Il-1RAP inhibitor for treating or preventing hidradenitis suppurativa

Abstract

The disclosure relates to the field of inflammatory skin disorders. Particularly, the present disclosure provides the use of IL-IRAP inhibitors, as well as of pharmaceutical compositions comprising thereof, for treating Hidradenitis suppurativa.

Description

[0001] IL-1 RAP INHIBITOR FOR TREATING OR PREVENTING HIDRADENITIS SUPPURATIVA

[0002] FIELD OF THE INVENTION

[0003] The invention relates to the treatment of autoimmune diseases. Specifically, it lies in the field of inflammatory skin disorders. Particularly, the present invention provides the use of IL-1RAP inhibitors, as well as of pharmaceutical compositions comprising such inhibitors, for treating Hidradenitis suppurativa.

[0004] BACKGROUND

[0005] Hidradenitis suppurativa (HS, also known as acne in versa) is an immune-mediated inflammatory disorder originating from the hair follicles, characterized by deep-seated nodules, abscess, sinus tracts, and scars localized in the intertriginous areas. It can be associated with substantial pain and comorbidities, including metabolic, psychiatric, and autoimmune disorders, as well as an increased risk of skin cancer.

[0006] HS can be described as mild, moderate or severe using the Hurley Staging System, wherein Stage 1 (mild) typically presents as inflammatory nodule or abscess formation, single or multiple, without sinus tracts and scarring; Stage 2 (moderate) typically presents as recurrent abscesses and nodules with sinus tract formation or scarring: single or multiple widely separated lesions; and Stage 3 (severe) typically presents as diffuse or near-diffuse involvement with multiple interconnected sinus tracts, scarring, and abscesses across entire area. See, e.g., Jemec GBE. Hidradenitis suppurativa. N Engl J Med. 2012;366(2):158-164.

[0007] The prevalence of HS ranges from 1% to 4% in Europe and the United States in the general population, although the true incidence is probably underestimated. HS usually manifests after puberty in the second and third decades of life, with a female predominance (female-to-male ratio of 3:1). Prepubertal onset (before 11 years of age) is estimated to occur in 2-7% of patients with HS.

[0008] The disease is associated with significant morbidity and several co-morbidities, such as smoking and obesity, both leading to cardiovascular comorbidities. Given the pain and physical deterioration associated with the painful lesions of HS, it has been reported that the quality of life related to health is lower for patients with HS than other dermatological diseases. In addition, a recent study estimated that up to 20% of patients with HS report the coexistence of depression, and patients with HS report a high level of stigmatization.

[0009] The pathogenesis of HS is not fully understood. Current evidence highlights a complex multifactorial pathogenesis. Evidence suggests the involvement of pro-inflammatory cytokines in immune dysregulation in HS, with elevated levels of tumor necrosis factor (TNF)-a, interleukin (IL)- IB, IL- 17 and interferon (IFN)-y observed in HS lesions. Data also indicate the involvement of T helper (Th) cells, which accumulate in HS lesions, in the pathogenesis of HS. In addition, studies have shown that antimicrobial peptides (AMPs) like cathelicidin (LL-37) and human P- defensin are increased in HS lesions compared with normal skin of HS patients. A number of studies have reported increased mRNA and / or protein interleukins in HS patients’ skin or serum and their suitability as inflammatory markers of the disease. Alterations in the skin, in the context of HS, have been reported for IL-ip, CXCL-8 / IL-8, IL-17 / IL-17A, IL-32, and IL-36 / IL-36a / IL- 36p / fL-36y. Alterations in the serum have been reported for IL-ip, IL-6, CXCL-8 / IL-8, IL-10, IL- 12p70, and IL-17 / IL-17A.

[0010] Treatment of HS has been a challenge because of the complex multifactorial pathogenesis, the lack of effective therapies and frequent exacerbations, with a negative impact on quality of life. Current treatment for HS consists of topical (e.g., antiseptic washes, topical antibiotics, resorcinol 15% cream) and systemic approaches (e.g., oral and intravenous antibiotics as monotherapy (tetracyclines, ertapenem, dalbavancin) or in combination (clindamycin and rifampicin)). When the lesions are aggravated, alternatives for the management of the disease can include surgical procedures (e.g., incision and drainage for acute flares, de-roofing, narrow margin excision, wide local excision), retinoids, dapsone, oral zinc, immunosuppressive agents, surgical excision, and monoclonal antibodies, such as tumor necrosis factor [TNF] inhibitor adalimumab, and interleukin- 17 (IL- 17) inhibitors sekukinumab and bimekizumab.

[0011] While there have been proposed multiple therapeutic approaches for the management of HS, including combinational treatments, they have provided a limited success in the treatment of the disease, which indicates that effective management of HS remains elusive in many cases.

[0012] Therefore, there is still the need for further therapeutic approaches for an optimal management of HS.

[0013] SUMMARY OF THE INVENTION

[0014] The inventors solve this problem by the methods and uses of the invention. In particular, the inventors have discovered that an IL-1RAP inhibitor or a pharmaceutical composition comprising such an IL- 1 RAP inhibitor can be used to treat Hidradenitis Suppurativa.

[0015] As it is shown below, the administration of an IL-1RAP inhibitor provides a significant reduction in relevant inflammatory cytokines, such IFNy, IL-17A, IL-17F, CXCL8, IL- 10, IL-36a, IL36G, or IL-6, among others (see Example 1) and provides an improvement in HS lesion count in patients clinically treated with such IL- 1 RAP inhibitor.

[0016] From the data provided below the following beneficial effects are derived from administering an IL- 1 RAP inhibitor: a. broad-spectrum effect, significantly reducing the expression level of several inflammatory cytokines (i.e., multitarget modulation). This broad-spectrum effect is indicative of the suitability of an IL- 1 RAP inhibitor in the management of HS, which is characterized, as discussed in previous passages, as being an inflammatory skin disease; b. the reduction provided by the IL- 1 RAP inhibitor ex vivo was achieved 24 h after the administration. That is, IL-1RAP inhibitor’s onset of action starts immediately after administration. c. the favorable safety and tolerability profile observed both in healthy subjects and HS patients treated with the IL- 1 RAP inhibitor, along with a low immunogenicity risk. d. the improvement in HS lesion count in patients treated with the IL-1RAP inhibitor. The data provided in this application show that an IL- 1 RAP inhibitor can provide an effective amelioration in inflammatory skin diseases such as HS, in a very short period of time.

[0017] Altogether, the data provided herein support the suitability of inhibiting IL- 1 RAP for the efficient management of HS. This is the first time that such beneficial effects of an IL- 1 RAP inhibitor are reported in HS.

[0018] In view of the above, the present invention provides an IL- 1 RAP inhibitor for use in treating or preventing HS. This aspect can also be formulated as the use of an IL- 1 RAP inhibitor for the manufacture of a medicament for the treatment of HS. This aspect can alternatively be formulated as a method for treating HS, the method comprising administering to a subject in need thereof, a therapeutically effective amount of an IL- 1 RAP inhibitor.

[0019] In some embodiments, the IL- 1 RAP inhibitor is a small molecule, a receptor antagonist, an antibody or an antigen-binding fragment thereof.

[0020] In some embodiments, the IL-1RAP inhibitor is an antibody or an antigen -binding fragment thereof. In some embodiments, the anti-IL-lRAP antibody or antigen-binding fragment thereof comprises a first heavy chain CDR region (CDR-H1), a second heavy chain CDR region (CDR- H2), and a third heavy chain CDR region (CDR-H3) wherein CDR-H1 comprises an amino acid sequence selected from SEQ ID NOs: 5, 6 and 120; CDR-H2 comprises an amino acid sequence selected from SEQ ID NOs: 7, 8 and 121; CDR-H3 comprises an amino acid sequence selected from SEQ ID NOs: 9 to 14 and 122. Preferably, the CDR-H1 may comprise SEQ ID NO: 5, CDR-H2 may comprise SEQ ID NO: 7 and CDR-H3 may comprise SEQ ID NO: 9. In some embodiments, the anti-IL-lRAP antibody or fragment thereof further comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 15.

[0021] In some embodiments, the IL-1RAP antibody or the antigen-binding fragment thereof comprises heavy and light chain variable regions having, respectively, the amino acid sequence of SEQ ID NO: 16 and SEQ ID NO: 15, or SEQ ID NO: 80 and SEQ ID NO: 81, or SEQ ID NO: 82 and SEQ ID NO: 83, or SEQ ID NO: 84 and SEQ ID NO: 83, or SEQ ID NO: 85 and SEQ ID NO: 86, or SEQ ID NO: 87 and SEQ ID NO: 88, or SEQ ID NO: 89 and SEQ ID NO: 90, or SEQ ID NO: 91 and SEQ ID NO: 92, or SEQ ID NO: 93 and SEQ ID NO: 94, or SEQ ID NO: 95 and SEQ ID NO: 96, or SEQ ID NO: 97 and SEQ ID NO: 98, or SEQ ID NO: 99 and SEQ ID NO: 100, or SEQ ID NO: 101 and SEQ ID NO: 102, or SEQ ID NO: 103 and SEQ ID NO: 104 or SEQ ID NO: 105 and SEQ ID NO: 106, or SEQ ID NO: 107 and SEQ ID NO: 108.

[0022] In some embodiments, the IL-1RAP antibody or the antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence of SEQ ID NO: 16 and a light chain variable region having an amino acid sequence of SEQ ID NO: 15.

[0023] In some embodiments, the IL-1RAP inhibitor for use in treating or preventing hidradenitis suppurativa is administered in the form of a pharmaceutical composition, comprising one or more pharmaceutically acceptable excipient(s), carrier(s) or vehicle(s).

[0024] In some embodiments, a therapeutically effective amount of the anti-IL-lRAP inhibitor is administered to a patient in need thereof, wherein said administration reduces the severity of HS in the patient. In some embodiments, the severity of HS in the patient is assessed by one or more of Hurley Staging, HiSCR, IHS4, total AN count, draining fistula count, NRS and HiSQOL.

[0025] BRIEF DESCRIPTION OF DRAWING

[0026] Fig. 1. Cytokine inhibition by IL-1RAP antibody treatment of HS skin samples. Each point corresponds to mean +SD of three biopsies treated with Isotype control or with an anti-IL-lRAP antibody. * p < 0.05, ** p < 0.01; *** p < 0.001, t-test vs Isotype control.

[0027] Fig. 2. Blood neutrophil count in placebo and IL-1RAP treatment HS patients.

[0028] Fig. 3. Draining fistula count over time in patients treated with IL-1RAP or placebo.

[0029] Fig. 4. AN count over time in patients treated with IL-1RAP or placebo.

[0030] Fig. 5. Total lesions count over time in patients treated with IL-1RAP or placebo.

[0031] Fig. 6. IHS4 score over time in patients treated with IL-1RAP or placebo.

[0032] Fig. 7. Inflammatory biomarkers assessment in patients treated with IL-1RAP or placebo.

[0033] DETAILED DESCRIPTION All terms as used in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.

[0034] 1L-1RAP inhibitor

[0035] The invention uses an IL- 1 RAP inhibitor for treating HS.

[0036] Interleukin- 1 receptor accessory protein (IL-1RAP or IL-lRAcP or IL-1R3) is a component of the interleukin 1 receptor complex, which initiates signaling events that result in the activation of interleukin- 1 responsive genes. IL-1RAP serves as the common cellular membrane co-receptor for several receptors in the IL-1 family, including interleukin-1 receptor 1 (IL-1R1), ST2 (also known as interleukin- 1 receptor- like 1) and interleukin- 1 receptor-like 2 (IL-1RL2). IL- 1 RAP is a necessary component of the ternary signaling complex formed by one of the IL-1 family cytokines noted above, the cytokine's specific cognate receptor, and the IL-1RAP co-receptor. Thus, IL- 1RAP serves an important function in the IL-1 family signal transduction pathways, since it is required to facilitate particular downstream signaling pathways stimulated by the IL-1 family cytokines IL-la, IL-ip, IL-33, IL-36a, IL-36P, and fL-36y.

[0037] As used herein, the term “IL-1RAP inhibitor” refers to any molecule (small or large, such as a peptide, polypeptide, antibody or fragment thereof) that decreases IL- 1 RAP activity or the activity of any of the related downstreatm signaling pathways stimulated by the IL-1 family cytokines. A skilled person will be able to ascertain whether a given molecule is an inhibitor of IL-1RAP. For example, the inhibitory activity can be determined by testing for expansion of Chronic myeloid leukemia (CML) cells in response to IL- 1 stimulation. An inhibitor suitable for use in the invention will be able to reduce IL-1 induced expansion compared to a control culture which was not contacted with the inhibitor.

[0038] Suitable inhibitors are known to a skilled person and include for example antibodies or fragments thereof, small molecules, receptor antagonists, etc.

[0039] The inhibitory activity of an inhibitor of IL- 1 RAP can also be determined by determining the level (either in the form of nucleic acid or protein) of inflammatory cytokine markers such as IL-1, IL- 6, IL-8, IL- 18, MIP-1, IL- 10, TNF-a, IL-17A, IL-17F, IL-22, IL-23, IL-33, IL-36 or IFN-y using both well-known protocols and commercial kits (following manufacturer’s instructions).

[0040] In one embodiment, IL- 1 RAP activity is determined by measuring the level of expression (either in the form of nucleic acid or protein) of one or more inflammatory cytokines selected from IL-1, IL-6, IL-8, IL- 18, MIP-1, IL- 10, TNF-a, IL-17A, IL-17F, IL-22, IL-23, IL-36 or IFN-y. In one embodiment, IL-1RAP activity is determined by measuring the level of expression (either in the form of nucleic acid or protein) of IL-1, IL-6, IL-8, IL- 18, MIP-1, IL- 10, TNF-a, IL-17A, IL-17F, IL- 22, IL-23, IL-36 and IFN-y. An illustrative non-limitative example of how the determination of these cytokines can be performed is provided in the section of Examples, below.

[0041] Suitable inhibitors will reduce IL-1RAP activity by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%. It is understood that the reduction will be assessed relative to a control, for example a cell culture which is not contacted with an inhibitor.

[0042] In some embodiments, the IL- 1 RAP inhibitor is a small molecule, a receptor antagonist, an antibody or an antigen -binding fragment thereof. Preferably, the inhibitor is an antibody, e.g. an antibody that binds specifically to human IL-1RAP.

[0043] The antibody may be capable of decreasing, inhibiting, and / or fully blocking intracellular signaling by IL- 1 RAP-mediated pathways, including the IL-1, IL-33, and / or IL-36 signaling pathways, including signaling stimulated by binding of one or more of the following agonists: IL-la, IL-ip, IL-33, IL-36a, IL-36P, and fL-36y. The antibody may inhibit all three of IL-1, IL-33, and IL-36 signaling pathways. The antibody may inhibit one or two of IL-1, IL-33, and IL-36 signaling pathways.

[0044] In some embodiments, the ability of the antibody to decrease, inhibit, and / or fully block intracellular signaling is determined as IC50 of the antibody using a reporter cell-based blocking assay with the agonist(s) IL-la, IL-ip, IL-33, IL-36a, IL-36P, and fL-36y at a concentration of about EC50. In some embodiments the anti IL- 1 RAP antibody decreases an intracellular signal initiated by one or more of IL-la, IL-ip, IL-33, IL-36a, IL-36P, and IL-36y agonist binding to its cognate receptor by at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100%. In some embodiments the anti IL- 1RAP antibody inhibits IL-la, IL-ip, and / or IL-36y stimulated release of IL-8 from primary human lung fibroblasts (PHLF) optionally, wherein at an IL-la, IL-ip, and / or IL-36y concentration of about EC50 the antibody has an IC50 of 10 nM or less, 5 nM or less, or 1 nM or less. In some embodiments the anti-IL-lRAP antibody inhibits IL-33 stimulated release of IL-6 from primary human monocytes; optionally, wherein at an IL-ip concentration of about EC 50 the antibody has an IC50 of 10 nM or less, 5 nM or less, or 1 nM or less. In some embodiments the anti-IL-lRAP antibody inhibits IL-33 stimulated release of IFN-y from human natural killer (NK) cells; optionally, wherein at an IL-33 concentration of about EC50 the antibody has an IC50 of 10 nM or less, 5 nM or less, or 1 nM or less. In some embodiments, the antibody inhibits IL-36P stimulated release of IL-8 from human epidermal keratinocytes (HEKn); optionally, wherein at an IL-36P concentration of about EC60 the antibody has an IC50 of 10 nM or less, 5 nM or less, or 2 nM or less. In some embodiments, the antibody inhibits IL-33 stimulated phosphorylation in basophils; optionally, wherein at an IL-33 concentration of about EC56 the antibody has an IC50 of 75 nM or less, 50 nM or less, or 45 nM or less. In some embodiments, the antibody inhibits IL-33 stimulated release of IFN-y from CD4+ T cells; optionally, wherein at an IL-33 concentration of about EC34 the antibody has an IC50 of 75 nM or less, 50 nM or less, or 45 nM or less. In some embodiments, the antibody inhibits one or more of IL-la, IL-ip, IL-36a, IL-36P and IL-36y stimulated release of IL- 8 from human whole blood; optionally, wherein at an IL- 8 concentration of about EC80 the antibody has an IC50 of 10 nM or less, 5 nM or less, or 2 nM or less. In some embodiments, the antibody inhibits one or more of IL-la, IL-ip, IL-36a, IL-36P and fL-36y stimulated release of IL-6 from human whole blood; optionally, wherein at an IL-6 concentration of about EC80 the antibody has an IC50 of 10 nM or less, 5 nM or less, or 2 nM or less.

[0045] IL-1RAP antibodies

[0046] The invention relates to the use of an IL- 1 RAP inhibitor for treating HS. Preferably, the inhibitor is an antibody or a fragment thereof, e.g. an antibody or a fragment thereof that binds specifically to human IL- 1 RAP. In the context of the invention, the term “antibody” as used herein, is intended to refer to an immunoglobulin molecule comprised of four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CHI, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from aminoterminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0047] “Complementarity determining region,” or “CDR,” as used herein, refers to the regions within the variable region which have the highest sequence variability and / or are involved in antigen recognition. Generally, native antibodies comprise four chains with six CDRs; three in the heavy chain variable regions, VH (Hl, H2, H3), and three in the light chain variable regions, VL (LI, L2, L3). Unless otherwise indicated, CDR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991). Exemplary CDRs (CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3) occur at amino acid residues 24-34 of LI, 50-56 of L2, 89-97 of L3, 26-35 or 31-35 of Hl, 50-65 or 50-65 of H2, and 93-102 or 95-102 of H3. (Kabat et al., supra). Alternative methods to Kabat et al., (supra) which collected and aligned the sequences of different members of the immunoglobulin superfamily, have been proposed such as Chothia et al., (Chothia - J Mol Biol. 1987 Aug 20;196(4):901-17 and Nature. 1989 Dec 21-28;342(6252):877-83.) and Lefranc et al., (IMGT - Nucleic Acids Res. 1999 Jan l;27(l):209-12.) who proposed a unified numbering scheme for immunoglobulin variable domain germ line sequences. All such alternative definitions are encompassed by the current invention and the sequences provided in this specification are not intended to exclude alternatively defined CDR sequences which may only comprise a portion of the CDR sequences provided in the sequence listing. In particular the CDR sequences in accordance with Chothia et al., occur at amino acid residues 26-31 of Hl, 52-65 of H2, and 95- residues 27-38 of Hl, 56-65 of H2, and 105-117 of H3.

[0048] In the context of the invention, the term "antigen-binding fragment" of an antibody (or simply "antibody fragment"), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (i.e., IL-1RAP). It has been shown that the antigenbinding function of an antibody can be performed by fragments of a full-length antibody. Binding fragments include Fab, Fab', F(ab')2, Fabc, Fv, single chains, and single-chain antibodies. Examples of binding fragments encompassed within the term "antigen-binding fragment" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment, which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv)). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding fragment" of an antibody.

[0049] In some embodiments, the anti-IL-lRAP antibody or fragment thereof comprises a first heavy chain CDR region (CDR-H1), a second heavy chain CDR region (CDR-H2), and a third heavy chain CDR region (CDR-H3) wherein CDR-H1 comprises an amino acid sequence selected from SEQ ID NOs: 5, 6 and 120; CDR-H2 comprises an amino acid sequence selected from SEQ ID NOs: 7, 8 and 121; CDR-H3 comprises an amino acid sequence selected from SEQ ID NOs: 9 to 14 and 122. In some embodiments, the CDR-H1 may comprise SEQ ID NO: 5, CDR-H2 may comprise SEQ ID NO: 7 and CDR-H3 may comprise SEQ ID NO: 9.

[0050] In some embodiments, the anti-IL-lRAP antibody or fragment thereof further comprises a first light chain CDR region (CDR-L1), a second heavy chain CDR region (CDR-L2), and a third heavy chain CDR region (CDR-L3) wherein CDR-L1 comprises the amino acid sequence of SEQ ID NO: 117; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 118 and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 119.

[0051] In other embodiments, the anti-IL-lRAP antibody or fragment thereof, further comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO: 15.

[0052] In some preferred embodiments, the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 5, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 7, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 9, CDR-L1 comprises the amino acid sequence of SEQ ID NO: 117; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 118 and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 119. In some embodiments, the anti-IL-lRAP antibody or fragment thereof may comprise a heavy chain variable region having an amino acid sequence with an identity of at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 99% with respect to SEQ ID NO: 16 or 25 to 79, and / or a light chain variable region having an amino acid sequence with an identity of at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 99% with respect to SEQ ID NO: 15.

[0053] In some embodiments, the anti-IL- 1RAP antibody or fragment thereof may comprise a heavy chain variable region having an amino acid sequence selected from SEQ ID NO: 16 or 25 to 79, and / or a light chain variable region having an amino acid sequence set forth in SEQ ID NO: 15.

[0054] In some embodiments, the anti-IL- 1RAP antibody or fragment thereof may comprise heavy and light chain variable regions having respectively an amino acid sequence with an identity of at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 99% with respect to SEQ ID NO: 16 and SEQ ID NO: 15, or SEQ ID NO: 80 and SEQ ID NO: 81, or SEQ ID NO: 82 and SEQ ID NO: 83, or SEQ ID NO: 84 and SEQ ID NO: 83, or SEQ ID NO: 85 and SEQ ID NO: 86, or SEQ ID NO: 87 and SEQ ID NO: 88, or SEQ ID NO: 89 and SEQ ID NO: 90, or SEQ ID NO: 91 and SEQ ID NO: 92, or SEQ ID NO: 93 and SEQ ID NO: 94, or SEQ ID NO: 95 and SEQ ID NO: 96, or SEQ ID NO: 97 and SEQ ID NO: 98, or SEQ ID NO: 99 and SEQ ID NO: 100, or SEQ ID NO: 101 and SEQ ID NO: 102, or SEQ ID NO: 103 and SEQ ID NO: 104, or SEQ ID NO: 105 and SEQ ID NO: 106, or SEQ ID NO: 107 and SEQ ID NO: 108. In some embodiments, the anti-IL-lRAP antibody or fragment thereof may comprise heavy and light chain variable regions having, respectively, the amino acid sequence of SEQ ID NO: 16 and SEQ ID NO: 15, or SEQ ID NO: 80 and SEQ ID NO: 81, or SEQ ID NO: 82 and SEQ ID NO: 83, or SEQ ID NO: 84 and SEQ ID NO: 83, or SEQ ID NO: 85 and SEQ ID NO: 86, or SEQ ID NO: 87 and SEQ ID NO: 88, or SEQ ID NO: 89 and SEQ ID NO: 90, or SEQ ID NO: 91 and SEQ ID NO: 92, or SEQ ID NO: 93 and SEQ ID NO: 94, or SEQ ID NO: 95 and SEQ ID NO: 96, or SEQ ID NO: 97 and SEQ ID NO: 98, or SEQ ID NO: 99 and SEQ ID NO: 100, or SEQ ID NO: 101 and SEQ ID NO: 102, or SEQ ID NO: 103 and SEQ ID NO: 104, or SEQ ID NO: 105 and SEQ ID NO: 106, or SEQ ID NO: 107 and SEQ ID NO: 108.

[0055] In some embodiments, the anti-IL- 1RAP antibody or fragment thereof may comprise a heavy chain variable region having an amino acid sequence of SEQ ID NO: 16 and a light chain variable region having an amino acid sequence of SEQ ID NO: 15.

[0056] The anti-IL- 1 RAP antibody or fragment thereof may bind to human IL- 1 RAP with a binding affinity of IxlO'8M or less, 1 x 10'9M or less, 1 x 10'10M or less, or 1 x 10'11M or less; optionally, wherein the binding affinity is measured by equilibrium dissociation constant (KD) to IL-1RAP polypeptide of SEQ ID NO: 1 or SEQ ID NO: 2.

[0057] The anti-IL- 1RAP antibody or fragment thereof may decrease an IL-1 stimulated signal, an IL-33 stimulated signal, and / or an IL-36 stimulated signal by at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100%; optionally, wherein the decrease in signal is measured by a cell-based blocking assay; optionally, wherein the IL-1, IL-33, and / or IL-36 stimulated signals are stimulated by an agonist selected from IL-la, IL-ip, IL-33, IL-36a, IL-36P, and IL-36y.

[0058] The anti-IL- 1 RAP antibody or fragment thereof may decrease an intracellular signal initiated by one or more of IL-la, IL-ip, IL-33, IL-36a, IL-36P, and IL-36y agonist binding to its cognate receptor by at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100%; optionally, wherein the decrease in intracellular signal is measured by a cell-based blocking assay.

[0059] The anti-IL-lRAP antibody or fragment thereof may inhibit IL-la, IL-ip, and / or IL-36P stimulated release of IL-8 from primary HaCaT keratinocytic cell line. It may inhibit IL-36P stimulated release of IL-8 from primary human mononuclear cells. It may inhibit IL-33 stimulated release of IFNy from primary human mononuclear cells. It may inhibit neutrophil activation upon incubation with HaCaT conditioned medium post-stimulation with IL-ip and IL-36p.

[0060] In some embodiments, the antibody inhibits one or more of IL- la, IL-ip, IL-36a, IL-36P and IL- 367 stimulated release of IL-8 from human whole blood; optionally, wherein at an IL-8 concentration of about EC80 the antibody has an IC50 of 10 nM or less, 5 nM or less, or 2 nM or less. In some embodiments, the antibody inhibits one or more of IL-la, IL-ip, IL-36a, IL-36P and IL-36y stimulated release of IL-6 from human whole blood; optionally, wherein at an IL-6 concentration of about EC80 the antibody has an IC50 of 10 nM or less, 5 nM or less, or 2 nM or less.

[0061] The anti-IL-lRAP antibody or fragment thereof may inhibit IL-la, IL-ip, IL-36a, IL-36P and / or IL-36 y stimulated release of IL-8 in human whole blood. It may inhibit IL-la, IL-ip, IL-36a, IL- 36p and / or IL-36 y stimulated release of IL-6 in human whole blood. It may IL-la, IL-ip, IL-36a, IL-36P and / or IL-36 y stimulated release of MIP-1 in human whole blood.

[0062] The antibody may bind to amino acid residues within domain 2 of human IL-1RAP. The antibody may bind to amino acid residues within domain 3 of human IL-1RAP. It may cross-react with a cynomolgus monkey IL-1RAP polypeptide of SEQ ID NO: 3. In addition or alternatively the antibody may cross-react with a mouse IL-1RAP polypeptide of SEQ ID NO: 4.

[0063] The antibody may be a monoclonal antibody. It may be a human, humanized, or chimeric antibody. It may be a full-length antibody of class IgG, optionally, wherein the class IgG antibody has an isotype selected from IgGl, IgG2, IgG3, and IgG4.

[0064] In some embodiments the antibody of class IgG comprises a CL region having an amino acid sequence as set forth in SEQ ID NO: 127.

[0065] In some embodiments, the anti-IL-lRAP antibody comprises a human IgGl Fc region. In other embodiments, the anti-IL-lRAP antibody comprises a human IgG4 Fc region.

[0066] Human IgG Fc regions are disclosed in the art. The amino acid sequence of an exemplary human IgGl Fc region is set forth in SEQ ID NO: 24. The amino acid sequence of an exemplary human IgG4 Fc region is set forth in SEQ ID NO: 123.

[0067] In some embodiments, the anti-IL-lRAP antibody may be a variant of an antibody as disclosed herein. For example, antibodies with improved binding affinity and / or other biological properties of the antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into and / or substitutions of residues within the amino acid sequences of the antibody, amino acid substitution, insertion and / or deletion variants; glycosylation variants; Fc region variants; cysteine engineered variants; and derivatized variants.

[0068] Sites for mutagenesis can include the CDRs and FRs. Typical “conservative” amino acid substitutions and / or substitutions based on common side-chain class or properties are well-known in the art and can be used in the embodiments of the present disclosure. The present disclosure also contemplates variants based on non-conservative amino acid substitutions in which a member of one of amino acid side chain class is exchanged for an amino acid from another class.

[0069] Amino acid side chains are typically grouped according to the following classes or common properties: (1) hydrophobic: Met, Ala, Vai, Leu, He, Norleucine; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) chain orientation influencing: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.

[0070] Techniques are well-known in the art for amino acid substitution into an antibody and subsequent screening for desired function, e.g., retained / improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.

[0071] Amino acid substitution variants can include substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have modifications in certain biological properties (e.g., increased affinity, reduced immunogenicity) relative to the parent antibody and / or will have substantially retained certain biological properties of the parent antibody. An exemplary substitutional variant is an affinity matured antibody, which may be conveniently generated, e.g., using phage display-based affinity maturation techniques. The antibody may comprise a variant Fc region, optionally a variant Fc region that alters effector function (e.g., a variant resulting in an increase or decrease of effector function), a variant Fc region that exhibits decreased CDC activity, ADCC activity, and / or ADCP activity, a variant Fc region that exhibits decreased cytotoxic activity on human monocytes, neutrophils, and / or Jurkat cells, or a variant Fc region the alters antibody half-life.

[0072] The antibody or antigen-binding fragment thereof may comprise a human Fc region sequence, said sequence comprising a modification of the human wildtype sequence to reduce Fc receptor binding (optionally the L234A / L235A (LALA) modification in a IgGl Fc region, or the S228P / F234A / L235A (P-FALA) modification in a IgG4 Fc region). In some embodiments, the anti-IL-lRAP antibody comprises a Fc region comprising the amino acid sequence selected from SEQ ID NO: 22, SEQ ID NO: 23 or SEQ ID NO: 124.

[0073] Other modifications of the human Fc wildtype sequence to increase serum half-life (optionally the M252Y / S254T / T256E (YTE) modification or M428L / N434S (LS) modifications) are also considered within the scope of this invention. In some embodiments, the anti-IL-lRAP antibody comprises a Fc region comprising the amino acid sequence of SEQ ID NO: 125 or 126.

[0074] In other embodiments, the Fc region comprises modifications to reduce Fc receptor binding and modifications to increase serum half-life. In some embodiments, the anti-IL-lRAP antibody comprises a Fc region comprising the amino acid sequence of SEQ ID NO: 128 or 129.

[0075] The antibody may be an immunoconjugate, optionally, wherein the immunoconjugate comprises a therapeutic agent for treatment of an IL- 1 RAP-mediated disease or condition (preferably HS).

[0076] The antibody may be a multi-specific antibody, optionally a bispecific antibody. It may be a synthetic antibody, wherein the CDRs are grafted onto a scaffold or framework other than an immunoglobulin scaffold or framework; optionally, a scaffold selected from an alternative protein scaffold and an artificial polymer scaffold.

[0077] Suitable anti-IL-lRAP antibodies are available commercially. Suitable anti-IL-lRAP antibodies are also disclosed in the art, and include, for example, the antibodies described in W02024062074, WO2024231251, W02024011189, WO2022243536, W02022170008, WO2022053715, WO2022136569, W02021030484, W02020261097, W02020037154, W02019028190, WO2018231827, WO2018206565, WO2017191325, W02016020502, W02016207304, W02018071910 or WO2015132602, which are hereby incorporated by reference. Not limiting examples of available anti-IL-lRAP antibodies are SAR445399, LEO-158968, 3G5, BFB-759, BI-5041, VH5.GL VL4, GSK3903371A, hllC5, CAN01, CAN03, CAN10, CAN04 or nadunolimab, hum54.9D7 or ISB88O.

[0078] In some embodiments, the anti-IL-lRAP antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 109 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 110. In some embodiments, the anti-IL- 1RAP antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 111 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 112. In some embodiments, the anti- IL- 1RAP antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 113 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 114. In some embodiments, the anti-IL- 1RAP antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 115 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 116.

[0079] In some preferred embodiments, the anti-IL- 1 RAP antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 19 or 20 and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 17.

[0080] In some preferred embodiments, the anti-IL- 1 RAP antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 20 and / or a light chain comprising the amino acid sequence set forth in SEQ ID NO: 17.

[0081] In some embodiments, the IL-1RAP inhibitor may be a fragment of an antibody as disclosed herein. Antibody fragments useful for the invention include Fab, Fab'. Fab'-SH, F(ab')2, Fv, and scFv fragments. In some embodiments, the antibody fragment is a single-domain antibody which comprise all or a portion of the heavy chain variable region or all or a portion of the light chain variable region of an antibody as disclosed herein.

[0082] The inhibitor may be a small molecule. Means for preparing such inhibitors will be known to a skilled person and are described for example in Sarabu et al. (Drug Des Discov. 1998 May;15(3):191-8.).

[0083] Pharmaceutical compositions, uses and methods of treatment

[0084] The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the inhibitor as described herein. The pharmaceutical composition will further comprise a pharmaceutically acceptable excipient(s), carrier(s) or vehicle(s).

[0085] The diluent or carrier will be a physiologically / pharmaceutically acceptable diluent or carrier which refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound. A pharmaceutically acceptable excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of a compound.

[0086] Pharmaceutical compositions suitable for the delivery of inhibitors of the invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001.

[0087] The pharmaceutically acceptable diluents or carriers which are admixed with the inhibitor, for example the antibody, to form the compositions of this invention are well-known per se and the actual diluents or carriers used depend inter alia on the intended method of administering the compositions. Examples include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additional suitable carriers for formulations of the compounds of the present invention can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, Philadelphia, Pa., 2001.

[0088] The compositions for use in the context of the invention may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends on the intended mode of administration and therapeutic application. Typical preferred compositions are in the form of injectable or infusible solutions, such as compositions like those used for passive immunization of humans with other antibodies or other IL- 1 RAP inhibitors.

[0089] A pharmaceutical composition according to the invention is preferably administered parenterally. For example, it may be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques. In a most preferred embodiment, the pharmaceutical composition is administered intravenously.

[0090] Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

[0091] The pharmaceutical compositions of the invention may be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free injection.

[0092] The pharmaceutical composition of the invention can be administered by inhalation, typically in the form of a dry powder from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer, or nebulizer, with or without the use of a suitable propellant. For intranasal use, the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.

[0093] The pharmaceutical compositions of the invention may be administered via the nasal mucosa. Typical compositions for nasal mucosa administration are typically applied by a metering, atomizing spray pump and are in the form of a solution or suspension in an inert vehicle such as water optionally in combination with conventional excipients such as buffers, anti-microbials, tonicity modifying agents and viscosity modifying agents.

[0094] A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the antibody, antibody fragment, or other IL- 1 RAP inhibitor may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody, antibody fragment, other IL-1RAP inhibitor to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody, antibody fragment, or other IL- 1 RAP inhibitor are outweighed by the therapeutically beneficial effects.

[0095] The pharmaceutical composition may be administered to a patient once or over a series of treatments. Various dosing schedules include but are not limited to single or multiple administrations (e.g. multiple administration over various time-points), bolus administration, and pulse infusion are contemplated herein.

[0096] The dosage of the antibody in the composition can depend on the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, the previous therapy administered to the patient, the patient's clinical history and response to the antibody, and the discretion of the attending physician.

[0097] Depending on the type and severity of the disease, about 1 pg / kg to 15 mg / kg of anti-IL-lRAP antibody in a formulation of the present disclosure is an initial candidate dosage for administration to a human subject, whether, for example, by one or more separate administrations, or by continuous infusion. Generally, the administered dosage of the antibody would be in the range from about 0.05 mg / kg to about 10 mg / kg. In some embodiments, one or more doses of about 0.5 mg / kg, 2.0 mg / kg, 4.0 mg / kg or 10 mg / kg (or any combination thereof) may be administered to a patient.

[0098] Dosage administration can be maintained over several days or longer, for example, administration can continue until the disease is sufficiently treated, as determined by methods known in the art. In some embodiments, an initial higher loading dose may be administered, followed by one or more lower doses. However, other dosage regimens may be useful. The progress of the therapeutic effect of dosage administration can be monitored by conventional techniques and assays.

[0099] Accordingly, the administration of the anti-IL-lRAP antibody may comprise a daily dosage from about 1 mg / kg to about 100 mg / kg. In some embodiments, the dosage of anti-IL-lRAP antibody comprises a daily dosage of at least about 1 mg / kg, at least about 5 mg / kg, at least about 10 mg / kg, at least about 20 mg / kg, or at least about 30 mg / kg.

[0100] The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages or may be suitable for two or more administrations.

[0101] The anti-IL-lRAP inhibitor (for example the anti-IL-lRAP antibody) may be the only active ingredient in the pharmaceutical composition. The pharmaceutical composition may also comprise one or more additional active ingredients.

[0102] In some embodiments, the anti-IL-lRAP inhibitor may be given in combination with at least one or more further active agents.

[0103] The term "combination" as in the phrase "IL-1RAP inhibitor is administrated in combination with one or more further active agents" includes concomitant administration (co-administration) of a first agent (IL-1RAP inhibitor) and one or more further agents, which for example may be dissolved or intermixed in the same pharmaceutically acceptable carrier, or administration of IL- 1RAP inhibitor, as a first agent, followed by the second agent(s), or administration of the second agents, followed by the first agent. The present invention, therefore, includes methods of combination therapeutic treatment and combination pharmaceutical compositions.

[0104] In some embodiments, the IL-1RAP inhibitor and the one or more active agent are administered separately, consecutively, or simultaneously.

[0105] In some embodiments, the one or more active agent are selected from the group comprising antiseptic and antiperspirant agents, tetracycline, intralesional triamcinolone, finasteride, methotrexate, cyclosporin, FK506, rapamycin, mycophenolate, mofetil, leflunomide, NSAIDs, corticosteroids, phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signaling by proinflammatory cytokines, IL-ip converting enzyme inhibitors, TNF-a converting enzyme inhibitors, T-cell signaling inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6- mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors, and antiinflammatory cytokines (e.g., IL-4, IL-10, IL-12, IL-13, TGFP).

[0106] For example, adalimumab (a fully humanized monoclonal antibody that targets soluble and transmembrane TNF-alpha) or secukinumab (a fully human monoclonal antibody that targets IL- 17 A) or bimekizumab (a humanized monoclonal antibody that targets IL- 17 A and IL-17F) are indicated for the treatment of HS. In some embodiments the composition may be administered in combination with an anti-TNF-alpha antibody, preferably adalimumab, or an anti-IL-17A antibody, preferably secukinumab or bimekizumab.

[0107] In some embodiments, the IL- 1 RAP inhibitors as defined herewith, optionally in combination with the one or more active agents, are administered by parenteral route.

[0108] In some embodiments, the pharmaceutical compositions comprising the IL-1RAP inhibitors, the one or more pharmaceutically acceptable carrier, excipient or vehicle, and in optionally in combination with the one or more active agents, are administered by parenteral route. In some preferred embodiments, the pharmaceutical compositions are administered by subcutaneous route.

[0109] Hidradenitis suppurativa (HS)

[0110] The inhibitors and compositions according to the invention are for use in treating or preventing Hidradenitis Suppurativa.

[0111] The terms “treat”, "treatment" or “treating”, as used within the context of the present invention is meant to include therapeutic treatment, as well as prophylactic or suppressive measures, for the treatment of HS. The term "treatment" as used herein may mean a complete regression where no symptoms are visible. It may also mean a reduction in symptoms, for example an improvement in disease severity as measured, for example, by the Hurley Staging System. For example, the terms “treat”, “treating” or “treatment” may include administration of an IL-1RAP inhibitor prior to or following the onset of HS thereby preventing or removing signs of the disease or disorder. As another example, administration of an IL- 1 RAP inhibitor after clinical manifestation of HS to combat the symptoms and / or complications and disorders associated with HS may be included in the definition of "treatment" of the disease. Further, administration of the agent after onset and after clinical symptoms and / or complications have developed where administration affects clinical parameters of the disease or disorder and perhaps amelioration of the disease, may also be included in the definition of "treatment" of the HS.

[0112] The terms “prevent”, “prevention” or “preventing”, as used within the context of the present invention refers to prophylactic treatment of a patient to prevent the development of symptoms, to pre-emptively reduce the severity of symptoms or to prevent disease progression to more severe stages of the disease.

[0113] The terms "disease", "disorder" and "condition" may be used herein interchangeably, unless the context clearly dictates otherwise.

[0114] Treatment success can be assessed using any of the classification systems mentioned below.

[0115] HS can be described as mild, moderate or severe using the Hurley Staging System, wherein Stage 1 (mild) typically presents as inflammatory nodule or abscess formation, single or multiple, without sinus tracts and scarring; Stage 2 (moderate) typically presents as recurrent abscesses and nodules with sinus tract formation or scarring: single or multiple widely separated lesions; and Stage 3 (severe) typically presents as diffuse or near-diffuse involvement with multiple interconnected sinus tracts, scarring, and abscesses across entire area. See, e.g., Jemec GBE. Hidradenitis suppurativa. N Engl J Med. 2012;366(2):158-164.

[0116] Hurley staging is the most common system used in clinical trials for classification of severity. Similarly, Hidradenitis Suppurativa Clinical Response (HiSCR) is the most used system to evaluate therapeutic outcomes in patients with hidradenitis suppurativa during clinical trials. The HiSCR evaluation includes the objective counting of HS lesions. Thus, the HiSCR is generally defined as at least a 50% reduction in the abscesses and nodules (AN) count with no increase in abscess count and no increase in draining fistula count relative to baseline (HiSCR50). The threshold of 50% reduction in AN count is the defined level that is clinically appropriate and meaningful to the patient regarding improvement in quality of life and pain level (Kimball, 2014; Giamarellos-Bourboulis, 2008). HiSCR is a valid and meaningful endpoint for assessing HS treatment effectiveness in controlling inflammatory manifestations in patients with HS with >3 ANs (Kimball, 2014).

[0117] HiSCR can also refer to at least a 75% reduction in the abscesses and nodules (AN) count with no increase in abscess count and no increase in draining fistula count relative to baseline. Thus, HiSCR75 is becoming a relevant endpoint and has already been used in several clinical studies for assessing HS treatment effectiveness.

[0118] Other severity assessment tools are emerging, such as the International Hidradenitis Suppurativa Severity Score (IHS4). IHS4 is a validated tool that dynamically assesses HS severity and can also be used in the clinical trials setting (Zouboulis, et al., Development and validation of IHS4, a novel dynamic scoring system to assess hidradenitis suppurativa / acne inversa severity. Br J Dermatol 2017;177:1401-1409). The IHS4 score is determined by the number of nodules (multiplied by 1) plus the number of abscesses (multiplied by 2) plus the number of draining tunnels (multiplied by 4). A total score of 3 or less signifies mild, 4-10 signifies moderate and 11 or higher signifies severe disease.

[0119] Therefore, both HiSCR and IHS4 scores can be used as meaningful endpoints for assessing HS treatment effectiveness.

[0120] The term “AN count” is often directed to the total abscess and inflammatory nodule counts.

[0121] HS is associated with painful, deep-seated, inflamed lesions. Pain is experienced by the majority of HS patients and is greater than that associated with other skin diseases, such as eczema, psoriasis, skin tumours, and acne (Tsentemeidou 2022). Skin Pain NRS is an 11-point scale in which patients are asked to rate their skin pain over the prior 24 hours, where 0 is no skin pain and 10 is pain as bad as you can imagine (Kimball 2024, Sil verberg 2024). As example, Skin Pain NRS 30 / 50 means at least a 30% to 50% reduction from baseline in skin pain NRS.

[0122] In addition to HiSCR and IHS4 scores, total AN count and NRS can also be used as endpoints for assessing HS treatment effectiveness. Hidradenitis Suppurativa Quality of Life Score (HiS-QOL) is an HS-specific health-related quality of life instrument for which there is strong evidence for validity and reliability in assessing patient-centered outcomes in clinical trials (Kirby, Br J Dermatol. 2020 Aug;183(2):340-348). The HiSQOL has 17-items, including 4 symptom items, 5 psychosocial items, and 8 activity- adaptation items, and has a 7-day recall period. The item scores are summed to create a total ranging from 0 to 68, with higher scores indicating more severe impact on health-related quality of life. The sub-scale scores range from 0 to 16 for symptoms, 0 to 20 for psychosocial, and 0 to 32 for activities-adaptations.

[0123] The invention typically results into a clinical response in the treated patient. The clinical response can be assessed by measuring an improvement according to a single classification system, for example improvement in Hurley staging or HiSCR. In some embodiments, the clinical response is assessed by measuring an improvement according to HiSCR50, HiSCR75 or IHS4. Preferably, the clinical response is assessed by improvement of two or more classification systems. Thus, in some embodiments, the patient shows improvements according to HiSCR (either HiSCR50, HiSCR75 or both) and IHS4.

[0124] In some embodiments, the present invention provides an IL- 1RAP inhibitor for use in the treatment of HS, more particularly for the treatment of a subject wherein the HS before the treatment is moderate-to- severe HS, e.g., Hurley Stage 2 (moderate) HS or Hurley Stage 3 (severe) HS.

[0125] In some embodiments, the HS patient before the treatment is characterized by lesions displaying or associated with NETosis, anti-histone antibodies, and / or activated macrophages.

[0126] In some embodiments, the HS severity in the patient after the treatment is improved by at least one Hurley Stage, e.g., severe to moderate, mild, or normal, or moderate to mild or normal.

[0127] In some embodiments, after the treatment, the subject experiences an improvement in one or more of (i) frequency of HS flare-ups and associated pain; (ii) psychosocial impact of HS, e.g., social life or ability to work; or (iii) restriction in range of motion due to HS.

[0128] In some embodiments, the present invention provides an IL- 1 RAP inhibitor for use in the treatment of HS, wherein a therapeutically effective amount of the anti-IL-lRAP inhibitor is administered to a patient in need thereof, and wherein said administration reduces the severity of HS in the patient. In some embodiments, the severity of HS in the patient after the treatment is assessed by one or more of Hurley Staging, HiSCR, IHS4, total AN count, draining fistula count, NRS and HiSQOL. In some preferred embodiments, the severity is assessed by IHS4 and total AN count. In some preferred embodiments, the severity is assessed by IHS4 and draining fistula count. In some preferred embodiments, the severity is assessed by IHS4, total AN count, and draining fistula count.

[0129] In some embodiments, the severity of HS in the patient after the treatment, when assessed by using Hurley Staging, HiSCR and / or IHS4, is reduced by at least 30%, by at least 40%, by at least 50%, by at least 60%, by at least 70% or by at least 80%.

[0130] HiSCR, IHS4, total AN count, draining fistula count, NRS and / or HiSQOL can also be used to assess the clinical response of a HS patient treated with the IL-1RAP inhibitor of the present invention.

[0131] The invention further provides the following embodiments:

[0132] In some embodiments, the invention provides a method for treating or preventing Hidradenitis Suppurativa, the method comprising administering an IL-1RAP inhibitor. In some embodiments, the IL- 1 RAP inhibitor is a small molecule, a receptor antagonist, an antibody or an antigen-binding fragment thereof. In some preferred embodiments, the IL-1RAP inhibitor is an antibody or an antigen-binding fragment thereof.

[0133] In some embodiments of the methods of the present invention, the IL- 1 RAP antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising a first CDR (CDR Hl), a second CDR (CDR- H2), and a third CDR (CDR-H3), wherein: CDR-H1 comprises an amino acid sequence selected from SEQ ID NOs: 5, 6 and 120; CDR-H2 comprises an amino acid sequence selected from SEQ ID NOs: 7, 8 and 121; CDR-H3 comprises an amino acid sequence selected from SEQ ID NOs: 9 to 14 and 122; and / or b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15.

[0134] In other embodiments, CDR-H1 comprises SEQ ID NO: 5, CDR H2 comprises SEQ ID NO: 7 and CDR-H3 comprises SEQ ID NO: 9. In some embodiments, the IL-1RAP antibody or the antigen-binding fragment thereof comprises:

[0135] (a) a heavy chain variable region having an amino acid sequence with an identity of at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 99% with respect to SEQ ID NO: 16 or 25 to 79, and / or

[0136] (b) a light chain variable region having an amino acid sequence with an identity of at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 99% with respect to SEQ ID NO: 15.

[0137] In some embodiments, the IL-1RAP antibody or the antigen-binding fragment thereof comprises heavy and light chain variable regions having respectively an amino acid sequence with an identity of at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 99% with respect to SEQ ID NO: 16 and SEQ ID NO: 15, or SEQ ID NO: 80 and SEQ ID NO: 81, or SEQ ID NO: 82 and SEQ ID NO: 83, or SEQ ID NO: 84 and SEQ ID NO: 83, or SEQ ID NO: 85 and SEQ ID NO: 86, or SEQ ID NO: 87 and SEQ ID NO: 88, or SEQ ID NO: 89 and SEQ ID NO: 90, or SEQ ID NO: 91 and SEQ ID NO: 92, or SEQ ID NO: 93 and SEQ ID NO: 94, or SEQ ID NO: 95 and SEQ ID NO: 96, or SEQ ID NO: 97 and SEQ ID NO: 98, or SEQ ID NO: 99 and SEQ ID NO: 100, or SEQ ID NO: 101 and SEQ ID NO: 102, or SEQ ID NO: 103 and SEQ ID NO: 104, or SEQ ID NO: 105 and SEQ ID NO: 106, or SEQ ID NO: 107 and SEQ ID NO: 108.

[0138] In some embodiments, the IL-1RAP antibody or the antigen-binding fragment thereof comprises heavy and light chain variable regions having, respectively, the amino acid sequence of SEQ ID NO: 16 and SEQ ID NO: 15, or SEQ ID NO: 80 and SEQ ID NO: 81, or SEQ ID NO: 82 and SEQ ID NO: 83, or SEQ ID NO: 84 and SEQ ID NO: 83, or SEQ ID NO: 85 and SEQ ID NO: 86, or SEQ ID NO: 87 and SEQ ID NO: 88, or SEQ ID NO: 89 and SEQ ID NO: 90, or SEQ ID NO: 91 and SEQ ID NO: 92, or SEQ ID NO: 93 and SEQ ID NO: 94, or SEQ ID NO: 95 and SEQ ID NO: 96, or SEQ ID NO: 97 and SEQ ID NO: 98, or SEQ ID NO: 99 and SEQ ID NO: 100, or SEQ ID NO: 101 and SEQ ID NO: 102, or SEQ ID NO: 103 and SEQ ID NO: 104, or SEQ ID NO: 105 and SEQ ID NO: 106, or SEQ ID NO: 107 and SEQ ID NO: 108.

[0139] In some preferred embodiments, the IL- 1 RAP antibody or the antigen-binding fragment thereof of the methods of the present invention comprises (a) a heavy chain variable region having the amino acid sequence of SEQ ID NO: 16 and (b) a light chain variable region having the amino acid sequence of SEQ ID NO: 15.

[0140] In some preferred embodiments, the IL-1RAP antibody comprising a IgG Fc region, optionally, wherein the IgG Fc region is selected from IgGl, IgG2, IgG3, and IgG4. In some preferred embodiments, the Fc region comprises the E234A / E235A (EAEA) modification.

[0141] In some preferred embodiments, the IE-1RAP antibody is a humanized antibody.

[0142] The present invention provides a method for treating or preventing Hidradenitis Suppurativa as described herein, wherein the IE-1RAP inhibitor is administered in the form of a pharmaceutical composition, comprising one or more pharmaceutically acceptable excipient(s), carrier(s) or vehicle(s).

[0143] The present invention provides a method for treating or preventing Hidradenitis Suppurativa as described herein, wherein the IE- 1 RAP inhibitor is administered in combination with at least one or more active agent. In some preferred embodiments, the one or more active agent are administered separately, consecutively, or simultaneously.

[0144] The present invention provides a method for treating or preventing Hidradenitis Suppurativa as described herein, wherein i) the IE- 1 RAP inhibitor, optionally in combination with the one or more active agents, or a pharmaceutical composition comprising the IL-1RAP inhibitor, ii) the one or more pharmaceutically acceptable carrier, excipient or vehicle, and iii) optionally the one or more active agents is administered by parenteral route.

[0145] The present invention provides a method for treating or preventing Hidradenitis Suppurativa as described herein, wherein a therapeutically effective amount of the anti-IL-lRAP inhibitor is administered to a patient in need thereof, and wherein said administration reduces the severity of HS in the patient. In some preferred embodiments, the severity of HS in the patient is assessed by Hurley Staging, HiSCR, IHS4, total AN count, draining fistula count, NRS and / or HiSQOL.

[0146] Other

[0147] It is to be understood that the different embodiments disclosed may be tailored to the specific needs in the art. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to be limiting.

[0148] The singular forms “a”, “an”, and “the” include plural references unless the content clearly dictates otherwise.

[0149] The term “about” shall generally mean an acceptable degree of error or variation for the quantity measured given the nature or precision of the measurements. Typical, exemplary degrees of error or variation are within 5 percent or within 3 percent or within 1 percent of a given value or range of values. For example, the expression of "about 100" includes 105 and 95 or 103 and 97 or 101 and 99, and all values in between (e.g., 95.1, 95.2, etc. for range of 95-105; or 97.1, 97.2, etc. for the range of 97-103; 99.1, 99.2, etc. for the range of 99- 101). Numerical quantities given herein are approximates, unless stated otherwise, meaning that the term "about" can be inferred when not expressly stated.

[0150] For the purposes of the present invention, any ranges given include both the lower and the upper end-points of the range.

[0151] Furthermore, when referring to “>r” herein, this means equal to or greater than x. When referred to “<x” herein, this means less than or equal to x.

[0152] For the purpose of this invention, in order to determine the percent identity of two sequences (such as two polynucleotide or two polypeptide sequences), the sequences are aligned for optimal comparison purposes (e.g. gaps can be introduced in a first sequence for optimal alignment with a second sequence). The nucleotide or amino acid residues at each position are then compared. When a position in the first sequence is occupied by the same nucleotide or amino acid as the corresponding position in the second sequence, then the nucleotides or amino acids are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions / total number of positions in the reference sequence x 100).

[0153] Typically the sequence comparison is carried out over the length of the reference sequence. For example, if the user wished to determine whether a given (“test”) sequence is 95% identical to SEQ ID NO: 1, SEQ ID NO: 1 would be the reference sequence. To assess whether a sequence is at least 95% identical to SEQ ID NO: 1 (an example of a reference sequence), the skilled person would carry out an alignment over the length of SEQ ID NO: 1, and identify how many positions in the test sequence were identical to those of SEQ ID NO: 1. If at least 95% of the positions are identical, the test sequence is at least 95% identical to SEQ ID NO: 1. If the sequence is shorter than SEQ ID NO: 1, the gaps or missing positions should be considered to be non-identical positions.

[0154] The skilled person is aware of different computer programs that are available to determine the homology or identity between two sequences. For instance, a comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. A number of mathematical algorithms for rapidly obtaining the optimal alignment and calculating identity between two or more sequences are known and incorporated into a number of available software programs. Examples of such programs include the MATCHBOX, MULTAIN, GCG, FASTA, and ROBUST programs for amino acid sequence analysis, among others. Preferred software analysis programs include the ALIGN, CLUSTAL W, and BLAST programs (e.g., BLAST 2.1, BL2SEQ, and later versions thereof).

[0155] For amino acid sequence analysis, a weight matrix, such as the BLOSUM matrixes (e.g., the BLOSUM45, BLQSUM50, BLOSUM62, and BLQSUM80 matrixes), Gonnet matrixes, or PAM matrixes (e.g., the PAM30, PAM70, PAM120, PAM 160, PAM250, and PAM350 matrixes), are used in determining identity.

[0156] The BLAST programs provide analysis of at least two amino acid sequences, either by aligning a selected sequence against multiple sequences in a database (e.g., GenSeq), or, with BL2SEQ, between two selected sequences. BLAST programs are preferably modified by low complexity filtering programs such as the DUST or SEG programs, which are preferably integrated into the BLAST program operations. If gap existence costs (or gap scores) are used, the gap existence cost preferably is set between about -5 and - 15. Similar gap parameters can be used with other programs as appropriate. The BLAST programs and principles underlying them are further described in, e.g., Altschul et al., "Basic local alignment search tool”, 1990, J. Mol. Biol, v. 215, pages 403-410.

[0157] For multiple sequence analysis, the CLUSTAL W program can be used. The CLUSTAL W program desirably is run using "dynamic" (versus "fast") settings. Amino acid sequences are evaluated using a variable set of BLOSUM matrixes depending on the level of identity between the sequences. The CLUSTAL W program and underlying principles of operation are further described in, e.g., Higgins et al., "CLUSTAL V: improved software for multiple sequence alignment”, 1992, CABIOS, 8(2), pages 189-191.

[0158] In an embodiment, the percent identity between two amino acid or nucleic acid sequences is determined using the Needleman and Wunsch (1970) algorithm which has been incorporated into the GAP program in the Accelrys GCG software package (available at http: / / www.accelrys.com / products / gcg / ), using either a Blosum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

[0159] The following examples illustrate the invention.

[0160] EXAMPLES

[0161] Example 1

[0162] Samples from three HS patients were obtained and treated ex vivo with an anti-IL-lRAP antibody. The lesional skin samples were obtained from HS patients with chronic, active disease (Hurley stage II or III).

[0163] The day after surgery, 4 mm punch biopsies of the samples were placed in punched-out holes in a transwell membrane of a 12-well plate with the epidermis exposed to air and the dermis immersed in culture media. Subsequently, the skin biopsies were cultured for 24 h at 37°C 5% CO2 atmosphere in the presence of an anti-IL-lRAP antibody at 200 nM or Isotype control.

[0164] The anti-IL- 1RAP antibody used is described in WO2022053715 and corresponds to a fully human monoclonal anti-IL- 1 RAP antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 20 and a light chain having the amino acid of SEQ ID NO: 17.

[0165] Targeted gene expression analysis in skin homogenates for disease-related pro-inflammatory cytokines was conducted, using an 24-gene array card (Applied Biosystems TaqMan Array Card) including genes [IL-8 / CXCL-8, DEFB4B, IFN-a, IFN-p, IFN-y, IE- 10, IE- 12, TNF-a, IL-17A, IL-17F, IL-18, IL-19, IL- lb, IL-22, IL-23, IL-32, IL-36a, IL-36y, IL-6, S100A7, S100A8, S100A9 and ; housekeeping genes: GAPDH and a-actin], following manufacturer’s instructions. Results are represented as fold change of gene expression of each marker upon treatment with the IL- 1RAP antibody relative to the isotype control. (Fig. 1). Ex vivo treatment of HS lesional skin samples with the IL-1RAP antibody led to a significant downregulation of a broad range of disease-related pro-inflammatory cytokines, chemokines and anti-microbial peptides including IL-17A, IL-17F, TNF-a, IFN-g, IL-6; IL-8, IL-10, IL-36a, IL- 367 or S100A7 / 8.

[0166] Overall, treatment with the anti-IL-lRAP antibody led to a broad amelioration of inflammation in HS skin explant supporting the suitability of an IL- 1 RAP inhibitor in the management of HS.

[0167] Example 2

[0168] The safety, tolerability, pharmacokinetics, immunogenicity and pharmacodynamics of an anti- IL-1RAP antibody was assessed in healthy subjects and in subjects with HS.

[0169] The exemplary anti-IL-lRAP antibody used in this study is disclosed in WO2022053715, and corresponds to a fully human monoclonal anti-IL- 1RAP antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 20 and a light chain having the amino acid of SEQ ID NO: 17.

[0170] The study was conducted in three parts: i) Part 1, in which healthy volunteers received single ascending doses (SAD) of the IL-1RAP antibody; ii) Part 2, in which healthy volunteers received multiple ascending doses (MAD) of the IL-1RAP antibody; and iii) Part 3, in which HS patients received repeating doses of the IL-1RAP antibody.

[0171] Screening:

[0172] The inclusion criteria for healthy subjects included the following: male or female aged 18 to 65 years, with a body mass index (BMI) within the range of 18.5 to 29.9 kg / m2 and body weight of >50 kg. The inclusion criteria for HS patients included the following: Male or female aged 18 to 65, with a BMI within the range 18.5 to 34.9 kg / m2, and body weight of >50 kg; current diagnosis of HS with signs and symptoms consistent with HS for at least 3 months; HS lesions must be present in at least two distinct anatomic areas and at least one of which must be at least Hurley Stage II or III on evaluation at Screening, a total AN count of >5 at Screening and an inadequate response to an appropriate trial of antibiotics.

[0173] The main exclusion criteria for healthy subjects and HS patients included the following: Previous treatment with the IL-1RAP antibody of the invention.

[0174] Known hypersensitivity to the IL- 1 RAP antibody or any of its excipients.

[0175] Hypersensitivity or reaction to a prior biologic therapy, that was clinically significant.

[0176] History of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, inflammatory, or allergic disease (including drug allergies, any active seizure disorder requiring therapy with antiepileptic drugs, active peptic ulcer disease, gastrointestinal bleeding, chronic gastritis, inflammatory bowel disease or chronic diarrhea, but excluding mild seasonal allergies or stable, well-controlled thyroiditis). Note that subjects with thyroid hormone deficiency, hypertension, hyperlipidemia, or diabetes mellitus may be included in Part 3 of the study.

[0177] Active chronic or acute infection requiring treatment with systemic antimicrobials, antivirals, antiparasitics, antiprotozoals, or antifungals.

[0178] A positive test for SARS CoV-2.

[0179] Presence of skin comorbidities that may interfere with study assessments.

[0180] Subject has current tuberculosis (TB) or any history of active or latent TB, regardless of prior treatment.

[0181] History of malignancy (other than successfully treated basal cell or squamous cell carcinoma of the skin), regardless of outcome.

[0182] Clinically significant ECG abnormality.

[0183] Known history of liver disease or clinically significant abnormal liver function.

[0184] Impaired renal function.

[0185] Congenital or acquired immunosuppressive condition that would put subject at risk during the study.

[0186] Neutropenia.

[0187] Subject is pregnant or breastfeeding.

[0188] In addition, the following exclusion criteria were also considered for HS patients:

[0189] HS with > 20 draining fistulas at Screening.

[0190] Concurrent use of the following medications / treatments: anti-TNFa agents.

[0191] Systemic immunosuppressants / immunomodulators or other systemic treatments for HS. Phototherapy within 28 days prior to Day - 1. Systemic antivirals or antifungals within 28 days prior to Day - 1 , or systemic antibiotics within 28 days prior to Day -1 (with some exceptions).

[0192] Oral analgesics including opioids within 14 days prior to Day -1.

[0193] Topical treatments for HS within 14 days prior to Day -1.

[0194] Prescription and OTC medications other than those used for the treatment of HS within 14 days or 5 half-lives (whichever is longer) before Day -1, except for hormonal contraceptives, thyroid replacement medications.

[0195] Subject has had surgical intervention for the treatment of HS within 3 months prior to Day - 1, except that incision and draining of abscesses is permitted up to 1 week before Day -1.

[0196] Subjects has any other active skin disease or condition that could interfere with the assessment of HS.

[0197] Subject smokes >10 cigarettes per day.

[0198] Day -1 corresponds to the day previous to the first dosing with the I1-1RAP antibody.

[0199] Objectives

[0200] The primary objective of Parts 1 and 2 of this trial was to evaluate the safety and tolerability of single or repeated doses of the IL-1RAP antibody administered subcutaneously to healthy adult subjects.

[0201] Secondary objectives of Parts 1 and 2 were to assess the serum PK of free IL-1RAP antibody and to assess the immunogenicity of the IL-1RAP antibody (i.e. formation of anti-drug antibodies [ADA] to the IL- 1 RAP antibody).

[0202] Exploratory objectives of Parts 1 and 2 were to assess the effect of IL-1RAP antibody on soluble IL-1RAP (sIL-lRAP) levels in serum and to assess the effect of IL-1RAP antibody on cytokine and chemokine production in ex vivo stimulated whole blood.

[0203] For Part 3, the primary objective was also to evaluate the safety and tolerability of repeated doses of the IL-1RAP antibody administered subcutaneously to HS patients. Similarly, the secondary objectives were to assess the serum PK of free IL-1RAP antibody and to assess the immunogenicity of the IL- 1 RAP antibody. Exploratory objectives in Part 3 included the same exploratory objectives as described for Part 1, plus the following additional objectives: To assess clinical response in subjects with HS; to assess the effect of the IL-1RAP antibody on plasma / serum biomarkers in subjects with HS and to assess the effect of the IL- 1 RAP antibody on skin biomarkers in patients with HS.

[0204] The safety assessments for the study are accepted measures for ensuring safety of subjects during a clinical trial. Vital signs, physical examinations, 12-lead electrocardiograms (ECGs), and clinical laboratory parameters were assessed throughout the study.

[0205] The PK sampling schedule was considered appropriate given the information available. The collection of samples for PK analysis for up to 10 weeks after a single dose and for up to 8 weeks following the final administration in Parts 2 and 3 allowed characterization of the PK profile of the IL-1RAP antibody following SC dosing.

[0206] PD assessments (sIL-lRAP and ex vzvo-stimulated whole blood) were included to enable assessment of target engagement and proof of mechanism.

[0207] The clinical response assessments included total abscess and inflammatory count [total AN], Hidradenitis Suppurativa Clinical Response [HiSCR], Numerical Rating Scale for skin pain [NRS], International Hidradenitis Suppurativa Severity Score [IHS4]), draining fistulas count and Hidradenitis Suppurativa Quality of Life Score (HiSQOL), which are standard tools used for the assessment of the severity of the patient’s HS (abscesses, nodules, fistulas, etc) and its associated pain.

[0208] Study results

[0209] In part 1, a total of 40 healthy volunteers received single ascending doses (SAD) of the IL-1RAP antibody by subcutaneous injection. The study evaluated the safety and tolerability of the antibody based on the frequency and severity of adverse events (AEs), the number of subjects who had dose-limiting adverse reactions, and the changes from baseline in vital sign parameters, physical examination findings, ECGs, and clinical laboratory measures. The PK parameters of free antibody were also assessed, inter alia maximum serum concentration (Cmax), time to reach maximum serum concentration (tmax), area under the serum concentration-time curve (AUC) from zero to time of the last quantifiable concentration (AUCo-t) and from zero to infinity (AUCo-°o), elimination halflife (ti / 2), apparent clearance (CL / F), and apparent volume of distribution during terminal phase (Vd / F) as applicable. The number (percentage) of antidrug antibodies (ADA)-positive subjects and titer of ADA was also determined.

[0210] The effect of the antibody on cytokine and chemokine production in ex-vivo stimulated whole blood was also assessed. The serum concentration of free soluble IL-1RAP and fold-change from baseline, among other analyses, were also conducted.

[0211] In part 2, a total of 24 healthy volunteers received multiple ascending doses (MAD) of the IL-1RAP antibody by subcutaneous injection. The study evaluated the same parameters evaluated in part 1.

[0212] The antibody was tested on HS patients in part 3 of the study. In particular, the HS patients received repeated doses of the antibody by subcutaneous injection.

[0213] In addition to the parameters evaluated in part 1 and 2 in healthy volunteers, which were evaluated in HS patients in part 3, the clinical response to an anti-IL-lRAP antibody of HS patients was evaluated for the first time. To assess the clinical response in subject with HS, the proportion of subjects with HS who achieved a Hidradenitis Suppurativa Clinical Response (HiSCR) was evaluated, as well as the change from baseline in total abscess and inflammatory nodule count (AN count) and draining fistulas count. The proportion of subjects with HS who achieved at least a 30% reduction and at least a 1-unit reduction from baseline in the numeric rating scale for the Subject’s Global Assessment of Skin Pain (NRS30) was also measured. Other HS severity parameters were also used, such as the change from baseline in HS-associated skin pain, the change from baseline in International Hidradenitis Suppurativa Severity Score System (IHS4), or the change from baseline in Hidradenitis Suppurativa Quality of Life (HiSQOL), among others.

[0214] Lesion photography was also performed on patients at different timepoints.

[0215] Finally, the effect of the antibody on serum and skin biomarkers in subject with HS was also evaluated.

[0216] Single doses and multiple doses of the exemplary anti-IL-lRAP antibody were generally well tolerated in healthy adults. No serious adverse events (SAEs) were reported during Parts 1 and 2, and no participant discontinued treatment due to an adverse event (AE). In Parts 1 and 2, 22.5% and 29.2% of participants, respectively, reported 1 or more AE. Most AEs were mild in intensity, and no severe AEs were reported. Study drug-related AEs consisted of mild erythema at the injection site.

[0217] Decreased neutrophil counts were observed in both antibody-treated participants (23.3% and 50.0% of participants in the SAD and MAD cohorts, respectively) and the placebo group (10.0% and 33.3% of participants in the SAD and MAD cohorts, respectively). The decreases were not dose-dependent and resolved spontaneously. A decrease in neutrophils is consistent with the mechanism of action (MoA) of the IL-1RAP antibody. Among the antibody-treated participants who experienced neutropenia, neutrophil decrease was most marked with the first dose and thereafter showed a tendency toward recovery prior to the next administration. Most decreases were mild or moderate, with 1 participant in one of the MAD cohorts showing severe neutrophil decrease (0.5 to <1.0x109 cells / L) following the last dose.

[0218] The results of Parts 1 and 2 showed approximately linear PK for the doses used, with an apparent terminal half-life (P / z) of approximately 3 weeks. There was a low prevalence of anti-drug antibody (ADA), with 1 participant each in Parts 1 and 2 having low-titer, treatment-emergent ADA.

[0219] In summary, the use of the IL-1RAP antibody of the invention, demonstrated a favorable safety and tolerability profile in healthy volunteers, along with a low immunogenicity risk.

[0220] In part 3 of the study, three HS patients received multiple doses of the IL-1RAP antibody of the invention, and two HS patients were treated similarly with placebo. The baseline disease characteristics of the HS patients in part 3 are summarized in table 1.

[0221]

[0222] Table 1. Part 3 baseline disease characteristics

[0223] Multiple doses were generally well tolerated in HS patients. No serious adverse events (SAEs) were reported and no participant discontinued treatment due to an adverse event (AE). No patient (0%) in the IL- 1 RAP antibody treatment arm reported adverse events. Both the patients (100%) in placebo arm, reported 1 or more AE. 3 AEs were reported in 2 placebo patients. None of the AE was severe, or was considered related to the study treatment. No injection site reactions or hypersensitivity reactions were observed. Two HS patients exposed to the IL-1RAP antibody reached sporadic Grade 2 blood neutrophil count decrease (Figure 2).

[0224] The repeat doses of the IL-1RAP antibody in HS patients resulted in a similar apparent terminal half-life (E / z) to that observed in healthy volunteers. None of the patients developed ADA.

[0225] The total number of lesions, including abscesses, nodules and draining fistulas, in the patients treated with the IL-1RAP antibody, rapidly and sustainedly declined (Figures 3 to 5).

[0226] IHS4 score was measured at different time points of the treatment and compared to baseline. There was an important reduction in IHS4 in patients treated with IL-1RAP antibody compared to those treated with placebo (Figure 6).

[0227] It was observed that the administration of the IL- 1 RAP antibody provided a broad-spectrum effect in HS patients, reducing the amount of several pro -inflammatory cytokines, including Lipocain-2 and IL-6 (figure 7).

[0228] In summary, there was a positive signal of improvements in HS lesion count after the treatment with the IL- 1 RAP antibody. Worsening of HS was not reported in any of the IL- 1 RAP antibody exposed patient, whereas it was reported in both the placebo exposed patients.

[0229] Informal sequence listing

Claims

CLAIMS1. An IL- 1 RAP inhibitor for use in treating or preventing Hidradenitis Suppurativa.

2. The IL-1RAP inhibitor for use according to claim 1, wherein the IL-1RAP inhibitor is a small molecule, a receptor antagonist, an antibody or an antigen-binding fragment thereof.

3. The IL- 1 RAP inhibitor for use according to claim 1 or 2, wherein the IL- 1 RAP inhibitor is an antibody or an antigen-binding fragment thereof.

4. The IL-1RAP antibody or the antigen-binding fragment thereof, for use according to claim3, wherein the antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising a first CDR (CDR-H1), a second CDR (CDR-H2), and a third CDR (CDR-H3), wherein: CDR-H1 comprises an amino acid sequence selected from SEQ ID NOs: 5, 6 and 120; CDR-H2 comprises an amino acid sequence selected from SEQ ID NOs: 7, 8 and 121; CDR-H3 comprises an amino acid sequence selected from SEQ ID NOs: 9 to 14 and 122; and / or b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 15.

5. The IL- 1 RAP antibody or the antigen-binding fragment thereof for use according to claim4, wherein CDR-H1 comprises SEQ ID NO: 5, CDR-H2 comprises SEQ ID NO: 7 and CDR-H3 comprises SEQ ID NO: 9.

6. The IL- 1 RAP antibody or the antigen-binding fragment thereof for use according to any one of claims 3 to 5, wherein the IL- 1 RAP antibody or the antigen -binding fragment thereof comprises:(a) a heavy chain variable region having an amino acid sequence with an identity of at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 99% with respect to SEQ ID NO: 16 or 25 to 79, and / or(b) a light chain variable region having an amino acid sequence with an identity of at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 99% with respect to SEQ ID NO: 15.

7. The IL- 1 RAP antibody or the antigen-binding fragment thereof for use according to any one of claims 3 to 6, wherein the IL-1RAP antibody or the antigen-binding fragment thereof comprises:heavy and light chain variable regions having respectively an amino acid sequence with an identity of at least 80%, preferably at least 85%, preferably at least 90%, preferably at least 95%, preferably at least 99% with respect to SEQ ID NO: 16 and SEQ ID NO: 15, or SEQ ID NO: 80 and SEQ ID NO: 81, or SEQ ID NO: 82 and SEQ ID NO: 83, or SEQ ID NO: 84 and SEQ ID NO: 83, or SEQ ID NO: 85 and SEQ ID NO: 86, or SEQ ID NO: 87 and SEQ ID NO: 88, or SEQ ID NO: 89 and SEQ ID NO: 90, or SEQ ID NO: 91 and SEQ ID NO: 92, or SEQ ID NO: 93 and SEQ ID NO: 94, or SEQ ID NO: 95 and SEQ ID NO: 96, or SEQ ID NO: 97 and SEQ ID NO: 98, or SEQ ID NO: 99 and SEQ ID NO: 100, or SEQ ID NO: 101 and SEQ ID NO: 102, or SEQ ID NO: 103 and SEQ ID NO: 104, or SEQ ID NO: 105 and SEQ ID NO: 106, or SEQ ID NO: 107 and SEQ ID NO: 108.

8. The IL- 1 RAP antibody or the antigen-binding fragment thereof for use according to any one of claims 6 or 7, wherein the IL- 1 RAP antibody or the antigen -binding fragment thereof comprises heavy and light chain variable regions having, respectively, the amino acid sequence of SEQ ID NO: 16 and SEQ ID NO: 15, or SEQ ID NO: 80 and SEQ ID NO: 81, or SEQ ID NO: 82 and SEQ ID NO: 83, or SEQ ID NO: 84 and SEQ ID NO: 83, or SEQ ID NO: 85 and SEQ ID NO: 86, or SEQ ID NO: 87 and SEQ ID NO: 88, or SEQ ID NO: 89 and SEQ ID NO: 90, or SEQ ID NO: 91 and SEQ ID NO: 92, or SEQ ID NO: 93 and SEQ ID NO: 94, or SEQ ID NO: 95 and SEQ ID NO: 96, or SEQ ID NO: 97 and SEQ ID NO: 98, or SEQ ID NO: 99 and SEQ ID NO: 100, or SEQ ID NO: 101 and SEQ ID NO: 102, or SEQ ID NO: 103 and SEQ ID NO: 104, or SEQ ID NO: 105 and SEQ ID NO: 106, or SEQ ID NO: 107 and SEQ ID NO: 108.

9. The IL- 1 RAP antibody or the antigen-binding fragment thereof for use according to any one of claims 3 to 8, wherein the IL- 1 RAP antibody or the antigen -binding fragment thereof comprises:(a) a heavy chain variable region having the amino acid sequence of SEQ ID NO: 16 and(b) a light chain variable region having the amino acid sequence of SEQ ID NO: 15.

10. The IL-1RAP antibody for use according to any one of claims 3 to 9, further comprising a IgG Fc region, optionally, wherein the IgG Fc region is selected from IgGl, IgG2, IgG3, and IgG4.

11. The IL- 1 RAP antibody for use according to claim 10, wherein the IgG Fc region is IgGl.

12. The IL-1RAP antibody for use according to claim 10 or 11, wherein the Fc region comprises the L234A / L235A (LALA) modification.

13. The IL- 1 RAP antibody for use according to any one of claims 3 to 12, wherein the antibody is a humanized antibody.

14. The IL- 1RAP inhibitor for use according to any one of the preceding claims, wherein the IL- 1RAP inhibitor is administered in the form of a pharmaceutical composition, comprising one or more pharmaceutically acceptable excipient(s), carrier(s) or vehicle(s).

15. The IL- 1RAP inhibitor for use according to any one of the preceding claims, wherein the IL- 1RAP inhibitor is administered in combination with at least one or more active agent.

16. The IL- 1 RAP inhibitor for use according to claim 15, wherein the IL- 1 RAP inhibitor and the one or more active agent are administered separately, consecutively, or simultaneously.

17. The IL- 1 RAP inhibitor for use according to any one of the preceding claims, wherein a. the IL- 1 RAP inhibitor as defined in any one of claims 1-14, optionally in combination with the one or more active agents, or b. the pharmaceutical composition comprising i. the IL-1RAP inhibitor as defined in any of claims 1-14, ii. the one or more pharmaceutically acceptable carrier, excipient or vehicle, and iii. optionally the one or more active agents is administered by parenteral route.

18. The IL- 1 RAP inhibitor for use according to any of one of claims 1 to 14, wherein a therapeutically effective amount of the anti-IL-lRAP inhibitor is administered to a patient in need thereof, and wherein said administration reduces the severity of HS in the patient.

19. The IL- 1 RAP inhibitor for use according to claim 18, wherein the severity of HS in the patient is assessed by one or more of Hurley Staging, HiSCR, IHS4, total AN count, draining fistula count, NRS and HiSQOL.

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