Therapeutic approaches for the management of hidradenitis suppurativa

Abstract

The present invention provides the use of an IL-21 inhibitor, as well as pharmaceutical formulations, and dosage forms comprising the same for use in the treatment or prophylaxis of Hidradenitis Suppurativa (HS).

Description

[0001] THERAPEUTIC APPROACHES FOR THE MANAGEMENT OF HIDRADENITIS SUPPURATIVA

[0002] FIELD

[0003] The present invention is related to the field of inflammatory skin disorders. Particularly, the present invention provides the use of IL-21 inhibitors, as well as of pharmaceutical compositions comprising thereof, for treating Hidradenitis suppurativa.

[0004] BACKGROUND

[0005] Hidradenitis suppurativa (HS, also known as acne inversa) 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. Given the pain and physical deterioration associated with the painful lesions of this disease, 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 cathelici din (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 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 / IL-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 (e.g., oral and intravenous antibiotics as monotherapy (tetracyclines, ertapenem, dalbavancin or in combination (clindamycin and rifampicin)) approaches. 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 the tumor necrosis factor [TNF] inhibitor monoclonal antibody adalimumab.

[0011] While there have been proposed multiple therapeutic approaches for the managing 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 of further therapeutic approaches for an optimal management of HS.

[0013] SUMMARY OF THE INVENTION

[0014] The present inventors provide a therapeutic approach to HS based on the use of IL-21 inhibitors, in particular anti-IL-21 antibodies.

[0015] As it is shown below, the administration of an IL-21 inhibitor provides a significant reduction in relevant inflammatory cytokines, such as IL-17A, IL-17F, IL-36, IL-22 and IL-23, among others (see Table 4).

[0016] From the data provided below the following beneficial effects are derived from administering an IL-21 inhibitor: a. broad-spectrum effect, significantly reducing the expression level of several inflammatory cytokines (i.e., multitarget modulation). This broadspectrum effect is indicative of the suitability of an IL-21 inhibitor in the management of HS, which is characterized, as discussed in previous passages, as being an inflammatory skin disease; b. in some cases the reduction in inflammatory cytokine expression can reach values higher than 40%; and c. the remarkable reduction provided by the IL-21 inhibitor was achieved 24 h after the administration. That is, IL-21 inhibitor’s onset of action starts immediately after administration.

[0017] The data provided in Table 4, therefore, show that an IL-21 inhibitor can provide an effective amelioration in inflammatory skin diseases such as HS, in a very short period of time.

[0018] Altogether, the data provided herein support the suitability of inhibiting IL-21 for the efficient management of HS.

[0019] It is the first time that such beneficial effects are reported in HS.

[0020] In view of the above, the present invention provides an IL-21 inhibitor for use in the treatment of HS. This aspect can also be formulated as the use of an IL-21 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-21 inhibitor.

[0021] DESCRIPTION OF FIGURES

[0022] Fig. 1 shows the IL-21 expression in HS skin samples.

[0023] Fig. 2 shows that IL-21 concentration in serum is remarkably increased in patients suffering from HS (HS) compared to healthy subjects (H).

[0024] Fig. 3 shows STAT3 inhibition by IL-21 inhibitors of the present invention. DETAILED DESCRIPTION

[0025] All terms as used herein 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.

[0026] For the purposes of the present invention, any ranges given include both the lower and the upper endpoints of the range.

[0027] The present invention provides the use of IL-21 inhibitors in the treatment of HS in a subject.

[0028] 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. For example, the terms “treat”, “treating” or “treatment” may include administration of an IL-21 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-21 inhibitor after clinical manifestation of HS to combat the symptoms and / or complications and disorders associated with HS comprises "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, comprises "treatment" of the HS.

[0029] The term "in need thereof include mammals, such as humans, already having HS, including those in which the disease or disorder is to be prevented.

[0030] The term "subject" is interchangeably with "patient" in the context of the invention. In one embodiment, a subject refers to an individual who may be treated therapeutically with an IL-21 inhibitor, e.g., a human IL-21 antibody, or an antigen-binding portion thereof.

[0031] 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. 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).

[0032] HiSCR can also refer to at least a 75% reduction in the 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. Another endpoint is HiSCR90, which refers to at least a 75% reduction in the count of AN, with no increase in the number of abscesses or draining fistulas compared to baseline.

[0033] 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, 2017). 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. IHS4-55, a novel dichotomous IHS4 version, based on a 55% reduction of the total score was used.

[0034] Therefore, both HiSCR and IHS4 scores can be used as meaningful endpoints for assessing HS treatment effectiveness.

[0035] 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.

[0036] The invention typically effects 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 Hi SCR.

[0037] “IL-21” (also referred as “IL-21 ligand”) is a multifunctional cytokine that regulates the functional activity of various immune cells. It has a four-a-helix coiling structure and belongs to the shared y-chain cytokine family, which also includes IL-2, IL-4, IL-7, IL- 9, and IL-15. The IL-21 gene is located on chromosome 4 in humans. Several CD4 + T cells are capable of producing this cytokine. T follicular helper (TFH) and T helper 17 (TH17) cells are the major producers.

[0038] “IL-21 receptor” (IL-21R) is a heterodimer composed of the common y chain (CD 132) and an IL-21 -specific a chain. The a chain of IL-21R is essential for binding to IL-21, while the y chain is required for intracellular signaling. IL-21R is mainly expressed in lymphoid tissues, such as the thymus, lymph nodes and spleen, also in some non-immune cells.

[0039] Unless otherwise specified, when the description, examples and claims refer to “IL-21”, they will refer to IL-21 ligand.

[0040] As used herein, the term “IL-21 inhibitor” refers to any molecule (small or large, such as a peptide, polypeptide, antibody or fragment thereof, for instance) that decreases or blocks IL-21 activity.

[0041] In the context of the invention, “IL-21 activity” embraces the cell division and proliferation elicited by the interaction between IL-21 and its cognate receptor. These cell processes are mediated by a complex cytokine cascade. Therefore, IL-21 activity can be determined using “direct methods” based on determining the concentration of cells resulting from division and proliferation, or by “indirect methods” based on determining the level of inflammatory cytokine markers such as IL-17A, IL-17F, IL-22, IL-23, IL-36 or IFN-y, using both well-known protocols and commercial kits (following manufacturer’s instructions). In one embodiment, IL-21 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- 17 A, IL-17F, IL-22, IL-23, IL-36 or IFN- y. In one embodiment, IL-21 activity is determined by measuring the level of expression (either in the form of nucleic acid or protein) of 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. The decrease in the IL- 21 activity may be confirmed when there is a reduction in cell concentration and / or expression level of the markers after administering the inhibitor, e.g., a reduction relative to baseline which corresponds to a therapeutic benefit, for example an improvement in a patient suffering from HS as measured on the Hurley staging system. For example, in certain embodiments, the IL-21 inhibitor reduces the level of expression (either in the form of nucleic acid or protein) of one or more of IL-17A, IL-17F, IL-22, IL-23, IL-36 and IFN- y, relative to baseline, by at least 5%, e.g., at least 10%, e.g., at least 20%.

[0042] In certain embodiments, the IL-21 inhibitor reduces the level of expression (either in the form of nucleic acid or protein) of one or more of IL-17A, IL-17F, IL-22, IL-23, IL-36 and IFN- y, relative to baseline, from 5% to 80%, from 10 to 70%, from 15 to 60% or from 20 to 50%.

[0043] In one embodiment, an IL-21 inhibitor is provided for use in reducing cytokine levels in a subject with HS. In one embodiment the level of one or more of IL-22, IL-36, IL-17F, IL-17A, IFN- y, and IL-23 is reduced. In one embodiment, the level of reduction is at least 20% at the mRNA level relative to base line.

[0044] Several IL-21 inhibitors have been disclosed and are commercially available to those skilled in the art, as it will be discussed in detailed below. All of them are suitable in the context of the invention.

[0045] In one embodiment, the IL-21 inhibitor blocks the binding of IL-21 to IL-21R. The ability to block the IL-21 to receptor binding can be measured using any suitable protocol, well- known to those skilled in the art. In one embodiment, the blockade of the binding is determined by incubating the inhibitor with BaF3 cells expressing the IL-21 receptor sequence and measuring the level of STAT3 -phosphorylation following ligand-receptor interaction ("phosphor-STAT3 neutralization assay").

[0046] In one embodiment, the IL-21 inhibitor binds to IL-21 ligand. In an alternative embodiment, the IL-21 inhibitor binds to IL-21 receptor. In these embodiments, the IL- 21 inhibitor includes anti-IL-21 antibodies, particularly monoclonal anti-IL-21 antibodies, or antigen-binding fragments thereof, e.g., molecules capable of inhibiting interaction of IL-21 and its receptor, and inhibiting IL-21 activity.

[0047] The IL-21 inhibitor may be assayed for specific binding by any method known in the art. Illustrative non-limitative examples are immunoassays, including competitive and noncompetitive assay systems, such as western blots, radioimmunoassays, ELISA (enzyme linked immunosorbent assay), "sandwich" immunoassays, immunoprecipitation assays, precipitin reactions, gel diffusion precipitin reactions, immunodiffusion assays, agglutination assays, complement-fixation assays, immunoradiometric assays, fluorescent immunoassays, or protein A immunoassays, to name just a few. Such assays are routine and well known in the art.

[0048] In one embodiment, the binding of the IL-21 inhibitor to IL-21 is determined by any suitable immunoassay technique, particularly ELISA technique. Optimization of the reagents and conditions suitable to use in the assay can be easily performed by those skilled in the art. By the way of example, the binding is determined by performing the following protocol: a recombinant human IL-21 sequence (SEQ ID NO: 38) and a recombinant mutant human IL-21 sequence (SEQ ID NO: 39) are immobilized onto the surface of an ELISA plate (for instance, 96 well polystyrene) in a volume of 100 pL / well at a concentration of 1 pg / mL in Coating Buffer (0.1 M Na2COs, pH 9.6). Plates can then be incubated overnight at 4°C after which unbound protein is aspirated and the plate washed twice with 300 pL / well of Wash Buffer (PBS-Tween defined as 0.137M NaCl, 0.0022M KC1, 0.0067M Na2HPO4, 0.0020M KH2PO4, 0.05% v / w polysorbate 20, pH 7.2). Wells are next blocked with 200 pL / well of Blocking Buffer (PBS-Tween plus 1% w / v bovine serum albumin (BSA)) for 1 hour, after which the plates are washed twice with Wash Buffer. Antibody dilutions can be prepared in 5% fetal bovine serum (FBS) / Iscove's Modified Dulbecco's Media (IMDM) medium and adjusted to 1 pg / ml. Duplicate samples of each antibody dilution is then transferred to the assay plates, 100 pL / well, in order to bind anti -human IL-21 proteins. Following 1 hour incubation at room temperature, the wells are aspirated and the plates washed twice as described above. Horseradish peroxidase (HRP) labeled Goat anti Mouse IgG, Fc specific or Goat anti Rat IgG, Fc specific, or Goat anti Human IgG, Fc specific (Jackson ImmunoResearch Laboratories, West Grove, PA) at a dilution of 1 :5000 with 5% FBS / IMDM medium is then added to each well, 100 pL / well, and the plates incubated at ambient temperature for 1 hour. After removal of unbound HRP conjugated antibody, the plates are washed five times, 100 pL / well of tetra methyl benzidine (TMB) (BioFX Laboratories, Owings Mills, MD) added to each well and the plates incubated for 3 minutes at ambient temperature. Color development can be stopped by the addition of 100 pL / well of 450nm TMB Stop Reagent (BioFX Laboratories, Owings Mills, MD) and the absorbance values of the wells read on a Molecular Devices Spectra MAX 340 instrument at 450 nm.

[0049] 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 amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Variable regions and CDRs in an antibody sequence may be identified by aligning the sequences against a database of known variable regions (frameworks and CDRs are defined according to the Kabat numbering scheme herein - (Kabat, EA, Wu, TT, Perry, HM, et al. Sequences of Proteins of Immunological Interest, Fifth Edition. US Department of Health and Human Services, Public Health Service, National Institutes of Health, NIH Publication No. 91-3242, 1991).

[0050] In the context of the invention, the term "anti gen -binding portion" or "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-21). It has been shown that the antigen-binding 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 portion" 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 portion" of an antibody.

[0051] Still further, an antibody or antigen-binding portion thereof may be part of a larger immunoadhesion molecules, formed by covalent or non-covalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules. Antibody portions, such as Fab and F(ab')2 fragments, can be prepared from whole antibodies using conventional techniques, such as papain or pepsin digestion, respectively, of whole antibodies. Moreover, antibodies, antibody portions and immunoadhesion molecules can be obtained using routine recombinant DNA techniques.

[0052] In one embodiment, the IL-21 inhibitor is an anti-IL-21 antibody, particularly a human antibody, or fragment thereof which binds to IL-21. In an alternative embodiment, the IL- 21 inhibitor is an anti-IL-21 antibody or fragment thereof which binds to IL-21 receptor.

[0053] In one embodiment, the IL-21 inhibitor is selected from those anti-IL-21 monoclonal antibodies and antibody fragments disclosed in WO 2010 / 055366 or WO2015 / 169789, the content of which are incorporated by reference in its entirety, for example: (i) an anti- IL-21 antibody that comprises (i.l) a heavy chain variable region (VH) comprising one or more of: CDR1 having sequence SEQ ID NO: 1, CDR2 having sequence SEQ ID NO: 2, and / or CDR3 having sequence SEQ ID NO: 3; and (i.2) a light chain variable region (VL) comprising one or more of: CDR1 having sequence SEQ ID NO: 4, CDR2 having sequence SEQ ID NO: 5, and / or CDR3 having sequence SEQ ID NO: 6; (ii) an anti-IL- 21 antibody comprising (ii.l) a heavy chain variable region (VH) comprising CDRs 1 to 3 with sequences SEQ ID NOs: 1 to 3, respectively; and (ii .2) a light chain variable region (VL) comprising one or more CDRs 1 to 3 of SEQ ID NOs: 4 to 6, respectively; (iii) an antibody comprising all six SEQ ID NOs: 1 to 6; or (iv) an antigen-binding fragment (e.g., antigen-binding fragment (Fab), single chain variable fragment (scFv) or nanobody) comprising at least SEQ ID NOs: 1-3 or at least SEQ ID NOs: 4-6, or all six of SEQ ID NOs: 1 to 6. In one embodiment, the anti-IL-21 antibody comprises (i) a heavy chain comprising a variable region having a sequence with at least 80% of identity with respect to SEQ ID NO: 7; and (ii) a light chain comprising a variable region having a sequence with at least 80% of identity with respect to SEQ ID NO: 8. In another embodiment, the anti-IL-21 antibody comprises (i) a heavy chain comprising a variable region consisting of SEQ ID NO: 7; and (ii) a light chain comprising a variable region consisting of SEQ ID NO: 8.

[0054] In one embodiment, the IL-21 inhibitor is an anti-IL-21 monoclonal antibody or an antigen-binding fragment thereof, comprising (a) a heavy chain with a sequence identity of at least 80% with respect to SEQ ID NO: 9, provided that CDRs 1 to 3 correspond to sequences SEQ ID NO: 1 to 3; and (b) a light chain with a sequence identity of at least 80% with respect SEQ ID NO: 10, provided that CDRs 1-3 correspond to sequences SEQ ID NO: 4-6. In another embodiment, the anti-IL-21 monoclonal antibody or an antigenbinding fragment thereof comprises (a) a heavy chain comprising or consisting of SEQ ID NO: 9; and (b) a light chain comprising or consisting of SEQ ID NO: 10 (both already disclosed in WO2015 / 169789). In another embodiment, the anti-IL-21 monoclonal antibody comprises: (a) a heavy chain consisting of SEQ ID NO: 9 and (b) a light chain consisting of SEQ ID NO: 10.

[0055] Table 1

[0056] Other illustrative, non-limitative examples of anti-IL-21 antibodies suitable in the context of the invention are: a. an anti-human IL-21 monoclonal antibody comprising: (a) a heavy chain comprising one or more CDRs selected from CDR1 having sequence SEQ ID NO: 11, CDR2 having sequence SEQ ID NO: 2, or CDR3 having sequence SEQ ID NO: 3; and / or (b) a light chain comprising one or more CDRs selected from CDR1 having sequence SEQ ID NO: 4, CDR2 having sequence SEQ ID NO: 5, and / or CDR3 having sequence SEQ ID NO: 6; for example, particularly the antibody comprises all six CDRs of SEQ ID NOS: 11, 2, 3, 4, 5, and 6; b. an antibody fragment (e.g., antigen-binding fragment (Fab), single chain variable fragment (scFv) or nanobody) comprising at least SEQ ID NOS: 11, 2, and 3; or at least SEQ ID NOS: 4, 5, and 6; or all six CDRs of SEQ ID NOS: 11, 2, 3, 4, 5, and 6; c. an anti-human IL-21 monoclonal antibody, Fab or scFv comprising (i) a heavy chain including a variable region with at least 80% of sequence identity with respect to the amino acid sequence defined by residues 20 to 145 of SEQ ID NO: 12, and (ii) a light chain including a variable region with at least 80% of sequence identity with respect to the amino acid sequence defined by residues 21 to 126 of SEQ ID NO: 13; d. an anti -human IL-21 monoclonal antibody produced by the hybridoma designated 362.597.3, deposited with the American Type Culture Collection having the ATCC Patent Deposit Designation PTA-8786, or a mammalian cell line expressing the same antibody; or an antibody binding to the same epitope as the antibody produced by the hybridoma designated 362.597.3, e.g. binding to the epitope defined in scope r or s below; e. an anti -human IL-21 monoclonal antibody that comprises (i) a heavy chain including a variable region with at least 80% identity to amino acid residues 20 to 141 of SEQ ID NO: 14; a light chain including a variable region with at least 80% identity to amino acid residues 21 to 126 of SEQ ID NO: 15; f. an anti-human IL-21 monoclonal antibody comprising: (i) a heavy chain comprising one or more of: CDR1 having sequence SEQ ID NO: 16, CDR2 having sequence SEQ ID NO: 17, and / or CDR3 having sequence SEQ ID NO: 18; and / or (ii) a light chain comprising one or more of: CDR1 having sequence SEQ ID NO: 19, CDR2 having sequence SEQ ID NO: 20, and / or CDR3 having sequence SEQ ID NO: 21; particularly, an antibody comprising all six CDRs of SEQ ID NOS: 16, 17, 18, 19, 20, and 21; g. an antibody fragment (e.g., antigen-binding fragment (Fab), single chain variable fragment (scFv) or nanobody) comprising at least SEQ ID NOS: 16, 17, and 18; or at least SEQ ID NOS: 19, 20, and 21; or all six CDRs of SEQ ID NOS: 16-21; h. an anti-human IL-21 monoclonal antibody, Fab or scFv, comprising (i) a heavy chain including a variable region with amino acid residues 1 to 141 or 20 to 141 of SEQ ID NO: 14, and (ii) a light chain including a variable region with amino acid residues 1 to 126 or 21 to 126 of SEQ ID NO: 15; i. an anti -human IL-21 monoclonal antibody produced by the hybridoma designated 362.75.1.1, deposited with the American Type Culture Collection having the ATCC Patent Deposit Designation PTA-8791, or a mammalian cell line expressing the same antibody; or an antibody binding to the same epitope as the antibody produced by the hybridoma designated 362.75.11; j. an anti-human IL-21 monoclonal antibody comprising: (i) a heavy chain comprising one or more of: CDR1 having sequence SEQ ID NO: 22, CDR2 having sequence SEQ ID NO: 23, and / or CDR3 having sequence SEQ ID NO: 24; and / or (ii) a light chain comprising one or more of: CDR1 having sequence SEQ ID NO: 25, CDR2 having sequence SEQ ID NO: 26, and / or CDR3 having sequence SEQ ID NO: 27; for example, an antibody comprising all six CDRs of SEQ ID NOS: 22-27; k. an antibody fragment (e.g., antigen-binding fragment (Fab), single chain variable fragment (scFv) or nanobody) comprising at least SEQ ID NOS: 22, 23, and 24; or at least SEQ ID NOS: 25, 26, and 27; or all six CDRs of SEQ ID NOS: 22-27; l. an anti-human IL-21 monoclonal antibody, Fab or scFv comprising (i) a heavy chain including a variable region comprising or consisting of amino acids residues 1 to 136 or 20 to 136 of SEQ ID NO: 28; and (ii) a light chain including a variable region with comprising or consisting of amino acid residues 1 to 129 or 23 to 129 of SEQ ID NO: 29; m. an anti-IL-21 antibody produced by the hybridoma designated 366.552.11, wherein the hybridoma is deposited with the American Type Culture Collection having the ATCC Patent Deposit Designation PTA-8787, or a mammalian cell line expressing the same antibody; or an antibody binding to the same epitope, as the antibody produced by the hybridoma designated 366.552.11; n. an anti -human IL-21 monoclonal antibody comprising or an antigenbinding thereof: (a) a heavy chain region comprising one or more of: CDR1 having sequence SEQ ID NO: 30, CDR2 having sequence SEQ ID NO: 31, and / or CDR3 having sequence SEQ ID NO: 32; and / or (b) a light chain region comprising one or more of: CDR1 having sequence SEQ ID NOS: 33, CDR2 having sequence SEQ ID NO: 34 and / or CDR3 having sequence SEQ ID NO: 35; particularly, the antibody comprises all six CDRs of SEQ ID NOS: 30-35; o. an anti-human IL-21 monoclonal antibody, Fab or scFv comprising: (i) a heavy chain including a variable region comprising or consisting of amino acids residues 1 to 139 or 20 to 139 of SEQ ID NO: 36; and (ii) a light chain including a variable region comprising or consisting of amino acid residues 1 to 129 or 23 to 129 of SEQ ID NO: 37; p. an anti-IL-21 antibody produced by the hybridoma designated 366.328.10, deposited with the American Type Culture Collection having the ATCC Patent Deposit Designation PTA-8789, or a mammalian cell line expressing the same antibody; or an antibody binding to the same epitope, as the antibody produced by the hybridoma designated 366.328.10; q. an anti-IL-21 antibody produced by the hybridoma designated 366.345.6.11, deposited with the American Type Culture Collection having the ATCC Patent Deposit Designation PTA-8788, or a mammalian cell line expressing the same antibody; or an antibody binding to the same epitope as the antibody produced by the hybridoma designated 366.345.6.11; or r. a monoclonal antibody that binds to a discontinuous epitope in an IL-21 protein, the discontinuous epitope comprising the fragment defined from residue IIe45 to residue Leu56 of SEQ ID NO: 38 (which is provided in Table 3, below) as well as the fragment defined from residue Glul29 to residue Leul44 of SEQ ID NO: 38. s. a monoclonal antibody that binds to a discontinuous epitope in an IL-21 protein, the discontinuous epitope comprising the fragment defined from residue Ile45 to residue Leu56 of SEQ ID NO: 39 (which is provided in Table 3, below) as well as the fragment defined from residue Glul29 to residue Leul44 of SEQ ID NO: 39.

[0057] In one embodiment, the anti-IL-21 antibody comprises a Fc portion selected the group consisting of IgGl, IgG2 and IgG4, e.g., wherein the Fc portion has reduced effector function. In another embodiment, the anti-IL-21 antibody comprises:

[0058] (I)

[0059] CDRs with sequences SEQ ID NO: 1 to 6, or alternatively with sequences SEQ ID NO: 11 and 2-6, or alternatively with sequences SEQ ID NO: 16 to 21, or alternatively with sequences SEQ ID NO: 22 to 27, or alternatively, with sequences SEQ ID NO: 30 to 35; or a VH sequence comprising or consisting of sequence SEQ ID NO: 7, 12, 14, 28, or 36, and a VL sequence comprising or consisting of SEQ ID NO: 8, 13, 15, 29 or 37; and

[0060] (II) a Fc portion corresponding to the Fc portion of IgGl, IgG2, IgG3 or IgG4.

[0061] SEQ ID NOs 11-37 are provided in Table 2 below:

[0062] Table 2

[0063]

[0064] SEQ ID NO: 38 and 39 are provided in table 3.

[0065] Table 3:

[0066] Other examples of IL-21 inhibitors contemplated herein include avizakimab (e.g., disclosed in U.S. Pat. No. 10,022,443), KNK-003 (also SAR-445419), AWT-008 (a recombinant IL-21 and anti-human serum albumin (HAS) single domain nanobody fusion protein that acts by targeting interleukin 21 receptor), 2P-2, AB-821, HCW-9206, ID-13015, WTX-712, BB-2112, HCW-9212, denenicokin, and PF-05230900.

[0067] Avizakimab is an antibody having a heavy chain according to SEQ ID NO: 40 (with a variable region SEQ ID NO: 48) and a light chain of sequence SEQ ID NO: 41 (with a variable region SEQ ID NO: 49). The six CDRs are: CDRH1 (SEQ ID NO: 42: DYWMH), CDR-H2 (SEQ ID NO: 43: TIDPSDQYTIYSQNFKG), CDR-H3 (SEQ ID NO: 44: YGFAMDY), CDR-L1 (SEQ ID NO: 45: RASQDISNFLN), CDR-L2 (SEQ ID NO: 46: YTSRLHS), and CDR-L3 (SEQ ID NO: 47: QQGHTLPRT).

[0068] In another embodiment of the invention the IL-21 inhibitor is an antibody selected from: a. an anti -human IL-21 monoclonal antibody or an antigen-binding fragment thereof comprising: (i) a heavy chain comprising one or more of CDRH1 having sequence SEQ ID NO: 42, CDRH2 having sequence SEQ ID NO: 43 and / or CDRH3 having sequence SEQ ID NO: 44; and / or (b) a light chain comprising one or more of CDRL1 having sequence SEQ ID NO: 45, CDRL2 having sequence SEQ ID NO: 46, and CDRL3 having sequence SEQ ID NO: 47; for example an antibody comprising either or both of SEQ ID NOs: 48 and / or 49; b. an anti -human IL-21 monoclonal antibody or an antigen-binding fragment thereof comprising (i) a heavy chain including a variable region with a sequence having an identity of at least 80% with SEQ ID NO: 48, and (ii) a light chain including a variable region with a sequence having an identity of at least 80% with SEQ ID NO: 49; particularly an anti-human IL-21 monoclonal antibody or an antigen-binding fragment thereof comprising (i) a heavy chain including a variable region comprising or consisting of SEQ ID NO: 48, and (ii) a light chain including a variable region comprising or consisting of SEQ ID NO: 49; and c. an anti -human IL-21 monoclonal antibody or an antigen-binding fragment thereof comprising (i) a heavy chain sequence having an identity of at least 80% with sequence SEQ ID NO: 40, and (b) a light chain sequence having an identity of at least 80% with sequence SEQ ID NO: 41; particular the heavy chain comprises or consists of SEQ ID NO: 40 and the light chain comprises or consists of SEQ ID NO: 41.

[0069] In the context of the present invention, the term "identity" refers to the percentage of residues that are identical in the two sequences when the sequences are optimally aligned. If, in the optimal alignment, a position in a first sequence is occupied by the same amino acid residue as the corresponding position in the second sequence, the sequences exhibit identity with respect to that position. The level of identity between two sequences (or "percent sequence identity") is measured as a ratio of the number of identical positions shared by the sequences with respect to the size of the sequences (i.e., percent sequence identity = (number of identical positions / total number of positions) x 100). In one embodiment, optionally in combination with any of the embodiments provided above or below, the identity is of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100%.

[0070] In the context of the invention, the amino acid modification is conservative, i.e., does not devoid the ability of the resulting antibody or fragment thereof to bind IL-21.

[0071] In one embodiment, the amino acid modification(s) consist(s) of one or more conservative amino acid substitutions. In the context of the invention, a “conservative amino acid substitution,” as used herein, is one in which one amino acid residue is replaced with another amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0072] In another embodiment of the invention, the antibody or antigen-binding fragment thereof referred in previous passages, comprises:

[0073] (a) a variable region in the heavy chain with an identity of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with respect to SEQ ID NO: 7, 12, 14, 28, 36 or 48; and / or (b) a variable region in the light chain with an identity of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with respect to SEQ ID NO: 8, 13, 15, 29, 37 or 49.

[0074] Particularly the antibody or fragment thereof has a heavy chain comprising a variable region with an identity of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with respect to SEQ ID NO: 7; and a light chain comprising a variable region with an identity of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with respect to SEQ ID NO: 8.

[0075] In another embodiment of the invention, the antibody or antigen-binding fragment thereof comprises:

[0076] (a) a heavy chain with an identity of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with respect to SEQ ID NO: 9 or 40; and / or

[0077] (b) a light chain with an identity of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with respect to SEQ ID NO: 10 or 41.

[0078] Particularly the antibody or fragment thereof has a heavy chain with an identity of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with respect to SEQ ID NO: 9; and a light chain with an identity of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% with respect to SEQ ID NO: 10.

[0079] 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 1 MATCH-BOX, 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).

[0080] 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.

[0081] 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.

[0082] 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.

[0083] In an embodiment, one or more of the amino acids forming part of the antibody or antigenbinding fragment thereof is covalently attached to a moiety, such as glycosylation, acetylation, pegylation, phosphylation, or amidation moieties, derivatization with known protecting / blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications may be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. In one embodiment, the covalent modifications are not considered when determining the percentage of identity.

[0084] In one embodiment, the IL-21 inhibitor, as defined in any of the above embodiments, is administered in the form of a pharmaceutical composition.

[0085] The pharmaceutical composition suitable in the context of the invention includes a therapeutically effective amount of the IL-21 inhibitor, together with one or more excipients, carriers or vehicles.

[0086] 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 portion, or other IL-21 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 portion, other IL-21 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 portion, or other IL-21 inhibitor are outweighed by the therapeutically beneficial effects. Administration may consist of a single dose or multiple doses (e.g., 2 or 4 doses) at various intervals, e.g., daily, weekly, monthly, at e.g., e.g., l-200mg / kg, l-200mg / kg, l-100mg / kg, l-25mg / kg, e.g., 4mg / kg, 6mg / kg, 8mg / kg, 12mg / kg.

[0087] The carrier is preferably a pharmaceutically acceptable carrier, and the form and character of the pharmaceutically acceptable carrier is dictated by the amount of active ingredient with which it is to be combined and the route of administration. A source for general information about suitable formulations disclosed herein is described in Remington: The Science and Practice of Pharmacy (Academic Press) 23rded. (2020).

[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-21 inhibitors.

[0089] As will be appreciated by the skilled artisan, the route and / or mode of administration will vary depending upon the desired results. In certain embodiments, the active compound may be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems. In one embodiment, the antibody or other IL-21 inhibitor is administered by parenteral route, such as by intravenous or subcutaneous injection.

[0090] Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.

[0091] Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable to high drug concentration. Sterile injectable solutions can be prepared by incorporating the active compound (i.e., antibody, antibody portion, or other IL-21 inhibitor) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.

[0092] Degradable polymer microspheres have been designed to maintain high systemic levels of therapeutic proteins. Microspheres are prepared from degradable polymers such as poly(lactide-co-glycolide) (PLG), polyanhydrides, poly (ortho esters), nonbiodegradable ethylvinyl acetate polymers, in which proteins are entrapped in the polymer (Gombotz and Pettit, Bioconiugate Chem. 6:332, 1995; Ranade, "Role of Polymers in Drug Delivery," in Drug Delivery Systems, Ranade and Hollinger (eds.), pages 51-93 (CRC Press 1995); Roskos and Maskiewicz, "Degradable Controlled Release Systems Useful for Protein Delivery," in Protein Delivery: Physical Systems, Sanders and Hendren (eds.), pages 45-92 (Plenum Press 1997); Bartus et al., Science 281 : 1 161 , 1998; Putney and Burke, Nature Biotechnology 16: 153, 1998; Putney, Curr. Opin. Chem. Biol. 2:548, 1998). Polyethylene glycol (PEG)-coated nanospheres can also provide carriers for intravenous administration of therapeutic proteins (see, for example, Gref et al., Pharm. Biotechnol. 10: 167, 1997).

[0093] The IL-21 inhibitors may be given in combination with at least one or more further active agents.

[0094] The term "combination" as in the phrase "IL-21 in combination with one or more further active agents" includes concomitant administration (co-administration) of a first agent (IL-21) and one or more further agents, which for example may be dissolved or intermixed in the same pharmaceutically acceptable carrier, or administration of IL-21, 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.

[0095] The term "concomitant" includes administering an agent in the presence of a second agent. A concomitant therapeutic treatment method includes methods in which the first, second, third, or additional agents are co-administered. A concomitant therapeutic treatment method also includes methods in which the first or additional agents are administered in the presence of a second or additional agents, wherein the second or additional agents, for example, may have been previously administered. A concomitant therapeutic treatment method may be executed step-wise by different actors. For example, one actor may administer to a subject a first agent and a second actor may administer to the subject a second agent, and the administering steps may be executed at the same time, or nearly the same time, or at distant times, so long as the first agent (and additional agents) are after administration in the presence of the second agent (and additional agents). The actor and the subject may be the same entity (e.g., human).

[0096] The term “epitope” refers to any protein determinant capable of specific binding to an immunoglobulin or T-cell receptor. Epitope determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar sides chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. More specifically, the phrase “binding to the same epitope” as used herein refers to binding to the same epitope of an antibody determined by competitive binding assay. “Discontinuous epitopes” are conformational epitopes formed from at least two separate regions in the primary sequence of the IL-21 protein.

[0097] The additional one or more active agents may be selected from antiseptic, antiperspirant, anti-androgen, anti-inflammatory, antibiotics, or anti-infective agents and may be natural agents or synthetic agents. Examples of the additional one or more active agents include without limitation, antiseptic and antiperspirant agents (e.g., 6.25% aluminum chloride hexahydrate in absolute ethanol), anti-inflammatory or anti-antiandrogen therapy such as tetracycline, intralesional triamcinolone, or finasteride. It can also be combined with agents, such as methotrexate, cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signaling by proinflammatory cytokines such as TNFa, or IL-1 (e.g., IRAK, NIK, IKK, p38 or MAP kinase inhibitors), IL-ip converting enzyme inhibitors, TNFa converting enzyme inhibitors, T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g., soluble p55 or p75 TNF receptors, sIL- 1RI, sIL-lRII, sIL-6R) and anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-12, IL-13 and TGFP).The one or more active agents may be used or administered separately, simultaneously or consecutively with the IL-21 inhibitor disclosed herein.

[0098] In one embodiment, the subject being treated with the IL-21 inhibitor is also being treated with an IL-17 antagonist. In an alternative embodiment, the subject being treated with the IL-21 inhibitor is not also being treated with an IL-17 antagonist.

[0099] The term “anti-infective agents”, as used herein, refers to agents that are generally known to treat viral, fungal, parasitic, or bacterial infections. In some embodiments, the anti- infective agent is an antibiotic selected from clarithromycin, ciprofloxacin, and metronidazole.

[0100] The term “antibiotic”, as used herein, refers to a chemical substance that inhibits the growth of, or kills, microorganisms. Moreover, the term encompasses antibiotics that are produced by a microorganism, as well as synthetic antibiotics (e.g., analogs).

[0101] The present invention also pertains to packaged pharmaceutical compositions or kits for administering the IL-21 inhibitor for the treatment of hidradenitis suppurativa. In one instance of the present disclosure, the kit comprises an IL-21 inhibitor, such as an antibody or an antigen-binding fragment thereof, as defined in any of the preceding embodiments, and instructions for administration of the IL-21 inhibitor for treatment of hidradenitis suppurativa. Another aspect of the present invention pertains to kits containing a pharmaceutical composition comprising an IL-21 inhibitor, such as an antibody, and a pharmaceutically acceptable carrier and one or more pharmaceutical compositions each comprising an additional therapeutic agent useful for treating hidradenitis suppurativa, and a pharmaceutically acceptable carrier. Alternatively, the kit comprises a single pharmaceutical composition comprising an anti-IL-21 antibody, one or more further active agents useful for treating hidradenitis suppurativa, and a pharmaceutically acceptable carrier. The instructions may describe how and when administering them to treat hidradenitis suppurativa.

[0102] The package or kit alternatively can contain the IL-21 inhibitor (e.g., an anti-IL-21 antibody, or an antigen-binding portion thereof) and it can be promoted for use, either within the package or through accompanying information, for the uses or treatment of the disorders described herein. The packaged pharmaceuticals or kits further can include a second agent (as described herein) packaged with or co-promoted with instructions for using the second agent with a first agent (as described herein).

[0103] The invention further provides the following embodiments:

[0104] In some embodiments, the invention provides a method for treating HS, the method comprising administering to a subject in need thereof, a therapeutically effective amount of an IL-21 inhibitor. In a preferred embodiment, the IL-21 inhibitor inhibits binding of IL-21 to the IL-21 receptor. In another preferred embodiment the IL-21 inhibitor is an inhibitor that binds to IL-21 or IL-21 receptor and decreases, impairs, alters, blocks, inhibits or neutralize (fully or partially or otherwise) the activity, signaling, activation or function of IL-21 receptor and / or its protein, such as decreased immune function of one or more, in some embodiments, two or more of the following: NK cells, dendritic cells, T-cells, for example, impair the proliferation, differentiation and functionality of B cells, plasma cells, Thl7, Tfh / Tph, fibroblasts, neutrophils and macrophages. In a more preferred embodiment the IL-21 inhibitor is an anti-IL-21 antibody or an antigen-binding fragment thereof, e.g., anti-IL-21 antibody disclosed in WO 2010 / 055366 or WO2015 / 169789, the contents of which are incorporated by reference in their entirety. In another preferred embodiment the IL-21 inhibitor is avizakimab (e.g., disclosed in U.S. Pat. No. 10,022,443), KNK-003 (also SAR-445419), AWT-008 (a recombinant IL-21 and anti-human serum albumin (HAS) single domain nanobody fusion protein that acts by targeting interleukin 21 receptor), latikafusp (also AMG-256, a bifunctional fusion protein targeting PD-1 and -21R), 2P-2, AB-821, HCW-9206, ID-13015, WTX-712, BB- 2112, HCW-9212, denenicokin, orPF-05230900, or soluble IL-21 receptor. In apreferred embodiment the IL-21 inhibitor is a monoclonal IgG antibody wherein the heavy chain constant region has impaired effector function, e.g., comprises mutations to reduce Fc- mediated effector functions. In another preferred embodiment the IL-21 inhibitor is a monoclonal IgG antibody, anti gen -binding fragment (Fab), single chain variable fragment (scFv), or single domain antibody (e.g., VHH antibody) which binds IL-21 and comprises: a) a heavy chain region comprising one or more regions selected from: i) a heavy chain variable region CDR1 set forth in SEQ ID NO: 1; ii) a heavy chain variable region CDR2 set forth in SEQ ID NO:2; and iii) a heavy chain variable region CDR3 set forth in SEQ ID NO:3; and / or b) a light chain region comprising one or more regions selected from: i) a light chain variable region CDR1 set forth in SEQ ID NO:4; ii) a light chain variable region CDR2 set forth in SEQ ID NO: 5; and iii) a light chain variable region CDR3 set forth in SEQ ID NO:6.

[0105] In a preferred embodiment the IL-21 inhibitor is a monoclonal IgG antibody which binds IL-21 and comprises: a) a heavy chain region comprising: i) a heavy chain variable region CDR1 set forth in SEQ ID NO: 1; ii) a heavy chain variable region CDR2 set forth in SEQ ID NO:2; and iii) a heavy chain variable region CDR3 set forth in SEQ ID NO:3; and b) a light chain region comprising: i) a light chain variable region CDR1 set forth in SEQ ID NO:4; ii) a light chain variable region CDR2 set forth in SEQ ID NO:5; and iii) a light chain variable region CDR3 set forth in SEQ ID NO:6. In another preferred embodiment the IL-21 inhibitor is an antibody which binds IL-21 and comprises a heavy chain including a variable region with an identity of at least 80%, preferably 85%, preferably, 90%, preferably 95%, preferably 99% identity to SEQ ID NO: 7; and / or a light chain including a variable region with an identity of at least 80%, preferably 85%, preferably, 90%, preferably 95%, preferably 99% identity to SEQ ID NO: 8. In a still more preferred embodiment the IL-21 inhibitor is an anti-IL-21 antibody having a heavy chain comprising SEQ ID NO: 7, and a light chain comprising SEQ ID NO: 8.

[0106] In a preferred embodiment the IL-21 inhibitor is an anti-IL-21 antibody which comprises: (a) a heavy chain with at least 80%, preferably 85%, preferably, 90%, preferably 95%, preferably 99% identity to amino acid sequence of SEQ ID NO: 9; and / or (b) a light chain with at least 80%, preferably 85%, preferably, 90%, preferably 95%, preferably 99% identity of amino acid sequence of SEQ ID NO: 10. In a more preferred embodiment the IL-21 inhibitor is an anti-IL-21 antibody which comprises (a) a heavy chain consisting of SEQ ID NO: 9, and (b) a light chain consisting of amino acid sequence of SEQ ID NO: 10.

[0107] In another preferred embodiment the IL-21 inhibitor is an anti -human IL-21 monoclonal antibody comprising: (a) a heavy chain variable region comprising one or more of: (i) CDR1 having SEQ ID NO: 11, (ii) CDR2 having sequence SEQ ID NO: 2, and / or (iii) CDR3 having sequence SEQ ID NO: 3; and / or (b) a light chain variable region comprising one or more of: (i) a CDR1 having sequence SEQ ID NO: 4, (ii) CDR2 having sequence SEQ ID NO: 5, and CDR3 having sequence SEQ ID NO: 6.

[0108] In a preferred embodiment the anti -human IL-21 monoclonal antibody: comprises amino acids residues 20 to 145 of SEQ ID NO: 12 and amino acid residues 21 to 126 of SEQ ID NO: 13; or, alternatively, comprises amino acid residues 1 to 145 of SEQ ID NO: 12 and amino acid residues 21 to 126 of SEQ ID NO: 13; or, alternatively, it is produced by the hybridoma designated 362.597.3, deposited with the American Type Culture Collection having the ATCC Patent Deposit Designation PTA-8786, or a mammalian cell line expressing the same antibody; or an antibody binding to the same epitope as the antibody produced by the hybridoma designated 362.597.3, e.g. binding to the epitope defined in scope r or s below;

[0109] In another preferred embodiment the IL-21 inhibitor is an anti -human IL-21 monoclonal antibody comprising at least 80% identity to amino acid residues 20 to 141 of SEQ ID NO: 14 and at least 80% identity to amino acid residues 21 to 126 of SEQ ID NO: 15 for example, wherein any amino acid changes are conservative amino acid changes.

[0110] In another preferred embodiment the IL-21 inhibitor is an anti -human IL-21 monoclonal antibody comprising: (a) a heavy chain comprising a variable region including one or more of: (i) CDR1 having sequence SEQ ID NO: 16; (ii) CDR2 having sequence SEQ ID NO: 17; and / or CDR3 having sequence SEQ ID NO: 18; and / or (b) a light chain comprising a variable region including one or more of: (i) CDR1 having sequence SEQ ID NO: 19; (ii) CDR2 having sequence SEQ ID NO: 20; and / or (iii) CDR3 having sequence SEQ ID NO: 21; for example, wherein the anti -human IL-21 monoclonal antibody comprises amino acid residues 20 to 141 of SEQ ID NO: 14 and amino acid residues 21 to 126 of SEQ ID NO: 15; or wherein the anti -human IL-21 monoclonal antibody further comprises amino acid residues 1 to 141 of SEQ ID NO: 14 and amino acid residues 1 to 126 of SEQ ID NO: 15; for example wherein the anti-human IL-21 monoclonal antibody is produced by the hybridoma designated 362.75.1.1, deposited with the American Type Culture Collection having the ATCC Patent Deposit Designation PTA-8791, or a mammalian cell line expressing the same antibody.

[0111] In another preferred embodiment the IL-21 antibody is anti -human IL-21 monoclonal antibody comprising: (a) a heavy chain variable region comprising one or more of: (i) CDR1 having sequence SEQ ID NO: 22; (ii) CDR2 having sequence SEQ ID NO: 23; and / or (iii) CDR3 having sequence SEQ ID NO: 24; and / or (b) a light chain variable region comprising one or more of: (i) CDR1 having sequence SEQ ID NO: 25; (ii) CDR2 having sequence SEQ ID NO: 26; and / or (iii) CDR3 having sequence SEQ ID NO: 27; for example, wherein the IL-21 antibody is an anti-human IL-21 monoclonal antibody comprising amino acids residues 20 to 136 of SEQ ID NO: 28 and amino acid residues 23 to 129 of SEQ ID NO: 29; for example wherein the IL-21 antibody further comprises amino acid residues 1 to 136 of SEQ ID NO: 28 and amino acid residues 1 to 129 of SEQ ID NO: 29; for example, wherein the IL-21 antibody is produced by the hybridoma designated 366.552.11, wherein the hybridoma is deposited with the American Type Culture Collection having the ATCC Patent Deposit Designation PTA-8787, or a mammalian cell line expressing the same antibody.

[0112] In another preferred embodiment the IL-21 antibody is an anti -human IL-21 monoclonal antibody comprising: (a) a heavy chain variable region comprising one or more of: (i) CDR1 having sequence SEQ ID NO: 30; (ii) CDR2 having sequence SEQ ID NO: 31; and / or (iii) CDR3 having sequence SEQ ID NO: 32; and / or (b) a light chain variable region comprising one or more of: (i) CDR1 having sequence SEQ ID NO: 33; (ii) CDR2 having sequence SEQ ID NO: 34; and / or (iii) CDR3 having sequence SEQ ID NO: 35. In certain embodiments, the IL-21 antibody is an anti-human IL-21 monoclonal antibody comprising amino acids residues 20 to 139 of SEQ ID NO: 36 and amino acid residues 23 to 129 of SEQ ID NO: 37. In other embodiments, the IL-21 antibody further comprises amino acid residues 1 to 139 of SEQ ID NO: 36 and amino acid residues 1 to designated 366.328.10, or the IL-21 antibody is produced by the hybridoma deposited with the American Type Culture Collection having the ATCC Patent Deposit Designation PTA- 8789, or a mammalian cell line expressing the same antibody. In another preferred embodiment the IL-21 antibody is an antibody produced by the hybridoma designated 366.345.6.11, deposited with the American Type Culture Collection having the ATCC Patent Deposit Designation PTA-8788, or a mammalian cell line expressing the same antibody.

[0113] In another preferred embodiment the IL-21 antibody is an isolated monoclonal antibody that binds to a discontinuous epitope comprising one or more amino acids from residue IIe45 to residue Leu56 of SEQ ID NO: 38 and one or more amino acids from residue Glul29 to residue Leul44 of SEQ ID NO: 38.

[0114] In another preferred embodiment the IL-21 antibody is an isolated monoclonal antibody that binds to a discontinuous epitope comprising one or more amino acids from residue Ile45 to residue Leu56 of SEQ ID NO: 39 and one or more amino acids from residue Glul29 to residue Leul44 of SEQ ID NO: 39.

[0115] In another preferred embodiment the IL-21 antibody further comprises an Fc portion, and another embodiment, wherein the Fc portion is selected the group consisting of IgGl, IgG2 and IgG4.and another embodiment, wherein the Fc portion has reduced effector function.

[0116] In another preferred embodiment the IL-21 inhibitor inhibits one or more, preferably at least two, at least three interleukins selected from IL-22, IL-36, IL-17F, IL 17 A, IFNg, and / or IL-23. In a more preferred embodiment the IL-21 inhibitor inhibits interleukins selected from IL-17F and IL-22.

[0117] In another preferred embodiment the IL-21 inhibitor is selected from avizakimab, KNK- 003, AWT-008, latikafusp, 2P-2, AB-821, HCW-9206, ID-13015, WTX-712, BB-2112, HCW-9212, denenicokin, and PF-05230900.

[0118] In another preferred embodiment an inhibitory response is achieved after 24 hours of administering the IL-21 inhibitor.

[0119] In another preferred embodiment the IL-21 inhibitor is administered every 1, 2, or 3 months after day 1. In a more preferred embodiment the IL-21 inhibitor is administered every 3 months after day 1.

[0120] In another preferred embodiment the IL-21 inhibitor is administered by intravenous or subcutaneous injection.

[0121] In another preferred embodiment the IL-21 inhibitor is administered in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable excipient, diluent or carrier (e.g., use of a pharmaceutical composition comprising the IL-21 inhibitor and pharmaceutically acceptable excipient, diluent or carrier in any of the methods disclosed herein).

[0122] In another preferred embodiment further comprising administering at least one or more active agents.

[0123] In a more preferred embodiment the one or more active agent comprises natural agents (e.g. plant extracts) and / or synthetic agents. In a still more preferred embodiment the one or more active agents is selected from antiseptic, antiperspirant, anti-androgen, antiinflammatory, antibiotics, or anti-infective agents. In a still more preferred embodiment the one or more active agents is selected from antiseptic and antiperspirant agents (e.g., 6.25% aluminum chloride hexahydrate in absolute ethanol), tetracycline, intralesional triamcinolone, finasteride, methotrexate, cyclosporin, FK506, rapamycin, my cophenol ate, mofetil, leflunomide, NSAIDs such as ibuprofen, corticosteroids such as prednisolone, phosphodiesterase inhibitors, adenosine agonists, antithrombotic agents, complement inhibitors, adrenergic agents, agents which interfere with signaling by proinflammatory cytokines such as TNF-a or IL-1 (e.g., IRAK, NIK, IKK, p38, MAP kinase inhibitors), IL-ip converting enzyme inhibitors, TNF-a converting enzyme inhibitors, T-cell signaling inhibitors such as kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, azathioprine, 6-mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine receptors and derivatives thereof (e.g., soluble p55 or p75 TNF receptors, sIL-lRI, siL-lRII, sIL-6R) and anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-12, IL-13, TGFP).

[0124] In another preferred embodiment further comprising co-administration of an antibiotic selected from clarithromycin, ciprofloxacin, and metronidazole.

[0125] In another preferred embodiment further comprising administering topical agents (e.g., antiseptic washes, topical antibiotics, resorcinol 15% cream); antibiotics (e.g., oral and intravenous antibiotics as monotherapy (tetracyclines, ertapenem, dalbavancin or in combination (e.g., clindamycin and rifampicin)); a tumor necrosis factor (TNF) inhibitor, e.g., adalimumab or infliximab; and / or a monoclonal antibody that selectively inhibits interleukin 17, e.g., IL-17A and IL-17F, e.g. bimekizumab or secukinumab.

[0126] In another preferred embodiment the HS at the start of treatment is moderate-to-severe HS, e.g., Hurley Stage 2 (moderate) HS or Hurley Stage 3 (severe) HS.

[0127] In another preferred embodiment the HS at the start of treatment is characterized by lesions displaying or associated with NETosis, anti-histone antibodies, and / or activated macrophages.

[0128] In another preferred embodiment the HS after three months of treatment is improved by at least one Hurley Stage, e.g., severe to moderate, mild, or normal, or moderate to mild or normal. In a more preferred embodiment, the patient shows improvements according to HiSCR (such as HiSCR50, HiSCR75, or HiSCR90) and IHS4 (such as IHS4-55).

[0129] In another preferred embodiment after three months of 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.

[0130] The invention also provides a method for treating HS, the method comprising administering to a subject in need thereof, a pharmaceutical composition comprising means for inhibiting IL-21, for example, wherein the means for inhibiting IL-21 include an inhibitor as described herein, such as in any of Method 1, etseq., such as a monoclonal antibody which binds IL-21, e.g., as described in Method 1, et seq.

[0131] Throughout the description and claims the word "comprises" and its variations, are not intended to exclude other technical characteristics, additives, components, or steps. Additional objects, advantages and features of the invention will be apparent to those skilled in the art by examining the description or may be learned with the practice of the invention. The following examples and figures are provided by way of illustration and are not intended to limit the present invention. In addition, the present invention covers all possible combinations of the particular and preferred embodiments described herein.

[0132] EXAMPLES

[0133] Determination of IL-21 levels in skin samples by immunohistochemistry

[0134] Paraffin embedded tissue sections from excisional biopsies from patients with hidradenitis and healthy control skin were heated at 60°C for 30 minutes, de-paraffinized, and rehydrated. Slides were placed in Ph6 antigen retrieval buffer and heated at 125°C for 30 seconds in a pressure cooker water bath. After cooling, slides were treated with 3% H2O2 (5 minutes) and blocked using 10% goat serum (30 minutes). Overnight incubation (4°C) was performed using anti-IL-21 antibody (AB 118510, ABCAM, at working concentration 1 :250).

[0135] Slides were then washed, treated with the secondary antibody (Rabbit Anti-Goat IgG Antibody (H+L), Biotinylated, Vector Laboratories, BA-5000-1.5), 1.5mg, peroxidase (30 minutes) and diaminobenzidine substrate (Fisher Scientific, Cat. No. BDB550880, DAB SBSTR KIT), before imaging (Microscope, ZEISS, Model: Axio Observer 5).

[0136] Fig. 1 shows that IL-21 is highly expressed in tissue samples.

[0137] Determination of IL-21 levels in HS serum samples (mesoscale)

[0138] HS patient serum was obtained from 20 patients or healthy controls, and Mesoscale IL- 21 kit, following manufacturer’s instructions, used to measure IL-21 levels.

[0139] Fig. 2 shows that IL-21 was expressed at higher level in HS subjects with respect to healthy controls.

[0140] Effect of the administration of an IL-21 inhibitor on HS

[0141] Five lesional skin samples (2-3 biopsies by patient) were obtained from HS patients with chronic, active disease (Hurley stage II or III).

[0142] 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. After that, the skin biopsies were cultured for 24 h at 37°C 5% CO2 atmosphere with an anti-IL-21 antibody (mAb 5), from Creative Biolabs (HPAB-0315-CN) at 200 nM.

[0143] Gene expression in skin homogenates for some cytokine inflammatory markers was analysed, using an array card (Applied Biosystems TaqMan Array Card) including genes [IL22, IL23, IL36, IL17A, IL17F, fFNy; housekeeping genes: GAPDH and 0-actin], following manufacturer’s instructions, prior and after contacting the samples with the anti -IL-21 antibody mAb 5.

[0144] From these data, it was determined the % of inhibition of the expression for each marker, using the following formula:

[0145] % mRNA inhibit! on=[(Control level - Sample level ) / Control level] x 100 wherein: Control level= the level of expression prior to administering anti-IL-21 mAb 5;

[0146] Sample level= the level of expression after administering anti-IL-21 mAb 5

[0147] The results are summarized in Table 4 below:

[0148] Table 4:

[0149] Administration of IL-21 inhibitor provided a broad-spectrum effect, significantly reducing the amount of some interleukins, such as IL-17F and IL-22, just 24 hours after administration. The broad-spectrum and immediate effect is indicative of the suitability of an IL-21 inhibitor in the management of HS.

[0150] Effect of IL-21 inhibitor on T-cell pathway

[0151] Whole blood from healthy donors was used to isolate PBMCs using sedimentation PBMC isolation kits from Miltenyi. CD3 T-cells were subsequently isolated from PBMCs using CD3 isolation kits (StemCell). 1X105T-cells were plated out and stimulated with recombinant IL-21 10 nm (Miltenyi) with or without anti-IL-21 mAb 6 or anti IL-21 mAb 5 from Creative Biolab (ref. HPAB-0315-CN)) for 30 min at room temperature. Following 30 min the cells were lysed with lysis buffer (Revvity). pSTAT3 chemiluminescence were quantified using AlphaLISA SureFire Ultra Human pSTAT3 kit and Envision plate reader (both Revvity). IC50 values for each antibody were subsequently calculated using graphpad prism software and are shown in Table 5. Table 5:

[0152] Clinical study of anti-IL-21 antibody in adults with HS

[0153] A Phase 2 proof-of-concept, randomized, double-blind, placebo-controlled clinical study, was designed to evaluate the efficacy and safety of an anti-IL-21 monoclonal antibody in adult subjects with moderate-to-severe HS.

[0154] The anti-IL-21 antibody used in this study corresponded to mAb 6, as described herein.

[0155] The primary objective was to assess the efficacy of intravenous (IV) infusions of the anti- IL-21 antibody. The clinical response assessments, HiSCR, total number of abscesses and inflammatory nodules (AN) count, Skin Pain numerical rating scale (NRS), International Hi dradenitis Suppurativa Severity Score (IHS4), Hidradenitis Suppurativa Quality of Life Score (HiSQOL), and monitoring of HS flares, were used as standard tools for assessing the severity of HS (abscesses, nodules, fistulas, etc), its associated pain, and its impact on quality of life. As these efficacy measures were commonly used in randomised controlled trials in patients with HS, the results from this trial were benchmarked against those obtained in randomised controlled trials of other therapeutic agents used for the treatment of HS. Efficacy was primarily evaluated by the proportion of participants who achieved HiSCR50 at week 12 of the study, indicating a >50% reduction in AN count with no increase in abscess count and no increase in draining fistula count relative to baseline. Efficacy was also evaluated using the HiSCR75, HiSCR90, IHS4-55 and other known by the skilled person at week 12.

[0156] Safety, PK and immunogenicity were also evaluated. The safety assessments for the trial included accepted measures for ensuring participant safety during a clinical trial. Vital signs, physical examinations, local tolerance, 12-lead electrocardiograms (ECGs), and clinical laboratory parameters were performed throughout the trial. Additionally, PK and anti-drug antibody (ADA) sampling were conducted to characterize the pharmacokinetic profile and immunogenicity of the anti-IL-21 antibody following IV administration.

[0157] The main inclusion criteria were being male or female between 18 and 65 years old inclusive, with a body mass index (BMI) of <40 kg / m2 and a body weight of >45 kg at the time of signing the informed consent. A diagnosis of moderate-to-severe HS was defined as a total of >5 inflammatory lesions (ie, number of abscesses plus number of inflammatory nodules) at both the Screening and Baseline visits, with a clinical history of HS for at least 6 months. HS lesions had to be present in at least 2 distinct anatomic areas (eg, left and right axilla), one of which had to be at least Hurley Stage II or Hurley Stage III at both the Screening and Baseline visits.

[0158] The main exclusion criteria included having syndromic HS, i.e., HS associated with genetic background, follicular plugging or structural disorders, autoinflammatory pathogenesis, as per Investigator’s judgment. HS with >20 draining tunnels at both the Screening and Baseline visits was also excluded. The presence of skin comorbidities that could have interfered with trial assessments, in the opinion of the Investigator, (e.g. cystic Acne, follicular pyodermas, bacterial cellulitis, actinomycosis, Candida intertrigo, extensive condyloma) was considered exclusionary. Surgical intervention for the treatment of HS within 3 months prior to Baseline was also an exclusion criterion. Ongoing medical conditions (e.g. inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis) requiring systemic immunosuppressive / immunomodulating treatments (eg, methotrexate, ciclosporin, corticosteroids, anti-TNFa agents, JAK-inhibitors) during the trial were grounds of exclusion.

[0159] A total of 50 participants, aged 18 to 65 years inclusive, with moderate-to-severe HS were randomized in a 3:2 ratio to receive doses of either:

[0160] Treatment arm: anti-IL-21 antibody mAb 6 IV infusion

[0161] Placebo arm: Saline solution for IV infusion

Claims

CLAIMS1. An IL-21 inhibitor for use in a method of treating or preventing hi dradenitis suppurativa (HS).

2. The IL-21 inhibitor for use according to claim 1, wherein the IL-21 inhibitor blocks the binding of IL-21 to the IL-21 receptor.

3. The IL-21 inhibitor for use according to any one of the preceding claims, wherein the IL-21 inhibitor binds to IL-21.

4. The IL-21 inhibitor for use according to any one of the preceding claims, wherein the IL-21 inhibitor is an anti-IL-21 antibody, or an antigen-binding fragment thereof.

5. The IL-21 for use according to any one of the preceding claims, wherein the anti- IL-21 antibody, or an antigen-binding fragment thereof comprises: a) a heavy chain comprising one, two or all three of: CDR1 with SEQ ID NO: 1, CDR2 with SEQ ID NO: 2, and / or CDR3 with SEQ ID NO: 3; and / or b) a light chain comprising one, two or all three of: CDR1 with SEQ ID NO:4, CDR2 with SEQ ID NO: 5, and / or CDR3 with SEQ ID NO: 6.

6. The IL-21 inhibitor for use according to claim 5, which comprises all six CDRs with sequences SEQ ID NO: 1 to 6.

7. The IL-21 inhibitor for use according to any one of the preceding claims, wherein the IL-21 inhibitor comprises (i) a heavy chain including a variable region with a sequence having an identity of at least 80%, preferably 85%, preferably, 90%, preferably 95%, preferably 99% with respect to SEQ ID NO: 7, and / or (ii) a light chain including a variable region with an identity of at least 80%, preferably 85%, preferably, 90%, preferably 95%, preferably 99% with respect to SEQ ID NO: 8.

8. The IL-21 inhibitor for use according to any of the foregoing claims, wherein the IL-21 inhibitor is an anti-IL-21 antibody comprising a heavy chain with an identity of at least 80%, preferably 85%, preferably, 90%, preferably 95%, preferably 99% or 100% with respect to SEQ ID NO. 9; and a light chain with an identity of at least 80%, preferably 85%, preferably, 90%, preferably 95%, preferably 99% or 100% with respect to SEQ ID NO. 10; particularly, the IL-21inhibitor comprises a heavy chain consisting of SEQ ID NO: 9 and a light chain consisting of SEQ ID NO: 10.

9. The IL-21 inhibitor for use according to any of the preceding claims, wherein the IL-21 inhibitor is administered in the form of a pharmaceutical composition, comprising one or more pharmaceutically acceptable excipient(s), carrier(s) or vehicle(s).

10. The IL-21 inhibitor for use according to any one of the preceding claims, wherein the IL-21 inhibitor is administered in combination with at least one or more active agent.

11. The IL-21 inhibitor for use according to claim 9, wherein the IL-21 inhibitor and the one or more active agent are administered separately, consecutively, or simultaneously.

12. The IL-21 inhibitor for use according to any one of the claims 10-11, wherein 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 anti-inflammatory cytokines (e.g., IL-4, IL-10, IL-12, IL-13, TGFP).

13. The IL-21 inhibitor for use according to any of the preceding claims, wherein a. the IL-21 inhibitor as defined in any one of the preceding claims 1-8, optionally in combination with the one or more active agents, or b. the pharmaceutical composition comprising i. the IL-21 inhibitor as defined in any of the preceding claims 1-8, ii. the one or more pharmaceutically acceptable carrier, excipient or vehicle, andiii. optionally the one or more active agents is administered by parenteral route.

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