Anti-IL-36R antibody for the treatment of neutrophilic dermatosis

Abstract

This invention provides a pharmaceutical composition for treating Netherton syndrome. [Solution] A pharmaceutical composition comprising an anti-interleukin-36 receptor (anti-IL-36R) antibody, comprising a light chain variable region containing a specific amino acid sequence and a heavy chain variable region containing a specific amino acid sequence.

Description

[Technical Field]

[0001] Sequence List This application includes a sequence listing, which was submitted via EFS-Web in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on 12 July 2021, is named 09-0705-WO-1-2021-07-15-SL.txt and is 146,374 bytes in size.

[0002] Technical field of inventions The present invention relates to the administration of anti-interleukin-36 receptor (anti-IL-36R) antibodies to subjects having neutrophilic dermatosis (ND), such as hidradenitis suppurativa (HS) or subkeratinous pustulosis (Sneddon-Wilkinson disease), and to the treatment and / or prevention of neutrophilic dermatosis in said subjects. More specifically, the present invention relates to the administration of spesolimab to subjects suffering from neutrophilic dermatosis.

[0003] background Neutrophilic dermatosis is a heterogeneous group of inflammatory skin disorders that present with distinctive clinical features but are unified histopathologically by the presence of sterile, primarily neutrophilic infiltrates. The heterogeneous morphology of the skin lesions associated with these disorders makes diagnosis difficult. Furthermore, a thorough evaluation is required to rule out similar diseases and diagnose any potentially associated infectious, inflammatory, and neoplastic processes. While some neutrophilic dermatosis cases resolve spontaneously, most require treatment to achieve remission. Delays in diagnosis and treatment can lead to significant patient morbidity and even mortality.

[0004] Neutrophilic dermatoses may occur in isolation or more than one type may be present in the same individual. Examples of neutrophilic dermatoses include hidradenitis suppurativa (HS); acute generalized exanthematous pustulosis; acute febrile neutrophilic dermatosis (Sweet's syndrome); nonmicrobial pustulosis of the cutaneous folds (APF); Behçet's disease; intestinal accessory syndrome (intestinal dermatitis-arthritis syndrome); and intestinal dermatitis-arthritis syndrome (BADAS).

[0005] Typical treatments include corticosteroids, topical lotions and moisturizers, antibiotics, antivirals, and antifungals. However, most treatment options only result in transient and incomplete symptom remission. Therefore, there is a need in the art for novel targeted therapies for the treatment and / or prevention of neutrophilic dermatosis.

[0006] Summary of the Invention The present invention addresses the above need by providing a biological therapeutic agent, particularly an antibody, that conjugates to IL-36R as a first-line, second-line, third-line, or subsequent-line therapy for the treatment of neutrophilic dermatosis.

[0007] In one embodiment, the present invention relates to a method for treating, preventing or relieving neutrophilic dermatosis (ND) in a subject, comprising the step of administering to the subject a therapeutically effective amount of an anti-IL-36R antibody or its antigen-binding fragment (as disclosed herein). In one embodiment related to this aspect, the anti-IL-36R antibody is spesolimab.

[0008] In one embodiment, the present invention relates to a method for treating a skin disorder associated with neutrophilic dermatopathy in a patient, the method(s) comprising the step of administering or having administered to a patient a therapeutically effective amount of the anti-IL-36R antibody of the present invention or its antigen-binding fragment (as disclosed herein). In one embodiment related to this aspect, the anti-IL-36R antibody is spesolimab.

[0009] In one embodiment, the present invention relates to a method for treating a skin inflammation associated with neutrophilic dermatopathy in a subject, the method comprising administering or having administered to the subject a therapeutically effective amount of the anti-IL-36R antibody of the present invention or its antigen-binding fragment (as disclosed herein). In one embodiment related to this aspect, the anti-IL-36R antibody is spesolimab.

[0010] In one embodiment, the present invention relates to a method for preventing or reducing neutrophilic infiltrations in affected skin tissue in a subject suffering from neutrophilic dermatopathy, the method comprising administering or having administered to the subject a therapeutically effective amount of the anti-IL-36R antibody of the present invention or its antigen-binding fragment. In one embodiment related to this aspect, the anti-IL-36R antibody is spesolimab.

[0011] In one embodiment, the present invention relates to a method for reducing microbial colonization on the skin of a subject having neutrophilic dermatosis, comprising the step of administering a therapeutically effective amount of an anti-IL-36R antibody or its antigen-binding fragment, as disclosed herein, to the subject. In one embodiment related to this aspect, the colonization is of a microorganism selected from the group consisting of Staphylococcus aureus, Streptococcus species, Pseudomonas aeruginosa, Bacteroides species, molluscum contagiosum virus, herpes simplex virus, coxsackievirus, vaccinia virus, Candida albicans, Dermatophytes, Trichophyton species, Penicillium species, Cladosporium species, Alternaria species, and Aspergillus species. In another embodiment related to this aspect, the microorganism is Staphylococcus aureus. In another embodiment related to this aspect, Staphylococcus aureus colonization is reduced by at least 10% or at least 20% from baseline after administration of an anti-IL-36R antibody or its antigen-binding fragment, as disclosed herein. In one embodiment related to this aspect, the anti-IL-36R antibody is a spesolimab.

[0012] In one embodiment, the present invention relates to a method for reducing susceptibility to skin infection in a subject having neutrophilic dermatosis, comprising the step of administering a therapeutically effective dose of an anti-IL-36R antibody or its antigen-binding fragment (as disclosed herein) to the subject. In one embodiment related to this aspect, the skin infection is caused by a microorganism selected from the group consisting of Staphylococcus aureus, Streptococcus species, Pseudomonas aeruginosa, Bacteroides species, Herpes simplex virus, Molluscum contagiosum virus, Coxsackievirus, Candida albicans, Dermatophytes, Trichophyton species, Penicillium species, Cladosporium species, Alternaria species, and Aspergillus species. In another embodiment related to this aspect, the microorganism is Staphylococcus aureus (S. aureus). In another embodiment related to this aspect, the anti-IL-36R antibody is spesolimab.

[0013] In one embodiment relating to any of the above aspects, the second therapeutic agent is administered to the subject before, after, or simultaneously with an anti-IL-36R antibody or its antigen-binding fragment. In the relevant embodiment, the second therapeutic agent is selected from the group consisting of antibacterial agents, antiviral agents, antifungal agents, another IL-36R antagonist, IgE inhibitors, corticosteroids, NSAIDs, IL-4R antagonists, and interferon-γ.

[0014] In one embodiment relating to any of the above aspects, the anti-IL-36R antibody comprises a) a light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 or 141 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111, or 142 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0015] In one embodiment relating to any of the above aspects, the anti-IL-36R antibody comprises a) a light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region including the amino acid sequence of SEQ ID NO: 141 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111, or 142 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0016] In one embodiment relating to any of the above aspects, the anti-IL-36R antibody is: ia) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 102 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or II.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 103 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or III.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 104 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or IV. a) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 105 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) A heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3); or V. a) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 106 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) A heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3); or VI. a) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) A heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3); or VII. a) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 104 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) A heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 141 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111 or 142 (H-CDR2); the amino acid sequence of SEQ ID NO: 72 (H-CDR3) comprises.

[0017] In one embodiment related to any of the above aspects, the anti-IL-36R antibody is (i) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or (ii) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or (iii) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or (iv) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87; or (v) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88; or (vi) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89; or (vii) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or (viii) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 85; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101; or (ix) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; or (x) A light chain variable region comprising the amino acid sequence of SEQ ID NO: 86; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101 comprising.

[0018] In one embodiment related to any of the above aspects, the anti-IL-36R antibody is i. A light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125; or ii. A light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126; or iii. A light chain comprising the amino acid sequence of SEQ ID NO: 115; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or iv. A light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 125; or v. A light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 126; or vi. A light chain comprising the amino acid sequence of SEQ ID NO: 118; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 127; or vii. A light chain containing the amino acid sequence of SEQ ID NO: 123; and a heavy chain containing the amino acid sequence of SEQ ID NO: 138; or viii. A light chain containing the amino acid sequence of SEQ ID NO: 123; and a heavy chain containing the amino acid sequence of SEQ ID NO: 139; or ix. Light chain containing the amino acid sequence of SEQ ID NO: 124; and heavy chain containing the amino acid sequence of SEQ ID NO: 138 Includes.

[0019] In one embodiment relating to any of the above aspects and embodiments, neutrophilic dermatosis includes: hidradenitis suppurativa (HS); acute generalized exanthematous pustulosis; acute febrile neutrophilic dermatosis (Sweet's syndrome); nonmicrobial pustulosis of the dermal folds (APF); Behçet's disease; intestinal tract syndrome (intestinal-associated dermatitis-arthritis syndrome); intestinal-associated dermatosis-arthritis syndrome (BADAS); pustular psoriasis mediated by CARD14 (CAMPS); cryopyrin-associated periodic syndromes (CAPS); interleukin-36 receptor antagonist deficiency (DIRTA); interleukin-1 receptor antagonist deficiency (DIRA); persistent erythema elevateds; histiocyte The following are selected from the group consisting of: neutrophilic dermatitis; acropustulosis of the limbs; neutrophilic dermatosis of the dorsum of the hand; neutrophilic eccrine hidradenitis; neutrophilic urticarial dermatosis; palisade granulomatous neutrophilic dermatitis; psoriasis vulgaris; pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome; pyoderma gangrenosum (PG); pyoderma gangrenosum and acne (PAPA); suppurative arthritis; skin lesions of Behçet's disease; Still's disease; subkeratinous pustulosis (Sneddon-Wilkinson's disease); synovitis, acne, pustulosis-ossification; osteitis (SAPHO) syndrome; rheumatic neutrophilic dermatitis (RND); and ichthyosis (and its subtypes, e.g., Netherton syndrome, i.e., NS).

[0020] In related embodiments, neutrophilic dermatosis is hidradenitis suppurativa (HS). In related embodiments, neutrophilic dermatosis is acute generalized exanthematous pustulosis. In related embodiments, neutrophilic dermatosis is acute febrile neutrophilic dermatosis (Sweet's syndrome). In related embodiments, neutrophilic dermatosis is nonmicrobial pustulosis of the skin folds (APF). In related embodiments, neutrophilic dermatosis is Behçet's disease. In related embodiments, neutrophilic dermatosis is intestinal accessory syndrome (intestinal dermatitis-arthritis syndrome). In related embodiments, neutrophilic dermatosis is intestinal dermatitis-arthritis syndrome (BADAS). In related embodiments, neutrophilic dermatosis is CARD14-mediated pustular psoriasis (CAMPS). In related embodiments, neutrophilic dermatosis is cryopin-associated periodic syndromes (CAPS). In related embodiments, neutrophilic dermatopathy is interleukin-36 receptor antagonist deficiency (DIRTA). In related embodiments, neutrophilic dermatopathy is interleukin-1 receptor antagonist deficiency (DIRA). In related embodiments, neutrophilic dermatopathy is persistent erythema elevateds. In related embodiments, neutrophilic dermatopathy is histiocytic neutrophilic dermatitis. In related embodiments, neutrophilic dermatopathy is acropustulosis of the limbs in children. In related embodiments, neutrophilic dermatopathy is neutrophilic dermatopathy of the dorsum of the hand. In related embodiments, neutrophilic dermatopathy is neutrophilic eccrine hidradenitis. In related embodiments, neutrophilic dermatopathy is neutrophilic urticarial dermatopathy. In related embodiments, neutrophilic dermatopathy is palisade granulomatous neutrophilic dermatitis. In related embodiments, neutrophilic dermatopathy is psoriasis vulgaris. In related embodiments, neutrophilic dermatopathy is pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome. In related embodiments, neutrophilic dermatopathy is pyoderma gangrenosum (PG). In related embodiments, neutrophilic dermatopathy is pyoderma gangrenosum and acne (PAPA). In related embodiments, neutrophilic dermatopathy is suppurative arthritis. In related embodiments, neutrophilic dermatopathy is a skin lesion of Behçet's disease. In related embodiments, neutrophilic dermatopathy is Still's disease. In related embodiments, neutrophilic dermatopathy is subkeratotic pustulosis (Sneddon-Wilkinson disease).In related embodiments, neutrophilic dermatopathy includes synovitis, acne, pustulosis-ossification, and osteitis (SAPHO) syndrome. In related embodiments, neutrophilic dermatopathy includes rheumatic neutrophilic dermatitis (RND). In related embodiments, neutrophilic dermatopathy includes ichthyosis (and its subtypes, e.g., Netherton syndrome, i.e., NS).

[0021] In any of the above embodiments and other embodiments related to the embodiments described herein, the anti-IL-36R antibody is administered to a subject suffering from neutrophilic dermatosis in a dose ranging from about 0.001 to about 1000 mg.

[0022] It will be understood that any of the methods, administration plans, and / or drug prescription plans disclosed herein are equally applicable to the use of any anti-IL-36R antibody disclosed in such methods, administration plans, and / or drug prescription plans, i.e., anti-IL-36R antibodies as disclosed herein for the treatment, prevention, reduction, and / or remission of any of the disclosed diseases and / or conditions. In other words, the present invention also provides the use of anti-IL-36R antibodies as disclosed herein for the manufacture of pharmaceuticals for the treatment, prevention, reduction, and / or remission of any of the disclosed diseases and / or conditions.

[0023] Additional features and advantages of the present invention will become apparent from the review of the subsequent detailed description set forth below, and in part from the text, or can be learned through the practice of the art in question. It should be understood that both the previous general description and the following detailed description are illustrative and explanatory, and are intended to provide a further description of the present invention as claimed.

[0024] The accompanying drawings, included and incorporated herein and constituting part thereof, serve to illustrate aspects of the technology covered and, together with the text, illustrate the principles of the present invention. [Brief explanation of the drawing]

[0025] [Figure 1] Figure 1 shows IL-36 antagonist ligands (IL-36RA / IL1F5, IL-38 / ILF10) that inhibit the signal transduction cascade. [Figure 2] Figure 2 shows the expression of IL-36 ligands in human skin biopsy material by Insights hybridization (ISH) technique. It shows formalin-fixed paraffin-embedded (FFPE) skin biopsy material from hidradenitis suppurativa samples with and without lesions, purchased from a vendor and stained for IL-36α,β,γ using an ISH probe. Increased expression of all three IL36 ligands α,β, andγ is observed in hidradenitis suppurativa skin samples.

[0026] Detailed description of the invention Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described, for such methods and conditions can be modified. Furthermore, it should be understood that the terms used herein are solely for the purpose of describing specific embodiments and are not intended to limit them, for the scope of the present invention will be limited only by the appended claims.

[0027] In the following detailed description, numerous specific details are provided to give a complete understanding of the invention. However, it will be apparent to those skilled in the art that the technology in question can be practiced without some of these specific details. In other cases, well-known structures and techniques are not described in detail so as not to obscure the invention.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this invention belongs.

[0029] While we do not wish to be bound by this theory, the inventors believe that neutrophilic dermatoses (NDs) are a heterogeneous group of conditions, but they share common features and overlapping pathophysiologies involving the IL-36 pathway. Neutrophilic dermatoses are primarily characterized by skin signs resulting from neutrophil accumulation, but IL-36 plays a crucial role in driving disease signs, particularly pustular NDs, such as subkeratotic pustulosis (Sneddon-Wilkinson disease); pustular psoriasis; acute generalized exanthematous pustulosis (AGEP); acropustulosis of the limbs (IA); Behçet's disease; pustulosis, ossification and osteitis (SAPHO) syndrome; gut-associated dermatopathies-arthritis syndrome (BADAS); neutrophilic dermatoses of the dorsum of the hand (NDDH); and nonmicrobial pustulosis of the skin folds (APF). Furthermore, blocking the IL-36 pathway may be beneficial in skin inflammations accompanied by papules, nodules, and plaques, such as acute febrile neutrophilic dermatosis (Sweet's syndrome), rheumatic neutrophilic dermatitis (RND), neutrophilic eccrine hidradenitis (NEH), persistent erythema elevata (EED), or skin inflammations accompanied by ulcers, such as pyoderma gangrenosum (PG). Blocking IL-36 is also beneficial in patients with ichthyosis (and its subtypes, such as Netherton syndrome, i.e., NS).

[0030] In one embodiment, the present invention relates to a method for treating, preventing or relieving neutrophilic dermatosis (ND) in a subject, comprising the step of administering to the subject a therapeutically effective dose of an anti-IL-36R antibody or its antigen-binding fragment (as disclosed herein). In one embodiment related to this aspect, the anti-IL-36R antibody is spesolimab.

[0031] While I don't want to be fixated on this theory, it is thought that anti-IL-36R antibodies or their antigen-binding fragments bind to human IL-36R, thereby interfering with the binding of IL-36 agonists and thus at least partially blocking the signaling cascade from IL-36R to inflammatory mediators involved in neutrophilic dermatosis. This is illustrated by Figure 1. IL-36R is also known as IL-1RL2 and IL-1Rrp2. Agonist-acting IL-36 ligands (α, β, or γ) have been reported to trigger the signaling cascade by binding to the IL-36 receptor and subsequently forming heterodimers with IL-1 receptor co-protein (IL-1RAcP).

[0032] The anti-IL-36R antibody of the present invention is disclosed herein, for example, in U.S. Patent No. 9,023,995, the entirety of which is incorporated herein by reference.

[0033] definition The phrases "one aspect" do not mean that such an aspect is essential to the present invention or that such an aspect applies to all components of the subject technology. Disclosure relating to one aspect may apply to all components or to one or more components. One aspect may provide one or more examples of the disclosure. The phrases "one aspect" may refer to one or more aspects, and vice versa. The phrases "one embodiment" do not mean that such an embodiment is essential to the subject technology or that such an embodiment applies to all components of the subject technology. Disclosure relating to one embodiment may apply to all embodiments or to one or more embodiments. One embodiment may provide one or more examples of the disclosure.

[0034] The term "approximately" generally refers to an acceptable degree of error or deviation in a measured quantity, taking into account the nature or accuracy of the measurement. Typically, exemplary degrees of error or deviation are within 5%, 3%, or 1% of a given number or range of numbers. For example, the expression "approximately 100" includes 100 and 95, or 103 and 97, or 101 and 99, and all numbers in between (e.g., for the range of 95-105, 95.1, 95.2, etc.; or for the range of 97-103, 97.1, 97.2, etc.; for the range of 99-101, 99.1, 99.2, etc.). Quantities expressed herein are approximate unless otherwise specified, meaning that the term "approximately" can be inferred if not explicitly stated.

[0035] In this context, "pharmaceutical composition" refers to a dosage form in which the biological activity of the active ingredient(s) is clearly effective, and which contains no additional ingredients that are significantly toxic to the subject to whom the composition is to be administered, whether liquid or powder. Such a composition is sterile.

[0036] For the purposes of the procedure, the term “subject” refers to any animal classified as a mammal (including humans), domesticated animals and agricultural animals, as well as animals kept for zoos, sports, or as pets, such as dogs, horses, cats, and cattle. Preferably, the mammal is a human.

[0037] As used herein, terms such as “to treat” and “treating” mean to alleviate symptoms, eliminate the cause of symptoms, either transiently or permanently, or prevent or slow the onset of symptoms of a named disorder or condition. These terms include therapeutic, preventive, or inhibitory measures for a disease or disorder that produce any clinically desirable or beneficial effect, including but not limited to the alleviation or remission of one or more symptoms, or the regression, slowing, or cessation of the progression of the disease or disorder. For example, the term “treatment” includes the administration of a drug before or after the onset of symptoms of a disease or disorder, thereby preventing or eliminating one or more signs of the disease or disorder. Another example includes the administration of a drug after the clinical signs of a disease to combat the symptoms of the disease. Furthermore, the administration of a drug after the onset and after the occurrence of clinical symptoms, where the administration affects clinical parameters of the disease or disorder, such as the degree of tissue damage or whether the treatment results in remission of the disease, includes “treatment” or “therapy” as used herein. Furthermore, the composition of the present invention, either alone or in combination with another therapeutic agent, should be considered an effective treatment of the underlying disorder, insofar as it reduces or remits at least one symptom of the disorder being treated compared to the symptoms of the disorder without the use of the humanized anti-IL-36R antibody composition.

[0038] The term "therapeutic dose" is used to refer to the amount of a drug that reduces or eliminates one or more symptoms of the disorder being treated. In another embodiment, the therapeutic dose refers to a target serum concentration that has been shown to be effective, for example, in slowing the progression of a disease.

[0039] Any methods and materials similar to or equivalent to those described herein may be used in carrying out the present invention, but preferred methods and materials are described herein. All publications mentioned herein are incorporated herein by reference in their entirety for illustrative purposes.

[0040] As previously described, neutrophilic dermatoses (NDs) are a heterogeneous group of conditions with common features and overlapping pathophysiologies. Examples of neutrophilic dermatoses include: hidradenitis suppurativa (HS); acute generalized exanthematous pustulosis; acute febrile neutrophilic dermatosis (Sweet's syndrome); nonmicrobial pustulosis of the cutaneous folds (APF); Behçet's disease; intestinal accessory syndrome (intestinal dermatitis-arthritis syndrome); intestinal dermatitis-arthritis syndrome (BADAS); pustular psoriasis mediated by CARD14 (CAMPS); cryopyrin-associated periodic syndromes (CAPS); interleukin-36 receptor antagonist deficiency (DIRTA); interleukin-1 receptor antagonist deficiency (DIRA); persistent erythema elevateds; histiocytic neutrophilic dermatitis; and pediatric dermatoses. Examples include acropustulosis; neutrophilic dermatosis of the dorsum of the hand; neutrophilic eccrine hidradenitis; neutrophilic urticarial dermatitis; palisade granulomatous neutrophilic dermatitis; psoriasis vulgaris; pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome; pyoderma gangrenosum (PG); pyoderma gangrenosum and acne (PAPA); suppurative arthritis; skin lesions of Behçet's disease; Still's disease; subkeratotic pustulosis (Sneddon-Wilkinson disease); synovitis, acne, pustulosis-ossification; osteitis (SAPHO) syndrome; rheumatic neutrophilic dermatitis (RND); and ichthyosis (and its subtypes, e.g., Netherton syndrome, i.e., NS).

[0041] For example, hidradenitis suppurativa (HS) is an inflammatory disease characterized by recurrent painful abscesses and fistulas. Patients with hidradenitis suppurativa objectively have one of the lowest quality of life (QOL) scales of all skin diseases. The lesions typically occur in the axillae, groin, submammary glands, and / or anogenital area of ​​the body. The lesions of hidradenitis suppurativa can progress to form sinus ducts and extensive abscesses. Sequelae include significant pain, scarring, and psychological distress. Various inflammatory pathways contribute to the progression of the disease. IL36 ligand has been shown to be upregulated in the lesioned skin and circulating blood of patients with hidradenitis suppurativa (Di Caprio et al., 2017; Hessam et al., 2018 (Thomi et al., 2017)).

[0042] IL36R is a novel member of the IL1R family that forms a heterodimeric complex with the IL1R accessory protein (IL1RAcp) and IL1Rrp2, which are associated with epithelial-mediated inflammation and barrier dysfunction. The heterodimeric IL36R system with stimulant ligands (IL36α, IL36β, IL36γ) and inhibitory ligands (IL36Ra and IL38) shares many structural and functional similarities with other members of the IL1 / ILR family, such as IL1, IL18, and IL33. All IL1 family members (IL1α, IL1β, IL18, IL36α, IL36β, IL36γ, and IL38) transmit signals through specific congeneral receptor proteins. Upon ligand binding, these proteins recruit a common IL1RAcP subunit, activating the NFκβ and MAP kinase pathways in receptor-positive cell types (Dinarello, 2011; Towne et al., 2004; Towne et al., 2011). Human genetic studies have established a strong link between IL36R signaling and skin inflammation, as demonstrated by the development of generalized pustular psoriasis in patients with loss-of-function mutations in IL36Ra that disrupt IL36R signaling (Marrakchi et al., 2011).

[0043] Since there are no animal model data for hidradenitis suppurativa, the expression and function of this pathway in cell types associated with various diseases are linked to skin inflammation. IL36R is expressed in epithelial cells (e.g., keratinocytes, intestinal epithelial cells), cutaneous fibroblasts, and immune cells (myeloid cells, B cells, and T cells). Mice lacking the IL36R receptor showed significantly reduced skin inflammation and keratinocyte proliferation compared to wild-type controls.

[0044] Given the strong link between the IL36 pathway and neutrophilic dermatosis, I do not wish to adhere to this theory, but it is thought that the biological function of IL36R may be responsible for the pathophysiological function of these conditions, and therefore, blocking IL36R activation may be beneficial in patients with neutrophilic dermatosis.

[0045] Therefore, the present invention includes a method for treating a subject in need thereof, the method comprising the step of administering a therapeutically effective amount of anti-IL36R antibody or its antigen-binding fragment to the subject. As used herein, the expression “subject in need thereof” means a human or non-human animal exhibiting one or more symptoms of neutrophilic dermatosis, such as neutrophil infiltration, pustules, etc., in affected skin tissue, and / or diagnosed with a neutrophilic dermatosis condition.

[0046] In one embodiment, a subject suffering from neutrophilic dermatosis may also have a skin infection selected from the group consisting of impetigo, cellulitis, infectious dermatitis, herpetic eczema, folliculitis, infectious rash, mycosis, tinea versicolor, Staphylococcus aureus infection, and streptococcal infection. Microorganisms that cause infections include, but are not limited to, Staphylococcus aureus, Streptococcus species, Pseudomonas aeruginosa, Bacteroides species, herpes simplex virus, coxsackievirus, molluscum contagiosum virus, vaccinia virus, Candida albicans, dermatophytes, Trichophyton species, Penicillium species, Cladosporium species, Alternaria species, and Aspergillus species.

[0047] The present invention provides a method for reducing microbial colonization on the skin of a subject having neutrophilic dermatopathy, comprising the step of administering a therapeutically effective amount of anti-IL-36R antibody or its antigen-binding fragment to the subject. In certain embodiments, the present invention provides a method for reducing Staphylococcus aureus colonization on the skin of a patient with neutrophilic dermatopathy. In some embodiments, microbial colonization is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75% compared to baseline upon administration of anti-IL-36R antibody.

[0048] Colony formation by microorganisms can be measured using tests and procedures known in the art, such as by PCR, microbial culture, microscopy and staining, or immunofluorescence. In certain embodiments, colony formation by microorganisms can be measured by the presence of microbial protein biomarkers known in the art, such as microbial toxins, e.g., toxin 1 of toxic shock syndrome by Staphylococcus aureus. Methods for detecting and / or quantifying such biomarkers are known in the art.

[0049] The antibody of the present invention The anti-IL36R antibody of the present invention is disclosed in U.S. Patent No. 9,023,995 or WO2013 / 074569, the entire contents of each of which are incorporated herein by reference.

[0050] As used herein, the term "antibody" includes immunoglobulin molecules containing four polypeptide chains, i.e., two heavy chains (H) and two light chains (L) interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). In a typical antibody, each heavy chain includes a heavy chain variable region (abbreviated herein as HCVR or V H and) and a heavy chain constant region. The heavy chain constant region includes three domains, i.e., C H 1, C H 2, and C H 3. Each light chain includes a light chain variable region (abbreviated herein as LCVR or V L and) and a light chain constant region. The light chain constant region includes one domain (C L 1). The V H region and the V L region can be further subdivided into hypervariable regions named complementarity determining regions (CDRs) with more conserved regions named framework (FR) regions spaced apart. Each V H and V LIt consists of three CDRs and four FRs aligned from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In various embodiments of the present invention, the FRs of the anti-IL-36R antibody (or its antigen-binding fragment) may be identical to the human germline sequence or may be naturally or artificially modified. The common amino acid sequence may be defined based on a parallel analysis of two or more CDRs.

[0051] As used herein, the term “antibody” also includes the antigen-binding fragment of a complete antibody molecule. As used herein, terms such as “antigen-binding portion” and “antigen-binding fragment” of an antibody include any naturally occurring, enzymatically obtained, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies may be derived from, for example, a complete antibody molecule using any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques, including manipulation and expression of DNA encoding the antibody variable domain and optionally constant domain. Such DNA is known and / or readily available from, for example, commercially available sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. DNA may be sequenced and manipulated by chemical or molecular biological techniques, for example, by aligning one or more variable domains and / or constant domains into appropriate configurations, or by introducing codons, creating cysteine ​​residues, modifying, adding, or deleting amino acids.

[0052] Non-limiting examples of antigen-binding fragments include (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv(scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable region of an antibody (e.g., isolated complementarity-determining regions (CDRs), e.g., CDR3 peptides) or constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deleted antibodies, chimeric antibodies, antibodies with CDR implantation, diabodies, tribodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, divalent nanobodies, etc.), small modular immunotherapy drugs (SMIPs), and shark variable IgNAR domains, are also included in the expression “antigen-binding fragment” as used herein.

[0053] The antigen-binding fragment of an antibody will typically contain at least one variable domain. The variable domain may also be of any size or amino acid composition and will generally contain at least one CDR adjacent to or in-frame with one or more framework sequences. L V bound to the domain H In antigen-binding fragments having a domain, V H Domain and V L Domains can be located relative to each other in any suitable arrangement. For example, the variable region may be a dimer, V H -V H , V H -V L , or V L -V L It contains a dimer. Alternatively, the antigen-binding fragment of the antibody is a monomer V H Domain or V L It may contain a domain.

[0054] The antibody used in the method of the present invention may be a human antibody. As used herein, the term "human antibody" is intended to include antibodies having a variable region and a constant region derived from a human germline immunoglobulin sequence. Nevertheless, the human antibody of the present invention may contain amino acid residues not encoded by the human germline immunoglobulin sequence (e.g., mutations introduced by site-directed mutagenesis in vitro or somatic mutation in vivo) in the CDR, particularly in CDR3. However, as used herein, the term "human antibody" is not intended to include antibodies in which a CDR sequence derived from the germline of another mammalian species, such as a mouse, has been transplanted into a human framework sequence.

[0055] The antibodies used in the methods of the present invention may be recombinant human antibodies. As used herein, the term “recombinant human antibody” is intended to include all human antibodies prepared, expressed, produced, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into host cells (as further described below), antibodies isolated from a recombinant combinatorial human antibody library (as further described below), antibodies isolated from animals (e.g., mice) that are transgenic for human immunoglobulin genes (see, for example, Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295), or antibodies prepared, expressed, produced, or isolated by any other means including the step of splicing a human immunoglobulin gene sequence into another DNA sequence. Such recombinant human antibodies have a variable region and a constant region derived from a human germline immunoglobulin sequence. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, if transgenic animals for human immunoglobulin sequences are used, in vivo somatic mutagenesis), and thus the recombinant antibody V H Region and V L The amino acid sequence of the region is that of the human germline V HArray and V L These sequences are derived from and related to other sequences, but may not naturally exist within the in vivo human antibody germline repertoire.

[0056] According to certain embodiments, the antibody used in the method of the present invention specifically binds to IL-36R. Terms such as "specifically bind" mean that the antibody or its antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis and surface plasmon resonance. For example, an antibody that "specifically binds" to IL-36R, as used in the context of the present invention, has a K content of less than approximately 1000 nM, less than approximately 500 nM, less than approximately 300 nM, less than approximately 200 nM, less than approximately 100 nM, less than approximately 90 nM, less than approximately 80 nM, less than approximately 70 nM, less than approximately 60 nM, less than approximately 50 nM, less than approximately 40 nM, less than approximately 30 nM, less than approximately 20 nM, less than approximately 10 nM, less than approximately 5 nM, less than approximately 4 nM, less than approximately 3 nM, less than approximately 2 nM, less than approximately 1 nM, or less than approximately 0.5 nM when measured by surface plasmon resonance assay. D This includes antibodies that bind to human IL-36R antibodies. However, isolated antibodies that specifically bind to human IL-36R antibodies may cross-react to other antigens, such as IL-36R molecules derived from other (non-human) species.

[0057] In certain exemplary embodiments relating to any aspect of the present invention, an anti-IL-36R antibody or its antigen-binding fragment that can be used in the context of the method of the present invention comprises: a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 or 141 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111, or 142 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0058] According to a particular embodiment, an anti-IL-36R antibody or its antigen-binding fragment is ia) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 102 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or II.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 103 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or III.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 104 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or IV.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 105 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or Va) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 106 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or VI.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 140 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or VII.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 104 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 141 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111 or 142 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3). Includes.

[0059] According to a particular embodiment, an anti-IL-36R antibody or its antigen-binding fragment is (i) Light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 87; or (ii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 88; or (iii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 89; or (iv) Light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 87; or (v) Light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 88; or (vi) Light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 89; or (vii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 85; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 100; or (viii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 85; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 101; or (ix) Light chain variable region containing the amino acid sequence of SEQ ID NO: 86; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 100; or (x) Light chain variable region containing the amino acid sequence of SEQ ID NO: 86; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 101 Includes.

[0060] According to a particular embodiment, an anti-IL-36R antibody or its antigen-binding fragment is i. A light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 125; or ii. A light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 126; or iii. A light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 127; or iv. A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 125; or v. A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 126; or vi. A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 127; or vii. A light chain containing the amino acid sequence of SEQ ID NO: 123; and a heavy chain containing the amino acid sequence of SEQ ID NO: 138; or viii. A light chain containing the amino acid sequence of SEQ ID NO: 123; and a heavy chain containing the amino acid sequence of SEQ ID NO: 139; or ix. Light chain containing the amino acid sequence of SEQ ID NO: 124; and heavy chain containing the amino acid sequence of SEQ ID NO: 138 Includes.

[0061] In one embodiment, what is described and disclosed herein are anti-IL-36R antibodies, in particular humanized anti-IL-36R antibodies, and compositions and products comprising one or more anti-IL-36R antibodies, in particular one or more humanized anti-IL-36R antibodies of the present invention. Also described are antigen-binding fragments of anti-IL-36R antibodies, in particular binding substances comprising humanized anti-IL-36R antibodies.

[0062] Use of antibodies in therapy The role of neutrophils in skin inflammation is increasingly being elucidated. The role of the IL-36 pathway in genetically-based generalized pustular psoriasis, and its demonstrable inhibition using spesorimab, are clear, and the involvement of the same pathway in other similar neutrophilic dermatoses (NDs), which are heterogeneous sets of manifestations with common and overlapping pathophysiology, is being recognized. Since the disease is primarily characterized by skin manifestations due to neutrophil accumulation, complications in additional tissues are also observed. Our research suggests that the IL-36R pathway plays a crucial role in promoting disease signs in pustular neutrophilic dermatoses, such as subkeratosis pustulosis (Sneddon-Wilkinson disease), pustular psoriasis, palmoplantar pustulosis, acute generalized exanthematous pustulosis (AGEP), acropustulosis of the limbs (IA), Behçet's disease, pustulosis, ossification and osteitis (SAPHO) syndrome, gut-associated dermatopathies-arthritis syndrome (BADAS), neutrophilic dermatosis of the dorsum of the hand (NDDH), and nonmicrobial pustulosis of the skin folds (APF). Therefore, blocking the IL-36 pathway may be beneficial in skin inflammations accompanied by papules, nodules, and plaques, such as acute febrile neutrophilic dermatosis (Sweet's syndrome), rheumatic neutrophilic dermatitis (RND), neutrophilic eccrine hidradenitis (NEH), persistent erythema elevata (EED), or skin inflammations accompanied by ulcers, such as pyoderma gangrenosum (PG). Blocking IL-36 may also be beneficial in patients with ichthyosis (and its subtypes, such as Netherton syndrome, i.e., NS).

[0063] The present invention provides an anti-IL-36R antibody and a pharmaceutical composition for use in reducing, tapering, or blocking the IL-36 pathway, which is useful for the treatment or prevention of neutrophilic dermatosis in subjects, preferably humans.

[0064] In one embodiment, the present invention relates to a method for treating, preventing or relieving neutrophilic dermatosis (ND) in a subject, comprising the step of administering to the subject a therapeutically effective dose of an anti-IL-36R antibody or its antigen-binding fragment (as disclosed herein). In one embodiment related to this aspect, the anti-IL-36R antibody is spesolimab.

[0065] In one embodiment, the present invention relates to a method for treating a skin disorder associated with neutrophilic dermatopathy in a patient, the method(s) comprising the step of administering or having administered to a patient a therapeutically effective amount of the anti-IL-36R antibody of the present invention or its antigen-binding fragment (as disclosed herein). In one embodiment related to this aspect, the anti-IL-36R antibody is spesolimab.

[0066] In one embodiment, the present invention relates to a method for treating a skin inflammation associated with neutrophilic dermatopathy in a subject, the method comprising administering or having administered to the subject a therapeutically effective amount of the anti-IL-36R antibody of the present invention or its antigen-binding fragment (as disclosed herein). In one embodiment related to this aspect, the anti-IL-36R antibody is spesolimab.

[0067] In one embodiment, the present invention relates to a method for preventing or reducing neutrophilic infiltrates in affected skin tissue in a subject suffering from neutrophilic dermatopathy, the method comprising administering or having administered to a subject a therapeutically effective amount of the anti-IL-36R antibody of the present invention or its antigen-binding fragment. In one embodiment related to this aspect, the anti-IL-36R antibody is spesolimab.

[0068] In one embodiment, the present invention relates to a method for reducing microbial colonization on the skin of a subject, comprising the step of administering to the subject a therapeutically effective amount of an anti-IL-36R antibody or an antigen-binding fragment thereof, as disclosed herein. In one embodiment related to this aspect, the colonization is of a microorganism selected from the group consisting of Staphylococcus aureus, Streptococcus species, Pseudomonas aeruginosa, Bacteroides species, Molluscum contagiosum virus, Herpes simplex virus, Coxsackievirus, Vaccinia virus, Candida albicans, Dermatophytes, Trichophyton species, Penicillium species, Cladosporium species, Alternaria species, and Aspergillus species. In another embodiment related to this aspect, the microorganism is Staphylococcus aureus. In another embodiment related to this aspect, Staphylococcus aureus colonization is reduced by at least 10% or at least 20% from baseline after administration of an anti-IL-36R antibody or an antigen-binding fragment thereof, as disclosed herein. In another embodiment related to this aspect, the anti-IL-36R antibody is a spesolimab.

[0069] In one embodiment, the present invention relates to a method for reducing susceptibility to skin infection in a subject having neutrophilic dermatosis, comprising the step of administering a therapeutically effective amount of an anti-IL-36R antibody or its antigen-binding fragment (as disclosed herein) to the subject. In another embodiment related to this aspect, the skin infection is caused by a microorganism selected from the group consisting of Staphylococcus aureus, Streptococcus species, Pseudomonas aeruginosa, Bacteroides species, Herpes simplex virus, Molluscum contagiosum virus, Coxsackievirus, Vaccinia virus, Candida albicans, Dermatophytes, Trichophyton species, Penicillium species, Cladosporium species, Alternaria species, and Aspergillus species. In another embodiment related to this aspect, the microorganism is Staphylococcus aureus (S. aureus). In one embodiment related to this aspect, the anti-IL-36R antibody is spesolimab.

[0070] In one embodiment relating to any of the above aspects, the second therapeutic agent is administered to the subject before, after, or simultaneously with an anti-IL-36R antibody or its antigen-binding fragment. In the relevant embodiment, the second therapeutic agent is selected from the group consisting of antibacterial agents, antiviral agents, antifungal agents, another IL-36R antagonist, IgE inhibitors, corticosteroids, NSAIDs, IL-4R antagonists, and interferon-γ.

[0071] In one embodiment relating to any of the above aspects, the anti-IL-36R antibody comprises a) a light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 or 141 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111, or 142 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0072] In one embodiment relating to any of the above aspects, the anti-IL-36R antibody comprises a) a light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 35, 102, 103, 104, 105, 106, or 140 (L-CDR2); the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) a heavy chain variable region including the amino acid sequence of SEQ ID NO: 141 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111, or 142 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3).

[0073] In one embodiment relating to any of the above aspects, the anti-IL-36R antibody is: ia) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 102 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or II.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 103 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or III.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 104 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or IV.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 105 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or Va) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 106 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or VI.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 140 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110 or 111 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3); or VII.a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); amino acid sequence of SEQ ID NO: 104 (L-CDR2); amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 141 (H-CDR1); amino acid sequence of SEQ ID NO: 62, 108, 109, 110, 111 or 142 (H-CDR2); amino acid sequence of SEQ ID NO: 72 (H-CDR3). Includes.

[0074] In one embodiment relating to any of the above aspects, the anti-IL-36R antibody is: (i) Light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 87; or (ii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 88; or (iii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 89; or (iv) Light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 87; or (v) Light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 88; or (vi) Light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 89; or (vii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 85; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 100; or (viii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 85; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 101; or (ix) Light chain variable region containing the amino acid sequence of SEQ ID NO: 86; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 100; or (x) Light chain variable region containing the amino acid sequence of SEQ ID NO: 86; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 101 Includes.

[0075] In one embodiment relating to any of the above aspects, the anti-IL-36R antibody is: i. A light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 125; or ii. A light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 126; or iii. A light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 127; or iv. A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 125; or v. A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 126; or vi. A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 127; or vii. A light chain containing the amino acid sequence of SEQ ID NO: 123; and a heavy chain containing the amino acid sequence of SEQ ID NO: 138; or viii. A light chain containing the amino acid sequence of SEQ ID NO: 123; and a heavy chain containing the amino acid sequence of SEQ ID NO: 139; or ix. Light chain containing the amino acid sequence of SEQ ID NO: 124; and heavy chain containing the amino acid sequence of SEQ ID NO: 138 Includes.

[0076] In one embodiment relating to any of the above aspects and embodiments, neutrophilic dermatosis includes: hidradenitis suppurativa (HS); acute generalized exanthematous pustulosis; acute febrile neutrophilic dermatosis (Sweet's syndrome); nonmicrobial pustulosis of the dermal folds (APF); Behçet's disease; intestinal tract syndrome (intestinal-associated dermatitis-arthritis syndrome); intestinal-associated dermatosis-arthritis syndrome (BADAS); pustular psoriasis mediated by CARD14 (CAMPS); cryopyrin-associated periodic syndromes (CAPS); interleukin-36 receptor antagonist deficiency (DIRTA); interleukin-1 receptor antagonist deficiency (DIRA); persistent erythema elevateds; histiocyte The following are selected from the group consisting of: neutrophilic dermatitis; acropustulosis of the limbs; neutrophilic dermatosis of the dorsum of the hand; neutrophilic eccrine hidradenitis; neutrophilic urticarial dermatosis; palisade granulomatous neutrophilic dermatitis; psoriasis vulgaris; pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome; pyoderma gangrenosum (PG); pyoderma gangrenosum and acne (PAPA); suppurative arthritis; skin lesions of Behçet's disease; Still's disease; subkeratinous pustulosis (Sneddon-Wilkinson's disease); synovitis, acne, pustulosis-ossification; osteitis (SAPHO) syndrome; rheumatic neutrophilic dermatitis (RND); and ichthyosis (and its subtypes, e.g., Netherton syndrome, i.e., NS).

[0077] In related embodiments, neutrophilic dermatosis is hidradenitis suppurativa (HS). In related embodiments, neutrophilic dermatosis is acute generalized exanthematous pustulosis. In related embodiments, neutrophilic dermatosis is acute febrile neutrophilic dermatosis (Sweet's syndrome). In related embodiments, neutrophilic dermatosis is nonmicrobial pustulosis of the skin folds (APF). In related embodiments, neutrophilic dermatosis is Behçet's disease. In related embodiments, neutrophilic dermatosis is intestinal accessory syndrome (intestinal dermatitis-arthritis syndrome). In related embodiments, neutrophilic dermatosis is intestinal dermatitis-arthritis syndrome (BADAS). In related embodiments, neutrophilic dermatosis is CARD14-mediated pustular psoriasis (CAMPS). In related embodiments, neutrophilic dermatosis is cryopyrin-associated periodic syndromes (CAPS). In related embodiments, neutrophilic dermatopathy is interleukin-36 receptor antagonist deficiency (DIRTA). In related embodiments, neutrophilic dermatopathy is interleukin-1 receptor antagonist deficiency (DIRA). In related embodiments, neutrophilic dermatopathy is persistent erythema elevateds. In related embodiments, neutrophilic dermatopathy is histiocytic neutrophilic dermatitis. In related embodiments, neutrophilic dermatopathy is acropustulosis of the limbs in children. In related embodiments, neutrophilic dermatopathy is neutrophilic dermatopathy of the dorsum of the hand. In related embodiments, neutrophilic dermatopathy is neutrophilic eccrine hidradenitis. In related embodiments, neutrophilic dermatopathy is neutrophilic urticarial dermatopathy. In related embodiments, neutrophilic dermatopathy is palisade granulomatous neutrophilic dermatitis. In related embodiments, neutrophilic dermatopathy is psoriasis vulgaris. In related embodiments, neutrophilic dermatopathy is pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome. In related embodiments, neutrophilic dermatopathy is pyoderma gangrenosum (PG). In related embodiments, neutrophilic dermatopathy is pyoderma gangrenosum and acne (PAPA). In related embodiments, neutrophilic dermatopathy is suppurative arthritis. In related embodiments, neutrophilic dermatopathy is a skin lesion of Behçet's disease. In related embodiments, neutrophilic dermatopathy is Still's disease. In related embodiments, neutrophilic dermatopathy is subkeratotic pustulosis (Sneddon-Wilkinson disease).In related embodiments, neutrophilic dermatopathy includes synovitis, acne, pustulosis-ossification, and osteitis (SAPHO) syndrome. In related embodiments, neutrophilic dermatopathy includes rheumatic neutrophilic dermatitis (RND). In related embodiments, neutrophilic dermatopathy includes ichthyosis (and its subtypes, e.g., Netherton syndrome, i.e., NS).

[0078] In any of the above embodiments or other embodiments related to the embodiments described herein, the anti-IL-36R antibody is administered to a subject suffering from neutrophilic dermatosis in a dose ranging from about 0.001 to about 1000 mg.

[0079] In any of the above embodiments or other embodiments related to the embodiments described herein, the anti-IL-36R antibody is spesolimab.

[0080] In any of the above embodiments or other embodiments related to the embodiments described herein, the therapeutically effective dose of anti-interleukin-36 receptor (anti-IL-36R) antibody is in the range of about 0.001 to about 1000 mg.

[0081] In another embodiment relating to any of the above-described aspects or embodiments described herein, the second therapeutic agent is administered to the subject before, after, or simultaneously with the anti-IL-36R antibody.

[0082] In any of the above embodiments or other embodiments related to the embodiments described herein, the second therapeutic agent is selected from the group consisting of antibacterial agents, antiviral agents, antifungal agents, anti-IL-36R antibodies, IgE inhibitors, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), IL-4R antagonists, and interferon-γ.

[0083] Pharmaceutical composition The antibodies of the present invention can be incorporated into pharmaceutical compositions suitable for administration to a subject. The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers, diluents and / or excipients, in single or multiple doses. The pharmaceutical compositions for administration are designed to suit the selected mode of administration and may use pharmaceutically acceptable diluents, carriers and / or excipients as appropriate, such as dispersants, buffers, surfactants, preservatives, solubilizers, isotonic agents, stabilizers, etc. The compositions are designed in accordance with prior art, which provides an overview of formulation techniques generally known to those skilled in the art, such as Remington, The Science and Practice of Phannacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA 1995.

[0084] The pharmaceutical composition comprising the anti-IL-36R monoclonal antibody of the present invention may be administered to subjects suffering from neutrophilic dermatosis as described herein using standard administration techniques, including oral, intravenous, intraperitoneal, subcutaneous, intrapulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.

[0085] The antibody of the present invention may be administered orally, parenterally, by inhalation, or topically. Preferably, the antibody of the present invention can be incorporated into a pharmaceutical composition suitable for parenteral administration. As used herein, the term parenteral includes intravenous, intramuscular, subcutaneous, rectal, vaginal, or intraperitoneal administration. Peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection is preferred. Vehicles suitable for such injections are known in the art.

[0086] Pharmaceutical compositions typically must be sterile and stable under the conditions of manufacture and storage within the provided container, such as a sealed vial or syringe. Therefore, pharmaceutical compositions may be sterile filtered after formulation or otherwise made microbiologically acceptable. Typical compositions for intravenous infusion may have a large volume of liquid, such as 250–1000 ml, e.g., sterile Ringer's solution, physiological saline, dextrose solution, and Hank's solution, and an antibody concentration of a therapeutically effective dose (e.g., 1–100 mg / mL or higher). The dose may be modified depending on the type and severity of the disease. As is well known in the medical field, the dose for any one subject depends on many factors, including the patient's physique, body surface area, age, the specific compound to be administered, sex, time and route of administration, overall health, and other drugs administered concurrently. Typical doses may be, for example, in the range of 0.001–1000 mg, however, doses below or above this exemplary range are also possible, particularly considering the aforementioned factors.

[0087] product In another embodiment, the product includes a substance useful for treating the above-mentioned disorder. The product includes a container and a label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container may be made of a variety of materials, such as glass or plastic. The container may hold a composition effective for treating the condition and may have a sterile access port. For example, the container may be an infusion bag or a vial with a stopper that can be pierced by a subcutaneous needle. The active substance in the composition is a humanized anti-IL-36R antibody. A label on or attached to the container indicates that the composition is for use in treating a selected condition. The product may further include a second container containing a pharmaceutically acceptable buffer, such as phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and a package insert containing instructions for use.

[0088] The present invention is further described in the following embodiments, which do not limit the scope of the invention.

[0089] Examples The following examples are intended to further illustrate, and not limit, certain preferred embodiments of the disclosure. Those skilled in the art will recognize or be able to identify numerous equivalents to the specific substances and procedures described herein.

[0090] Example 1: Treatment of a patient with neutrophilic dermatosis In this embodiment, the anti-IL-36R antibody of the present invention is used to treat patients with neutrophilic dermatosis.

[0091] After administration of anti-IL-36R antibody, 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% of patients 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% showed improvement from baseline or compared to placebo.

[0092] Example 2: Treatment of patients with hidradenitis suppurativa (HS) In this embodiment, the anti-IL-36R antibody of the present invention is used to treat patients with hidradenitis suppurativa.

[0093] After administration of anti-IL-36R antibody, 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% of patients 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% showed improvement from baseline or compared to placebo.

[0094] While specific aspects and embodiments of the present invention are described herein, these are presented merely as examples and do not limit the scope of the invention. In fact, the novel methods and systems described herein can be embodied in various other forms without departing from their spirit. The appended claims and their equivalents cover such forms or modifications that would fall within the scope and spirit of the invention.

[0095] All patents and / or publications, including journal articles, cited herein are expressly incorporated by reference.

Claims

1. A method for treating neutrophilic dermatosis in a subject, comprising the step of administering a therapeutically effective dose of an anti-interleukin-36 receptor (anti-IL-36R) antibody to the subject.

2. Neutrophilic dermatopathy includes hidradenitis suppurativa (HS); acute generalized exanthematous pustulosis; acute febrile neutrophilic dermatopathy (Sweet's syndrome); nonmicrobial pustulosis of the skin folds (APF); Behçet's disease; intestinal accessory syndrome (intestinal dermatitis-arthritis syndrome); intestinal dermatitis-arthritis syndrome (BADAS); pustular psoriasis mediated by CARD14 (CAMPS); cryopin-associated periodic syndromes (CAPS); interleukin-36 receptor antagonist deficiency (DIRTA); interleukin-1 receptor antagonist deficiency (DIRA); persistent erythema elevateds; histiocytic neutrophilic dermatitis; acropustulosis of the limbs; and neutrophils of the back of the hand. The method of claim 1, selected from the group consisting of neutrophilic dermatosis; neutrophilic eccrine hidradenitis; neutrophilic urticarial dermatosis; palisade granulomatous neutrophilic dermatitis; psoriasis vulgaris; pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome; pyoderma gangrenosum (PG); pyoderma gangrenosum and acne (PAPA); suppurative arthritis; skin lesions of Behçet's disease; Still's disease; subkeratotic pustulosis (Sneddon-Wilkinson disease); synovitis, acne, pustulosis-ossification, and osteitis (SAPHO) syndrome; rheumatic neutrophilic dermatitis (RND); and ichthyosis (and its subtypes, e.g., Netherton syndrome, i.e., NS).

3. Anti-IL-36R antibody, I. a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 102 (L-CDR2); and the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3); or II. a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 103 (L-CDR2); and the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequences of SEQ ID NO: 62, 108, 109, 110, or 111 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3); or III. a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 104 (L-CDR2); and the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequences of SEQ ID NO: 62, 108, 109, 110, or 111 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3); or IV. a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 105 (L-CDR2); and the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequence of SEQ ID NO: 62, 108, 109, 110, or 111 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3); or V. a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 106 (L-CDR2); and the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequences of SEQ ID NO: 62, 108, 109, 110, or 111 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3); or VI. a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 140 (L-CDR2); and the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 53 (H-CDR1); the amino acid sequences of SEQ ID NO: 62, 108, 109, 110, or 111 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3); or VII. a) Light chain variable region including the amino acid sequence of SEQ ID NO: 26 (L-CDR1); the amino acid sequence of SEQ ID NO: 104 (L-CDR2); and the amino acid sequence of SEQ ID NO: 44 (L-CDR3); and b) Heavy chain variable region including the amino acid sequence of SEQ ID NO: 141 (H-CDR1); the amino acid sequences of SEQ ID NOs: 62, 108, 109, 110, 111, or 142 (H-CDR2); and the amino acid sequence of SEQ ID NO: 72 (H-CDR3). The method of claim 1, including the method of claim 1.

4. Anti-IL-36R antibody, (i) a light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 87; or (ii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 88; or (iii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 77; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 89; or (iv) Light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 87; or (v) Light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 88; or (vi) Light chain variable region containing the amino acid sequence of SEQ ID NO: 80; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 89; or (vii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 85; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 100; or (viiii) Light chain variable region containing the amino acid sequence of SEQ ID NO: 85; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 101; or (ix) Light chain variable region containing the amino acid sequence of SEQ ID NO: 86; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 100; or (x) Light chain variable region containing the amino acid sequence of SEQ ID NO: 86; and heavy chain variable region containing the amino acid sequence of SEQ ID NO: 101 The method of claim 1, including the method of claim 1.

5. Anti-IL-36R antibody, i. A light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 125; or ii. A light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 126; or iii. A light chain containing the amino acid sequence of SEQ ID NO: 115; and a heavy chain containing the amino acid sequence of SEQ ID NO: 127; or iv. A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 125; or v. A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 126; or vi. A light chain containing the amino acid sequence of SEQ ID NO: 118; and a heavy chain containing the amino acid sequence of SEQ ID NO: 127; or vii. A light chain containing the amino acid sequence of SEQ ID NO: 123; and a heavy chain containing the amino acid sequence of SEQ ID NO: 138; or viiii. A light chain containing the amino acid sequence of SEQ ID NO: 123; and a heavy chain containing the amino acid sequence of SEQ ID NO: 139; or ix. Light chain containing the amino acid sequence of SEQ ID NO: 124; and heavy chain containing the amino acid sequence of SEQ ID NO: 138 The method of claim 1, including the method of claim 1.

6. The method according to claim 1, wherein the anti-IL-36R antibody is spesolimab.

7. The method according to claim 1, wherein the therapeutically effective dose of anti-interleukin-36 receptor (anti-IL-36R) antibody is in the range of approximately 0.001 to approximately 1000 mg.

8. The method according to claim 1, wherein the second therapeutic agent is administered to the subject before, after, or simultaneously with the anti-IL-36R antibody.

9. The method of claim 8, wherein the second therapeutic agent is selected from the group consisting of antibacterial agents, antiviral agents, antifungal agents, anti-IL-36R antibodies, IgE inhibitors, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), IL-4R antagonists, and interferon-γ.

10. The method of claim 2, wherein the neutrophilic dermatosis is hidradenitis suppurativa (HS).

11. The method of claim 2, wherein the neutrophilic dermatosis is ichthyosis (and its subtype, e.g., Netherton syndrome, i.e., NS).

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