with silvery scales representing the primary lesion of typical plaque psoriasis. Additionally, the histopathological specific features of GPP are well-defined spongiform Kogoya pustules located in the subcorneal part of the epidermis. GPP may be associated with systemic symptoms (fever, increased CRP and neutrophilia) and severe extracutaneous manifestations (hepatic, renal failure, CV shock). While patients with GPP may have preexisting or concomitant PV, it appears possible to clinically distinguish patients with primary plaque disease (PV) who have a secondary pustular component from patients who have primary pustular disease (GPP) with a concomitant plaque component by based on the sequence of presentation (primary lesion as pustules rather than plaques) and the localization of GPP pustules on an erythematous basis rather than PsO plaques.

Because descriptions for GPP are not consistent in standard dermatology guidelines, the European Expert Network on Rare and Severe Forms of Psoriasis (ERASPEN) has certain uniform criteria that include as key diagnostic criteria for acute GPP the presence of primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulization is limited to psoriatic plaques), with or without systemic inflammation, with or without plaque psoriasis, either recurrent (>1 episode) or persistent (>3 months).

Chronic GPP describes a state between exacerbations of the disease, which may be characterized by a complete absence of symptoms or the persistence of residual skin symptoms such as erythema and desquamation and mild pustulization.

Current treatment options to combat acute GPP and subcutaneous response are limited and do not provide long-term effectiveness. There is currently no approved treatment for GPP in the US and EU, although retinoids, cyclosporine, or methotrexate are recommended. Although these treatments are described as extremely effective or effective in 70-84% of patients (J Am Acad Dermatol. 2012;67(2):279-88), these data are based on a retrospective study of a group of people from Japan without clearly defined endpoints (Japanese Journal of Dermatology. 2010;120(4):815-39). Moreover, these treatments cannot be used long-term due to side effects and contraindications (retinoids: teratogenicity, hair loss; cyclosporine: excessive hair growth, nephrotoxicity; MTX: hepatotoxicity).

Biologic agents (mainly TNF inhibitors, sometimes IL-1 or IL-17 inhibitors) are increasingly used to treat more severe, extensive, or treatment-resistant patients with GPP, based on small published case series. However, these drugs are also associated with limitations in efficacy (incomplete and delayed responses are common) and safety, as well as contraindications (infusion reactions, tuberculosis, cardiovascular disease). Thus, there is a need in the field for new targeted therapies to treat and/or prevent GPP.

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Summary of the invention

The present invention addresses the above-described need by providing biological drugs, particularly antibodies, that bind to IL-36R and provide therapeutic or prophylactic treatment for acute and/or chronic GPP and associated signs and symptoms, such as GPP exacerbation.

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

In a second aspect, the present invention provides a method of treating moderate to severe GPP in a patient, comprising administering to or by the patient a therapeutically effective amount of an anti-IL-36R antibody.

In a third aspect, the present invention relates to a method of reducing or ameliorating the signs and symptoms of an acute phase exacerbation of GPP in a patient, wherein the method comprises administering to or by a patient a therapeutically effective amount of an anti-IL-36R antibody.

In a fourth aspect, the present invention provides a method of reducing the severity and duration of a GPP exacerbation, wherein the method comprises administering to or by a patient a therapeutically effective amount of an anti-IL-36R antibody.

In a fifth aspect, the present invention relates to a method of treating a skin disorder associated with acute GPP, wherein the method comprises administering to or by a patient a therapeutically effective amount of an anti-IL-36R antibody.

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

In one embodiment relating to any of the first to fifth aspects, the anti-IL-36R antibody comprises:

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

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

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

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

V. a) a light chain variable region containing the amino acid sequence presented in SEQ ID NO: 26 (L-CDR1); the amino acid sequence shown in SEQ ID NO: 106 (L-CDR2); the amino acid sequence shown in SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region containing an amino acid sequence representing

- 2 046186 included in SEQ ID NO: 53 (H-CDR1); the amino acid sequence shown in SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence shown in SEQ ID NO: 72 (H-CDR3).

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

In one embodiment relating to any of the first to fifth aspects, the anti-IL-36R antibody comprises:

(I) a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or (II) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or (III) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or (IV) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or (V) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or (VI) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or (VII) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 100; or (VIII) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 101; or (IX) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 100; or (X) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 101.

In one embodiment relating to any of the first to fifth aspects, the anti-IL-36R antibody comprises:

I. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 125; or

II. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 126; or

III. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 127; or

IV. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 125; or

V. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 126; or

VI. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 127; or

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VII. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 123; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 138; or

VIII. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 123; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 139; or

IX. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 124; and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 138.

In one embodiment of any of the first to fifth aspects, the anti-IL-36R antibody is administered in one or more intravenous doses. In a similar embodiment, each of the one or more intravenous doses includes 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg of said anti-IL-36R antibody.

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, anti-IL-36R is administered in a single intravenous dose of approximately 10 mg per kilogram 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 300 mg intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single 350 mg intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single 450 mg intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single 600 mg intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single 700 mg intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single 750 mg intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single 800 mg intravenous dose. In another embodiment related to any of the above aspects, the anti-IL36R 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 900 mg intravenous dose.

In another embodiment related to any of the first to fifth aspects, 1, 2 or 3 intravenous doses are administered. In another embodiment related to any of the above aspects, 2 or 3 intravenous doses are administered at intervals of 2, 4, 6, 8, 10 or 12 weeks.

In another embodiment, related to any of the above embodiments or aspects one through five, administration results in one or more of the following efficacy endpoints:

(a) a score of 0 or 1 on the Generalized Pustular Psoriasis Global Assessment (GPPGA) in Week 1;

(b) GPPGA pustulization subscore 0, indicating no visible pustules in Week 1;

(c) psoriasis area and generalized pustular psoriasis severity index (GPPASI) 75 in Week 4;

(d) change from baseline in the visual analogue scale (VAS) pain score at Week 4;

(e) change from baseline in Psoriasis Symptom Score (PSS) at Week 4;

(e) change from baseline in the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue score at Week 4;

(g) GPPGA 0 or 1 in Week 4;

(h) subscore O GPPGA pustulization, indicating the absence of visible pustules in Week 4;

(i) GPPASI 50 in Weeks 1 and 4; or (j) change from baseline in the GPPASI severity subscore of pustules, erythema, or desquamation in Weeks 1 and 4.

In another embodiment, related to the above-described embodiment, the proportion of patients responding to administration is statistically significantly higher compared to placebo patients for one or more endpoints (a)-(k).

In a sixth aspect, the present invention provides a method for preventing the recurrence of a GPP exacerbation in a patient treated with one or more intravenous doses of an anti-IL36R antibody in accordance with any of the first to fifth aspects or the above embodiments, wherein said method comprises administering to the patient a prophylactically effective amounts of anti-IL-36R antibody in one or more subcutaneous doses.

In a seventh aspect, the present invention relates to a method for achieving 0 overall

- 4 046186 evaluating generalized pustular psoriasis (GPPGA) in a patient treated with one or more intravenous doses of an anti-IL-36R antibody in accordance with any of the first through fifth aspects or the above embodiments, wherein the method includes administering to the patient an effective amount of the antibody to IL-36R in one or more subcutaneous doses.

In an eighth aspect, the present invention relates to a method of achieving complete relief of GPP symptoms in a patient treated with one or more intravenous doses of an anti-IL-36R antibody in accordance with any of the first to fifth aspects or the above embodiments, wherein said method comprises administering to the patient an effective amount of an anti-IL36R antibody in one or more subcutaneous doses; where GPP symptoms include pustule, erythema, or desquamation and complete relief includes a GPPGA score of 0.

In one embodiment of any of aspects six through eight, each of the one or more subcutaneous doses comprises 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of said anti-IL-36R antibody.

In one embodiment related to any of aspects six through eight or similar embodiment(s), 1, 2, 3 or more subcutaneous doses are administered to the patient and wherein the first subcutaneous dose is administered after the last intravenous dose.

In one embodiment related to any of aspects six through eight or similar embodiment(s), the first subcutaneous dose is administered at 2-8 weeks, 4-6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks. , after the last intravenous dose and a second subcutaneous dose is administered 4, 6, 8, 10 or 12 weeks after the first subcutaneous dose.

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

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

In one embodiment related to any of aspects six through eight or similar embodiment(s), at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% patients remain in clinical remission as measured by change from baseline in the GPPASI severity subscore of pustules, erythema, or desquamation at Weeks 12, 24, 36, 48, 60, or 72 of treatment. In a similar embodiment, the proportion of patients responding to administration is statistically significantly higher compared to patients on placebo for any of the specified endpoints.

In a ninth aspect, the present invention provides a method of treating GPP in a patient, comprising administering to the patient a therapeutically effective amount of one or more intravenous doses of an anti-IL-36R antibody, in accordance with aspects one through five and similar embodiments thereof, followed by administration of one or more several subcutaneous doses of an antibody to IL-36R.

In one embodiment of the ninth aspect, after 1 or 2 or 3 intravenous doses of the anti-IL-36R antibody, 1 or 2 or 3 subcutaneous doses of the anti-IL-36R antibody are administered.

In one embodiment of the ninth aspect, after 1 intravenous dose of the anti-IL-36R antibody, 1 or 2 or 3 subcutaneous doses of the anti-IL-36R antibody are administered.

In one embodiment of the ninth aspect, after 2 intravenous doses of the anti-IL-36R antibody, 1 or 2 or 3 subcutaneous doses of the anti-IL-36R antibody are administered.

In one embodiment of the ninth aspect, after 3 intravenous doses of the anti-IL-36R antibody, 1 or 2 or 3 subcutaneous doses of the anti-IL-36R antibody are administered.

In one embodiment related to the ninth aspect and a similar embodiment thereof, each of the one or more intravenous doses includes 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 each of one or more subcutaneous doses includes 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of anti-IL-36R antibody. In a similar embodiment, intravenous doses are administered at intervals of 2, 4, 6, 8, 10, or 12 weeks, subcutaneous doses are administered at intervals of 4, 6, 8, 10, or 12 weeks, and the first subcutaneous dose is administered after 2 to 8 weeks. 4-6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks after the last IV dose.

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

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

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In one embodiment, a method of treatment in accordance with any of the aspects described in the present invention includes administering to a mammal or patient a therapeutic amount of a stable pharmaceutical preparation comprising from about 20 mg/ml to about 150 mg/ml of an anti-IL-36R antibody (disclosed in the present invention), from about 20 mM to about 80 mM of a pharmaceutically acceptable buffer (eg, acetate buffer), from about 100 mM to about 250 mM of a pharmaceutically acceptable tonicity agent (eg, sucrose), from about 0 mM to about 80 mM of a pharmaceutically acceptable stabilizing agent (eg, arginine) or a pharmaceutically acceptable salt thereof, from about 0 to about 150 mM of a pharmaceutically acceptable salt (eg, sodium chloride), and a pharmaceutically acceptable surfactant (eg, polysorbate 20) in an amount of from about 0 g/L to approximately 1.5 g/L, wherein treating generalized pustular psoriasis (GPP) in a patient, or treating moderate to severe GPP in a patient, or reducing or ameliorating the signs and symptoms of the acute phase of a flare-up of GPP in a patient, or reduce the severity and duration of a GPP flare in a patient, or treat a skin disorder associated with an acute GPP flare in a patient, or prevent or inhibit a GPP flare in a patient, or achieve a score of 0 for the Generalized Pustular Psoriasis Global Assessment (GPPGA) in a patient, or achieve complete relieving GPP symptoms in a patient. In a similar embodiment, the stable pharmaceutical preparation is an aqueous pharmaceutical preparation. In a similar embodiment, the pH value of the aqueous pharmaceutical preparation is about 5 to about 7. In a similar embodiment, the pharmaceutical preparation is for intravenous administration to a mammal or patient. In a similar embodiment, the pharmaceutical preparation is for subcutaneous administration to a mammal or patient. In a similar embodiment, the pharmaceutical preparation for intravenous administration includes an antibody to IL-36R in an amount of approximately 60 mg/ml. In a similar embodiment, the pharmaceutical preparation for subcutaneous administration includes an antibody to IL-36R in an amount of approximately 150 mg/ml.

In a tenth aspect, the present invention relates to a method of treating GPP in a patient, comprising (a) obtaining a biological sample from said patient, wherein the biological sample is obtained from a source including lesional skin or whole blood;

(b) determining the gene expression profile of one or more genes;

(c) administering to the patient an effective amount of an anti-IL-36R antibody in accordance with any of the embodiments of aspects one through five.

In one tenth aspect embodiment, the one or more genes are IL12B, IL1B, IL6, CXCL1, IL23A, TNF, IL17C, IL24, or IL1B in diseased skin, and IL1B, S100A9, S100A12, S100A8, MMP25, MMP9, or CD177 in whole blood.

Additional features and advantages of the present invention will be set forth in the description below and, in part, will be apparent from the description or may be learned by practice of the claimed technology. It should be appreciated that both the above general description and the following detailed description are illustrative and explanatory and are intended to provide further explanation of the claimed present invention.

Brief description of the figures

The accompanying figures, which are presented to provide a further understanding of the present invention and are incorporated into and constitute a part of the present invention, illustrate aspects of the claimed technology and, together with the description, serve to explain the principles of the present invention.

In fig. 1 shows changes in clinical response when treated with an anti-IL-36R antibody of the present invention up to Week 20; Panel A shows the percentage of patients achieving a Physician's Global Assessment of Generalized Pustular Psoriasis (GPPGA) score of 0 (clear) or 1 (virtually clear); Panel B shows the percentage change from baseline for the generalized pustular psoriasis area and severity index (GPPASI); and Panel C shows the percentage of patients achieving pustule clearance (based on the GPPASI component severity score). The analysis includes all patients with at least one post-baseline value available. One patient received methotrexate after Week 4 for pain management and therefore data for Weeks 12 and 20 were excluded (counted as non-response for GPPGA and pustule clearance). For Week 1, two of three patients with the IL36RN mutation achieved GPPGA 0 or 1; for Week 4, all three patients achieved a GPPGA of 0 or 1. *In Week 2, the GPPGA score was missing for one patient.

In fig. Figure 2 shows the GPPASI 50/75/90 response rates through Week 20. This figure shows over time the proportion of patients who achieved a reduction of greater than 50%, 75%, or 90% for the generalized pustular psoriasis area and severity index (GPPASI 50 , 75, or 90) in dynamics. Analysis includes all patients with at least one available value after baseline

- 6 046186 nya. One patient received methotrexate after Week 4 for pain management and therefore data for Weeks 12 and 20 are reported as non-response.

In fig. Figure 3 presents GPPASI subscores up to Week 20. In this figure, individual and mean percentage changes are presented for severity subscores for area and the Generalized Pustular Psoriasis Severity Index (GPPASI) for pustules (panel A), erythema (panel B), and scaling (panel WITH). The analysis includes all patients with at least one post-baseline value available. One patient received methotrexate after Week 4 for pain management and therefore data for Weeks 12 and 20 were excluded.

In fig. Figure 4 shows the change from baseline for the FACIT-F to Week 4. The mean (SD) change from baseline for the FACIT-F score over time is presented. The analysis includes all patients with at least one post-baseline value available. FACIT-F=Functional Assessment of Chronic Illness Therapy-Fatigue Scale; SD=Standard Deviation.

In fig. Figure 5 shows the change from baseline for Pain-VAS to Week 4. The mean (SD) change from baseline for Pain-VAS over time is presented. The analysis includes all patients with at least one post-baseline value available. SD=Standard Deviation; VAS=Visual Analog Scale. *N=6.

In fig. Figure 6 shows the change from baseline for PSS to Week 4. The mean (SD) change from baseline for PSS over time is presented. The analysis includes all patients with at least one post-baseline value available. PSS=Psoriasis Symptom Score; SD=Standard Deviation.

In fig. Figure 7 shows the change from baseline for CRP to Week 4. The mean (SD) change from baseline for CRP is presented over time. CRP=C-reactive protein; SD=Standard Deviation.

In fig. Figure 8 shows the absolute number of neutrophils up to Week 4. The absolute number of neutrophils over time is presented. The analysis includes all patients with at least one post-baseline value available. SD=Standard Deviation.

In fig. Figure 9 presents the study design as discussed in Example 2.

Detailed Description of the Invention

In the following detailed description, various specific details are presented in order to provide a thorough understanding of the present invention. However, one skilled in the art will appreciate that the claimed technology may be practiced without some of these specific details. In other cases, well-known structures and techniques are not presented in detail so as not to obscure the understanding of the present invention.

A phrase such as an aspect does not imply that such aspect is essential to the present invention or that such aspect applies to all configurations of the claimed technology. The disclosure related to an aspect may apply to all configurations, or to one or more configurations. An aspect may provide one or more examples of disclosure. A phrase such as aspect can refer to one or more aspects and vice versa. A phrase such as an exercise does not imply that such practice is essential to the claimed technology or that such practice applies to all configurations of the claimed technology. Disclosure related to an implementation may apply to all implementations or to one or more implementations. An implementation may provide one or more examples of disclosure.

The inventors have unexpectedly discovered, in particular, that inhibition of the interleukin-36 metabolic pathway using a single dose of a humanized anti-interleukin-36R (amu-IL^R) monoclonal antibody according to the present invention leads to rapid and sustained remission of clinical symptoms in patients with acute generalized pustular psoriasis and that there is no recurrence of GPP flares 20 weeks after a single dose.

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

Without wishing to be limited by theory, it is believed that anti-IL-36R antibodies or antigen-binding fragments thereof bind to human amu-IL^R and thereby interfere with the binding of IL-36 agonists, and thereby block at least partially the IL-36 signaling cascade. 36R for inflammatory mediators. Antibodies to IL36R according to the present invention are described in US patent

- 7 046186 No. 9,023,995 or WO 2013/074569, the entire contents of each of which are incorporated into the present invention by reference.

Acute GPP exacerbations of varying severity occur in most patients and may be idiopathic or triggered by external stimuli such as infections, corticosteroid use or withdrawal, stress, or pregnancy. Moderate to severe GPP exacerbations cause significant morbidity and mortality due to mild morbidity, painful skin lesions, excessive fatigue, high fever, neutrophilia in the peripheral blood and acute phase response and sepsis. The acute phase is associated with a mean length of hospitalization of 10 days (range 3–44 days). The observed mortality rate of 7% reported in a retrospective study of 102 cases of GPP at a tertiary hospital in Johor, Malaysia, is likely to be an underestimate as not all GPP patients were included in the study. Mortality rates are also likely to be underestimates due to lack of identification of the cause of death, such as GPP, and most cases are due to infectious complications and extracutaneous manifestations such as renal, hepatic, respiratory and cardiac failure. Following response to treatment or spontaneous resolution of the exacerbation, it is estimated that up to 50% of patients may suffer from chronic GPP, which is characterized by persistent erythema and desquamation, and may also include joint symptoms.

Based on the limitations described above, currently available treatment options are not suitable for lifelong treatment and do not provide long-term responses in most patients. Therefore, there is an urgent need to develop (i) a highly effective treatment with a rapid onset of action for patients in the acute phase of exacerbation of GPP; and (ii) an effective treatment for chronic GPP that reliably prevents exacerbation and is safe and tolerable for lifelong treatment.

The classic presentation of GPP exacerbation, as described by von Zumbusch, is strongly correlated with polymorphisms in the IL36-R signaling pathway. Individuals with loss-of-function mutations in the IL36RN gene, which encodes the endogenous IL36R antagonist (IL-36RN), have a significantly higher incidence of GPP, indicating that uncontrolled upregulation of IL36 signaling due to defective IL36RN antagonism leads to the inflammatory episodes observed in GPP . Genetic studies in humans have demonstrated the presence of GPP clusters in families with a loss-of-function mutation in IL36RN, which results in uncontrolled IL36R signaling. Mutations in other genes associated with the IL36 pathway, such as CARD14, also lead to GPP. Recently published gene expression studies indicate robust upregulation of IL-1 and IL-36 in GPP, including neutrophil chemokine expression, infiltration, and pustule formation, suggesting that the IL-1/IL-36 inflammatory axis is a strong driver of disease pathology in GPP. GPP. Additionally, a recent meta-analysis examined 233 published cases of GPP. 49 (21.0%) of 233 cases were found to carry recessive IL36RN alleles. These 49 recessive IL36RN alleles, defined by the GPP phenotype, are characterized by early onset and high risk of systemic inflammation.

IL36R is a cell surface receptor involved in inflammatory responses in the skin and intestine. It is a new member of the IL1R family that forms a heterodimeric complex with the IL1R accessory protein. The heterodimeric IL36R system with stimulatory (IL36a, ΓΕ36β, IL36y) and inhibitory ligands (IL36Ra) has various structural and functional similarities to other members of the IL1/IL1R family, such as IL1, IL18 and IL33 (R17-3602). All members of the IL1 family (IL1a, ΓΕ1β, IL18, IL36a, IL36e, IL36y, and IL38) signal through a unique, cognate receptor protein that, upon ligand binding, hijacks the common IL1RacP subunit and activates the NFkB and MAP kinase pathways in cell types receptor positive. In human skin tissues, IL36R is expressed in keratinocytes, dermal fibroblasts, and infiltrating myeloid cells. Activation of IL36R in skin tissue triggers the production of inflammatory mediators (eg, CCL20, MIP-1e, TNF-α, IL12, IL17, IL23, TGF-β) and modulates the expression of tissue remodeling genes (eg, MMPs, TGF-β). Therefore, the association between GPP and mutations in IL36RN is somewhat similar to the well-established infantile sterile multifocal osteomyelitis, periostitis, and pustulosis caused by lack of interleukin-1 receptor antagonist. In this case, the absence of a receptor antagonist allows interleukin-1 to act unopposed, leading to life-threatening systemic inflammation involving the skin and bones. These characteristic clinical signs respond to empirical treatment with the recombinant interleukin-1 receptor antagonist anakinra.

I. Definitions

The term approximately will generally denote the acceptable degree of error or variation of a quantity measured given the nature or accuracy of the measurements. Typically, exemplary degrees of error or variation are in the 5% range or in the 3% range or in the 1% range of a given value or range of values. For example, the expression of approximately 100 includes 105 and

- 8 046186 or 103 and 97 or 101 and 99, and all values in this range (for example, 95.1, 95.2, etc. for the range 95105; or 97.1, 97.2, etc.) etc. for the range 97-103; 99.1, 99.2, etc. for the range 99-101). Numerical values presented in the present invention are approximate unless specifically stated otherwise, indicating that the term approximate may be assumed if not explicitly stated.

Pharmaceutical drug or drug refers to the process as well as the product of the process in which the active drug or agent is combined with chemical substances to obtain the final medical or medicinal product, hence the final drug refers to medical products such as liquids, powders or compositions. Therefore, in one embodiment, the pharmaceutical preparation is a pharmaceutical composition.

A pharmaceutical composition in this context refers to a liquid or powder preparation that is in such a form that it allows the biological activity of the active component(s) to be realized effectively and which does not contain additional components that are significantly toxic in subjects who will composition is introduced. Such compositions are sterile. Powder refers to a freeze-dried or lyophilized or spray-dried pharmaceutical composition for parenteral use. The powder is reconstituted or dissolved, typically in water. Lyophilization is a low-temperature dehydration process that involves freezing the product, reducing the pressure, then removing the ice by sublimation. Freeze drying results in a high quality product due to the low temperature used in the processing process. For a well-formulated lyophilized product, the defined configuration and appearance of the product is maintained over time and the quality of the rehydrated product is extremely good. Spray drying is another method of producing anhydrous powder from a liquid or slurry by rapid drying with hot gas to achieve a consistent particle size distribution.

As used in the present invention, the terms intravenous dose, subcutaneous dose refer to the time sequence of administration of the anti-IL-36R antibody. Therefore, the intravenous dose is the dose that is administered at the beginning of the treatment regimen (also referred to as the initial dose); it may also be referred to as an initial dose or an induction dose. A subcutaneous dose is a dose that is administered after an intravenous dose, which may also be referred to as a follow-up dose or maintenance dose. Intravenous, subcutaneous doses may all contain the same amount of anti-IL-36R antibody or antigen-binding fragment thereof, but may generally differ from each other in the amount of antibody administered or frequency of administration. In an embodiment, the intravenous dose may be equal to or greater than the subcutaneous dose. The intravenous dose, which may be referred to interchangeably as an initial dose or an induction dose, may be a single dose or, alternatively, a series of doses. The subcutaneous dose, which may also be referred to as a follow-up dose or maintenance dose, may be a single dose or, alternatively, a series of doses to be administered.

In certain embodiments, the amount of anti-IL-36R antibody contained in the induction/initial/intravenous and maintenance/subsequent/subcutaneous doses varies within certain limits during the course of treatment. In certain embodiments, one or more of the induction/initial/intravenous doses each contains a first amount of an antibody or an antigen-binding fragment thereof and one or more of the maintenance/follow-up/subcutaneous doses each contain a second amount of an antibody or an antigen-binding fragment thereof. In some embodiments, the first amount of the antibody or fragment thereof is 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, or 5x the second or subsequent amount of the antibody or antigen-binding fragment thereof. In certain embodiments, one or more (e.g., 1, 2, 3, 4, or 5 or more) initial doses are administered at the beginning of the treatment regimen as loading doses or loading doses, followed by subsequent doses that are administered less frequently ( for example, maintenance doses). In one embodiment, the intravenous dose, induction dose, or initial dose is approximately 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 follow-up dose is approximately 150 mg, 225 mg, or 300 mg. In another embodiment, the subcutaneous dose or maintenance or follow-up dose is administered at least two weeks after the intravenous, induction or initial dose.

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

- 9 046186

As used herein, the term tonicity adjusting agent or tonicity regulator or tonicity adjusting agent refers to substances that provide an osmotic pressure equivalent to that of the body's serum, including salts (eg, sodium chloride, potassium chloride, magnesium chloride) or sugars ( eg sucrose, trehalose, sorbitol, magnesium sulfate ( _MgSO4 ), glycerol, mannitol or dextrose). Additionally, the sugars present in the solution act as a cryoprotectant for the protein, allowing the drug substance to be frozen without damage. This provides the possibility of transporting in frozen form and long-term storage of the drug substance before filling the drug product. Typical tonicity agents of the present invention include sodium chloride, potassium chloride, magnesium chloride (salts) and/or sucrose, trehalose, sorbitol, magnesium sulfate (MgSO ₄ ), glycerol, mannitol or dextrose (sugars).

As used in the present invention, the term stabilizer or stabilizing agent refers to substances that contribute to the stability of the active ingredient in a pharmaceutical preparation. Typical stabilizing agents of the present invention include arginine, histidine, glycine, cysteine, proline, methionine, lysine, or pharmaceutically acceptable salts thereof.

As used in the present invention, the term surfactant refers to substances that have the tendency to reduce the surface tension of the liquid in which they are dissolved. Typical surfactants of the present invention include poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80.

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

The term monoclonal antibody (mAb) refers to an antibody that is extremely specifically directed against a single antigenic determinant, an epitope. Thus, the monoclonal modifier is an indicator of antibody targeting to an identical epitope and should not be considered to require production of the antibody by any particular route. It is understood that monoclonal antibodies can be produced using any techniques or techniques known in the art; including, for example, the hybridoma method (Kohler et al., 1975, Nature 256:495), or recombinant DNA methods known in the art (see, for example, US Pat. No. 4,816,567), or methods for isolating recombinantly produced monoclonals using phage antibody libraries using techniques described in Clackson et al., 1991, Nature 352: 624-628, and Marks et al., 1991, J. Mol. Biol. 222:581-597.

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

Chimeric antibodies consist of the heavy and light chain variable regions of an antibody from one species (eg, non-human mammal, such as mouse) and the heavy and light chain constant regions of another species (eg, human) antibody and can be made by linking DNA sequences encoding antibody variable regions from a first species (eg, mouse) with DNA sequences for antibody constant regions from a second species (eg, human) and transforming the host with an expression vector containing the linked sequences, allowing the production of a chimeric antibody. Alternatively, a chimeric antibody may also be an antibody in which one or more heavy and/or light chain regions or domains are identical to, homologous to, or a variant of the corresponding sequence in a monoclonal antibody from an immunoglobulin of a different class or isotype, or from a consensus sequence or germline sequences. A chimeric antibody may include fragments of such antibodies, provided that the antibody fragments exhibit the desired biological activity of its parent antibody, such as binding to the same epitope (see, for example, US Pat. No. 4,816,567; and Morrison et al., 1984, Proc. Natl Acad Sci USA 81: 6851-6855).

Terms, antibody fragment, anti-IL-36R antibody fragment, anti-IL36R antibody epitope fragment, humanized anti-IL-36R antibody fragment, humanized anti-IL-36R antibody epitope fragment, humanized anti-IL-36R antibody variant epitope fragment refers to a portion of a full-length anti-IL-36R antibody IL-36R, in which the variable region or functional ability, for example, specific binding of an IL-36R epitope, is retained. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fd, Fv, scFv and scFv-Fc fragment, diabody, linear antibody, single chain antibody, minibody, diabody formed from antibody fragments , and multispecific antibodies formed from antibody fragments.

- 10 046186

The term intravenous infusion refers to the administration of an agent into a vein into an animal or human patient over a period of time greater than about 15 minutes, typically in the range of about 30-90 minutes.

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

The term subcutaneous administration refers to the administration of an agent under the skin of an animal or human patient, preferably in a pocket between the skin and underlying tissue, through a relatively slow, sustained delivery from a drug reservoir. Piercing or pulling the skin upward and away from the underlying tissue can create a pocket.

The term subcutaneous infusion refers to the administration of a drug under the skin of an animal or human patient, preferably into a pocket between the skin and underlying tissue, by relatively slow, 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, infusion can be accomplished by subcutaneously implanting a drug delivery pump implanted under the skin of an animal or human patient, where the pump delivers a predetermined amount of drug over a predetermined period of time, such as 30 minutes, 90 minutes, or a period of time, covering the duration of the treatment protocol.

The term subcutaneous bolus refers to the administration of a drug under the skin of an animal or human patient, where the bolus delivery of the drug lasts less than about 15 minutes; in another aspect, less than 5 minutes, and in yet another aspect, less than 60 seconds. In yet another aspect, insertion into a pocket between the skin and underlying tissue, where the pocket can be created by piercing or pulling the skin upward and away from the underlying tissue.

The term mammal for medical purposes refers to any animal classified as a mammal, including humans, domestic, farm, and zoo animals, sporting, or pets such as dogs, horses, cats, cows, and others. Preferably, the mammal is a human.

The terms treatment and therapy and the like as used herein include therapeutic as well as prophylactic or suppressive measures for a disease or disorder resulting in any clinically desirable or beneficial effect, including, but not limited to, alleviation or attenuation of one or more several symptoms, regression, slowing or stopping the progression of a disease or disorder. Thus, for example, the term treatment includes administering an agent before or after the onset of a symptom of a disease or disorder, thereby preventing or removing one or more symptoms of the disease or disorder. As another example, the term includes the administration of an agent after the clinical manifestation of a disease to combat symptoms of the disease. Additionally, the agent is administered after the onset of manifestation and after clinical symptoms, if the administration has an effect on the clinical parameters of the disease or disorder, such as the extent of tissue damage or the number or distribution of metastases, regardless of whether the treatment will or will not alleviate the disease, includes treating or treating as used in the present invention. In addition, since the compositions of the invention, either alone or in combination with another therapeutic agent, attenuate or alleviate at least one symptom of the disorder being treated compared to that symptom in the absence of administration of the humanized anti-IL-36R antibody composition, the result should be considered as an effective treatment for the underlying disorder, whether all symptoms of the disorder are relieved or not.

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

The term prophylactically effective amount is used to mean an amount effective in dosages and for a required period of time to achieve the desired prophylactic result. Typically, a prophylactic dose is used in subjects before the onset of a GPP exacerbation and/or before the onset of GPP symptoms, for example, to prevent or inhibit the occurrence of an acute exacerbation. In an embodiment, a subcutaneous dose, as contemplated by the present invention, is a prophylactic dose that is used in a patient with acute GPP, following an intravenous dose, to prevent a possible recurrence of a GPP exacerbation in the patient.

The term package insert is used to refer to instructions commonly included in commercial packaging of therapeutic products containing information regarding indications, use, administration, contraindications, and/or warnings related to

- 11 046186 to the use of such therapeutic products.

II. Antibodies

The anti-IL36R antibodies of the present invention are described in US Pat. No. 9,023,995 or WO 2013/074569, the entire contents of each of which are incorporated herein by reference.

In one aspect, the present invention describes and discloses anti-IL-36R antibodies, especially humanized anti-IL-36R antibodies, and compositions and articles comprising one or more anti-IL-36R antibodies, especially one or more humanized anti-IL-36R antibodies. 36R according to the present invention. Also described are binding agents that include an antigen binding fragment of an anti-IL-36 antibody, particularly a humanized anti-IL-36R antibody.

Mechanism of action

The anti-IL-36R antibody of the present invention is a humanized antagonistic monoclonal IgG1 antibody that blocks IL36R signaling in humans. It is believed that binding of the anti-IL-36R antibody of the present invention to IL36R prevents subsequent activation of IL36R by cognate ligands (IL36 α, β and γ) and downstream activation of proinflammatory and profibrotic pathways to reduce epithelial cell/fibroblast/immune cell mediated inflammation and interrupt inflammatory response that triggers the production of pathogenic cytokines in generalized pustular psoriasis (GPP). As provided by the present invention, the anti-IL-36R antibody of the present invention was tested and found to be effective for treating patients with acute generalized pustular psoriasis (GPP), a severe inflammatory skin disease driven by uncontrolled IL36 activity.

IL-36R is also known as IL-1RL2 and IL-1Rrp2. It has been described that agonistic IL-36 ligands (α, β, or γ) initiate a signaling cascade by interacting with the IL-36 receptor, which then forms a heterodimer with IL-1 receptor accessory protein (IL-1RAcP). IL-36 antagonistic ligands (IL-36RA/IL1F5, IL-38/ILF10) inhibit the signaling cascade.

The variable regions and CDRs of representative antibodies of the present invention are shown below: Mouse anti-IL-36R antibody sequences

The variable regions and CDRs of representative murine lead antibodies of the present invention (mouse lead) are presented below.

Amino acid sequences of the light chain variable region (VK) >33D10B12vK Protein (antibody 33D10)

QIVLTQSPAIMSASLGERVTMTCTASSSVSSSYLHWYQKKPGSSPKLWVYSTSN LASGVPVRFSGSGSGTSYSLTISSMEAEDAATYYCHQHHRSPVTFGSGTKLEMK (SEQ ID NO: 1) >172C8B12 vK protein (antibody 172C8)

DIQMTQSPASQSASLGESVTFTCLASQTIGTWLAWYQQRPGKSPQLLIYAATSLA DGVPSRFSGSGSGTQFSFNIRSLQAEDFASYYCQQVYTTPLTFGGGTKLEIK (SEQ ID NO: 2)

- 12 046186 >67E7E8 vK protein (antibody 67E7)

DIQMTQSPASQSASLGESVTFTCLASQTIGTWLGWYQQKPGKSPQLLIYRSTTLA DGVPSRFSGSGSGTKFSFKISSLQAADFASYYCQQLYSAPYTFGGGTKLEIR (SEQ ID NO: 3) >78C8D1 vK Protein (antibody 78C8)

DVLLTQTPLSLPVSLGDQASISCRSSQNIVHSNGNTYLQWYLQKPGQSPKLLIYK VSNRF S GVPDRF S GS GS GTDF TLKISRVE AEDLGV Y YCF QGSH VPF TF GAGTKLE LK (SEQ ID NO: 4) >81A1D1 vK Protein (antibody 81A1)

DIQMTQTTSSLSASLGDRVTISCRASQDIYKYLNWYQQKPDGTLKLLIYYTSGLH SGVPSRFSGSGSGTDFSLTISNLEPEDIATYFCQQDSKFPWTFGGDTKLEIK (SEQ ID NO: 5) >81B4E11 vK Protein (antibody 81B4)

QIVLTQ SP AIMS ASLGERVTMTCT AS S S VS S S YFHW YQQKPGS SPKLWIYRTSNL

ASGVPGRFSGSGSGTSYSLTISSMEAEDAATYYCHQFHRSPLTFGAGTKLELK (SEQ ID NO: 6) >73C5C10 vK protein (antibody 73C5)

DIVMTQSQKFLSTSVGVRVSVTCKASQDVGTNVLWYQQKIGQSPKPLIYSASYR HSGVPDRFTGSGSGTDFTLIISNVQSEDLAEYFCQQYSRYPLTFGPGTKLELK (SEQ ID NO: 7) >73F6F8 vK protein (antibody 73F6)

DIVMTQSQKFLSTSVGVRVSVTCKASQDVGTNVLWYQQKIGQSPKALIYSASYR HSGVPDRFTGSGSGTDFTLIITNVQSEDLAEYFCQQYSRYPLTFGPGTKLELK (SEQ ID NO: 8) >76E10E8 vK protein (antibody 76E10)

DIVMTQSQKFMSATVGGRVNITCKASQNVGRAVAWYQQKPGQSPKLLTHSAS NRYTGVPDRFTGSGSGTDFTLTITNMQSEDLADYFCQQYSSYPLTFGAGTKLDL

K (SEQ ID NO: 9) >89A12B8 vK protein (antibody 89A12)

DIQMTQSPASQSASLGESVTFSCLASQTIGTWLGWYQQKPGKSPQLLIYRATSLA DGVPSRFSGSGSGTNFSFKISSLQAEDLASYYCQQLYSGPYTFGGGTKLEIR (SEQ ID NO: 10)

- 13 046186

Variable heavy chain (VH) region amino acid sequences >33D10B12vH Protein (antibody 33D10)

QVQLQQSGTELLKPGASVKLSCKASGNTVTSYWMHWVKQRPGQGLEWIGEILP STGRTNYNENFKGKAMLTVDKSSSTAYMQLSSLASEDSAVYYCTIVYFGNPWF AYWGQGTLVTVSA (SEQ ID NO: I) >172С8В12 vH protein (antibody 172С8)

EVQLQQSGPELVKPGASVKLSCKASGYTFTDNYMNWVRQSHGKSLEWIGRVNP SNGDTKYNQNFKGKATLTVDKSLSTAYMQLNGLTSEDSAVYYCGRTKNFYSSY SYDDAMDYWGQGTSVTVSS (SEQ ID NO: 12) >67E7E8 vH protein (antibody 67E7)

EVQLQQSGAEFVRPGASVKFSCTASGFNIKDDYIHWVRQRPEQGLEWVGRIDPA NGNTKYAPKFQDKATITADTSSNTAYLQLSSLTSEDTAVYYCAKSFPNNYYSYD DAFAYWGQGTLVTVSA (SEQ ID NO: 13) >78C8D1 vH Protein (antibody 78C8)

QVQLKESGPVLVAPSQSLSITCTVSGFSLTKFGVHWIRQTPGKGLEWLGVIWAG GPTNYNSALMSRLTISKDISQSQVFLRIDSLQTDDTAMYYCAKQIYYSTLVDYW GQGTSVTVSS (SEQ ID NO: 14) >81A1D1 vH Protein (antibody 81A1)

QVQLKESGPGLVAPSQSLFITCTVSGFSLSSYEINWVRQVPGKGLEWLGVIWTGI TTNYNSALISRLSISKDNSKSLVFLKMNSLQTDDTAIYYCARGTGTGFYYAMDY WGQGTSVTVSS (SEQ ID NO: 15) >81B4E11 vH Protein (antibody 81B4)

QVQLQQPGADFVRPGASMRLSCKASGYSFTSSWIHWVKQRPGQGLEWIGEINP GNVRTNYNENFRNKATLTVDKSSTTAYMQLRSLTSADSAVYYCTVVFYGEPYF PYWGQGTLVTVSA (SEQ ID NO: 16) >73C5C10 vH Protein (antibody 73C5)

QVQLKESGPGLVAPSQSLSITCTVSGFSLTNYAVHWVRQFPGKGLEWLGVIWSD GSTDFNAPFKSRLSINKDNSKSQVFFKMNSLQIDDTAIYYCARKGGYSGSWFAY WGQGTLVTVSA (SEQ ID NO: 17) >73F6F8 vH protein (73F6 antibody)

QVQLKESGPGLVAPSQSLSITCTVSGFSLTNYAVHWVRQFPGKGLEWLGVIWSD GSTDYNAPFKSRLSINKDNSKSQVFFKMNSLQTDDTAIYYCARKGGYSGSWFA YWGQGTLVTVSA (SEQ ID NO: 18) >76E10E8 vH protein (antibody 76E10)

- 14 046186

QVQLKESGPVLVAPSQSLSITCTVSGFSLTNYGVHWVRQPPGKGLEWLGVIWPV GSTNYNSALMSRLSIHKDNSKSQVFLRMNSLQTDDTAIYYCAKMDWDDFFDY WGQGTTLTVSS(SEQ ID NO: 19) >89A12B8 vH Protein (antibody 89A12)

EVQLQQSGAELVRPGASVRLSCTASGFNIKDDYIHWVRQRPKQGLEWLGRIDPA NGNTKYDPRFQDKATITADTSSNTAYLHLSSLTSEDTAVYYCAKSFPDNYYSYD DAFAYWGQGTLVTVSA (SEQ ID NO: 20)

Amino acid sequences of light chain CDR-1 (L-CDR1) >33D10Gl L-CDR1

TASSSVSSSYLH (SEQ ID NO: 21) >172C8B12 L-CDR1

LASQTIGTWLA (SEQ ID NO: 22) >67E7E8 L-CDR1

LASQTIGTWLG (SEQ ID NO: 23) >78C8D1 L-CDR1

RSSQNIVHSNGNTYLQ (SEQ ID NO: 24) >81A1D1 L-CDR1

RASQDIYKYLN (SEQ ID NO: 25) >81B4E11 L-CDR1

TASSSVSSSYFH (SEQ ID NO: 26) >73C5C10 L-CDR1

KASQDVGTNVL (SEQ ID NO: 27) >73F6F8 L-CDR1

KASQDVGTNVL (SEQ ID NO: 27) >76E10E8 L-CDR1

KASQNVGRAVA (SEQ ID NO: 28) >89A12B8 L-CDR1

LASQTIGTWLG (SEQ ID NO: 29)

Light chain CDR-2 (L-CDR2) amino acid sequences >33D10B12 L-CDR2

STSNLAS (SEQ ID NO: 30) >172C8B12 L-CDR2

- 15 046186

AATSLAD (SEQ ID NO: 31) >67E7E8 L-CDR2

RSTTLAD (SEQ ID NO: 32) >78C8D1 L-CDR2

KVSNRFS (SEQ ID NO: 33) >81A1D1 L-CDR2

YTSGLHS (SEQ ID NO: 34) >81B4E11 L-CDR2

RTSNLAS (SEQ ID NO: 35) >73C5C10 L-CDR2

SASYRHS (SEQ ID NO: 36) >73F6F8 L-CDR2

SASYRHS (SEQ ID NO: 36) >76E10E8 L-CDR2

SASNRYT (SEQ ID NO: 37) >89A12B8 L-CDR2

RATSLAD (SEQ ID NO: 38)

Light chain CDR-3 (L-CDR3) amino acid sequences >33D10B12 L-CDR3

HQHHRSPVT (SEQ ID NO: 39) >172C8B12 L-CDR3

QQVYTTPLT (SEQ ID NO: 40) >67E7E8 L-CDR3

QQLYSAPYT (SEQ ID NO: 41) >78C8D1 L-CDR3

FQGSHVPFT (SEQ ID NO: 42) >81A1D1 L-CDR3

QQDSKFPWT (SEQ ID NO: 43) >81B4E11 L-CDR3

HQFHRSPLT (SEQ ID NO: 44) >73C5C10 L-CDR3

QQYSRYPLT (SEQ ID NO: 45)

- 16 046186 >73F6F8 L-CDR3

QQYSRYPLT (SEQ ID NO: 45) >76E10E8 L-CDR3

QQYSSYPLT (SEQ ID NO: 46) >89A12B8 L-CDR3

QQLYSGPYT (SEQ ID NO: 47)

Amino acid sequences of heavy chain CDR-1 (H-CDR1) >33D10B12 H-CDR1

GNTVTSYWMH (SEQ ID NO: 48) >172C8B12 H-CDR1

GYTFTDNYMN (SEQ ID NO: 49) >67E7E8 H-CDR1

GFNIKDDYIH (SEQ ID NO: 50) >78C8D1 H-CDR1

GFSLTKFGVH (SEQ ID NO: 51) >81A1D1 H-CDR1

GFSLSSYEIN (SEQ ID NO: 52) >81B4E11 H-CDR1

GYSFTSSWIH (SEQ ID NO: 53) >73C5C10 H-CDR1

GFSLTNYAVH (SEQ ID NO: 54) >73F6F8 H-CDR1

GFSLTNYAVH (SEQ ID NO: 54) >76E10E8 H-CDR1

GFSLTNYGVH (SEQ ID NO: 55) >89A12B8 H-CDR1

GFNIKDDYIH (SEQ ID NO: 56)

Amino acid sequences of heavy chain CDR-2 (H-CDR2) >33D10B12 H-CDR2

EILPSTGRTNYNENFKG (SEQ ID NO: 57) >172C8B12 H-CDR2

RVNPSNGDTKYNQNFKG (SEQ ID NO: 58)

- 17 046186 >67E7E8 H-CDR2

RIDPANGNTKYAPKFQD (SEQ ID NO: 59)

>78C8D1 H-CDR2 VIWAGGPTNYNSALMS (SEQ ID NO: 60) >81A1D1 H-CDR2 VIWTGITTNYNSALIS (SEQ ID NO: 61) >81B4E11 H-CDR2 EINPGNVRTNYNENF (SEQ ID NO: 62) >73C5C10 H-CDR2 VIWSDGSTDFNAPFKS (SEQ ID NO: 63) >73F6F8 H-CDR2 VIWSDGSTDYNAPFKS (SEQ ID NO: 64) >76E10E8 H-CDR2 VIWPVGSTNYNSALMS (SEQ ID NO: 65) >89A12B8 H-CDR2 RIDPANGNTKYDPRFQD (SEQ ID NO: 66)

Amino acid sequences of heavy chain CDR-3 (H-CDR3) >33D10B12 H-CDR3

VYFGNPWFAY (SEQ ID NO: 67) >172C8B12 H-CDR3

TKNFYSSYSYDDAMDY (SEQ ID NO: 68) >67E7E8 H-CDR3

SFPNNYYSYDDAFAY (SEQ ID NO: 69) >78C8D1 H-CDR3

QIYYSTLVDY (SEQ ID NO: 70) >81A1D1 H-CDR3

GTGTGFYYAMDY (SEQ ID NO: 71) >81B4E11 H-CDR3

VFYGEPYFPY (SEQ ID NO: 72) >73C5C10 H-CDR3

KGGYSGSWFAY (SEQ ID NO: 73) >73F6F8 H-CDR3

KGGYSGSWFAY (SEQ ID NO: 73) >76E10E8 H-CDR3

MDWDDFFDY (SEQ ID NO: 74) >89A12B8 H-CDR3

SFPDNYYSYDDAFAY (SEQ ID NO: 75)

- 18 046186

CDR sequences of mouse aHmu-IL-36R

Summarized results of CDR sequences of lead mouse antibodies are presented below.

Antibody 33D10 H-CDR sequences GNTVTSYWMH (H-CDR1) SEQ ID No: 48 Sequences L- CDR TASSSVSSSYLH (L-CDR1) SEQ ID No: 21 EILPSTGRTNYNENFKG (H-CDR2) SEQ ID No: 57 STSNLAS (L-CDR2)SEQ ID No: 30 VYFGNPWFAY (H-CDR3) SEQ ID No: 67 HQHHRSPVT (L-CDR3) SEQ ID No: 39 172С8 GYTFTDNYMN (H-CDR1) SEQ ID No: 49 LASQTIGTWLA (L-CDR1) SEQ ID No: 22 RVNPSNGDTKYNQNFKG (H-CDR2) SEQ ID No: 58 AATSLAD (L-CDR2)SEQ ID No: 31 TKNFYSSYSYDDAMDY (H-CDR3) SEQ ID No: 68 QQVYTTPLT (L-CDR3) SEQ ID No: 40 67E7 GFNIKDDYIH (H-CDR1) SEQ ID No: 50 LASQTIGTWLG (L-CDR1) SEQ ID No: 23 RIDPANGNTKYAPKFQD (H-CDR2) SEQ ID No: 59 RSTTLAD (L-CDR2)SEQ ID No: 32 SFPNNYYSYDDAFAY (H- CDR3) SEQ ID No: 69 QQLYSAPYT (L-CDR3) SEQ ID No: 41 78С8 GFSLTKFGVH (H-CDR1) SEQ ID No: 51 RSSQNIVHSNGNTYLQ (L- CDR1) SEQ ID No: 24 VIWAGGPTNYN SALMS (H-CDR2) SEQ ID No: 60 KVSNRFS (L-CDR2)SEQ ID No: 33

- 19 046186

QIYYSTLVDY (H-CDR3) SEQ ID No: 70 FQGSHVPFT (L-CDR3) SEQ ID No: 42 81A1 GFSLSSYEIN (H-CDR1) SEQ ID No: 52 VIWTGITTNYNSALIS (H- CDR2) SEQ ID No: 61 GTGTGFYYAMDY (H- CDR3) SEQ ID No: 71 RASQDIYKYLN (L-CDR1) SEQ ID No: 25 YTSGLHS (L-CDR2)SEQ ID No: 34 QQDSKFPWT (L-CDR3) SEQ ID No: 43 81B4 GYSFTSSWIH (H-CDR1) SEQ ID No: 53 EINPGNVRTNYNENF (H- CDR2) SEQ ID No: 62 VFYGEPYFPY (H-CDR3) SEQ ID No: 72 TASSSVSSSYFH (L-CDR1) SEQ ID No: 26 RTSNLAS (L-CDR2)SEQ ID No: 35 HQFHRSPLT (L-CDR3) SEQ ID No: 44 73С5 GFSLTNYAVH (H-CDR1) SEQ ID No: 54 VIWSDGSTDFNAPFKS (H- CDR2) SEQ ID No: 63 KGGYSGSWFAY (H-CDR3) SEQ ID No: 73 KASQDVGTNVL (L-CDR1) SEQ ID No: 27 SASYRHS (L-CDR2)SEQ ID No: 36 QQYSRYPLT (L-CDR3) SEQ ID No: 45 73F6 GFSLTNYAVH (H-CDR1) SEQ ID No: 54 VIWSDGSTDYNAPFKS (H- CDR2) SEQ ID No: 64 KGGYSGSWFAY (H-CDR3) SEQ ID No: 73 KASQDVGTNVL (L-CDR1) SEQ ID No:27 SASYRHS (L-CDR2)SEQ ID No: 36 QQYSRYPLT (L-CDR3) SEQ ID No: 45 76E10 GFSLTNYGVH (H-CDR1) SEQ ID No: 55 VIWPVGSTNYNSALMS (H- CDR2) SEQ ID No: 65 MDWDDFFDY (H-CDR3) SEQ ID No: 74 KASQNVGRAVA (L- CDR1) SEQ ID No: 28 SASNRYT (L-CDR2)SEQ ID No: 37 QQYSSYPLT (L-CDR3) SEQ ID No: 46 89A12 GFNIKDDYIH (H-CDR1) SEQ ID No: 56 RIDPANGNTKYDPRFQD (H-CDR2) SEQ ID No: 66 SFPDNYYSYDDAFAY (H- LASQTIGTWLG (L-CDR1) SEQ ID No: 29 RATSLAD (L-CDR2)SEQ ID No: 38 QQLYSGPYT (L-CDR3) SEQ ID No: 47

CDR3) SEQ ID No: 75

Sequences of a humanized anti-IL-36R antibody

Human to murine lead framework sequences were selected based on framework homology, CDR structure, conserved canonical residues, conserved interface packaged residues, and other parameters to produce humanized variable regions (see Example 5).

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

- 20 046186

Amino acid sequences of the light chain variable region (VK) >81B4vK32_3 uk protein

EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSTL ASGIPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 76) >81B4vK32_105 vK protein_____________________________________________

EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSILA SGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 77) >81B4vK32_l 16 vK protein________________________________________________

EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRL ASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 78) >81B4vK32_127 vK protein_____________________________________________

EIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSRL ASGVPDRFSGSGSGTDFTLTISRLEPEDFAVYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 79) >81B4vK32_138 vK protein

QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRL ASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGAGTKLEIK (SEQ ID NO: 80) >81B4vK32 140 vK protein

- 21 046186

QIVLTQSPGTLSLSPGERVTMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSQL ASGIPDRFSGSGGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 81) >81B4vK32_141 vK protein_____________________________________________

QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSKL ASGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 82) >81B4vK32_147 vK protein_____________________________________________

EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSHL ASGIPGRFSGSGSGTDFTLTISRLEPEDAAVYYCHQFHRSPLTFGQGTKLEIK (SEQ ID NO: 83) >73C5vK39_2 vK protein________________________________________________

EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYR HSGIPDRFSGSGSGTEFTLTISSLQSEDFAEYFCQQYSRYPLTFGQGTKLEIK (SEQ ID NO: 84) >73C5vK39_7 vK protein_______________________________________________

EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYR HSGIPDRFSGSGSGTEFTLTISSLQSEDFAVYYCQQYSRYPLTFGQGTKLEIK (SEQ ID NO: 85) >73C5vK39_15 vK protein_____________________________________________

EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYR HSGIPARFSGSGSGTEFTLTISSLQSEDFAEYYCQQYSRYPLTFGQGTKLEIK (SEQ ID NO: 86)

Amino acid sequences of the variable region of the heavy chain £KH)___________________________________________________________ >81B4vH33_49 vH Protein_______________________________________________

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINP GNVRTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYF PYWGQGTLVTVSS (SEQ ID NO: 87) >81B4vH33_85T vH Protein___________________________________________

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINP GNVRTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYF PYWGQGTLVTVSS (SEQ ID NO: 88) >81B4vH33_90 vH Protein_____________________________________________

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVKQAPGQGLEWMGEIN PGNVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPY FPYWGQGTLVTVSS (SEQ ID NO: 89)

- 22 046186 >81B4vH33_93 vH Protein_______________________________________________

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEINP GNVRTNYNENFRNRATLTRDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFP

YWGQGTLVTVSS (SEQ ID NO: 90) >81B4vH50_22 vH Protein________________________________________________

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEILP GVVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYF PYWGQGTLVTVSS (SEQ ID NO: 91) >81B4vH50_30 vH Protein

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINP GAVRTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYF PYWGQGTLVTVSS (SEQ ID NO: 92) >81B4vH51_13 vH Protein

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINP GLVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYF PYWGQGTLVTVSS (SEQ ID NO: 93) >81B4vH51_15 vH Protein_____________________________________________

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINP GAVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYF PYWGQGTLVTVSS (SEQ ID NO: 94) >81B4vH52_83 vH Protein_____________________________________________

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINP GSVRTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYF PYWGQGTLVTVSS (SEQ ID NO: 95) >73C5vH46_4 vH Protein________________________________________________

QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDG STDYNAPFKSRVTINKDTSKSQVSFKMSSVQAADTAVYYCARKGGYSGSWFAY WGQGTLVTVSS (SEQ ID NO: 96) >73C5vH46_19 vH Protein________________________________________________

QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDG STDYNAPFKSRVTISKDTSKNQVSLKMNSLTTDDTAVYYCARKGGYSGSWFAY WGQGTLVTVSS (SEQ ID NO: 97) >73C5vH46_40 vH Protein________________________________________________

QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDG STDYNAPFKSRVTISKDNSKSQVSLKMNSVTVADTAVYYCARKGGYSGSWFAY WGQGTLVTVSS (SEQ ID NO: 98) >73C5vH47_65 vH Protein_____________________________________________

QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWVRQPPGKGLEWIGVIWSD GSTDYNAPFKSRVTISKDTSKNQVSFKLSSVTVDDTAVYYCARKGGYSGSWFA YWGQGTLVTVSS (SEQ ID NO: 99) >73C5vH47_77 vH Protein________________________________________________

QVQLQESGPGLVAPSETLSLTCTVSGFSLTDYAVHWIRQFPGKGLEWIGVIWSD GSTDFNAPFKSRVTISKDTSKNQVSFKLSSVTTDDTAVYYCARKGGYSGSWFAY WGQGTLVTVSS (SEQ ID NO: 100) >73C5vH58_91 vH Protein_______________________________________________

QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDG STDYNAPFKSRVTISKDNSKSQVSFKMSSVTADDTAVYYCARKGGYSGSWFAY

WGQGTLVTVSS (SEQ ID NO: 101)_________________________________

CDR sequences from humanized variable regions derived from antibodies 81B4 and 73C5 described above are presented below.

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Amino acid sequences of L-CDR1 >81B4vK32_3 L-CDR1

TASSSVSSSYFH (SEQ ID NO: 26) >81B4vK32_105 L-CDR1

TASSSVSSSYFH (SEQ ID NO: 26) >81B4vK32_l 16 L-CDR1

TASSSVSSSYFH (SEQ ID NO: 26) >81B4vK32_127 L-CDR1

TASSSVSSSYFH (SEQ ID NO: 26) >81B4vK32_138 L-CDR1

TASSSVSSSYFH (SEQ ID NO: 26) >81B4vK32_140 L-CDR1

TASSSVSSSYFH (SEQ ID NO: 26) >81B4vK32_141 L-CDR1

TASSSVSSSYFH (SEQ ID NO: 26) >81B4vK32_147 L-CDR1

TASSSVSSSYFH (SEQ ID NO: 26) >73C5vK39_2 L-CDR1

KASQDVGTNVL (SEQ ID NO: 27) >73C5vK39 7 L-CDR1

- 24 046186

KASQDVGTNVL (SEQ ID NO: 27) >73C5vK39_15 L-CDR1

KASQDVGTNVL (SEQ ID NO: 27)

Amino acid sequences of L-CDR2 >81B4vK32_3 L-CDR2 (SEQ ID 102)

RTSTLAS >81B4vK32_105 L-CDR2 (SEQ ID 103) RTSILAS >81B4vK32_l 16 L-CDR2 (SEQ ID 104) RTSRLAS >81B4vK32_127 L-CDR2 (SEQ ID 104) RTSRLAS >81B4vK32_138 L-CDR2 (SEQ ID 104 ) RTSRLAS >81B4vK32_140 L- CDR2 (SEQ ID 105) RTSQLAS> 81B4VK32_141 L-CDR2 (SEQ ID 106) RTSKRAS> 81B4VK32_147 L-CDR2 (Seq ID 140) RTSHLAS> 73C5VK39_2 L-CDR2 SASYRHS (SEQ ID NO: 36) 73> 73> 73> 73> 73> 73> 73> 73> 73> 73> 73> 73 C5VK39_7 L-CDR2

SASYRHS (SEQ ID NO: 36) >73C5vK39_15 L-CDR2

SASYRHS (SEQ ID NO: 36)

Amino acid sequences of L-CDR3 >81B4vK32_3 L-CDR3

HQFHRSPLT (SEQ ID NO: 44) >81B4vK32_105 L-CDR3

HQFHRSPLT (SEQ ID NO: 44) >81B4vK32_l 16 L-CDR3

HQFHRSPLT (SEQ ID NO: 44)

- 25 046186 >81B4vK32_127 L-CDR3

HQFHRSPLT (SEQ ID NO: 44) >81B4vK32_138 L-CDR3

HQFHRSPLT (SEQ ID NO: 44) >81B4vK32_140 L-CDR3

HQFHRSPLT (SEQ ID NO: 44) >81B4vK32_141 L-CDR3

HQFHRSPLT (SEQ ID NO: 44) >81B4vK32_147 L-CDR3 HQFHRSPLT (SEQ ID NO: 44) >73C5vK39_2 L-CDR3

QQYSRYPLT (SEQ ID NO: 45) >73C5vK39_7 L-CDR3

QQYSRYPLT (SEQ ID NO: 45) >73C5vK39_15 L-CDR3

QQYSRYPLT (SEQ ID NO: 45)

Amino acid sequences of H-CDR1 >81B4vH33_49 H-CDR1

GYSFTSSWIH (SEQ ID NO: 53) >81B4vH33_85T H-CDR1

GYSFTSSWIH (SEQ ID NO: 53) >81B4vH33_90 H-CDR1

GYSFTSSWIH (SEQ ID NO: 53) >81B4vH33_93 H-CDR1

GYSFTSSWIH (SEQ ID NO: 53) >81B4vH50_22 H-CDR1

GYSFTSSWIH (SEQ ID NO: 53) >81B4vH50_30 H-CDR1

GYSFTSSWIH (SEQ ID NO: 53)

- 26 046186 >81B4vH51_13 H-CDR1

GYSFTSSWIH (SEQ ID NO: 53) >81B4vH51_15 H-CDR1

GYSFTSSWIH (SEQ ID NO: 53) >81B4vH52_83 H-CDR1

GYSFTSSWIH (SEQ ID NO: 53) >73C5vH46_4 H-CDR1

GFSLTDYAVH (SEQ ID NO: 107) >73C5vH46_19 H-CDR1

GFSLTDYAVH (SEQ ID NO: 107) >73C5vH46_40 H-CDR1

GFSLTDYAVH (SEQ ID NO: 107) >73C5vH47_65 H-CDR1

GFSLTDYAVH (SEQ ID NO: 107) >73C5vH47_77 H-CDR1

GFSLTDYAVH (SEQ ID NO: 107) >73C5vH58_91 H-CDR1

GFSLTDYAVH (SEQ ID NO: 107)

Amino acid sequences of H-CDR2 >81B4vH33_49 H-CDR2

EINPGNVRTNYNENF (SEQ ID NO: 62) >81B4vH33_85T H-CDR2

EINPGNVRTNYNENF (SEQ ID NO: 62) >81B4vH33_90 H-CDR2

EINPGNVRTNYNENF (SEQ ID NO: 62) >81B4vH33_93 H-CDR2

EINPGNVRTNYNENF (SEQ ID NO: 62) >81B4vH50_22 H-CDR2

EILPGVVRTNYNENF (SEQ ID NO: 108) >81B4vH50_30 H-CDR2

EINPGAVRTNYNENF (SEQ ID NO: 109) >81B4vH51_13 H-CDR2

EINPGLVRTNYNENF (SEQ ID NO: 110)

- 27 046186 >81B4vH51_15 H-CDR2

EINPGAVRTNYNENF (SEQ ID NO: 109) >81B4vH52_83 H-CDR2

EINPGSVRTNYNENF (SEQ ID NO: 111) >73C5vH46_4 H-CDR2

VIWSDGSTDYNAPFKS (SEQ ID NO: 64) >73C5vH46_19 H-CDR2

VIWSDGSTDYNAPFKS (SEQ ID NO: 64) >73C5vH46_40 H-CDR2

VIWSDGSTDYNAPFKS (SEQ ID NO: 64) >73C5vH47_65 H-CDR2

VIWSDGSTDYNAPFKS (SEQ ID NO: 64) >73C5vH47_77 H-CDR2

VIWSDGSTDFNAPFKS (SEQ ID NO: 63) >73C5vH58_91 H-CDR2

VIWSDGSTDYNAPFKS (SEQ ID NO: 64)

Amino acid sequences of H-CDR3 >81B4vH33_49 H-CDR3

VFYGEPYFPY (SEQ ID NO: 72) >81B4vH33_85T H-CDR3

VFYGEPYFPY (SEQ ID NO: 72) >81B4vH33_90 H-CDR3

VFYGEPYFPY (SEQ ID NO: 72) >81B4vH33_93 H-CDR3

VFYGEPYFPY (SEQ ID NO: 72) >81B4vH50_22 H-CDR3

VFYGEPYFPY (SEQ ID NO: 72) >81B4vH50_30 H-CDR3

VFYGEPYFPY (SEQ ID NO: 72) >81B4vH51_13 H-CDR3

VFYGEPYFPY (SEQ ID NO: 72) >81B4vH51_15 H-CDR3

VFYGEPYFPY (SEQ ID NO: 72)

- 28 046186 >81B4vH52_83 H-CDR3

VFYGEPYFPY (SEQ ID NO: 72) >73C5vH46_4 H-CDR3

KGGYSGSWFAY (SEQ ID NO: 73) >73C5vH46_19 H-CDR3

KGGYSGSWFAY (SEQ ID NO: 73) >73C5vH46_40 H-CDR3

KGGYSGSWFAY (SEQ ID NO: 73) >73C5vH47_65 H-CDR3

KGGYSGSWFAY (SEQ ID NO: 73) >73C5vH47_77 H-CDR3

KGGYSGSWFAY (SEQ ID NO: 73) >73C5vH58_91 H-CDR3

KGGYSGSWFAY (SEQ ID NO: 73)

In one aspect, the variable region of the 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 the heavy chain or light chain of an antibody.

Heavy chain constant region linked downstream by a humanized variable heavy region:

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP IAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQ PENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGK (SEQ ID NO: 112)___________________________________________

Light chain constant region linked downstream to the humanized variable light region: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQE SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: FROM)_________________________________________________________

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

- 29 046186

Light chain amino acid sequences >81B4vK32_3 Light chain

EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSTL ASGIPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC (SEQ ID NO: 114) >81B4vK32_105 Light chain

EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSILA SGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTE QDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC (SEQ ID NO: 115) >81B4vK32_l 16 Light chain

EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRL ASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 116) >81B4vK32_127 Light chain

EIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSRL ASGVPDRFSGSGSGTDFTLTISRLEPEDFAVYYCHQFHRSPLTFGQGTKLEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 117) >81B4vK32_138 Light chain

QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLWIYRTSRL ASGVPDRFSGSGSGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGAGTKLEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC (SEQ ID NO: 118) >81B4vK32_140 Light chain

QIVLTQSPGTLSLSPGERVTMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSQL ASGIPDRFSGSGGTDFTLTISRLEPEDAATYYCHQFHRSPLTFGQGTKLEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC (SEQ ID NO: 119) >81B4vK32 141 Light chain

- 30 046186

QIVLTQSPGTLSLSPGERATMTCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSKL ASGVPDRFSGSGSGTDFTLTISRLEPEDFATYYCHQFHRSPLTFGQGTKLEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 120) >81B4vK32_147 Light chain

EIVLTQSPGTLSLSPGERATMSCTASSSVSSSYFHWYQQKPGQAPRLLIYRTSHL ASGIPGRFSGSGSGTDFTLTISRLEPEDAAVYYCHQFHRSPLTFGQGTKLEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC (SEQ ID NO: 121) >73C5vK39_2 Light chain

EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYR HSGIPDRFSGSGSGTEFTLTISSLQSEDFAEYFCQQYSRYPLTFGQGTKLEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHKV YACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 122) >73C5vK39_7 Light chain

EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYR HSGIPDRFSGSGSGTEFTLTISSLQSEDFAVYYCQQYSRYPLTFGQGTKLEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 123) >73C5vK39_15 Light chain

EIVMTQSPATLSVSPGVRATLSCKASQDVGTNVLWYQQKPGQAPRPLIYSASYR HSGIPARFSGSGSGTEFTLTISSLQSEDFAEYYCQQYSRYPLTFGQGTKLEIKRTV AAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVT EQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 124)

Heavy chain amino acid sequences_____________________ >81B4vH33_49 Heavy chain

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINP GNVRTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYF PYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALT SGVHTFP AVLQ S SGL YSLS S VVT V PS S SLGTQT YICNVNHKP SNTKVDK RVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 125)

- 31 046186 >81B4vH33_85T Heavy chain

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINP GNVRTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYF PYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALT SGVHTFP AVLQ S SGL YSLS S VVT VPS S SLGTQT YICNVNHKP SNTKVDK RVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 126) >81B4vH33_90 Heavy chain

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVKQAPGQGLEWMGEIN PGNVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPY FPYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKV DKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGF YPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS VMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 127) >81B4vH33_93 Heavy chain

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEINP GNVRTNYNENFRNRATLTRDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYFP YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 128) >81B4vH50_22 Heavy chain

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWMGEILP GVVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYF PYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALT SGVHTFP AVLQ S SGL YSLS SWT VPS S SLGTQT YICNVNHKP SNTKVDK RVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 129) >81B4vH50_30 Heavy chain

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQRPGQGLEWIGEINP GAVRTNYNENFRNRVTMTVDTSISTAYMELSRLRSDDTAVYYCTVVFYGEPYF PYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW

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NSGALT SGVHTFP AVLQ S SGL YSLS S VVT VPS S SLGTQT YICNVNHKP SNTKVDK RVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CK VSNK ALP API EKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 130) >81B4vH51_13 Heavy chain

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINP GLVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYF PYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALT SGVHTFP AVLQ S SGL YSLS SWT V PS S SLGTQT YICNVNHKP SNTKVDK RVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CK VSNK ALP APIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 131) >81B4vH51_15 Heavy chain

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINP GAVRTNYNENFRNKVTMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYF PYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALT SGVHTFP AVLQ S SGL YSLS SWT V PS S SLGTQT YICNVNHKP SNTKVDK RVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CK VSNK ALP APIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 132) >81B4vH52_83 Heavy chain

QVQLVQSGAEVKKPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGEINP GSVRTNYNENFRNKATMTVDTSISTAYMELSRLRSDDTAVYYCAVVFYGEPYF PYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW NSGALT SGVHTFP AVLQ S SGL YSLS SWT VPS S SLGTQT YICNVNHKP SNTKVDK RVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CK VSNK ALP APIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPS DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 133) >73C5vH46_4 Heavy chain

QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDG STDYNAPFKSRVTINKDTSKSQVSFKMSSVQAADTAVYYCARKGGYSGSWFAY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT QTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CK VSNK ALP APIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS

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DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 134) >73C5vH46_19 Heavy chain

QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDG STDYNAPFKSRVTISKDTSKNQVSLKMNSLTTDDTAVYYCARKGGYSGSWFAY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG DI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 135) >73C5vH46_40 Heavy chain

QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDG STDYNAPFKSRVTISKDNSKSQVSLKMNSVTVADTAVYYCARKGGYSGSWFAY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT QTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 136) >73C5vH47_65 Heavy chain

QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWVRQPPGKGLEWIGVIWSD GSTDYNAPFKSRVTISKDTSKNQVSFKLSSVTVDDTAVYYCARKGGYSGSWFA YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG DI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 137) >73C5vH47_77 Heavy chain

QVQLQESGPGLVAPSETLSLTCTVSGFSLTDYAVHWIRQFPGKGLEWIGVIWSD GSTDFNAPFKSRVTISKDTSKNQVSFKLSSVTTDDTAVYYCARKGGYSGSWFAY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 138) >73C5vH58 91 Heavy chain

QVQLQESGPGLVKPSETLSITCTVSGFSLTDYAVHWIRQPPGKGLEWIGVIWSDG STDYNAPFKSRVTISKDNSKSQVSFKMSSVTADDTAVYYCARKGGYSGSWFAY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT QTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHE DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS DIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 139)__________________________

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

In one aspect, an antibody of the present invention includes 3 light chain CDRs and 3 heavy chain CDRs, for example, as described above.

In one aspect, an antibody of the present invention includes a light chain and a heavy chain variable region as defined above. In one aspect, the light chain variable region of the invention is fused to a light chain constant region, for example a kappa or lambda constant region. In one aspect, the heavy chain variable region of the invention is fused to a heavy chain constant region, for example, IgA, IgD, IgE, IgG or IgM, especially IgG ₁ , IgG ₂ , IgG ₃ or IgG ₄ .

- 34 046186

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

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

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

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

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

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

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

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

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

Representative antibodies according to the present invention are presented below.

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Anti-sequence mild

Bl EIVLTQSPGTLSLSPGERATMSC

TASSSVSSSYFHWYQQKPGQAP RLLIYRT S IL A S G VPDRF S GS GS GTDFTLTISRLEPEDFATYYCHQ FHRSPLTFGQGTKLEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLL NNF YPRE AK VQ WK VDN ALQ S G NSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGL SSPVTKSFNRGEC (SEQ ID NO: 115)

В2 EIVLTQSPGTLSLSPGERATMSC

TASSSVSSSYFHWYQQKPGQAP RLLI YRT S IL A S G VPDRF S GS GS GTDFTLTISRLEPEDFATYYCHQ FHRSPLTFGQGTKLEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLL NNF YPRE AK VQ WK VDN ALQ S G NSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGL SSPVTKSFNRGEC (SEQ ID NO: 115)

B3 EIVLTQSPGTLSLSPGERATMSC

TASSSVSSSYFHWYQQKPGQAP RLLI YRT S IL A S G VPDRF S GS GS GTDFTLTISRLEPEDFATYYCHQ FHRSPLTFGQGTKLEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLL NNFYPREAKVQWKVDNALQSG

Table B

Heavy chain sequences

QVQLVQSGAEVKKPGASVKVSCKASG YSFTSSWIHWVRQAPGQGLEWIGEINP GNVRTNYNENFRNKATMTVDTSISTA YMELSRLRSDDTAVYYCAVVFYGEPY FPYWGQGTLVTVSSASTKGPSVFPLAP SSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSS VVTVPSSSLG TQTYICNVNHKPSNTKV DKRVEPKSCDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSLTCLVKGFY PSDI AVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 125)

QVQLVQSGAEVKKPGASVKVSCKASG YSFTSSWIHWVRQRPGQGLEWIGEINP GNVRTNYNENFRNRVTMTVDTSISTAY MELSRLRSDDTAVYYCTVVFYGEPYFP YWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSL GTS DIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 126)

QVQLVQSGAEVKKPGASVKVSCKASG YSFTSSWIHWVKQAPGQGLEWMGEIN PGNVRTNYNENFRNKVTMTVDTSISTA YMELSRLRSDDTAVYYCTVVFYGEPY FPYWGQGTLVTVSSASTKGPSVFPLAP SSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSS

- 36 046186

NSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGL SSPVTKSFNRGEC (SEQ ID NO: 115)

V VT VP S S SLGTQT YICN VNHKP SNTK V DKRVEPKSCDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPS REEMTKNQVSLTCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 127)

B4 QIVLTQSPGTLSLSPGERATMTC

TASSSVSSSYFHWYQQKPGQAP RLWIYRTSRLASGVPDRFSGSGS GTDFTLTISRLEPEDAATYYCHQ FHRSPLTFGAGTKLEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLL NNF YPRE AK VQ WK VDN ALQ S G NSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGL SSPVTKSFNR GEC (SEQ ID NO: 118)

B5 QIVLTQSPGTLSLSPGERATMTC

TASSSVSSSYFHWYQQKPGQAP RLWIYRTSRLASGVPDRFSGSGS GTDFTLTISRLEPEDAATYYCHQ FHRSPLTFGAGTKLEIKRTVAAP SVFIFPPSDEQLKSGTASVVCLL NNF YPRE AK VQ WK VDN ALQ S G NSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGL SSPVTKSFNR GEC (SEQ ID NO: 118)

B6 QIVLTQSPGTLSLSPGERATM

TCTASSSVSSSYFHWYQQKPG QAPRLWIYRTSRLASGVPDRF SGSGSGTDFTLTISRLEPEDAA TYYCHQFHRSPLTFGAGTKLE IKRTVAAPSVFIFPPSDEQLKS GTASVVCLLNNFYPREAKVQ WKVDNALQSGNSQESVTEQD SKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFN RG EC (SEQ ID NO: 118)

QVQLVQSGAEVKKPGASVKVSCKASG YSFTSSWIHWVRQAPGQGLEWIGEINP GNVRTNYNENFRNKATMTVDTSISTA YMELSRLRSDDTAVYYCAVVFYGEPY FPYWGQGTLVTVSSASTKGPSVFPLAP SSKSTSGGTAALGCLVKDYFPEPVTVS WNSGALTSGVHTFPAVLQSSGLYSLSS V VT VP S S SLGTQT YICN VNHKP SNTK V DKRVEPKSCDKTHTCPPCPAPEAAGGP SVFLFPPKPKDTLMISRTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPR EEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREP QVYTLPPSREEMTKNQVSL TCLVKGFY PSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 125)

QVQLVQSGAEVKKPGASVKVSCKASG YSFTSSWIHWVRQRPGQGLEWIGEINP GNVRTNYNENFRNRVTMTVDTSISTAY MELSRLRSDDTAVYYCTVVFYGEPYFP YWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSL GTQTYICNVNHKPSNTKVD KRVEPKSCDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPE VKFNW Y VD GVE VHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 126)

QVQLVQSGAEVKKPGASVKVSCKAS GYSFTSSWIHWVKQAPGQGLEWMG EINPGNVRTNYNENFRNKVTMTVDT SISTAYMELSRLRSDDTAVYYCTVVF YGEPYFPYWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYF PEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSVVTVPSS SLGTQTYICNVN HKPSNTKVDKRVEPKSCDKTHTCPP CPAPEAAGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKAL PAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGF YPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEA LHNHYTQKSLSLSPGK (SEQ ID NO: 127)

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Anti Sequence Light Body Chain

Cl EIVMTQSPATLSVSPGVRATLSC

KASQDVGTNVLWYQQKPGQAP RPLIYSASYRHSGIPARFSGSGS GTEFTLTISSLQSEDFAEYYCQQ YSRYPLTFGQGTKLEIKRTVAA PSVFIFPPSDEQLKSGTASVVCL LNNF YPRE AK VQ WK VDN ALQ S GNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQG LSSP VTKSFNRGEC (SEQ ID NO: 124)

C2 EIVMTQSPATLSVSPGVRATLSC

KASQDVGTNVLWYQQKPGQAP RPLIYSASYRHSGIPDRFSGSGS GTEFTLTISSLQSEDFAVYYCQQ YSRYPLTFGQGTKLEIKRTVAA PSVFIFPPSDEQLKSGTASVVCL LNNF YPRE AKVQ WK VDN ALQ S GNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQG LS SPVTKSFNRGEC (SEQ ID NO: 123)

Table C

Heavy chain sequences

QVQLQESGPGLVAPSETLSLTCTVSGFS LTDYAVHWIRQFPGKGLEWIGVIWSD GSTDFNAPFKSRVTISKDTSKNQVSFKL SSVTTDDTAVYYCARKGGYSGSWFAY WGQGTL VT VS S ASTKGP S VFPL AR S SK STSGGTAALGCLVKDYFPEPVTVSWNS GALTSGVHTFPAVLQSSGLYSLS SVVT VPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPEAAGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTC LVKGFYPS DIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 138)

QVQLQESGPGLVKPSETLSITCTVSGFS LTDYAVHWIRQFPGKGLEWIGVIWSD GSTDYNAPFKSRVTISKDNSKSQVSFK MS S VT ADDT A VYYC ARKGGYSGS WF A YWGQGTLVTVSSASTKGPSVFPLAPSS KSTSGGTAALGCLVKDYFPEPVTVSW NSGALTSGVHTFPAVLQSSGLYSLSSV VT VPS S SLGTQT YICNVNHKP SNTK VD KRVEPKSCDKTHTCPPCPAPEAAGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVS HEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQV SLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYSKLTVDKSRWQQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 139)

C3 EIVMTQSPATLSVSPGVRATLSC KASQDVGTNVLWYQQKPGQAP RPLIYSASYRHSGIPDRFSGSGS GTEFTLTISSLQSEDFAVYYCQQ YSRYPLTFGQGTKLEIKRTVAA PSVFIFPPSDEQLKSGTASVVCL LNNF YPRE AKVQ WK VDN ALQ S GNSQESVTEQDSKDSTYSLSSTL TLS KADYEKHKVYACEVTHQG LSSPVTKSFNRGEC (SEQ ID NO:

123)

VPS S SLGTQT YICNVNHKP SNTK VDKR VEPKSCDKTHTCPPCPAPEAAGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSH EDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQV YTLPPSREEMTKNQVSLTCLVKGF YPS DIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVM HEALHNHYTQKSLSLSPGK (SEQ ID NO: 138)

In some aspects, the humanized antibody exhibits blocking activity such that it reduces the binding of IL-36 ligand to the IL-36 receptor by at least 45%, by at least 50%, by at least 55%, by 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 the antibody can be measured by assessing the biological effects of IL-36, such as the production of IL-8, IL-6, and GM-CSF to determine whether IL-36 receptor-mediated signaling will be inhibited.

- 38 046186

In a further aspect, the present invention provides a humanized anti-IL-36R antibody having favorable biophysical properties. In one aspect, the humanized anti-IL36R antibody of the present invention is provided in at least 90% monomeric form, or at least 92% monomeric form, or at least 95% monomeric form in a buffer. In a further aspect, the humanized anti-IL-36R antibody of the present invention remains in at least 90% monomeric form, or at least 92% monomeric form, or at least 95% monomeric form in buffer for one month or within four months.

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

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

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

In a further embodiment, the present invention provides an anti-IL-36R antibody or an antigen-binding fragment thereof that competitively binds to a human anti-IL-36R 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 described in the present invention. The ability of an antibody or antigen binding fragment to competitively bind IL-36R can be measured using competitive binding assays known in the art.

- 39 046186

Humanized antibodies to IL-36R do not necessarily include specific amino acid substitutions in the germline consensus or framework regions. Specific substitution of amino acid residues at these framework positions can improve various antibody functions, including binding affinity and/or stability, beyond that which has been demonstrated in humanized antibodies formed by direct replacement of CDRs or HVLs in human germline framework regions.

In some embodiments, the present invention describes other monoclonal antibodies with a light chain variable region having the amino acid sequence presented in any of SEQ ID NO: 1-10. In some embodiments, the present invention describes other monoclonal antibodies with a heavy chain variable region having the amino acid sequence presented in any of SEQ ID NO: 11-20. By placing such CDRs into the human heavy and light chain FR consensus variable domains, useful humanized antibodies of the present invention will be obtained.

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

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

In a further embodiment, the present invention provides an anti-IL-36R antibody or an 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 of at least 90% identical at least 93% identical or at least 95% identical to the amino acid sequence of the light chain variable domain framework regions having the 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 heavy chain variable domain framework regions with the amino acid sequence of SEQ ID NO: 89. B In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In a further embodiment, the present invention provides an anti-IL-36R antibody or an 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 of at least 90% identical at least 93% identical or at least 95% identical to the amino acid sequence of the light chain variable domain framework regions having the 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 heavy chain variable domain framework regions with the amino acid sequence of SEQ ID NO: 88. In one In an embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In a further embodiment, the present invention provides an anti-IL-36R antibody or an 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 of at least 90% identical at least 93% identical or at least 95% identical to the amino acid sequence of the light chain variable domain framework regions having the 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 heavy chain variable domain framework regions with the amino acid sequence of SEQ ID NO: 89. In one In an embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

- 40 046186

In a further embodiment, the present invention provides an anti-IL-36R antibody or an 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 of at least 90% identical at least 93% identical or at least 95% identical to the amino acid sequence of the light chain variable domain framework regions having the 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 heavy chain variable domain framework regions with the amino acid sequence of SEQ ID NO: 87. B In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In a further embodiment, the present invention provides an anti-IL-36R antibody or an 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 of at least 90% identical at least 93% identical or at least 95% identical to the amino acid sequence of the light chain variable domain framework regions having the 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 heavy chain variable domain framework regions with the amino acid sequence of SEQ ID NO: 88. B In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In a further embodiment, the present invention provides an anti-IL-36R antibody or an 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 of at least 90% identical at least 93% identical or at least 95% identical to the amino acid sequence of the light chain variable domain framework regions having the 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 heavy chain variable domain framework regions with the amino acid sequence of SEQ ID NO: 87. In one In an embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In a further embodiment, the present invention provides 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 of at least 90% identical at least 93% identical or at least 95% identical to the amino acid sequence of the light chain variable domain framework regions having the 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 heavy chain variable domain framework regions with the amino acid sequence of SEQ ID NO: 100. In one In an embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In a further embodiment, the present invention provides an anti-IL-36R antibody or an 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 of at least 90% identical at least 93% identical or at least 95% identical to the amino acid sequence of the light chain variable domain framework regions having the 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 heavy chain variable domain framework regions with the amino acid sequence of SEQ ID NO: 101. In one In an embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In a further embodiment, the present invention provides an anti-IL-36R antibody or an antigen-binding fragment thereof comprising a humanized lung variable domain

- 41 046186 chains 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 variable framework regions a light chain domain having the 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 to at least 93% identical or at least 95% identical to the amino acid sequence of the heavy chain variable domain framework regions with the amino acid sequence of SEQ ID NO: 100. In one embodiment, the anti-IL-36R antibody is a humanized monoclonal antibody.

In some specific embodiments, the humanized antibodies to IL-36R described in the present invention contain at least a heavy or light chain variable domain comprising a CDR or HVL from murine monoclonal antibodies or humanized antibodies as described in the present invention, and FR variable human germline heavy and light chain domains.

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

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

a) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequence from SEQ ID NO: 21, 30, 39, 48, 57 and 67, respectively; or

b) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequence from SEQ ID NO: 22, 31, 40, 49, 58 and 68, respectively; or

c) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequence from SEQ ID NO: 23, 32, 41, 50, 59 and 69, respectively; or

d) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequence from SEQ ID NO: 24, 33, 42, 51, 60 and 70, respectively; or

e) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequence from SEQ ID NO: 25, 34, 43, 52, 61 and 71, respectively; or

f) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequence from SEQ ID NO: 26, 35, 44, 53, 62 and 72, respectively; or

g) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequence from SEQ ID NO: 27, 36, 45, 54, 63 and 73, respectively; or

h) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequence from SEQ ID NO: 27, 36, 45, 54, 64 and 74, respectively; or

i) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequence from SEQ ID NO: 27, 36, 45, 54, 64 and 73, respectively; or

j) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequence from SEQ ID NO: 28, 37, 46, 55, 65 and 74, respectively; or

k) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequence from SEQ ID NO: 29, 38, 47, 56, 66 and 75, respectively.

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

a) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequence from SEQ ID NO: 26, 103, 44, 53, 62 and 72, respectively; or

b) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequence from SEQ ID NO: 26, 104, 44, 53, 62 and 72, respectively; or

c) L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3 sequence from SEQ ID NO: 27, 36, 45, 107, 63 and 73, respectively; or

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

In one aspect, the anti-IL-36R antibody or antigen-binding fragment thereof comprises a light chain variable region comprising the combination of L-CDR1, L-CDR2 and L-CDR3 as represented by you

- 42 046186 above, and a heavy chain variable region including the combination of H-CDR1, H-CDR2 and H-CDR3 presented above.

In specific embodiments, it is contemplated that chimeric antibodies in which CDR regions are switched (i.e., for example, one or two CDRs of one of the murine antibodies or a humanized antibody that is derived therefrom are switched to a similar CDR from another murine antibody or humanized antibody antibodies derived from it) between these exemplary immunoglobulins can provide useful antibodies.

In certain embodiments, the humanized anti-IL-36R antibody is an antibody fragment. In general, various antibody fragments have been discussed above and there are techniques that have been developed to obtain antibody fragments. Fragments can be obtained by proteolytic cleavage of intact antibodies (see, for example, Morimoto et al., 1992, Journal of Biochemical and Biophysical Methods 24:107-117; and Brennan et al., 1985, Science 229:81). Alternatively, the fragments can be produced directly in recombinant host cells. For example, Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab') ₂ fragments (see, eg, Carter et al., 1992, Bio/Technology 10:163-167). Using another approach, F(ab') ₂ fragments can be isolated from direct culture of recombinant host cells. Other techniques for producing antibody fragments are known to those skilled in the art. Thus, in one aspect, the present invention provides antibody fragments comprising the CDRs described in the present invention, especially one of the combinations of L-CDR1, L-CDR2, L-CDR3, H-CDR1, H-CDR2 and H-CDR3, described in the present invention. In a further aspect, the present invention provides antibody fragments comprising the variable regions described in the present invention, for example, one of the combinations of light chain variable regions and heavy chain variable regions described in the present invention.

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

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

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

The effector domain of an antibody may be derived from any suitable vertebrate species and isotypes. Isotypes from different animal species differ in their ability to mediate effector functions. For example, the ability of human immunoglobulin to mediate CDC and ADCC/ADCP is generally in the order IgM»IgG ₁ MgG ₃ >IgG ₂ >IgG ₄ and IgG|»IgG3>IgG2/IgM/IgG. ₁ . respectively. Mouse immunoglobulins mediate CDC and ADCC/ADCP in general in the order mouse IgM»IgG ₃ >>IgG _2b >IgG _2a >>IgG ₁ and IgG _2b >IgG _2a >IgG1>>IgG ₃ , respectively. In another example, mouse IgG _2a mediates ADCC, while both mouse IgG _2a and IgM mediate CDC.

III. Pharmaceutical Dosages and Administration

The anti-IL-36R antibodies of the present invention are typically administered to a patient in the form of a pharmaceutical composition in which the antagonist is in admixture with a pharmaceutically acceptable carrier or excipient, for example, see Remington's Pharmaceutical Sciences and US. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, Pa. (1984). The pharmaceutical composition may be formulated in any manner suitable for the intended route of administration. Examples of pharmaceutical preparations include lyophilized powders, slurries, aqueous solutions, suspensions and sustained release preparations (see, for example, Hardman et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, N.Y.; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, N.Y.; Avis et al (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman et al. (ed.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman et al. (ed.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, N.Y.). Suitable routes of administration include intravenous administration (including intra-arterial administration) and subcutaneous administration.

In a first aspect, the present invention relates to a method of treating generalized pustular psoriasis (GPP) in a patient, wherein the method comprises administering to or by the patient

- 43 046186 a therapeutically effective amount of an antibody to IL-36R.

In a second aspect, the present invention provides a method of treating moderate to severe GPP in a patient, comprising administering to or by the patient a therapeutically effective amount of an anti-IL-36R antibody.

In a third aspect, the present invention relates to a method of reducing or ameliorating the signs and symptoms of an acute phase exacerbation of GPP in a patient, wherein the method comprises administering to or by a patient a therapeutically effective amount of an anti-IL-36R antibody.

In a fourth aspect, the present invention provides a method of reducing the severity and duration of a GPP exacerbation, wherein the method comprises administering to or by a patient a therapeutically effective amount of an anti-IL-36R antibody.

In a fifth aspect, the present invention relates to a method of treating a skin disorder associated with acute GPP, wherein the method comprises administering to or by a patient a therapeutically effective amount of an anti-IL-36R antibody.

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

In one embodiment relating to any of the first to fifth aspects, the anti-IL-36R antibody comprises:

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

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

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

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

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

VI. a) a light chain variable region containing the amino acid sequence shown in SEQ ID NO: 26 (L-CDR1); the amino acid sequence shown in SEQ ID NO: 140 (L-CDR2); the amino acid sequence shown in SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region containing an amino acid sequence representing

- 44 046186 included in SEQ ID NO: 53 (H-CDR1); the amino acid sequence shown in SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence shown in SEQ ID NO: 72 (H-CDR3).

In one embodiment relating to any of the first to fifth aspects, the anti-IL-36R antibody comprises:

(I) a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or (II) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or (III) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or (IV) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or (V) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or (VI) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or (VII) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 100; or (VIII) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 101; or (IX) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 100; or (X) a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 101.

In one embodiment relating to any of the first to fifth aspects, the anti-IL-36R antibody comprises:

I. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 125; or

II. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 126; or

III. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 127; or

IV. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 125; or

V. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 126; or

VI. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 127; or

VII. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 123; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 138; or

VIII. a light chain comprising the amino acid sequence set forth in SEQ ID NO: 123; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 139; or

IX. light chain comprising the amino acid sequence set forth in SEQ ID

- 45 046186

NO: 124; and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 138.

In one embodiment of any of the first to fifth aspects, the anti-IL-36R antibody is administered in one or more intravenous doses. In a similar embodiment, each of the one or more intravenous doses includes 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg of said anti-IL-36R antibody.

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, anti-IL-36R is administered in a single intravenous dose of approximately 10 mg per kilogram 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 300 mg intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single 350 mg intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single 450 mg intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single 600 mg intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single 700 mg intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single 750 mg intravenous dose. In another embodiment related to any of the above aspects, the anti-IL-36R antibody is administered in a single 800 mg intravenous dose. In another embodiment related to any of the above aspects, the anti-IL36R 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 900 mg intravenous dose.

Representative examples of doses and dosage regimens in accordance with the present invention are presented in table. 1. Although the 900 mg and 750 mg doses are described as examples, similar dosage regimens may equally apply to the 210 mg, 300 mg, 350 mg, 450 mg, 600 mg, 700 mg, and 800 mg doses.

Table 1

Doses and dosage regimens

Intravenous dose (mg) Intravenous dose frequency Frequency of intravenous administration Optional subcutaneous dose (mg) Frequency of subcutaneous doses Subcutaneous administration frequency 900 1 One time 150 0 - 900 1 One time 150 1 - 900 1 One time 150 2 At intervals of 4, 6, 8, 10 or 12 weeks 900 1 One time 150 3 At intervals of 4, 6, 8, 10 or 12 weeks 900 1 One time 225 0 -

- 46 046186

900 1 One time 225 1 - 900 1 One time 225 2 At intervals of 4, 6, 8, 10 or 12 weeks 900 1 One time 225 3 At intervals of 4, 6, 8, 10 or 12 weeks 900 1 One time 300 0 - 900 1 One time 300 1 - 900 1 One time 300 2 At intervals of 4, 6, 8, 10 or 12 weeks 900 1 One time 300 3 At intervals of 4, 6, 8, 10 or 12 weeks 900 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 0 - 900 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 1 - 900 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 2 At intervals of 4, 6, 8, 10 or 12 weeks 900 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 3 At intervals of 4, 6, 8, 10 or 12 weeks 900 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 0 - 900 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 1 - 900 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 2 At intervals of 4, 6, 8, 10 or 12 weeks 900 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 3 At intervals of 4, 6, 8, 10 or 12 weeks 900 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 0 - 900 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 1 - 900 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 2 At intervals of 4, 6, 8, 10 or 12 weeks

- 47 046186

900 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 3 At intervals of 4, 6, 8, 10 or 12 weeks 900 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 0 - 900 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 1 - 900 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 2 At intervals of 4, 6, 8, 10 or 12 weeks 900 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 3 At intervals of 4, 6, 8, 10 or 12 weeks 900 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 0 - 900 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 1 - 900 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 2 At intervals of 4, 6, 8, 10 or 12 weeks 900 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 3 At intervals of 4, 6, 8, 10 or 12 weeks 900 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 0 - 900 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 1 - 900 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 2 At intervals of 4, 6, 8, 10 or 12 weeks 900 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 3 At intervals of 4, 6, 8, 10 or 12 weeks 750 1 One time 150 0 - 750 1 One time 150 1 - 750 1 One time 150 2 At intervals of 4, 6, 8, 10 or 12 weeks 750 1 One time 150 3 At intervals of 4, 6, 8, 10 or 12 weeks 750 1 One time 225 0 - 750 1 One time 225 1 -

- 48 046186

750 1 One time 225 2 At intervals of 4, 6, 8, 10 or 12 weeks 750 1 One time 225 3 At intervals of 4, 6, 8, 10 or 12 weeks 750 1 One time 300 0 - 750 1 One time 300 1 - 750 1 One time 300 2 At intervals of 4, 6, 8, 10 or 12 weeks 750 1 One time 300 3 At intervals of 4, 6, 8, 10 or 12 weeks 750 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 0 - 750 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 1 - 750 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 2 At intervals of 4, 6, 8, 10 or 12 weeks 750 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 3 At intervals of 4, 6, 8, 10 or 12 weeks 750 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 0 - 750 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 1 - 750 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 2 At intervals of 4, 6, 8, 10 or 12 weeks 750 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 3 At intervals of 4, 6, 8, 10 or 12 weeks 750 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 0 - 750 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 1 - 750 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 2 At intervals of 4, 6, 8, 10 or 12 weeks 750 2 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 3 At intervals of 4, 6, 8, 10 or 12 weeks

- 49 046186

750 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 0 - 750 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 1 - 750 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 2 At intervals of 4, 6, 8, 10 or 12 weeks 750 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 150 3 At intervals of 4, 6, 8, 10 or 12 weeks 750 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 0 - 750 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 1 - 750 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 2 At intervals of 4, 6, 8, 10 or 12 weeks 750 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 225 3 At intervals of 4, 6, 8, 10 or 12 weeks 750 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 0 - 750 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 1 - 750 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 2 At intervals of 4, 6, 8, 10 or 12 weeks 750 3 At intervals of 2, 4, 6, 8, 10 or 12 weeks 300 3 At intervals of 4, 6, 8, 10 or 12 weeks

In one embodiment, the patient is administered 1, 2 or 3 intravenous doses according to the dosage regimen presented in table. 1.

In an embodiment related to any of the above aspects, the mammal or patient is assessed for improved clinical remission, as determined by:

(a) Score 0 or 1 on the Generalized Pustular Psoriasis Global Assessment (GPPGA) in Week 1;

(b) GPPGA pustulization subscore 0, indicating no visible pustules in Week 1;

(c) Psoriasis area and generalized pustular psoriasis severity index (GPPASI) 75 in Week 4;

(d) Change from baseline in the visual analogue scale (VAS) pain score in Week 4;

(e) Change from baseline in Psoriasis Symptom Score (PSS) at Week 4;

(f) Change from baseline in the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue score in Week 4;

(g) GPPGA 0 or 1 in Week 4;

(h) GPPGA Pustulization Subscore 0, indicating no visible pustules in Week 4;

(i) GPPASI 50 in Weeks 1 and 4; or (k) Change from baseline in the GPPASI severity subscore of pustules, erythema, or desquamation in Weeks 1 and 4. In a similar embodiment, the proportion of patients responding to administration is statistically significantly higher than patients on placebo for any of the specified endpoints.

In one embodiment, the present invention provides a method of treating generalized pustular psoriasis (GPP), a method of treating moderate to severe GPP, a method of reducing or alleviating the signs and symptoms of the acute phase of a GPP flare, a method of reducing the severity and duration of a GPP flare, or a method of treating a skin disorder associated with acute GPP in a patient, wherein said method(s) comprises administering to the patient or subject a therapeutically effective amount of an anti-IL-36R antibody according to the present invention in one or more intravenous doses of 210 mg, 300 mg , 350 mg, 450 mg, 600 mg, 700 mg, 750 mg,

- 50 046186

800 mg or 900 mg each, where more than one of the intravenous doses is administered at intervals of 2, 4, 6, 8, 10 or 12 weeks.

In one embodiment, the present invention provides a method of treating generalized pustular psoriasis (GPP), a method of treating moderate to severe GPP, a method of reducing or alleviating the signs and symptoms of the acute phase of a GPP flare, a method of reducing the severity and duration of a GPP flare, or a method of treating a skin disorder associated with acute GPP in a patient, wherein said method(s) comprises administering to the patient or patient a therapeutically effective amount of an anti-IL-36R antibody according to the present invention in a single 900 mg intravenous dose.

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

In a sixth aspect, the present invention provides a method for preventing the recurrence of a GPP exacerbation in a patient treated with one or more intravenous doses of an anti-IL36R antibody in accordance with any of the first to fifth aspects or the above embodiments, wherein said method comprises administering to the patient a prophylactically effective amounts of anti-IL-36R antibody in one or more subcutaneous doses.

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 doses of an anti-IL-36R antibody in accordance with any of the first to fifth aspects or the above embodiments. wherein the method comprises administering to the patient an effective amount of an anti-IL-36R antibody in one or more subcutaneous doses

In an eighth aspect, the present invention relates to a method of achieving complete relief of GPP symptoms in a patient treated with one or more intravenous doses of an anti-IL-36R antibody in accordance with any of the first to fifth aspects or the above embodiments, wherein said method comprises administering to the patient an effective amount of an anti-IL36R antibody in one or more subcutaneous doses; where GPP symptoms include pustule, erythema, or desquamation and complete relief includes a GPPGA score of 0.

In one embodiment of any of aspects six through eight, each of the one or more subcutaneous doses comprises 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of said anti-IL-36R antibody.

In one embodiment related to any of aspects six through eight or similar embodiment(s), 1, 2, 3 or more subcutaneous doses are administered to the patient and wherein the first subcutaneous dose is administered after the last intravenous dose.

In one embodiment related to any of aspects six through eight or similar embodiment(s), the first subcutaneous dose is administered at 2-8 weeks, 4-6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks. , after the last intravenous dose and a second subcutaneous dose is administered 4, 6, 8, 10 or 12 weeks after the first subcutaneous dose.

In one embodiment, the present invention provides a method for preventing relapse of a GPP exacerbation in a patient treated with one or more intravenous doses of an anti-IL-36R antibody according to the present invention, the method comprising administering to the patient a prophylactically effective amount of an anti-IL-36R antibody in one or more multiple subcutaneous doses of 225 mg, 300 mg, 450 mg, or 600 mg each of said anti-IL-36R antibody, where two or more subcutaneous doses are administered at intervals of 4, 6, 8, 10, or 12 weeks.

In one embodiment, the present invention provides a method of achieving a Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 or a method of achieving complete resolution of GPP symptoms in a patient treated with one or more intravenous doses of an anti-IL-36R antibody of the present invention, said method involves administering to a 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 each of said anti-IL-36R antibody, where two or more subcutaneous doses are administered at intervals of 4, 6, 8 10 or 12 weeks, and where GPP symptoms include pustule, erythema, or desquamation and complete relief includes a GPPGA score of 0.

In one embodiment, the present invention provides a method of achieving a Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 or a method of achieving complete resolution of GPP symptoms in a patient treated with one or more intravenous doses of an anti-IL-36R antibody of the present invention, said method involves administering to the patient an effective amount of an antibody to IL-36R in 1, 2, 3 subcutaneous doses of 225 mg, 300 mg,

- 51 046186

450 mg or 600 mg each of anti-IL-36R antibody, where 2 or 3 subcutaneous doses are administered at intervals of 4, 6, 8, 10, or 12 weeks, and where GPP symptoms include pustule, erythema, or scaling and complete resolution includes a GPPGA score of 0.

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

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

In one embodiment related to any of aspects six through eight or similar embodiment(s), at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% patients remain in clinical remission as measured by the change from baseline in the GPPASI severity subscore of pustules, erythema, or desquamation at Weeks 12, 24, 36, 48, 60, or 72 of treatment. In a similar embodiment, the proportion of patients responding to administration is statistically significantly higher compared to patients on placebo for any of the specified endpoints.

In an embodiment related to any of aspects six through eight, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission, as measured by the indicator GPPGA 0 or 1 at Week 12, 24, 36, 48, 60, or 72 of treatment. In an embodiment related to any of aspects six through eight, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission, as measured by change for GPPASI relative to baseline at Weeks 12, 24, 36, 48, 60, or 72 of treatment. In an embodiment related to any of aspects six through eight, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission, as measured by change GPPASI severity subscore of pustules, erythema, or desquamation relative to baseline at Weeks 12, 24, 36, 48, 60, or 72 of treatment. In a similar embodiment, the proportion of patients responding to administration is statistically significantly higher compared to patients on placebo for any of the specified endpoints.

In an embodiment related to any of aspects six through eight, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission, as measured by the indicator GPPGA 0 or 1 at Week 12, 24, 36, 48, 60, or 72 of treatment. In a similar embodiment, the improved effects were maintained at a higher percentage for the anti-IL-36R antibody of the present invention compared to placebo. In a similar embodiment, at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40% , 41%,

42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58% , 59%, 60%,

61%, 62%, 63%, 64%, 65%, 66%, 67%,68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77% , 78%, 79%,

80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of mammals or patients maintained improved effects at Weeks 12, 24, 36, 48, 60 or 72 treatments for the anti-IL-36R antibody of the present invention compared with placebo.

In an embodiment related to any of aspects six through eight, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission, as measured by change for GPPASI relative to baseline at Weeks 12, 24, 36, 48, 60, or 72 of treatment. In a similar embodiment, the improved effects were maintained at a higher percentage for the anti-IL-36R antibody of the present invention compared to placebo. In a similar embodiment, at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 3 0%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40 %, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%,68%, 69%, 70%, 71%, 72%, 73% , 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of mammals or patients maintained improved effects at Weeks 12, 24, 36, 48, 60, or 72 of treatment for the anti-IL-36R antibody of the present invention compared to placebo.

In an embodiment related to any of aspects six through eight, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission, as measured by change from baseline in the GPPASI severity subscore of pustules, erythema, or desquamation at weeks 12, 24, 36, 48, 60, or 72 of treatment. In a similar embodiment, the improved effects were maintained at a higher percentage for the anti-IL36R antibody of the present invention compared to placebo. In a similar 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%,

- 52 046186

45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61% , 62%, 63%, 64%, 65%, 66%, 67%,68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78 %, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of mammals or patients maintained improved effects at weeks 12, 24. 36, 48, 60 or 72 treatments for the anti-IL-36R antibody of the present invention compared to placebo.

In a ninth aspect, the present invention provides a method of treating GPP in a patient, comprising administering to the patient a therapeutically effective amount of one or more intravenous doses of an anti-IL-36R antibody, in accordance with aspects one through five and similar embodiments thereof, followed by administration of one or more several subcutaneous doses of an antibody to IL-36R.

In one embodiment of the ninth aspect, after 1 or 2 or 3 intravenous doses of the anti-IL-36R antibody, 1 or 2 or 3 subcutaneous doses of the anti-IL-36R antibody are administered.

In one embodiment of the ninth aspect, after 1 intravenous dose of the anti-IL-36R antibody, 1 or 2 or 3 subcutaneous doses of the anti-IL-36R antibody are administered.

In one embodiment of the ninth aspect, after 2 intravenous doses of the anti-IL-36R antibody, 1 or 2 or 3 subcutaneous doses of the anti-IL-36R antibody are administered.

In one embodiment of the ninth aspect, after 3 intravenous doses of the anti-IL-36R antibody, 1 or 2 or 3 subcutaneous doses of the anti-IL-36R antibody are administered.

In one embodiment related to the ninth aspect and a similar embodiment thereof, each of the one or more intravenous doses includes 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 each of one or more subcutaneous doses includes 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of anti-IL-36R antibody. In a similar embodiment, intravenous doses are administered at intervals of 2, 4, 6, 8, 10, or 12 weeks, subcutaneous doses are administered at intervals of 4, 6, 8, 10, or 12 weeks, and the first subcutaneous dose is administered after 2 to 8 weeks. 4-6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks after the last IV dose.

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

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

In another embodiment, the formulation comprises a therapeutic amount of an anti-IL36R antibody (disclosed herein) and

I) a pharmaceutically acceptable buffer; or

ii) a pharmaceutically acceptable tonicity adjusting agent; or

III) a pharmaceutically acceptable stabilizing agent; or

IV) a pharmaceutically acceptable salt; or

V) a pharmaceutically acceptable surfactant; or

vi) a pharmaceutically acceptable buffer and a pharmaceutically acceptable tonicity adjusting agent; or

vii) a pharmaceutically acceptable buffer, a pharmaceutically acceptable tonicity adjusting agent, and a pharmaceutically acceptable stabilizing agent; or

VIII) a pharmaceutically acceptable buffer, a pharmaceutically acceptable tonicity adjusting agent, a pharmaceutically acceptable stabilizing agent and a pharmaceutically acceptable salt; or

IX) a pharmaceutically acceptable buffer, a pharmaceutically acceptable tonicity adjusting agent, a pharmaceutically acceptable stabilizing agent, a pharmaceutically acceptable salt and a pharmaceutically acceptable surfactant;

each in pharmaceutically acceptable amounts and at a pharmaceutically acceptable pH.

In another embodiment, the anti-IL-36R antibody or antigen binding fragment 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, approximately 80 mg/ml, approximately 100 mg/ml, or approximately 150 mg/ml. In another similar embodiment, the pharmaceutically acceptable buffer is present in the formulation at a concentration ranging from about 20 mM to about 80 mM, or at a concentration of about 20 mM, about 25 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, approximately 60 mM. In another similar embodiment, the pharmaceutically acceptable tonicity adjusting agent is present in the formulation at a concentration ranging from about 100 mM to about 250 mM, or at a concentration of about 100 mM, about 120 mM, about 150 mM, about 180 mM, about

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200 mM. In another similar embodiment, the pharmaceutically acceptable stabilizing agent is present in the formulation at a concentration ranging from about 0 mM to about 80 mM, or at a concentration of about 25 mM or about 50 mM. In another similar embodiment, the pharmaceutically acceptable salt is present in the formulation at a concentration ranging from 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 similar embodiment, the pharmaceutically acceptable surfactant is present in the formulation at a concentration ranging from about 0 g/L to about 1.5 g/L, or at a concentration of about 0.1 g/L, 0.2 g/L l, 0.4 g/l, 0.5 g/l or 1 g/l. In an embodiment of the first aspect, the formulation has a pH value in the range of about 5 to about 8. In another similar embodiment, the pH value is about 5, about 5.5, about 6, about 6.5, about 7, approximately 7.5 or approximately 8.

In another embodiment, the buffer includes histidine, phosphate, succinate, citrate, acetate or TRIS; the tonicity adjusting agent is one or more sugars and/or polyols including sucrose, trehalose, sorbitol, magnesium sulfate (MgSO ₄ ), glycerol, mannitol or dextrose; the stabilizer includes an amino acid, including arginine, histidine, glycine, cysteine, proline, methionine, lysine, aspartate, glutamate or pharmaceutically acceptable salts thereof; salt includes sodium chloride (NaCl), magnesium chloride (MgCl ₂ ), potassium chloride (KCl), lithium chloride (LiCl), calcium chloride (CaCl ₂ ), boric acid salts or zinc chloride (ZnCl ₂ ); and the surfactant includes poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80.

In one embodiment, a method of treatment in accordance with any of the aspects described in the present invention includes administering to a mammal or patient a therapeutic amount of a stable pharmaceutical preparation comprising from about 20 mg/ml to about 150 mg/ml of an anti-IL-36R antibody, from about 20 mM to about 80 mM a pharmaceutically acceptable buffer (e.g., acetate buffer), about 100 mM to about 250 mM a pharmaceutically acceptable tonicity adjusting agent (e.g., sucrose), about 0 mM to about 80 mM a pharmaceutically acceptable stabilizing agent ( e.g., arginine) or a pharmaceutically acceptable salt thereof, from about 0 to about 150 mM of a pharmaceutically acceptable salt (e.g., sodium chloride), and a pharmaceutically acceptable surfactant (e.g., polysorbate 20) in an amount of about 0 g/L to about 1 .5 g/L, wherein it treats generalized pustular psoriasis (GPP) in a patient, or treats moderate to severe GPP in a patient, or reduces or alleviates the signs and symptoms of the acute phase of a sudden flare of GPP in a patient, or reduces the severity and duration of a GPP flare in a patient. the patient, or treat a skin disorder associated with acute GPP in the patient, or prevent or inhibit a GPP flare in the patient, or achieve a Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 in the patient, or achieve complete relief of GPP symptoms in the patient. In a similar embodiment, the stable pharmaceutical preparation is an aqueous pharmaceutical preparation. In a similar embodiment, the pH value of the aqueous pharmaceutical preparation is about 5 to about 7. In a similar embodiment, the pharmaceutical preparation is for intravenous administration to a mammal or patient. In a similar embodiment, the pharmaceutical preparation is for subcutaneous administration to a mammal or patient. In a similar embodiment, the pharmaceutical preparation for intravenous administration includes an antibody to IL-36R in an amount of approximately 60 mg/ml. In a similar embodiment, the pharmaceutical preparation for subcutaneous administration includes an antibody to IL-36R in an amount of approximately 150 mg/ml. In a similar embodiment, an anti-IL-36R antibody comprising: (I) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 125; or (II) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or (III) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 127. In a similar embodiment, an anti-IL-36R antibody comprising: a variable a light chain region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or

- 54 046186 light chain variable region containing the amino acid sequence presented in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89.

In one embodiment, a method of treatment in accordance with any of the previous aspects includes administering to a mammal or patient a therapeutic amount of a stable pharmaceutical selected from the group consisting of:

I. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM LArginine, about 5 mM NaCl and about 1.0 g/L polysorbate 20 , with a pH of approximately 6.0;

II. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM LArginine, about 0.4 g/L polysorbate 20, with a pH of about 5.5 ;

III. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM Glycine, about 0.4 g/L polysorbate 80, with a pH of about 5.5 ;

IV. a formulation comprising from about 20 mg/ml to 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, with a pH of about 6 ,0;

V. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, about 0.2 g/L polysorbate 20, with a pH of about 6 ,5;

VI. a formulation comprising from about 20 mg/ml to about 150 mg/ml anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, about 0.4 g/L polysorbate 80, with a pH of about 6.5;

VII. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM LArginine, about 0.4 g/L polysorbate 20, with a pH of about 5 ,5;

VIII. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL-36R antibody, about 35 mM histidine, about 180 mM trehalose, about 25 mM LArginine, about 3 mM NaCl, about 0.4 g/L polysorbate 80 , with a pH of approximately 6.0;

IX. a preparation comprising from about 20 mg/ml to about 150 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, with a pH of about 5 ,5;

X. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 20 mM succinate, about 220 mM sucrose, about 0.1 g/L polysorbate 80, with a pH of about 6.0; And

XI. a formulation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 25 mM citrate, about 0.4 g/L polysorbate 20, with a pH of about 6.5, wherein generalized pustular psoriasis (GPP) is treated in the patient, or treating moderate to severe GPP in the patient, or reducing or ameliorating the signs and symptoms of the acute phase of a sudden exacerbation of GPP in the patient, or reducing the severity and duration of the GPP exacerbation in the patient, or treating a skin disorder associated with acute GPP in the patient, or prevent or inhibit GPP flares in the patient, or achieve a score of 0 for the generalized pustular psoriasis global score (GPPGA) in the patient, or achieve complete relief of GPP symptoms in the patient. In a similar embodiment, the stable pharmaceutical preparation is an aqueous pharmaceutical preparation. In a similar embodiment, the pharmaceutical preparation is for intravenous administration to a mammal or patient. In a similar embodiment, the pharmaceutical preparation is for subcutaneous administration to a mammal or patient. In a similar embodiment, the pharmaceutical preparation for intravenous administration includes an antibody to IL-36R in an amount of approximately 60 mg/ml. In a similar embodiment, the pharmaceutical preparation for subcutaneous administration includes an antibody to IL-36R in an amount of approximately 150 mg/ml. In a similar embodiment, an anti-IL-36R antibody comprising: (I) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 125; or (II) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or (III) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 127. In a similar embodiment, an anti-IL-36R antibody comprising: a variable a light chain region containing the amino acid sequence set forth in SEQ ID NO: 77; and variable region heavier

- 55 046186 loy chain containing the amino acid sequence presented in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89.

In one embodiment, a method of treatment in accordance with any of the previous aspects includes administering to a mammal or patient a therapeutic amount of a stable pharmaceutical selected from the group consisting of:

I. a preparation comprising approximately 20 mg/ml anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-Arginine, approximately 5 mM NaCl and approximately 1.0 g/L polysorbate 20, pH approximately 6.0;

II. a formulation comprising approximately 60 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-Arginine, approximately 0.4 g/L polysorbate 20, with a pH of approximately 5.5;

III. a formulation comprising approximately 20 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM Glycine, approximately 0.4 g/L polysorbate 80, with a pH of approximately 5.5;

IV. a formulation comprising approximately 150 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g/L polysorbate 20, with a pH of approximately 6.0;

V. a preparation comprising approximately 150 mg/ml anti-IL-36R antibody, approximately 25 mM histidine, approximately 180 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g/L polysorbate 20, with a pH of approximately 6.5;

VI. a formulation comprising approximately 20 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g/L polysorbate 80, with a pH of approximately 6.5;

VII. a preparation comprising approximately 150 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-Arginine, approximately 0.4 g/L polysorbate 20, with a pH of approximately 5.5;

VIII. a formulation comprising approximately 15 mg/ml anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-Arginine, approximately 3 mM NaCl, approximately 0.4 g/L polysorbate 80, with a pH of approximately 6 ,0;

IX. a formulation comprising approximately 80 mg/ml anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g/L polysorbate 20, with a pH of approximately 5.5;

X. a preparation comprising approximately 100 mg/ml anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g/L polysorbate 80, with a pH of approximately 6.0; And

XI. a preparation comprising approximately 60 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 0.4 g/L polysorbate 20, with a pH of approximately 6.5, wherein the patient is treated for generalized pustular psoriasis (GPP), or for moderate to severe GPP in a patient, or reduce or alleviate the signs and symptoms of the acute phase of a sudden exacerbation of GPP in a patient, or reduce the severity and duration of a GPP exacerbation in a patient, or treat a skin disorder associated with acute GPP in a patient, or prevent or inhibit GPP the patient experiences an exacerbation, or achieves a patient's Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0, or achieves complete resolution of the patient's GPP symptoms. In a similar embodiment, the stable pharmaceutical preparation is an aqueous pharmaceutical preparation. In a similar embodiment, the pharmaceutical preparation is for intravenous administration to a mammal or patient. In a similar embodiment, the pharmaceutical preparation is for subcutaneous administration to a mammal or patient. In a similar embodiment, the pharmaceutical preparation for intravenous administration includes an antibody to IL-36R in an amount of approximately 60 mg/ml. In a similar embodiment, the pharmaceutical preparation for subcutaneous administration includes an antibody to IL-36R in an amount of approximately 150 mg/ml. In a similar embodiment, an anti-IL-36R antibody comprising: (I) a mild

- 56 046186 chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or (II) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or (III) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising the amino acid sequence as set forth in SEQ ID NO: 127. In a similar embodiment, an anti-IL-36R antibody comprising: a variable a light chain region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89. In a tenth aspect, the present invention relates to a method of treating GPP in a patient, comprising (a) obtaining a biological sample from said patient, wherein the biological sample is obtained from a source, including affected skin or whole blood;

(b) determining the gene expression profile of one or more genes;

(c) administering to the patient an effective amount of an anti-IL-36R antibody in accordance with any of the embodiments of aspects one through five.

In one tenth aspect embodiment, the one or more genes are IL12B, IL1B, IL6, CXCL1, IL23A, TNF, IL17C, IL24, or IL1B in diseased skin, and IL1B, S100A9, S100A12, S100A8, MMP25, MMP9, or CD177 in whole blood.

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 set forth in SEQ ID NO: 26 (L-CDR1); the amino acid sequence shown in SEQ ID NO: 35, 102, 103, 104, 105, 106 or 140 (L-CDR2); the amino acid sequence shown in SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 53 (H-CDR1); the amino acid sequence shown in SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence shown in SEQ ID NO: 72 (H-CDR3).

In an embodiment related to any of the above aspects, the anti-IL36R antibody is an anti-IL-36R antibody according to the present invention. In one embodiment, an anti-IL36R antibody is described in US Patent No. 9,023,995 or WO 2013/074569. In an embodiment related to any of the above aspects, the improved effects (including remission or improved symptoms) last for 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 44, 45, 46, 47, 48, 49, 50, 51, or 52 weeks after administration of a single dose of the anti-IL-36R antibody of the present invention.

Pharmaceutical compositions and their administration

The antibodies of the present invention can be administered either alone or in combination with other agents. Examples of antibodies for use in such pharmaceutical compositions are antibodies that contain an antibody or antibody fragment having the light chain variable region amino acid sequence set forth in any of SEQ ID NOs: 1-10. Examples of antibodies for use in such pharmaceutical compositions are also those antibodies that contain a humanized antibody or antibody fragment having the heavy chain variable region amino acid sequence represented in any of ID NOs: 11-20.

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

Further examples of antibodies for use in such pharmaceutical compositions also include:

- 57 046186 are those antibodies that contain a humanized antibody or antibody fragment having a light chain variable region and a heavy chain variable region presented in any of SEQ ID NO: 77 and 89, SEQ ID NO: 80 and 88, SEQ ID NO: 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 NO: 85 and 10.

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

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

Various delivery systems are known and can be used to administer the IL-36R binding agent. Routes of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The IL-36R binding agent may be administered, for example, by infusion, bolus, or injection, and may be administered in conjunction with other biologically active agents, such as chemotherapeutic agents. Administration may be systemic or local. In preferred embodiments, administration is by subcutaneous injection. Preparations for such injections can be prepared, for example, in pre-filled syringes, so that they can be administered once every two weeks.

In one aspect, the invention provides an article including a subcutaneous administration device that delivers a fixed dose of an antibody of the present invention to a patient. In some embodiments, the subcutaneous administration device is a prefilled syringe, tube, or high volume infusion device. For example, the MyDose™ product from Roche, a single-use infusion device that provides subcutaneous administration of large amounts of liquid medication, can be used as an administration device. Various delivery devices such as refillable pen syringes and tube syringes can be used for subcutaneous delivery of the pharmaceutical composition of the present invention. Examples include, but are not limited to, AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUMALOG™ syringe -pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis, Ind.), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark ), BD™ pen (Becton Dickinson, Franklin Lakes, N.J.), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™, and OPTICLIK™ (Sanofi-Aventis, Frankfurt, Germany), to name just a few. Examples of disposable pen-type delivery devices that can be used for subcutaneous delivery of the pharmaceutical composition of the present invention include, but are not limited to, SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Eli Lilly), SURECLICK™ Syringe Tube (Amgen, Thousand Oaks, Calif.), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, L.P.), and the HUMIRA™ Syringe Pen (Abbott Labs, Abbott Park 111.), YPSOMATE™, YPSOMATE 2.25™, VAIROJECT™ (Ypsomed AG, Burgdorf, Switzerland), to name just a few. Additional information regarding examples of delivery devices that can be used with the antibody of the present invention can be found, for example, in CH 705992A2, WO 2009/040602, WO 2016/169748, WO 2016/179713.

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

In other embodiments, the anti-IL-36R antibody or agent is delivered using a controlled release system. In one embodiment, a pump can be used (see, for example, Langer, 1990, Science 249:1527-1533; Sefton, 1989, CRC Crit. Ref. Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery 88:507; Saudek et al. 1989, N. Engl. J. Med. 321:574). In another embodiment, polymeric materials can be used. (See, for example, Medical Applications of Controlled Release (Langer and Wise ed., CRC Press, Boca Raton, Fla., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball ed., Wiley, New York , 1984); Ranger and Peppas, 1983, Macromol. Sci. Rev. Macromol. Chem. 23:61. See also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105.) Other controlled release systems are discussed, for example, in Langer, supra.

- 58 046186

The IL-36R binding agent (eg, an anti-IL-36R antibody) can be administered in the form of pharmaceutical compositions comprising a therapeutically effective amount of the binding agent and one or more pharmaceutically compatible components.

In one embodiment, an anti-IL-36R antibody or antigen binding fragment thereof (described herein) is present in a pharmaceutical preparation (as described in co-pending U.S. Provisional Patent Application No. 62/815,405, filed March 8, 2019. the entire contents of which are thus incorporated herein by reference in their entirety) suitable for administration to a mammal or patient in accordance with any of the aspects described in the present invention. Various examples for this embodiment are described in numbered embodiments (1, 2, 3, etc.) below for reasons of convenience. They are presented in the form of examples and do not limit the claimed technology. It should be noted that any of the dependent embodiments can be combined in any combination, and placed into a corresponding independent embodiment, for example, embodiment 1. Other embodiments can be presented in a similar manner.

1. A pharmaceutical preparation, including:

a) an anti-IL-36R antibody or antigen-binding fragment thereof, as described herein, present at a concentration ranging from about 0.5 mg/ml to about 220 mg/ml; And

b) a pharmaceutically acceptable buffer present in a concentration ranging from about 20 mM to about 80 mM;

wherein the drug has a pH value ranging from about 5 to about 8 when in aqueous form.

2. The drug according to embodiment 1, where the drug is in liquid or powder form.

3. The preparation according to embodiment 1, wherein the anti-IL-36R antibody is present at a concentration ranging from about 10 mg/ml to about 200 mg/ml.

4. The preparation according to embodiment 1, wherein the anti-IL-36R antibody is present at a concentration of approximately 20 mg/ml.

5. The preparation according to embodiment 1, wherein the anti-IL-36R antibody is present at a concentration of approximately 60 mg/ml.

6. The preparation according to embodiment 1, wherein the anti-IL-36R antibody is present at a concentration of approximately 150 mg/ml.

7. The preparation according to embodiment 1, where the buffer includes histidine, phosphate, succinate, citrate, acetate or TRIS.

8. The preparation according to embodiment 1, where the buffer includes citrate or acetate.

9. The preparation according to embodiment 1, where the buffer includes histidine.

10. The preparation according to embodiment 1, where the buffer includes acetate.

11. The formulation of embodiment 1, wherein the formulation further comprises a pharmaceutically acceptable tonicity adjusting agent present at a concentration ranging from about 100 mM to about 250 mM.

12. The preparation according to embodiment 11, wherein the tonicity-regulating agent is one or more Sugars and/or polyols.

13. The preparation according to embodiment 11, wherein the tonicity adjusting agent is one or more Sugars and/or polyols, including sucrose, trehalose, sorbitol, magnesium sulfate (MgSO ₄ ), glycerol, mannitol or dextrose.

14. The preparation according to embodiment 11, wherein the tonicity-regulating agent includes sucrose or trehalose.

15. The preparation according to embodiment 11, wherein the tonicity-regulating agent includes sucrose.

16. The preparation according to embodiment 11, wherein the tonicity regulating agent includes trehalose.

17. The formulation of embodiment 1, wherein the formulation further comprises a pharmaceutically acceptable stabilizer present at a concentration ranging from about 0 mM to about 80 mM.

18. The preparation according to embodiment 17, where the stabilizer includes an amino acid, including arginine, histidine, glycine, cysteine, proline, methionine, lysine, aspartate, glutamate or pharmaceutically acceptable salts thereof.

19. The preparation according to embodiment 17, where the stabilizer includes L-arginine or pharmaceutically acceptable salts thereof.

20. The formulation of embodiment 1, wherein the formulation further comprises a pharmaceutically acceptable salt present in a concentration ranging from about 0 to about 150 mM.

21. The preparation according to embodiment 20, wherein the salt includes sodium chloride (NaCl), magnesium chloride (MgCl ₂ ), potassium chloride (KCl), lithium chloride (LiCl), calcium chloride (CaCl ₂ ), boric acid salts or zinc chloride (ZnCl ₂ ).

- 59 046186

22. The preparation according to embodiment 20, wherein the salt includes sodium chloride (NaCl).

23. The formulation according to embodiment 1, wherein the formulation further comprises a pharmaceutically acceptable surfactant present in a concentration ranging from about 0 g/L to about 1.5 g/L.

24. The formulation according to embodiment 23, wherein the surfactant comprises poloxamer 188, polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80.

25. The formulation according to embodiment 23, wherein the surfactant comprises polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80.

26. The formulation according to embodiment 23, wherein the surfactant comprises polysorbate 20.

27. The formulation according to embodiment 23, wherein the surfactant comprises polysorbate 80.

28. Pharmaceutical preparation, including:

a) an anti-IL-36R antibody or antigen-binding fragment thereof, as described herein, present at a concentration ranging from about 10 mg/ml to about 200 mg/ml;

b) acetate and/or histidine buffer present in a concentration ranging from about 20 mM to about 80 mM;

c) sucrose and/or trehalose present in a concentration ranging from about 100 mM to about 250 mM;

d) L-arginine and -/- or pharmaceutically acceptable salts thereof, present in a concentration ranging from about 0 mM to about 80 mM;

e) sodium chloride (NaCl) present in a concentration ranging from about 0 to about 150 mM; And

e) polysorbate 20 and/or polysorbate 80 present in a concentration ranging from about 0 g/L to about 1.5 g/L;

wherein the drug has a pH value ranging from about 5 to about 7 when in aqueous form.

29. Pharmaceutical preparation, including:

a) an anti-IL-36R antibody or antigen-binding fragment thereof, as described herein, present at a concentration of approximately 20 mg/ml;

b) citrate buffer present at a concentration of approximately 25 mM;

c) sucrose and/or trehalose present at a concentration of approximately 200 mM;

d) polysorbate 80, present at a concentration of approximately 0.4 g/l;

wherein the drug has a pH value ranging from about 6 to about 7 when in aqueous form.

30. Pharmaceutical preparation, including:

a) an anti-IL-36R antibody or an antigen-binding fragment thereof, as described herein, present at a concentration of approximately 60 mg/ml;

b) acetate buffer present at a concentration of approximately 45 mM;

c) sucrose and/or trehalose present at a concentration of approximately 150 mM;

d) L-arginine or pharmaceutically acceptable salts thereof, present at a concentration of approximately 25 mM; And

e) polysorbate 20, present at a concentration of approximately 0.4 g/l;

wherein the drug has a pH value in the range of about 5 to about 6 when in aqueous form.

31. Pharmaceutical preparation, including:

a) an anti-IL-36R antibody or antigen-binding fragment thereof, as described herein, present at a concentration of approximately 150 mg/ml;

b) acetate buffer present at a concentration of approximately 45 mM;

c) sucrose or trehalose present at a concentration of approximately 150 mM;

d) L-arginine or pharmaceutically acceptable salts thereof, present at a concentration of approximately 25 mM; And

e) polysorbate 20, present at a concentration of approximately 0.4 g/l;

wherein the drug has a pH value in the range of about 5 to about 6 when in aqueous form.

32. The pharmaceutical preparation according to any one of embodiments 1-31, wherein the preparation has an osmolality ranging from about 210 mOsmol/kg to about 390 mOsm/kg.

33. The pharmaceutical preparation according to any one of embodiments 1-32, wherein less than about 5% of the antibody is present in aggregated form in the preparation.

34. The pharmaceutical preparation according to any one of embodiments 1-33, where the preparation is sterile.

35. The pharmaceutical preparation according to any one of embodiments 1-34, where the preparation is stable during freezing and thawing.

36. The pharmaceutical preparation according to any one of embodiments 1-35, where the preparation includes water or

- 60 046186 restored with water.

37. The pharmaceutical preparation according to any one of embodiments 1-36, wherein the preparation has a pH in the range of about 5 to about 6 in liquid form or when reconstituted with water.

38. The pharmaceutical preparation according to any one of embodiments 1-37, wherein the preparation has a pH of approximately 6 in liquid or when reconstituted with water.

39. The pharmaceutical drug according to any of embodiments 1-37, where the drug has at least one characteristic feature selected from the group consisting of:

(I) increased shelf life (II) better temperature stability, (III) reduced aggregate formation, (IV) better chemical stability, (V) reduced viscosity, and compared to the reference product.

40. The pharmaceutical preparation according to any one of embodiments 1-37, wherein the preparation having at least one characteristic feature is selected from the group consisting of:

(a) reduced percentage of aggregates as measured by high performance size exclusion chromatography (HP-SEC), (b) high percentage of monomers as measured by HP-SEC, (c) high percentage of main peak (less degradation charged variants) measured by CEX, (d) lower percentages of non-instrumentally visible particulates such as >10 µm and >25 µm, and (e) lower turbidity in formazin nephelometric units (FNU), after storage of approx. at 40°C compared to the reference preparation.

41. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

i) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or ii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or iii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 127; wherein the drug is selected from the group consisting of:

I. a preparation comprising approximately 20 mg/ml anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-Arginine, approximately 5 mM NaCl and approximately 1.0 g/L polysorbate 20, pH approximately 6.0;

II. a formulation comprising approximately 60 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-Arginine, approximately 0.4 g/L polysorbate 20, with a pH of approximately 5.5;

III. a formulation comprising approximately 20 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM Glycine, approximately 0.4 g/L polysorbate 80, with a pH of approximately 5.5;

IV. a formulation comprising approximately 150 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g/L polysorbate 20, with a pH of approximately 6.0;

V. a preparation comprising approximately 150 mg/ml anti-IL-36R antibody, approximately 25 mM histidine, approximately 180 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g/L polysorbate 20, with a pH of approximately 6.5;

VI. a formulation comprising approximately 20 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g/L polysorbate 80, with a pH of approximately 6.5;

VI I. preparation comprising approximately 150 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-Arginine, approximately 0.4 g/L polysorbate 20, with a pH of approximately 5.5 ;

VII I. preparation comprising approximately 15 mg/ml anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-Arginine, approximately 3 mM NaCl, approximately 0.4 g/L polysorbate 80, c pH approximately 6.0;

IX. a formulation comprising approximately 80 mg/ml anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g/L polysorbate 20, with a pH of approximately 5.5;

X. a preparation comprising approximately 100 mg/ml anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g/L polysorbate 80, with a pH of approx.

- 61 046186 exactly 6.0; And

XI. a formulation comprising approximately 60 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 0.4 g/L polysorbate 20, with a pH of approximately 6.5.

42. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

i) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or ii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or iii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 127; wherein the formulation comprises approximately 20 mg/ml anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-Arginine, approximately 5 mM NaCl, and approximately 1.0 g/L polysorbate 20, with a pH of approximately 6 ,0.

43. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

i) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or ii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or iii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 127; wherein the formulation comprises approximately 60 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-Arginine, approximately 0.4 g/L polysorbate 20, with a pH of approximately 5.5.

44. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

i) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or ii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or iii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 127; wherein the formulation comprises approximately 20 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM Glycine, approximately 0.4 g/L polysorbate 80, with a pH of approximately 5.5.

45. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

i) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or ii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or iii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 127; wherein the formulation comprises approximately 150 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g/L polysorbate 20, with a pH of approximately 6.0.

46. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

i) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or ii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or iii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 127; wherein the formulation comprises approximately 150 mg/ml anti-IL-36R antibody, approximately 25 mM histidine, approximately 180 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g/L polysorbate 20, with a pH of approximately 6.5.

47. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

i) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or

- 62 046186 ii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or iii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 127; wherein the formulation comprises approximately 20 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g/L polysorbate 80, with a pH of approximately 6.5.

48. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

i) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or ii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or iii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 127; wherein the formulation comprises approximately 150 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-Arginine, approximately 0.4 g/L polysorbate 20, with a pH of approximately 5.5.

49. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

i) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or ii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or iii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 127; wherein the formulation comprises approximately 15 mg/ml anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-Arginine, approximately 3 mM NaCl, approximately 0.4 g/L polysorbate 80, with a pH of approximately 6 ,0.

50. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

i) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or ii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or iii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 127; wherein the formulation comprises approximately 80 mg/ml anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g/L polysorbate 20, with a pH of approximately 5.5.

51. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

i) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or ii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or iii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 127; wherein the formulation comprises approximately 100 mg/ml anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g/L polysorbate 80, with a pH of approximately 6.0.

52. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

i) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or ii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or iii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 127; wherein the formulation comprises approximately 60 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 0.4 g/L polysorbate 20, with a pH of approximately 6.5.

53. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

a light chain variable region containing an amino acid sequence representing

- 63 046186 included in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89;

wherein the formulation comprises: approximately 20 mg/ml anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-Arginine, approximately 5 mM NaCl, and approximately 1.0 g/L polysorbate 20, with a pH of approximately 6.0.

54. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89;

wherein the formulation includes: approximately 60 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-Arginine, approximately 0.4 g/L polysorbate 20, with a pH of approximately 5.5.

55. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region containing an amino acid sequence representing

- 64 046186 included in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89;

wherein the formulation comprises: approximately 20 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM Glycine, approximately 0.4 g/L polysorbate 80, with a pH of approximately 5.5.

56. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89;

wherein the formulation comprises: approximately 150 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g/L polysorbate 20, with a pH of approximately 6.0.

57. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region containing an amino acid sequence representing

- 65 046186 included in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89;

wherein the formulation comprises: approximately 150 mg/ml anti-IL-36R antibody, approximately 25 mM histidine, approximately 180 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g/L polysorbate 20, with a pH of approximately 6.5.

58. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89;

wherein the formulation comprises: approximately 20 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g/L polysorbate 80, pH approximately 6.5.

59. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; And

- 66 046186 heavy chain variable region containing the amino acid sequence presented in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89;

wherein the formulation includes: approximately 150 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-Arginine, approximately 0.4 g/L polysorbate 20, with a pH of approximately 5.5.

60. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89;

wherein the formulation includes: approximately 15 mg/ml anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-Arginine, approximately 3 mM NaCl, approximately 0.4 g/L polysorbate 80, with a pH of approximately 6.0.

61. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; And

- 67 046186 heavy chain variable region containing the amino acid sequence presented in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89;

wherein the formulation comprises: approximately 80 mg/ml anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g/L polysorbate 20, pH approximately 5.5.

62. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89;

wherein the formulation comprises: approximately 100 mg/ml anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g/L polysorbate 80, pH approximately 6.0.

63. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region containing an amino acid sequence representing

- 68 046186 included in SEQ ID NO: 89;

wherein the formulation comprises: approximately 60 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 0.4 g/L polysorbate 20, pH approximately 6.5.

64. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

i) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or ii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 126; or iii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 127; wherein the drug is selected from the group consisting of:

I. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM LArginine, about 5 mM NaCl and about 1.0 g/L polysorbate 20 , with a pH of approximately 6.0;

II. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM LArginine, about 0.4 g/L polysorbate 20, with a pH of about 5.5 ;

III. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM Glycine, about 0.4 g/L polysorbate 80, with a pH of about 5.5 ;

IV. a formulation comprising from about 20 mg/ml to 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, with a pH of about 6 ,0;

V. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, about 0.2 g/L polysorbate 20, with a pH of about 6 ,5;

VI. a formulation comprising from about 20 mg/ml to about 150 mg/ml anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, about 0.4 g/L polysorbate 80, with a pH of about 6.5;

VI I. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM LArginine, about 0.4 g/L polysorbate 20, c pH approximately 5.5;

VII I. preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL-36R antibody, about 35 mM histidine, about 180 mM trehalose, about 25 mM LArginine, about 3 mM NaCl, about 0.4 g/ l polysorbate 80, with a pH of approximately 6.0;

IX. a preparation comprising from about 20 mg/ml to about 150 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, with a pH of about 5 ,5;

X. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 20 mM succinate, about 220 mM sucrose, about 0.1 g/L polysorbate 80, with a pH of about 6.0; And

XI. a formulation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 25 mM citrate, about 0.4 g/L polysorbate 20, with a pH of about 6.5.

65. Pharmaceutical preparation, including:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 87; or

- 69 046186 light chain variable region containing the amino acid sequence presented in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 88; or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89;

wherein the drug is selected from the group consisting of:

I. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 40 mM histidine, about 120 mM sucrose, about 50 mM LArginine, about 5 mM NaCl and about 1.0 g/L polysorbate 20 , with a pH of approximately 6.0;

II. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM LArginine, about 0.4 g/L polysorbate 20, with a pH of about 5.5 ;

III. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 45 mM acetate, about 180 mM sucrose, about 25 mM Glycine, about 0.4 g/L polysorbate 80, with a pH of about 5.5 ;

IV. a formulation comprising from about 20 mg/ml to 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, with a pH of about 6 ,0;

V. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 25 mM histidine, about 180 mM sucrose, about 20 mM mannitol, about 0.2 g/L polysorbate 20, with a pH of about 6 ,5;

VI. a formulation comprising from about 20 mg/ml to about 150 mg/ml anti-IL-36R antibody, about 25 mM citrate, about 200 mM sucrose, about 0.4 g/L polysorbate 80, with a pH of about 6.5;

VII. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL-36R antibody, about 45 mM acetate, about 150 mM sucrose, about 25 mM LArginine, about 0.4 g/L polysorbate 20, with a pH of about 5 ,5;

VIII. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL-36R antibody, about 35 mM histidine, about 180 mM trehalose, about 25 mM LArginine, about 3 mM NaCl, about 0.4 g/L polysorbate 80 , with a pH of approximately 6.0;

IX. a preparation comprising from about 20 mg/ml to about 150 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, with a pH of about 5 ,5;

X. a preparation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 20 mM succinate, about 220 mM sucrose, about 0.1 g/L polysorbate 80, with a pH of about 6.0; And

XI. a formulation comprising from about 20 mg/ml to about 150 mg/ml anti-IL36R antibody, about 25 mM citrate, about 0.4 g/L polysorbate 20, with a pH of about 6.5.

66. A pharmaceutical product, including a vial or syringe comprising a pharmaceutical preparation in accordance with any of the previous embodiments for use in any of the aspects of the present invention.

67. The pharmaceutical product according to embodiment 66, which further includes a pre-assembled delivery device.

68. The pharmaceutical product according to embodiment 67, wherein the pre-assembled delivery device is a tube syringe or a syringe with or without a needle guard.

69. A pre-assembled delivery device comprising a pharmaceutical preparation in accordance with any of the preceding embodiments for use in any of the aspects of the present invention.

70. A pre-assembled delivery device according to embodiment 69, wherein said device is a tube syringe or a syringe with or without a needle guard.

71. Pre-assembled delivery device according to an embodiment

69, wherein said preparation is suitable for intravenous, subcutaneous or intramuscular administration.

72. A pre-assembled delivery device according to embodiment 70, wherein the tube syringe or syringe with a guard with or without a needle includes a pharmaceutical preparation comprising:

an antibody to IL-36R or an antigen-binding fragment thereof, comprising:

i) a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 125; or ii) a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118,

- 70 046186 and a heavy chain including the amino acid sequence as indicated in SEQ ID NO: 126; or a light chain comprising the amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including the amino acid sequence as set forth in SEQ ID NO: 127;

wherein the drug is selected from the group consisting of:

I. a preparation comprising approximately 20 mg/ml anti-IL-36R antibody, approximately 40 mM histidine, approximately 120 mM sucrose, approximately 50 mM L-Arginine, approximately 5 mM NaCl and approximately 1.0 g/L polysorbate 20, pH approximately 6.0;

II. a formulation comprising approximately 60 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-Arginine, approximately 0.4 g/L polysorbate 20, with a pH of approximately 5.5;

III. a formulation comprising approximately 20 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 180 mM sucrose, approximately 25 mM Glycine, approximately 0.4 g/L polysorbate 80, with a pH of approximately 5.5;

IV. a formulation comprising approximately 150 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 150 mM trehalose, approximately 25 mM methionine, approximately 0.2 g/L polysorbate 20, with a pH of approximately 6.0;

V. a preparation comprising approximately 150 mg/ml anti-IL-36R antibody, approximately 25 mM histidine, approximately 180 mM sucrose, approximately 20 mM mannitol, approximately 0.2 g/L polysorbate 20, with a pH of approximately 6.5;

VI. a formulation comprising approximately 20 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 200 mM sucrose, approximately 0.4 g/L polysorbate 80, with a pH of approximately 6.5;

VII. a preparation comprising approximately 150 mg/ml anti-IL-36R antibody, approximately 45 mM acetate, approximately 150 mM sucrose, approximately 25 mM L-Arginine, approximately 0.4 g/L polysorbate 20, with a pH of approximately 5.5;

VIII. a formulation comprising approximately 15 mg/ml anti-IL-36R antibody, approximately 35 mM histidine, approximately 180 mM trehalose, approximately 25 mM L-Arginine, approximately 3 mM NaCl, approximately 0.4 g/L polysorbate 80, with a pH of approximately 6 ,0;

IX. a formulation comprising approximately 80 mg/ml anti-IL-36R antibody, approximately 25 mM acetate, approximately 100 mM mannitol, approximately 50 mM NaCl, approximately 0.2 g/L polysorbate 20, with a pH of approximately 5.5;

X. a preparation comprising approximately 100 mg/ml anti-IL-36R antibody, approximately 20 mM succinate, approximately 220 mM sucrose, approximately 0.1 g/L polysorbate 80, with a pH of approximately 6.0; And

XI. a formulation comprising approximately 60 mg/ml anti-IL-36R antibody, approximately 25 mM citrate, approximately 0.4 g/L polysorbate 20, with a pH of approximately 6.5.

73. A pre-assembled delivery device according to embodiment 70, wherein the tube syringe or syringe with a needle guard includes:

a) approximately 300 mg of antibody in approximately 2 ml of preparation volume; or

b) approximately 225 mg of antibody in approximately 1.5 ml volume of preparation; or

c) approximately 150 mg of antibody in approximately 1 ml volume of the preparation; or

d) approximately 75 mg of antibody in approximately 0.5 ml volume of preparation; or

e) approximately 60 mg of antibody in approximately 0.4 ml of preparation volume.

74. The bottle according to embodiment 66, where the bottle includes:

a) approximately 1200 mg of antibody in approximately 20 ml volume of the preparation; or

b) approximately 900 mg of antibody in approximately 15 ml of preparation volume; or

c) approximately 600 mg of antibody in approximately 10 ml volume of the preparation; or

d) approximately 300 mg of antibody in approximately 150 ml volume of the preparation; or

e) approximately 1500 mg of antibody in approximately 2.5 ml of preparation volume.

75. A pharmaceutical product comprising: a vial containing from about 100 mg to 1500 mg of an anti-IL-36R antibody in powder form; instructions for reconstituting anti-IL-36R antibody; and instructions for preparing a reconstituted antibody for infusion, wherein the anti-IL-36R antibody comprises a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 118 and a heavy chain including an amino acid sequence as set forth in any of SEQ ID NOs: 125 , 126 or 127; and reconstitution instructions require reconstitution with water for injection to an extractive volume of 1-50 ml.

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-IL36R antibody) in lyophilized form, and (b) a second container containing a pharmaceutically acceptable diluent (e.g., a sterile water) for administration. A pharmaceutically acceptable diluent can be used to reconstitute or dilute the lyophilized anti-IL-36R antibody or agent. Optionally associated with such container(s) may be a notice in a form prescribed by a government agency regulating the manufacture, use or sale of pharmaceutical or biological products, where the notice reflects the approval of the manufacturing, use or safety authority for administration to humans .

Such combination treatment may have an additive or synergistic effect on disease parameters (eg, symptom severity, number of symptoms, or relapse rate).

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

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

Examples

Example 1 Inhibition of the IL-36 receptor for the treatment of generalized pustular psoriasis.

The antibody of the present invention, that is, the anti-IL-36R antibody of the present invention (described in the present invention as well as in US Pat. No. 9,023,995), is a humanized antagonistic monoclonal IgG1 antibody that blocks human IL36R signaling. It is proposed that the binding of the anti-IL-36R antibody of the present invention to IL36R prevents subsequent activation of IL36R by cognate ligands (IL36 α, β and γ) and downstream activation of pro-inflammatory and profibrotic pathways to reduce epithelial cell/fibroblast/immune cell-mediated inflammation and interrupts the inflammatory response that triggers the production of pathogenic cytokines in generalized pustular psoriasis (GPP).

Preclinical profiles of the anti-IL-36R antibody of the present invention and clinical data from studies in healthy volunteers indicate that the anti-IL-36R antibody of the present invention is safe, tolerable, and may address an unmet medical need in GPP patients.

Prerequisites.

Mutations in IL36RN are significantly involved in 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, was evaluated in this open-label, experimental, single-dose Phase I study in patients with acute generalized pustular psoriasis.

Methods.

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

Results.

The anti-IL-36R antibody of the present invention was well tolerated with no serious drug-related adverse events or safety signals. In Week 1, GPPGA score 0 or 1 was achieved in five patients, and in all patients for Week 4. Within 48 hours, pustules cleared in three patients, and in six patients for Week 2. Significant improvement for GPPASI was observed in all patients with mean (SD) percent change from baseline 73.2% (16.2) in Week 2; for Week 4, which further decreased to 82.0%. Effectiveness was generally maintained up to 20 weeks.

Conclusions.

Inhibition of the interleukin-36 pathway using a single dose of the anti-IL-36R antibody of the present invention results in rapid and sustained remission of clinical symptoms in patients with acute generalized pustular psoriasis. Alternatively, a single dose of the anti-IL-36R antibody of the present invention results in rapid and sustained remission of clinical symptoms, with no adverse safety signals, in patients with acute generalized pustular psoriasis, regardless of IL36RN mutation status.

Introduction.

Generalized pustular psoriasis is a rare, severe multisystem disease first described by von Zumbusch in 1909, which is characterized by recurrent acute exacerbations consisting of disseminated erythematous and pustular skin eruptions associated with general symptoms, including fever, and often involving extracutaneous organs; in which cases, life-threatening complications may develop. Biologically, most

- 72 046186 common features are high serum levels of C-reactive protein (CRP) and leukocytosis with neutrophilia, together with abnormal liver function tests. Epidemiological studies show a prevalence of only 1.76/million, highlighting the rarity of the disease.

Therapeutic intervention for generalized pustular psoriasis is a major challenge with a lack of treatments currently approved in the United States or Europe. Various anti-psoriatic strategies have been proposed based on the psoriasis vulgaris model, with the effectiveness of apheresis, and tumor necrosis factor inhibitors, interleukin-17 and interleukin-23, described in open studies and case reports formed the basis for approval for generalized pustular psoriasis in Japan . However, apheresis is limited to specialized centers, while the contribution of these key inflammatory cytokines to psoriasis vulgaris and the pathogenesis of generalized pustular psoriasis remains unclear.

Recently, major advances in our understanding of the mechanisms underlying pustular psoriasis have come from genetic studies that have identified homozygous or compound heterozygous loss-of-function mutations in the IL36RN gene in some patients with generalized pustular psoriasis. These mutations greatly alter the function of the IL36RN product interleukin-36 receptor antagonist (interleukin-36Ra), resulting in dysregulation of the pro-inflammatory interleukin-36 pathway (IL-36a, IL-36β and IL-36y), and leading to generalized pustular psoriasis according to the monogenic model. While these mutations have been found in other subtypes of pustular psoriasis, they have not been found in patients with plaque psoriasis alone, demonstrating the autoinflammatory nature of pustular psoriasis and establishing generalized pustular psoriasis as a distinct entity from plaque psoriasis.

This immunogenetic valuable information led to the establishment of the rationale for the therapeutic target of interleukin-36R in generalized pustular psoriasis. The results of this first human disease study using the anti-IL36R antibody of the present invention, a human monoclonal antibody targeting interleukin-36R, are described, assessing safety and efficacy in patients with severe exacerbation of generalized pustular psoriasis. To our knowledge, this is the first study to evaluate treatment in patients with acute generalized pustular psoriasis.

Methods.

Research plan.

This 20-week, multicenter, single-arm, open-label, phase I pilot study included patients from five countries (France, Malaysia, Republic of Korea, Taiwan, and Tunisia). Eligible patients received a single intravenous (IV) dose of 10 mg/kg of the anti-IL-36R antibody of the present invention and were followed for 20 weeks.

Patients.

Patients aged 18-75 years were eligible for inclusion in the study with a known and documented history of generalized pustular psoriasis, regardless of IL36RN mutation status, with previously documented fever and/or asthenia and/or myalgia and/or elevated CRP, and /or leukocytosis with neutrophilia presented with acute exacerbations affecting 10% or more of their body surface area (BSA) with erythema and the presence of pustules, and a physician global assessment of generalized pustular psoriasis (GPPGA) score of 3 or higher (attending physician examination of GPP severity at based on a modified PGA [see Appendix]; scores range from 0 [clear skin] to 4 [severe disease]) during treatment. Patients may continue to receive subcutaneous treatment with retinoids and/or methotrexate.

Patients were excluded if they had an emergency life-threatening exacerbation of generalized pustular psoriasis or acute generalized exanthematous pustulosis (see Table 2 for an overview of all inclusion/exclusion criteria). Patients who provided consent were included in the study in the absence of exacerbation. Screening (visit 1) was initiated several days or weeks before the patient was deemed eligible for treatment of an exacerbation of generalized pustular psoriasis (visit 2). For patients meeting the inclusion/exclusion criteria, treatment with BI 655130 began the day after Visit 2 (Visit 3).

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Table 2 Inclusion/exclusion criteria

Inclusion criteria

Patients can only be included in the study if they meet the following criteria:

1. Male or female patients, aged 18-75 years at the time of screening

2. With a known and documented history of generalized pustular psoriasis (GPP), regardless of IL36RN mutation status, with previously confirmed fever, and/or asthenia, and/or myalgia, and/or elevated C-reactive protein, and/or leukocytosis with neutrophilia in peripheral blood (above ULN)

3. Presence of exacerbation of GPP with at least 10% body surface area with erythema and pustules

4. GPPGA score of at least moderate severity

5. GPP patients receiving subcutaneous treatment with retinoids and/or methotrexate for at least 4 weeks or GPP patients not receiving any subcutaneous therapy at the screening visit

6. Signed and dated written informed consent before inclusion in the study in accordance with the rules for conducting qualitative clinical research and local legislation

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7. Women of reproductive potential* should be willing and able to use highly effective contraceptive methods on ICH M3 that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraceptive methods that meet these criteria is provided in the patient information. Male patients should be willing and able to use condoms. The contraceptive method must be continued until 20 weeks after administration of the anti-IL-36R antibody of the present invention.

* A woman is considered to have reproductive potential, that is, fertile, after menarche and before postmenopause unless she has been permanently sterilized. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Tubal ligation is NOT a permanent sterilization method. Postmenopausal status is defined as the absence of menstruation for 12 months without an alternative medical cause.

Exclusion criteria

Patients may not be allowed to participate in the study if any of the following general criteria apply:

1. Women who are pregnant, breastfeeding, or planning pregnancy during the study. Women who stopped breastfeeding before administration of the drug should not be excluded from participation in the study. They should not breastfeed until 20 weeks after receiving the study drug.

2. Sudden exacerbation of GPP that is life-threatening or requires treatment in the intensive care unit, as determined by the investigator. Life-threatening exacerbations primarily include, but are not limited to, cardiovascular/cytokine-triggered shock and pulmonary distress

3. Identified, current serious/severe infection

4. Acute generalized exanthematous pustulosis

5. Clinical manifestations in the patient considered due to the differential diagnosis of toxic epidermal necrosis or Stevens-Johnson syndrome

6. Currently participating or intending to participate in another experimental study at the time of this study

7. Previous inclusion in this study

8. Use of any restrictive drug as listed in Table 3, or any drug considered likely to interfere with the safe conduct of the study

9. Patients increasing the dose of their subcutaneous methotrexate and/or retinoid therapy in the 4 weeks preceding the screening visit

10. Background therapy with cyclosporine during the last 30 days preceding the screening visit

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11. Previous exposure to an interleukin-36 inhibitor

12. Severe, progressive, or uncontrolled renal, liver, hematologic, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms thereof, in the opinion of the investigator. Patients with less than a 3-fold increase in ULN aspartate aminotransferase and/or alanine aminotransferase and/or alkaline phosphatase and/or with a less than 2-fold ULN increase in total bilirubin on the day of infusion may be included, provided that no other cause of liver injury has been identified that differs from GPP

13. Known chronic or relevant acute infections, including active tuberculosis (TB), HIV or viral hepatitis; the QuantiFERON® TV test can be performed during screening. If the result is positive, then patients can participate in the study if further processing (in accordance with local practice/guidelines) conclusively establishes that the patient does not have evidence of active TV. If latent TV is identified, treatment can be initiated and maintained in accordance with local country guidelines.

14. Organ transplant patients (except corneal transplant >12 weeks before screening visit) or those who have received stem cell therapy (eg, Prochymal®)

15. History of lymphoproliferative disease, including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy and/or splenomegaly

16. Any documented active or suspected malignancy or history of malignancy within 5 years before the second screening visit, excluding favorable treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix

17. Evidence of a current or previous disease, medical condition (including chronic alcohol or drug abuse) other than GPP, surgery (i.e., organ transplant), medical testing (including vital signs and electrocardiogram), or laboratory data at the second screening visit outside the reference range that, in the opinion of the investigator, are clinically significant and may render the study participant ineligible for inclusion in the protocol or for completion of the study, adversely affect patient safety, or adversely affect the quality of the data

18. History of an allergic/hypersensitive reaction to a systemically administered biological agent or its excipients

19. The patient refuses hospitalization within 4 days after the infusion

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Table 3

Restrictive medications

Drug or Drug Class

Natalizumab, efalizumab, or agents that deplete B or T cells (eg, rituximab, alemtuzumab, or visilizumab), briakinumab, secukinumab, ustekinumab, guselkumab, tildrakizumab

IL-36R inhibitors

Duration of restriction (Until the end of the study visit*) months before screening (visit 2)

Not permitted before or during study participation

Brodalumab, ixekizumab Adalimumab, infliximab, experimental products for psoriasis (non-biological)

Etanercept, live virus vaccinations

Any investigational device or product (excluding products for psoriasis), other systemic immunomodulatory treatments, excluding background therapy with methotrexate (eg, cyclosporine A, corticosteroids^, cyclophosphamide), tofacitinib, apremilast, other systemic treatments for psoriasis, excluding background therapy using retinoids (eg, fumarates, any other known drug, for months before screening (Visit 2) weeks before screening (Visit 2) weeks before screening (Visit 2) days before screening (Visit 2) known to have possible benefit in psoriasis) , photochemotherapy (eg PUVA).

Phototherapy (eg, UVA, UVB), topical treatment for psoriasis or other skin condition (eg, corticosteroids^, vitamin D analogues, vitamin A analogues, pimecrolimus, retinoids, salicyl vaseline, salicylic acid, lactic acid, tacrolimus, tar, urea, anthralin, a-hydroxy, fruit acids) Anakinra days before screening (visit 2) days before screening (visit 2) *In case of worsening exacerbation, the use of a reserve drug is at the discretion of the investigator; in case any other acute parameter is set after

Day 28, use of restrictive medication is allowed

Ή 1e there are restrictions for corticosteroids with only topical action (for example, inhaled corticosteroids for the treatment of asthma or corticosteroid drops put into the eye or ear) ^Exception: Topical steroids of US class 6 (weak, such as desonide) or US class 7 ( less effective, such as hydrocortisone) for use on the face, armpits and/or genitals, limiting use to 24 hours before the study visit at which GPPASI is assessed. GPPASI=Generalized Pustular Psoriasis Area and Severity Index

All patients underwent genotyping to determine the IL36RN, CARD14, and

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AP1S3.

Genotyping.

To identify mutations in IL36RN, CARD14 and AP1S3, targeted resequencing was performed using Illumina MiSeq with Nextera Rapid Capture Custom Enrichment Kit (Illumina Inc., San Diego, CA). Sequences were aligned and mapped to human genome version 19 using MiSeq Reporter (Illumina Inc., San Diego, CA). A mutation was considered potentially pathogenic if there were correlations with published functional data or risk associated with generalized pustular psoriasis, or if the mutation was a sense substitution, or located in a known gene regulatory element (eg, start codon).

Evaluation of effectiveness and safety.

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, laboratory tests, vital signs, administration site reactions, and immunogenicity during the study. Immunogenicity assessments are described in the Appendix. Secondary endpoints at Week 2 included percent change from baseline in area and generalized pustular psoriasis severity index (GPPASI; a modified composite index based on PASI, (J Dermatolog Treat 2003;14:158–65), with the roughness component replaced by the pustule component ; scores range from 0 to, with higher scores indicating greater disease severity), proportion of patients with GPPGA 0 (clear) or 1 (virtually clear), change from baseline for Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F; instrument, based on 13 questions to monitor fatigue and its effects on patients; scores range from 0 to 52, with lower scores indicating greater fatigue), (J Pain Symptom Manage 1997;13:63-74) and change from baseline in patients whose pain was assessed using a visual analogue scale (Pain-VAS). See table. 4 regarding demographic and disease characteristics of patients at baseline.

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Table 4

Demographic and disease characteristics at baseline

6001003 3301001 2100104 2100103 Patient 34 26 31 47 Age (years) AND AND m M Gender (M/F) Mongol. n/a White White Race* Malaysia France Tunisia Tunisia A country 67.9 70.4 82.0 52.0 Body weight (kg) 29.8 26.5 25.9 19.1 BMI (kg/ ^m2 ) 9.7 19.9 5.0 46.9 Time from initial diagnosis (years) - - + + ^IL36RNf § AND - - - - CARD14 ^J presence of gene mutations :+/-) - - - - AP1S3 2 18 1 1 Time from this exacerbation to administration of the dose of the claimed antibody to IL-36R (days) 3 3 3 3 GPPGA (0-4) ^§ 26.2 20.3 52.5 22.2 GPPASI (0-72) ¹ 3.0 1.5 2.3 1.8 Pustule severity index (0-4)** 152.9 4.0 276.6 237.0 CRP (mg/1) 18 46 12 28 FACIT-F ¹ ' ¹ ' 80 60 90 95 Pain-VAS 13 8 12 10 PSS" Cysp, MTX, RET C.Y.S.P. RET RET Before systemic therapies

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Total (N=7) 8801001 8201002 6001004 38.6 (13.8) 58 22 52 M=3 F=4 AND M AND White = 2 Mongol. = 4 N/A= 1 Mongol. Mongol. Mongol. np Taiwan Republic of Kopeya Malaysia 62.8 (11.0) 52.8 56.9 57.6 23.3 (4.3) 20.1 18.2 23.7 16.4 (16.8) 29.3 0.1 4.0 3 (42.9%) + - - 1 (14.3%) + - - 0 - - - 5.3 (7.4) 1 0 14 3 (0) 3 3 3 27.5 (12.3) 16.7 33.4 21.0 2.3 (0.6) 2.8 1.8 2.8 69.4 (57.0) 0.80 n/a 82.8 31.7 (13.3) 46 32 40 72.1 (22.0) thirty 70 80 9.71 (3.1) 4 9 12 CYSP = 3 (42.9) MTX = 2 (28.6) RET = 4 (57.1) RET C.Y.S.P. MTX

Values represent mean (standard deviation) unless specifically stated otherwise.

* Race was indicated by the patient independently. Race is not specified for patient 3301001.

f Homozygous missense variant rs387906914 (patients 1 and 2), and intronic mutation variant rsl48755083 (patient 7).

J Heterozygous variant rs117360605 (patient 7).

§ Physician's Global Assessment for Generalized Pustular Psoriasis (GPPGA) is a physician's assessment of the general severity of GPP based on a modified PGA; scores range from 0 (clear skin) to 4 (severe disease).

The Generalized Pustular Psoriasis Area and Severity Index (GPPASI) is a modified summary score for patients with GPP based on the established PASI, with the roughness component replaced by the pustule component; scores range from 0 to 72, with higher scores indicating greater disease severity.

* * Pustule severity is based on the GPPASI component subscore and ranges from 0 to 4; higher scores indicate greater severity.

ff Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) scores ranging from 0 to 52; lower scores indicate greater fatigue.

JJ Psoriasis Symptom Scale (PSS) scores range from 0 to 16, with higher scores indicating greater severity of symptoms (psoriatic pain, redness, itching and burning).

C1=confidence interval; CRP=C-reactive protein; N/A=no data;

NA=not applicable; SD=standard deviation; VAS=Visual Analog Scale.

Other previously established efficacy endpoints include change and percentage change.

- 80 046186 opinions regarding baseline for pustule severity (based on GPPASI component), change and percentage change from baseline for GPPASI, proportion of patients with GPPGA score 0 or 1, proportion of patients with resolution of edema, change from baseline for pustular BSA, change and percent change from baseline for erythema severity (based on GPPASI component); change from baseline for FACIT-F and Pain-VAS at Weeks 1 and 4; change from baseline for the Psoriasis Symptom Scale (PSS; four patient items describe a measured clinical outcome, assessing psoriasis pain, redness, itching, and burning. Symptom severity is assessed using a 5-point Likert-type scale for scores ranging from 0 (none) to 4 (very severe) and an overall score is calculated by adding all subscores), (J Patient-Rep Outcomes 2017; 1:4) the proportion of patients with a PSS overall score of 0, and an improvement in Clinical Global Impression (an observer-rated scale measuring overall disease improvement , based on a 7-point scale, scores ranging from 1 [extremely much improvement] to 7 [extremely much worsening]) (Jpn J Dermatol 2010;120:815-39) (in Weeks 1, 2, and 4. Final efficacy points that were not previously defined included the proportion of patients achieving >50, >75, and >90 percent improvement for GPPASI over time and the percent change from baseline for peeling severity (GPPASI component).

Photo documentation of skin lesions was carried out at baseline and after treatment. Biochemical, cellular and pharmacogenomic biomarkers were assessed in skin and whole blood (see below for biomarker methodologies). Skin biopsies were performed at baseline and Week 1 (an additional optional biopsy was performed in Week 2).

Physician's Global Assessment of Generalized Pustular Psoriasis (GPPGA).

GPPGA is based on clinical assessment of the patient's skin manifestations. It is a modified PGA, the physician's assessment of psoriatic lesions, which has been adapted for the assessment of patients with generalized pustular psoriasis. (J Dermatolog Treat 2015;26(1):23-31) The examiner (or a qualified local specialist) scores the erythema, pustules and desquamation of all psoriatic lesions in the range of 0-4. Each component is assessed separately, the average is calculated, and the final GPPGA is determined from this composite score. A lower score subsequently indicates less severity, with 0 being clear and 1 being essentially clear. To receive a score of 0 or 1, the patient must be afebrile, in addition to the requirements for skin manifestations.

Generalized pustular psoriasis area and severity index (GPPASI).

The GPPASI is an adaptation of the PASI, an established measure of the severity and extent of psoriatic lesions in patients with psoriasis, for patients with generalized pustular psoriasis. (Dermatologica 1978; 157(4):238-44) Similar adaptations are used for palmoplantar psoriasis. (J Eur Acad Dermatol Venereol 2009;23(4):415-9) For GPPASI, the coarsening component is replaced by the pustule component. It is a tool that provides a quantitative score for the overall disease status of patients with generalized pustular psoriasis, and ranges from 0 to 72. It is a linear combination of the percentage of body surface area (a measure of body surface area) that is affected and the severity ( rated on a five-point scale ranging from 0 [least severe] to 4 [most severe] (See Table 5)) erythema, pustules, and scaling (desquamation) for four body sites (head, upper extremity, torso, and lower extremity ).

Table 5

Area and severity index of generalized pustular psoriasis

Index Erythema Pustules Peeling 0 Normal or post-inflammatory pigmentation No visible pustules No peeling or crusting

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1 Dull, diffuse pink or pale red Low density single small discrete pustules (non-coalescent) Superficial focal peeling or crusting limited to the periphery of the lesions 2 Light red Moderate density of grouped discrete small pustules (non-coalescent) Predominantly fine flaking or crusting 3 Bright red High density of pustules with some calcification Moderate peeling or crusting involving most or all lesions 4 Deep fiery red Very high density of pustules with pustular lakes Severe peeling or crusting involving most or all lesions

Individual indicator per body area = body area coefficient (head = 0.1, upper limb = 0.2, torso = 0.3, lower limb = 0.4) x body area area indicator x sum of the severity component indicators for the body area

Overall GPPASI score = sum of individual scores from all body areas

Immunogenicity assessment.

Plasma samples from all patients for evaluation of drug antibodies were collected predose and on days 7, 14, 21, 28, 84, and 140 postdose. Samples were analyzed to detect anti-IL-36R antibodies of the present invention using the validated Meso Scale Discovery® (MSD) electrochemiluminescent drug bridge (ECL) acid dissociation method at QPS, LLC, Newark, DE, USA. Drug antibody plasma samples and controls were first diluted in 0.3 M acetic acid, then neutralized using 1.5 M Tris base and a master mix that included biotin-labeled drug and sulfo-labeled drug, then transferred and incubated in MSD blocking streptavidin tablet. In the presence of a readout buffer containing tripropylamine, the sulfo marker produces an ECL signal that is triggered if voltage is applied using the MSD Sector Imager 600s. The resulting chemiluminescence was measured in relative light units, which are proportional to the amount of drug antibodies present in the plasma samples. The immunogenicity of the anti-IL-36R antibody of the present invention was assessed using a three-prong approach.

All drug antibody samples were first analyzed in a drug antibody screening assay. A sample is considered positive for anti-IL-36R antibodies according to the present invention if its response in the screening assay is greater than or equal to the plate-specific compartment cutoff, and if it is confirmed positive in the confirmatory assay (ECL response inhibited by addition excess of the anti-IL-36R antibody of the present invention above the confirmation separation limit). Samples that were confirmed to be positive for anti-IL-36R antibodies according to the present invention were further characterized in a titration assay. Titers were determined by analyzing 2-fold serial dilutions of the sample. The reporter titer was the highest dilution that produced an average ECL value greater than or equal to the plate-specific titration cutoff.

In the drug antibody validation assay, the sensitivity of the GPP plasma screening assay was shown to be 2.5 ng/ml using the anti-IL-36R antibody of the present invention and the positive control rabbit polyclonal antibody positive control. Additionally, positive control levels of 100 and 250 ng/ml were detected in the presence of at least 2000 μg/ml of the anti-IL-36R antibody of the present invention. None of the ADA samples had levels of the anti-IL-36R antibody of the present invention greater than 2000 μg/ml. Data obtained from the assay indicate that the method is suitable for screening, confirming and determining anti-IL-36R antibody titers of the present invention in plasma samples from patients in the present study.

Biomarker assessment.

The levels of CRP (not highly sensitive) and the absolute number of neutrophils were assessed,

- 82 046186 using standard methodologies with the help of local laboratories. Evaluation samples were collected at baseline before treatment and on days 7, 14, and 28.

Evaluation of pharmacogenomic biomarkers.

Global broadband RNA transcriptome sequencing was performed from lesional and nonlesional skin biopsies and whole blood from all patients using Illumina Hi-Seq 3000 (Illumina Inc., San Diego, CA). Data were normalized using TMM using the edgeR package; log 2 fold changes and corresponding FDR-corrected p-values were analyzed using the Iimma package (Bioconductor, US). (Genome Biol 2010;11(3):R25; Nucleic acids Res 2015;43(7):e47) In brief, the data were voom-transformed and correlations between paired measurements per patient were assessed using a paired correlation function. A linear model was fitted using the lmFit function and moderated t-statistics were analyzed on the computer to determine focal versus non-focal and pre- versus post-treatment with the anti-IL-36R antibody of the present invention. ( Nucleic acids Res 2015;43(15):e97; Genome Biol 2014;15(2):R29) Adjusted P-values <0.05 were considered significant.

Statistical analysis.

Due to the small sample size and lack of comparison, this study did not test any statistical hypotheses. Endpoints were described from start to finish and assessed using descriptive statistics methods. Safety analyzes included all treated patients (full analysis set; FAS); Efficacy analyzes were performed on patients who had baseline and at least one post-treatment measurement available for either GPPASI or GPPGA; and biomarker analyzes were performed on all treated patients who provided at least one observation for at least one biomarker matrix. Non-response imputation was used for binary efficacy endpoints after use of a rescue drug; for continuous endpoints, only observations collected before use of the reserve drug were pooled. One patient received a reserve treatment during treatment, therefore, data after such use (after Week 4) were interpreted as described.

Results.

Patients.

Of the 16 patients included in the screening, seven patients (three men and four women, aged 22 to 58 years) at five study sites who had a moderate to severe acute exacerbation received a single 10 mg/kg IV dose of antibody to IL-36R according to the present invention during the period from February to August. Baseline demographics and disease characteristics are described in Table. 3. Two patients carried a homozygous loss-of-function mutation of IL36RN (rs387906914/p.Leu27Pro), which is known to cause generalized pustular psoriasis, and one patient carried mutations potentially causing generalized pustular psoriasis, including a homozygous IL36RN mutation (rsl48755083) and a heterozygous CARD14 mutation (rs117360605/p.Arg275His). The mean (SD) time from initial diagnosis for all patients was 16.4 (16.8) years. All patients who had a moderate exacerbation had a GPPGA of 3 and a pustule subscore of 2-4 (moderate to very high density). The mean time interval (SD) between the onset of the current exacerbation and the infusion of the anti-IL-36R antibody according to the present invention was 5.3 (7.4) days (range: 0-18 days). All patients had previously received prior systemic treatment for generalized pustular psoriasis and this was stopped before receiving the anti-IL-36R antibody of the present invention; cyclosporine was discontinued 30 days before the anti-IL-36R antibody of the present invention was administered. All patients completed the study through Week 20, however, there were two protocol violations: One patient (patient 8201002) did not meet the inclusion criteria for a history of generalized pustular psoriasis but met other inclusion criteria, and the second patient (patient 6001004) received methotrexate in Week 4 to treat pain. Both patients were included in the FAS, however, only efficacy data up to Week 4 are included for patient 6001004.

Safety.

Before 20 weeks, four patients (57.1%) were interpreted as having drug-related adverse events (Table 6); all are classified as moderate or moderate. No severe or serious adverse events were described. Laboratory values were normal for most patients, two patients (28.6%) had low hemoglobin; two patients (14.3%) had elevated eosinophils, one patient had elevated creatine kinase, two patients had elevated triglycerides, and one patient had low glucose levels after treatment with the anti-IL-36R antibody of the present invention. Three patients (42.9%) were positive for drug antibodies at Week 2, maintaining until Week 20 with a maximum titer at Week 12 for two patients; no pre-existing antibodies to the drug were detected.

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Table 6

Adverse events up to Week 20*

Adverse event, η (%) 10 mg/kg anti-IL-36R antibody according to the present invention (N=7) Any adverse event 7 (100) Severe adverse event 0 Adverse event associated with taking a drug facilities Eosinophilia Vomit Chills Pain^ Infection of the upper respiratory tract Urinary infection ways Infusion-related reaction Arthralgia 4 (57.1) 2 (28.6) 1 (14.3) 1 (14.3) 1 (14.3) 2 (28.6) 1 (14.3) 1 (14.3) 1 (14.3) Adverse event leading to discontinuation of the study drug 0 Severe adverse event associated with taking a drug 0

*Adverse events were coded using the Medical Dictionary for Drug Regulatory Activities, version 20.1. Investigators classified the intensity of adverse events as mild, moderate, or severe f The patient described pain at the site of preexisting lesions located in both legs. Efficacy.

Clinical Endpoints.

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

Significant improvement for GPPASI was observed in all patients very early with a mean (SD) percentage change from baseline of 73.2% (16.2) at Week 2 (Figure 1B); for Week 4, which further decreased to 79.8%, and was maintained until Week 20 (83.6%). Within 48 hours of treatment, the pustules cleared completely in three patients (42.9%); pustules cleared in five patients (71.4%) for Week 1, and in six patients (85.7%) for Week 2 (Fig. 1C). For Week 1, 85.7% of patients achieved a GPPASI 50, for Week 4, 71.4% of patients achieved a GPPASI 75, and for Week 12, 57.1% of patients achieved a GPPASI 90 (Figure 2). The mean GPPASI erythema subscore decreased from baseline by 27.8%, 48.3%, and 53.5% in Weeks 1, 2, and 4, respectively. Similarly, the mean GPPASI desquamation subscore decreased from baseline by 38.1%, 49.6%, and 57.1% in Weeks 1, 2, and 4, respectively (Figure 3).

Patient-reported treatment outcomes.

The mean (SD) improvement in FACIT-F from baseline to Week 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, there was a mean (SD) change from baseline of -5.14 (3.18) for PSS in Week 2, which was also maintained through Week 4 (Figure 6).

Biomarker analysis.

A rapid decrease in CRP was observed, trending to normalization with a mean (SD) change for CRP from baseline to Week 2 of 64.2 (55.1) mg/dL, which was maintained until Week 4 (Figure 7). The absolute neutrophil count decreased rapidly until Week 2 and was maintained until Week 4 (Fig. 8).

Global transcriptomic analysis of lesion and nonlesional skin biopsies identified 3,276 genes that were differentially expressed (1,885 increased; 1,391 decreased) at baseline between lesional and nonlesional skin biopsies (adjusted P < 0.05, fold change > 2). After treatment for seven days with the anti-IL-36R antibody of the present invention, the expression of 1444 genes in the affected skin was highly upregulated or downregulated, reaching levels of adjacent unaffected skin; genes that

- 84 046186 Some are differentially expressed and have been associated with innate (e.g., IL6, TNF, and CXCL1) and Th1/Th17-mediated inflammation (e.g., IL1B, IL12B, and IL23A) and proinflammatory processes of keratinocyte activation (e.g., IL17C and IL24) (Table 7).

Table 7

Gene expression profile of affected relative to unaffected skin and before and after treatment with the anti-IL-36R antibody of the present invention

Gene Description Affected relative to unaffected skin at baseline (Log2FC) Affected skin relative to after treatment with the anti-IL36R antibody of the present invention in Week 1 (Log2FC) IL36A Interleukin 36 alpha 6.5042** -1.98 IL36B Interleukin 36 beta 1.3974 0.0258 IL36G Interleukin 36 gamma 3.7135** -0.9053 IL12B Interleukin 12V 5.5762** -3.4247* IL1B Interleukin 1 beta 4.4361** -2.2585* IL6 Interleukin 6 3.9185* -3.6732* CXCL1 Chemokine ligand 1 (C-X-C motif) 5.4683*** -2.6705* CXCL8 Interleukin 8 4.8027** -1.1786 IL23A Interleukin 23A 4.5025** -2.8952* TNF Tumor necrosis factor 1.7834*** -1.5952* IL17C Interleukin 17C 5.6359** -3.6090* IL24 Interleukin 24 8.0150* -4.3571*

Adjusted P-values: *P<0.05, **P<0.01, ***P<0.001. Data were normalized using TMM using the edgeR package. The Limma package was used to derive log 2 fold change and the corresponding false positive rate of adjusted P-values. TMM=Trimmed Mean of M-Values.

In all patients, IL-36a, IL-36y, and IL-8 were highly elevated in lesional skin biopsies; after seven days of treatment with the anti-IL-36R antibody of the present invention, the expression of IL-36a and IL-36y was greatly reduced in four patients, while IL-8 was greatly reduced in three patients (fold change >2). RNA expression analysis from whole blood identified differentially expressed genes (adjusted P < 0.05, fold change >2) at 7, 14, and 28 days (364, 476, and 568 genes, respectively). Proinflammatory mediator genes involved in neutrophil activation, such as IL1B, CD177, S100A8/9, S100A12, MMP9, and MMP25, were among those most significantly downregulated (Table 8).

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Table 8

Gene expression profile in whole blood before and after treatment with an anti-IL-36R antibody according to the present invention

Whole blood

Differential expression relative to baseline after treatment with an anti-IL36R antibody of the present invention (Log2FC)

Gene Description Day 1 Week 1 Week 2 Week 4 IL1B Interleukin 1 beta 0.0569 -0.8180* -0.9891** -1.1283** S100A9 S100 calcium- - binding protein A9 0.3686 -0.9398 -1.2238* -1.5496** S100A12 S100 calcium- - binding protein A12 0.5480 -1.3200* -1 8570** ” ’ 2.1336*** S100A8 S100 calcium- - binding protein A8 0.5096 -1.0197 -1.3282* -1.6132** MMP25 Matrix - metallopeptidase 25 0.2015 -0.5665 -1.0276** -0.8226* MMP9 Matrix - metallopeptidase 9 0.2247 -0.5728 -1.5403* -1.6919** CD 177 CD177 molecule 0.4945 -2.6019 -4.6062* -4.7470**

Adjusted P-values: *P<0.05, **P<0.01, ***P<0.001. Data were normalized using TMM using the edgeR package. The Limma package was used to derive log 2 fold change and the corresponding false positive rate of adjusted P-values. TMM=Trimmed Mean of M-Values.

Discussion.

In this first-in-human disease study to analyze the safety and efficacy of the anti-IL-36R antibody of the present invention, an anti-interleukin-36R human monoclonal antibody, patients with generalized pustular psoriasis were studied due to significant disease severity, high unmet need, and compelling evidence contributing to interleukin-36 dysregulation in the skin and systemic inflammation in this syndrome. In fact, the absence or impairment of interleukin-36Ra due to IL36RN mutation causes generalized pustular psoriasis, although the prevalence of such mutations varies among different groups, ranging from 5 to 70%, which has led to the identification of a new autoimmune syndrome called DITRA (deficiency of interleukin receptor antagonist -36). The relationship between the interleukin-36R inhibition strategy in generalized pustular psoriasis was confirmed using the genetically engineered DITRA mouse model, and with the help of increased knowledge regarding the structure and function of human interleukin-36R, which made it possible to obtain an antibody to IL-36R according to the present invention, which inhibits inflammatory effects of interleukin-36. The results from this pilot study demonstrate rapid resolution of systemic inflammation and efficacy, with five of seven patients becoming clear or substantially clear one week after infusion of the anti-IL-36R antibody of the present invention, and all patients achieving this status by Week 4. Evaluation of Efficacy for these very early time points was designed specifically to avoid the misattribution of drug intervention (in this noncomparative study) to the spontaneous, self-limiting course of exacerbations of generalized pustular psoriasis that typically occur over weeks to months—a disease characteristic that limits the impact of many therapeutic trials in generalized pustular psoriasis with late temporary efficacy endpoints. (Br J Dermatol 1968;80:771-93) Likewise, recommended successful treatments using a wide range of targeted biological agents, such as tumor necrosis factor inhibitors, interleukin-17 and interleukin-23, should be considered cautiously. (J Dermatol 2016;43:1011-7; Arch Dermatol 2012;148:14235; Ann Intern Med 2010;153:66-7) This early, robust response pattern in both the skin and systemic components suggests that that inhibition of interleukin-36R using a single dose of an anti-IL-36R antibody according to the present invention leads to rapid and prolonged shutdown of the inflammatory cascade in generalized pustular psoriasis. These early responses are also reflected in rapid improvements in patient-reported clinical outcomes (FACIT-F, Pain-VAS, and PSS). Another key observation is the similar efficacy observed in patients with and without IL36RN mutations, supporting the recent hypothesis that cytokines

- 86 046186 terleukin-36 is involved in skin inflammation not only in subtypes of pustular psoriasis with different genetic backgrounds, but also potentially in lesions caused by psoriasis vulgaris. This rapid improvement in clinical endpoints is reflected in the rapid improvement of the gene expression profile in affected skin to levels in adjacent normal skin within seven days, highlighting the central role of the interleukin-36 pathway in this disease. Differentially expressed genes in whole blood up to 28 days confirm the sustained and long-term clinical effect of a single dose of the anti-IL-36R antibody of the present invention.

Regarding tolerability, no clear treatment-emergent safety signals were identified, in addition to previously reported safety data in 124 healthy volunteers (unpublished data) and are consistent with the recent characterization of individuals with IL36R knockout mutations resulting in complete absence of interleukin-36R , but without any evidence of an increased risk of superinfection, nor a significant effect on innate and adaptive immune responses. (Sci Transl Med 2017;9).

Given the small number of patients in the study, no obvious association was found between immunogenicity and changes in either safety or efficacy.

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

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

Example 2: A multicenter, double-blind, randomized, placebo-controlled, phase II study to evaluate the efficacy, safety, and tolerability of the anti-IL-36R antibody of the present invention in patients with generalized pustular psoriasis (GPP) characterized by acute flares ranging from moderate to severe.

Current treatment options to control acute GPP, completely relieve symptoms, and prevent recurrence of exacerbations are limited and do not provide long-term effectiveness. There is currently no approved treatment for GPP in the US or Europe, although a combination of retinoids, cyclosporine, or methotrexate is recommended as an initial option to control worsening of chronic GPP. However, long-term use of these treatments is limited due to side effects and contraindications (retinoids: teratogenicity, hair loss; cyclosporine: excessive hair growth, nephrotoxicity; MTX: hepatotoxicity). Side effects such as hair loss, excessive hair growth, and teratogenicity particularly limit the use of these treatments in women. Biologic agents (mainly TNF inhibitors, occasionally IL-1 or IL-17 inhibitors) are increasingly used to treat more severe, advanced, or treatment-resistant patients with GPP, based on small published case series. However, these drugs are also associated with limitations in efficacy (incomplete and delayed reactions are common) and safety (risks of infection and infusion reactions).

Based on the limitations described above, current treatment options are not suitable for long-term treatment and do not provide long-term responses in most patients. Therefore, to address the highly unmet need in GPP, there is a critical need to develop (i) highly effective, rapid onset treatments for patients experiencing acute exacerbation of GPP; and (ii) develop an effective treatment that is also proven to reduce flares and result in complete resolution of manifestations such as widespread erythema and desquamation, and is safe and tolerable for lifelong treatment. Additionally, a search of the currently available literature did not reveal any published articles focusing on moderate to severe GPP exacerbation. Thus, our RoC approach and subsequently developed plan further addresses the needs of GPP treatment options.

The strong genetic link between the IL36 and GPP signaling pathway and experimental data identifying IL-36 as the dominant GPP-triggering cytokine suggests that inhibition of IL36R signaling by a humanized anti-IL36R antibody is the anti-IL-36R antibody of the present invention. may be beneficial for GPP treatment - similar to the strong responses observed in patients deficient in IL1R anta

- 87 046186 gonist, with sterile multifocal osteomyelitis after treatment with Anakinra. Additionally, recently characterized individuals with homozygous IL36R KO mutations show that normal immune function is broadly preserved, suggesting that inhibition of the IL36 signaling pathway does not impair host defense mechanisms.

Based on these rationales, an open-label, single-arm study was conducted to analyze experimentally a single dose of the anti-IL-36R antibody of the present invention in patients with GPP. A total of seven patients were treated with a single IV administration of 10 mg/kg anti-IL-36R antibody of the present invention.

As described above, inhibition of IL36R activity results in rapid and lasting improvement in GPP regarding clinical cutaneous and systemic symptoms. In the patients studied, the anti-IL-36R antibody of the present invention was well tolerated. Up to 20 weeks of study duration, only mild to moderate adverse events were reported. Additionally, no severe or serious adverse events were described.

Based on these results, the objective of this follow-up GPP study was to evaluate the efficacy, safety and tolerability of the anti-IL-36R antibody of the present invention compared to placebo in patients with GPP presenting as an acute exacerbation of moderate to severe intensity.

To enable further scientific research, patients were asked to voluntarily donate biological samples for storage in a biobank. If the patient consented, samples stored in the biobank could be used for future biomarker discovery and drug development projects, for example to identify patients who are more likely to benefit from treatment or experience an adverse event (AE), or to achieve mechanistic or genetic understanding drug effects and therefore better selection of patients for therapies.

Study objectives and endpoints.

Main goals.

To evaluate the efficacy, safety and tolerability of the anti-IL-36R antibody of the present invention in patients with generalized pustular psoriasis (GPP) presenting with an acute exacerbation of moderate to severe intensity.

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Summary of the clinical trial protocol

Number of included patients: At least 27 Number of patients for each treatment: 18 patients for the anti-IL-36R antibody of the present invention and 9 patients for placebo Diagnosis: Patients with generalized pustular psoriasis (GPP), presenting with an acute exacerbation of moderate to severe intensity. Main inclusion criteria and exceptions Main inclusion criteria: Patients were included in the study (screening) if they met the following criteria: • 1a) Patients with GPPGA 0 or 1 and with a known and documented history of GPP according to the European Expert Network on Rare and Severe Forms of Psoriasis (ERASPEN) criteria, regardless of IL36RN mutation status, with previously confirmed fever and/or asthenia and/or myalgia, and/or elevated C-reactive protein, and/or leukocytosis with neutrophilia in the peripheral blood. OR • 16) Patients with an acute exacerbation of moderate to severe intensity, meeting criteria (ERASPEN) for GPP known and documented in the history of GPP (per ERASPEN criterion), regardless of IL36RN mutation status, with previously confirmed fever, and/or asthenia, and/or myalgia, and/or elevated C-reactive protein, and/or leukocytosis with neutrophilia in the peripheral blood. OR • 1c) Patients with the first episode of an acute exacerbation of moderate to severe intensity with manifestations of fever and/or asthenia and/or myalgia and/or elevated C-reactive protein and/or leukocytosis with neutrophilia in the peripheral blood (above ULN) . For these patients, the diagnosis will be confirmed retrospectively by a central external assessor/committee. • Patients may or may not be receiving background treatment with retinoids and/or methotrexate and/or cyclosporine. Patients should discontinue retinoids/methotrexate/cyclosporine before receiving the first dose of the present invention anti-IL-36R antibody/placebo. • Patients are male or female, aged 18 to 75 years at the time of screening.

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• Signed and dated written informed consent before inclusion in the study in accordance with ICH-GCP and local legislation before starting any screening procedure. • Women of reproductive potential and fertile men should be willing and able to use highly effective contraceptive methods at ICH M3 (R2), which result in a low failure rate of less than 1% per year when used consistently and correctly. Application: A woman is considered to have reproductive potential, that is, fertile, after menarche and before postmenopause, unless she has been permanently sterilized. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Tubal ligation is not a permanent sterilization method. Postmenopausal status is defined as the absence of menstruation for 12 months without an alternative medical cause. Main exclusion criteria: • Patients with SAPHO syndrome (synovitis-acnepustulosis-hyperostosis-osteitis). • Patients with primary erythrodermic psoriasis vulgaris. • Patients with primary plaque-like psoriasis vulgaris without the presence of pustules or with pustules that are limited to psoriatic plaques. • Drug-induced acute generalized exanthematous pustulosis (AGEP). • Sudden exacerbation of GPP that is life-threatening or requires treatment in the intensive care unit, as determined by the investigator. Life-threatening exacerbations primarily include, but are not limited to, cardiac vascular/cytokine-triggered shock, pulmonary distress syndrome, or renal failure.[TMM before submitting TSM threshold] • Severe, progressive, or uncontrolled liver disease, defined as >3 times the upper limit of normal (ULN) for AST or ALT or alkaline phosphatase, or >2 times the ULN of total bilirubin. • Patients with escalation of their subcutaneous therapy with cyclosporine and/or methotrexate and/or retinoids within 2 weeks before receiving the first dose of the anti-IL-36R antibody of the present invention/placebo.

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• Initiation of systemic agents such as cyclosporine and/or retinoids and/or methotrexate 2 weeks before receiving the first dose of the anti-IL-36R antibody of the present invention/placebo. Treatment (Visit 2) should be initiated immediately in patients: • Which meet the inclusion criteria above • Who have a moderate to severe acute exacerbation of GPP, defined as the occurrence of: a) a Generalized Pustular Psoriasis Physician's Global Assessment (GPPGA) score of at least 3 (moderate), and b) presence of fresh pustules (new appearance or worsening of pustules), and c) a GPPGA pustulization score of at least 2 (weak), and d) at least 5% of the body surface area (BSA) covered by erythema and the presence of pustules • Those that do not meet any of the exclusion criteria described above. dose: 900 mg, single dose method of administration: IV products for comparisons: Placebo Comparator dose: Not applicable method of administration: IV Duration of treatment: Single dose Endpoints Primary endpoints: The composite primary endpoints of the study are: • Physician's global assessment of generalized pustular psoriasis (GPPO) score of 0 or 1 in Week 1. • GPPGA pustulization subscore 0, indicating no visible pustules in Week 1. Secondary endpoints: The secondary study endpoints in Week 4, which are included in the statistical testing strategy in a hierarchical order, followed by testing on the composite primary endpoints, are: • Psoriasis area and generalized pustular psoriasis severity index (GPPASI) 75 in Week 4. • Change from baseline in the Visual Analog Scale (VAS) score in Week 4. • Change from baseline in the Psoriasis Symptom Scale (PSS) score in Week 4. • Change relative to the initial level of the indicator Functional Assessment of Chronic Illness Therapy (FACIT) fatigue scores in Week 4. Secondary study endpoints that are not included in the statistical testing hierarchy are: • GPPGA 0 or 1 in Week 4. • GPPGA pustulization subscore 0, indicating no visible pustules in Week 4. • GPPASI 50 in Weeks 1, and 4. • Percentage reduction for GPPASI from baseline in Weeks 1, and 4. The following security endpoint is also defined: • Treatment-emergent adverse events (TEAEs).

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This study will be a single-dose placebo-controlled study of patients with moderate to severe acute GPP exacerbations receiving 900 mg of the anti-IL-36R antibody of the present invention and thereafter followed for an additional 12 weeks. Patients who met the inclusion/exclusion criteria of the subsequent open-label extension study will have the option to receive GPP treatment using subcutaneous dosing. See fig. 9 regarding further details of the study design.

Example 3: Treatment of Patients with Acute GPP Exacerbation.

In this example, an anti-IL36R antibody (eg, an anti-IL-36R antibody according to the present invention) was used to treat patients with acute GPP exacerbation. Initially, each patient had one or more of the inclusion criteria listed in Example 2. A single 900 mg IV dose of the anti-IL36R antibody of the present invention (in infusion solution at a concentration of 60 mg/ml) was administered to each patient.

Following administration of an anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the present invention), safety and efficacy evaluations revealed the following: At least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32% , 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49 %, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%,68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82% 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of patients achieved clinical remission as determined by (a) Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 or 1. in Week 1; (b) GPPGA Pustulization Subscore 0, indicating no visible pustules in Week 1; (c) Psoriasis area and generalized pustular psoriasis severity index (GPPASI) 75 in Week 4; (d) Changes from baseline in the visual analogue scale (VAS) pain score at Week 4; (e) Change from baseline in Psoriasis Symptom Score (PSS) at Week 4; (f) Changes from baseline in the Functional Assessment of Chronic Illness Therapy (FACIT) fatigue score at Week 4; (g) GPPGA 0 or 1 in Week 4; (h) GPPGA Pustulization Subscore 0, indicating no visible pustules in Week 4; (i) GPPASI 50 in Weeks 1 and 4; or (j) Change in the GPPASI severity subscore of pustules, erythema, or desquamation from baseline in Weeks 1 and 4 of treatment. The proportion of patients responding to administration was statistically significantly higher compared to patients on placebo for one or more endpoints (a)-(j).

Example 4. Prevention of recurrence of exacerbation in GPP patients.

In this example, a single 900 mg IV dose of the anti-IL36R antibody of the present invention (in infusion solution at a concentration of 60 mg/ml) was used to treat patients with acute GPP exacerbation. After the IV dose, as shown in Table. 1, additional subcutaneous doses of anti-IL36R antibody were administered to prevent recurrence of GPP exacerbation.

After the last dose of an anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the present invention) is administered, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission, as measured by a GPPGA score of 0 or 1 at Weeks 12, 24, 36, 48, 60, or 72. The improved effects were maintained at a higher percentage for the anti-IL-36R antibody of the present invention compared to placebo. At least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% , 26%, 27%, 28%, 29%, 30%, 31%,

32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48% , 49%, 50%,

51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67% ,68%, 69%,

70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86% , 87%, 88%,

89% or 90% of mammals or patients maintained improved effects at Weeks 12, 24, 36, 48, 60, or 72 after the last dose of anti-IL-36R, compared with placebo.

After the last dose of an anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the present invention) is administered, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain in clinical remission, as measured by the change in GPPASI from baseline at Weeks 12, 24, 36, 48, 60, or 72. The improved effects were maintained at a higher percentage for the anti-IL-36R antibody of the present invention compared to placebo. At least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% , 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42 %, 43%, 44%,

45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61% , 62%, 63%,

64%, 65%, 66%, 67%,68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80% , 81%, 82%,

83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of mammals or patients maintained improved effects at Weeks 12, 24, 36, 48, 60, or 72 after the last dose of anti-IL -36R, compared to placebo.

After the last dose of an anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the present invention) is administered, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients remain

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Claims (24)

in clinical remission, as measured by change in the GPPASI severity subscore of pustules, erythema, or scaling from baseline at Weeks 12, 24, 36, 48, 60, or 72. The improved effects were maintained at the higher percentage for anti-IL-36R antibody according to this invention compared to placebo. At least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% , 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42 %, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%,68%, 69%, 70%, 71%, 72%, 73%, 74%, 75% 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% of mammals or patients supported improved effects at Weeks 12, 24, 36, 48, 60, or 72 after the last dose of anti-IL-36R, compared with placebo. Example 5. Achieving complete relief of GPP symptoms in GPP patients. In this example, a single 900 mg IV dose of the anti-IL36R antibody of the present invention (in infusion solution at a concentration of 60 mg/ml) was used to treat patients with acute GPP exacerbation. After administration of the IV dose, as shown in Table. 1, additional subcutaneous doses of anti-IL36R antibody were administered to achieve complete relief of GPP symptoms in patients. After the last dose of an anti-IL-36R antibody (e.g., an anti-IL-36R antibody of the present invention), at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of patients completely GPP symptoms were relieved as measured by GPPGA 0 at Weeks 12, 24, 36, 48, 60, or 72. The improved effects were maintained at a higher percentage for the anti-IL-36R antibody of the present invention compared to placebo. At least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% , 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47% , 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66% , 67%,68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85% , 86%, 87%, 88%, 89%, or 90% of mammals or patients and maintained improved effects at Weeks 12, 24, 36, 48, 60, or 72 after the last dose of anti-[k-36E. compared to placebo. Although certain aspects and embodiments of the invention have been described, they are presented by way of example only and are not intended to limit the scope of the invention. Indeed, the new methods and systems described in the present invention may be implemented in various other forms without departing from the spirit of the invention. The appended claims and their equivalents are intended to cover such forms or modifications as fall within the scope and spirit of the invention. All patents and/or publications, including journal articles, cited in the present invention are expressly incorporated herein by reference. CLAIM 1. A method of reducing or alleviating the signs and symptoms of the acute phase of a sudden exacerbation of generalized pustular psoriasis (GPP) in a patient or reducing the severity and duration of GPP flares using an anti-IL-36R antibody containing a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ [D NO: 89, and wherein the anti-IL-36R antibody is administered in one or more intravenous doses, wherein one or more doses comprise(s) 900 mg of said anti-IL antibody -36R. 2. The method according to claim 1, wherein the anti-IL-36R antibody comprises i) a light chain comprising the amino acid sequence set forth in SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 127. 3. The method of claim 2, wherein the anti-IL-36R antibody is administered in 1, 2 or 3 intravenous doses. 4. The method according to claim 2, wherein the anti-IL-36R antibody is administered over an interval of 4-12 weeks. 5. A method of preventing the recurrence of a sudden exacerbation of GPP in a patient who was treated with intravenous administration of one or more doses of an antibody to IL-36R containing a light chain variable region containing the amino acid sequence presented in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89, and wherein an effective amount of an anti-IL-36R antibody is administered in one or more subcutaneous doses containing 150 mg, 225 mg, 300 mg, 450 mg, or 600 mg of the indicated anti-IL-36R antibody. 6. A method of treating GPP to a Generalized Pustular Psoriasis Global Assessment (GPPGA) score of 0 in a patient who was treated with intravenous administration of one or more doses of an anti-IL-36R antibody containing a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 80 ; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89, and wherein a prophylactically effective amount of an anti-IL-36R antibody is administered in one or more subcutaneous doses containing 150, 225, 300, 450, or 600 mg of said antibody to IL-36R. - 93 046186 7. The method of claim 5 or 6, wherein 1, 2, 3 or more subcutaneous doses are administered to the patient and wherein the first subcutaneous dose is administered after the last intravenous dose. 8. The method of claim 5 or 6, wherein the first subcutaneous dose is administered 2-8 weeks, 4-6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks after the last intravenous dose, and the second subcutaneous dose is administered 4 , 6, 8, 10, or 12 weeks after the indicated first subcutaneous dose. 9. A method of reducing or alleviating the signs and symptoms of the acute phase of a sudden exacerbation of GPP in a patient or reducing the severity and duration of GPP flares using an anti-IL36R antibody containing a light chain variable region containing the amino acid sequence presented in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89, and wherein the method comprises intravenous administration of an anti-IL-36R antibody in one or more intravenous doses, wherein one or more doses comprise(s) 900 mg of said anti-IL antibody -36R, followed by one or more subcutaneous doses of anti-IL-36R antibody. 10. The method according to claim 9, where after 1, or 2, or 3 intravenous doses of the anti-IL-36R antibody, 1, or 2, or 3 subcutaneous doses of the anti-IL-36R antibody are administered. 11. The method according to claim 9, where after 1 intravenous dose of the antibody to IL-36R, 1, or 2, or 3 subcutaneous doses of the antibody to IL-36R are administered. 12. The method according to claim 9, where after 2 intravenous doses of the anti-IL-36R antibody, 1, or 2, or 3 subcutaneous doses of the anti-IL-36R antibody are administered. 13. The method according to claim 9, where after 3 intravenous doses of the anti-IL-36R antibody, 1, or 2, or 3 subcutaneous doses of the anti-IL-36R antibody are administered. 14. The method according to any one of claims 9-13, wherein each of the one or more intravenous doses includes 900 mg of the antibody to IL-36R and each of the one or more subcutaneous doses includes 150, 225, 300, 450 or 600 mg of the specified antibody to IL-36R. 15. The method of claim 9, wherein intravenous doses are administered at intervals of 2, 4, 6, 8, 10, or 12 weeks, wherein subcutaneous doses are administered at intervals of 4, 6, 8, 10, or 12 weeks, and wherein the first subcutaneous dose is administered at 2-8 weeks, 4-6 weeks, 2 weeks, 4 weeks, 6 weeks, or 8 weeks after the last IV dose. 16. The use of an antibody to IL-36R to reduce or alleviate the signs and symptoms of the acute phase of a sudden exacerbation of GPP in a patient or reduce the severity and duration of outbreaks of GPP, wherein the antibody contains a light chain variable region containing the amino acid sequence set forth in SEQ ID NO: 80 ; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89, and wherein the anti-IL36R antibody is administered in one or more intravenous doses, wherein the one or more doses comprise(s) 900 mg of said anti-IL-36R antibody. 17. Use according to claim 16, wherein the anti-IL-36R antibody comprises i) a light chain comprising the amino acid sequence set forth in SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 127. 18. Use according to claim 17, wherein the anti-IL-36R antibody is administered in 1, 2 or 3 intravenous doses. 19. Use according to claim 17, wherein the anti-IL-36R antibody is administered over an interval of 4-12 weeks. 20. The use of an anti-IL-36R antibody to prevent the recurrence of a sudden exacerbation of GPP in a patient who was treated with intravenous administration of one or more doses of an anti-IL-36R antibody containing a light chain variable region containing the amino acid sequence presented in SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89, and wherein an effective amount of an anti-IL-36R antibody is administered as one or more subcutaneous doses containing 150, 225, 300, 450, or 600 mg of said anti-IL-36R antibody. IL-36R. 21. Use of an anti-IL-36R antibody for the treatment of GPP to Generalized Pustular Psoriasis Global Assessment (GPPGA) score 0 in a patient who was treated with intravenous administration of one or more doses of an antibody containing a light chain variable region containing the amino acid sequence set forth in SEQ ID NO : 80; and a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 89, and wherein a prophylactically effective amount of an anti-IL-36R antibody is administered in one or more subcutaneous doses containing 150, 225, 300, 450 or 600 mg of said antibody to IL-36R. 22. Use according to claim 20 or 21, wherein 1, 2, 3 or more subcutaneous doses are administered to the patient and where the first subcutaneous dose is administered after the last intravenous dose. 23. Use according to claim 20 or 21, where the first subcutaneous dose is administered 2-8 weeks, 4-6 weeks, 2 weeks, 4 weeks, 6 weeks or 8 weeks after the last intravenous dose and the second subcutaneous dose is administered 4, 6, 8, 10, or 12 weeks after the indicated first subcutaneous dose. 24. The use of an antibody to IL-36R to reduce or alleviate the signs and symptoms of the acute phase of a sudden exacerbation of GPP in a patient or reduce the severity and duration of GPP outbreaks, where the antibody contains a light chain variable region containing the amino acid sequence presented in SEQ ID NO: 80; and a heavy chain variable region containing -