Treatment of hidradenitis suppurativa using anti-BAFF-R antibodies

Abstract

The present disclosure relates to methods, therapeutic regimens, uses, kits and therapies for the treatment of hidradenitis suppurativa by employing molecules that inhibit B cell activating factor receptor (BAFF-R), such as anti-BAFF-R antibodies.

Description

Technical Field

[0001] This disclosure relates to methods, treatment regimens, uses, kits, and therapies for treating (especially in subjects in need) hidradenitis suppurativa, including administering (especially in a therapeutically effective amount) a molecule that inhibits the B-cell activating factor receptor (BAFF-R), such as an anti-BAFF-R antibody or a binding fragment thereof, especially ilmeniteb (collectively, the pharmaceuticals of the present invention, which are used interchangeably throughout this application), and related inventive embodiments as mentioned herein. Background Technology

[0002] Hidradenitis suppurativa (HS), also known as "acne paradox" or "Maladie de Verneuilh," is a chronic, relapsing, and debilitating inflammatory skin condition that typically manifests as deep, inflammatory, and painful lesions in parts of the body containing apocrine glands. The most common areas affected are the armpits, groin, and anogenital region (Jemec 2012; Fimmel and Zouboulis 2010).

[0003] Currently, HS is considered an inflammatory disease of pilosebaceous follicles with an underlying immune system imbalance occurring in genetically susceptible individuals (Kelly et al. 2014). Although HS is thought to be primarily caused by follicular blockage, it is an inflammatory skin disease characterized by a large number of neutrophils and macrophages in the inflammatory lesions (Lima et al. 2016, Shah et al. 2017). While the pathophysiology of HS remains largely unknown, the benefits of tumor necrosis factor α (TNFα) blockade have been described in larger studies (Kimball et al. 2016).

[0004] Evidence of efficacy for anti-IL1 therapy (Tzanetakou et al. 2016) and blocking IL-17A (Thorlacius et al. 2017, Schuch et al. 2018, Giuseppe et al. 2018, Jørgensen et al. 2018) or anti-IL-23 therapy (Sharon et al. 2012, Blok et al. 2016) has also been observed in smaller studies and / or case reports. Recently, research methods using the oral PDE4 inhibitor apremilast (Weber et al. 2017) or anti-complement 5a compounds (Kanni et al. 2018) have been described.

[0005] The disease begins after puberty and is more common in females than males (3:1). Risk factors include obesity and smoking. Although epidemiological prevalence estimates vary widely (0.03%–4.3%; Jemec 2012, Jemec and Kimball 2015) and there are geographical differences, the scientifically accepted prevalence is approximately 0.1%–1% (Garg et al. 2018).

[0006] The clinical presentation of HS is heterogeneous, but the disease tends to present as chronic, relapsing, deep, painful, inflammatory skin lesions, primarily inflammatory nodules and abscesses, leading to possible drainage and suppuration. During disease progression, the formation of sinus tracts and fistulas complicates the inflammatory lesions and may lead to hypertrophic scarring, potentially impacting functional use.

[0007] HS is associated with pain, foul-smelling discharge from wounds, and scar formation, and indeed frequently has devastating psychosocial effects. HS is a severely debilitating disease that significantly impacts quality of life (QoL), with multiple studies confirming that its effects are greater than those seen in other skin diseases (Deckers and Kimball 2016). HS patients also frequently suffer from depression, social isolation, impaired sexual health, and may have difficulty fulfilling their work responsibilities (Esmann and Jemec 2011, Fimmel and Zouboulis 2010, Janse et al. 2017).

[0008] HS is difficult to treat. The official European treatment guidelines were only established in 2015, recommending that patients be provided with adjuvant, pharmacological and surgical therapies (Zouboulis et al. 2015).

[0009] Although topical antibiotics can be used for mild cases, moderate to severe HS is best treated with long-term multi-systemic antibiotic therapy (usually a combination of tetracycline or clindamycin and rifampin), which can then be maintained for months or even years with chronic antibiotic therapy (Bettoli et al. 2016, Dessinioti et al. 2016, Zouboulis et al. 2015).

[0010] However, HS is a well-known chronic inflammatory disease, not a contagious one (Jemec 2012). Therefore, anti-inflammatory drugs are an alternative to antibiotics and may be a more suitable approach, or a supplement to antibiotics. Over time, the consequences of chronic, relapsing, and poorly treated inflammation are irreversible fibrosis, manifested as scarring and channels or sinuses that are often unresponsive to drug therapy. Once persistent anatomical changes occur, the only treatment option to reduce the volume of fibrotic tissue and improve function in the affected skin areas is surgery (Andersen and Jemec 2017). One of the future treatment goals should be to reduce persistent scarring and avoid surgery, which can be achieved by preventing inflammatory lesions, or may require specific treatment methods.

[0011] In 2015, adalimumab (Humira®), a recombinant human monoclonal immunoglobulin G1 (IgG1) antibody targeting soluble and membrane-bound TNF-α, received regulatory approval for the treatment of moderate to severe hidradenitis suppurativa (HS). The efficacy of adalimumab has been observed, with HiSCR (hidradenitis suppurativa clinical response) response rates exceeding those of placebo at 16% (adalimumab 41.8% vs. placebo 26%) and 31% (adalimumab 58.9% vs. placebo 27.6%), respectively, reported in the PIONEER I and II studies (Kimball et al. 2016). As captured in the adalimumab label, adalimumab is associated with an increased safety risk of serious infections, including tuberculosis, invasive fungal infections, and other opportunistic infections. An increased incidence of malignancies has also been reported with adalimumab use.

[0012] Therefore, there is an unmet need for systemic therapies that effectively reduce inflammation while having a favorable safety profile for patients with moderate to severe HS. Detailed Implementation

[0013] Although the pathogenesis of HS is not fully understood, this chronic skin disease is characterized by a high number of neutrophils, macrophages, and B cells / plasma cells in inflamed HS lesions. The presence and upregulation of B cells have also been previously observed in HS lesions (Hunger et al., 2008; van der Zee et al., 2012). B cells and plasma cells are detected in HS lesions, particularly in chronic lesions (relative to the early stages), compared to the surrounding lesions and healthy skin (van der Zee). In some samples, lymphoid follicles with CD20+ B cells were detected in chronic lesions. In a recent study conducted by Novartis (CJM112X2202) involving subjects with moderate to severe HS, histological samples showed extensive B cell infiltration in multiple germinal centers within the lesioned skin and tissue. In the same study, cell type signatures in gene expression data from skin biopsies not only showed a clear B cell signature but also a transcriptomic macrophage signature. Consistent with these observations, the abnormality and upregulation of circulating B cell subsets in HS patients was communicated at the European HS Foundation meeting in Rotterdam in 2018 (Musilova J, 2018). More recently, it has been reported that BAFF (B cell activating factor) is abundant in HS lesions, particularly in nodules and abscesses (Sabat et al., 2023), with myeloid cells (neutrophils) being the main producers of BAFF.

[0014] This invention provides potential disease-modifying therapies for HS that are well-tolerated, convenient for patients, and induce high remission rates (which are maintained even after the end of the treatment period).

[0015] On one hand, the present invention provides a method for treating (particularly in subjects in need) hidradenitis suppurativa (HS), comprising administering (particularly in a therapeutically effective amount) a molecule that inhibits the B-cell activating factor receptor (BAFF-R). In one embodiment, the BAFF-R-inhibiting molecule is an antibody against BAFF-R (anti-BAFF-R antibody) or a binding fragment thereof. In another embodiment, such an anti-BAFF-R antibody is unfucosylated. It has been shown that enhanced antibody-dependent cytotoxicity (ADCC) can improve clinical outcomes in autoimmune diseases such as lupus nephritis (LN) due to the use of unfucosylated antibodies (Furie et al. 2022).

[0016] In one embodiment, the anti-BAFF-R antibody or its binding fragment comprises CDR-H1, CDR-H2, and CDR-H3 having amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively, and CDR-L1, CDR-L2, and CDR-L3 having amino acid sequences of SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively.

[0017] In one embodiment, the anti-BAFF-R antibody or its binding fragment comprises VH having the amino acid sequence of SEQ ID NO: 3 and VL having the amino acid sequence of SEQ ID NO: 4, respectively.

[0018] In one embodiment, the anti-BAFF-R antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:1 and a light chain having the amino acid sequence of SEQ ID NO:2.

[0019] In one embodiment, the anti-BAFF-R antibody or a fragment thereof is imicumab or an imicumab fragment, or a binding fragment thereof. In some embodiments, the anti-BAFF-R antibody is imicumab.

[0020] B cell activating factor (BAFF) is a member of the tumor necrosis factor (TNF) family and is produced by many cell types, including antigen-presenting cells (B cells, monocytes / macrophages, dendritic cells), neutrophils, epithelial cells, and activated T cells. BAFF functions via its receptor (BAFF-R) expressed on most B cells. The BAFF-R signaling pathway is key involved in the activation of B cell effector functions, such as antibody production, allotype switching, B cell proliferation, maturation, and survival (Mackay et al. 2009).

[0021] Ilimumab's antigen specificity targets the BAFF receptor BAFF-R (Syn:BR3), which is expressed on the surface of both immature and mature B cells up to the lymphoblast stage. Therefore, progenitor B cells and pre-B cells that express CD20 but not BAFF-R are not expected to be affected by imatumab. Thus, compared to existing anti-CD20 antibody therapies for depleted B cells, imatumab targets a narrower spectrum of highly differentiated B cells.

[0022] Ilimumab is a glycoengineered (fucosylated-free), fully human IgG1 monoclonal antibody targeting BAFF-R expressed on the surface of B cells, thereby targeting B cells and their functions through two modes of action:

[0023] ADCC directly cleaved and depleted BAFF-R-expressing B cells through enhanced Fc (crystallizable fragment) regions due to their fucose deficiency; and

[0024] BAFF receptor blockade interrupts BAFF-mediated signaling for B cell maturation, proliferation, and survival (Bowman et al. 2022).

[0025] In preclinical studies, illuminumab significantly enhanced ADCC and cytokine production in B cells and was more effective at depleting B cells compared to approved anti-CD20 antibodies, including rituximab, olibutuzumab, and ofamumab (McWilliams et al. 2019).

[0026] Due to its dual activity, ilimibe combines rapid and effective B-cell depletion with sustained BAFF-R blockade to prevent pathogenic BAFF-driven rebound mechanisms (Genovese et al. 2010, Furie et al. 2011, Mariette 2012). Ilimumab's efficacy in primary Sjögren's syndrome (pSS) was demonstrated in a phase II study (Bowman SJ et al. 2021).

[0027] Studies of imatinib in HS have not yet been conducted. However, the use of imatinib in HS is supported by the following:

[0028] • Both B cells and plasma cells are present in HS lesions (Gudjonsson et al., 2020).

[0029] • It has recently been demonstrated that increased BAFF expression in HS is associated with the presence of B cells and plasma cells at the lesion site (Sabat, 2022).

[0030] • In adalimumab non-responders, there was an increase in B cells and plasma cells in the diseased skin at baseline (Hambly, 2022, BioRxiv).

[0031] • Autoantibodies are associated with disease severity and duration.

[0032] • BAFF-R pathway inhibition has been proven effective and safe in non-hematologic autoimmune diseases (BENLYSTA® Prescription Information).

[0033] Clinical studies of ilimibab have demonstrated its efficacy in treating other autoimmune diseases.

[0034] Therefore, through its dual mechanism of action, combined with existing data and the data disclosed in this application, it is expected to demonstrate the efficacy and safety of ilimibe in treating HS, especially by overcoming the aforementioned limitations of HS therapy through effective B-cell depletion and BAFF-R blockade.

[0035] As disclosed in this article, the use of anti-BAFF-R antibodies (such as ilimibe) to treat patients with HS is an effective treatment, and its clinical response can be assessed by, for example, the Simplified Hidradenitis Suppurative Clinical Response (HiSCR), the International Hidradenitis Suppurative Severity Scoring System (IHS4), the Hidradenitis Suppurative Physician Overall Assessment (HS-PGA) score and response rate, the HS inflammatory lesion count, or the Hidradenitis Suppurative Severity Assessment (SAHS).

[0036] In one embodiment, an anti-BAFF-R antibody or a fragment thereof, particularly ilmenite, is administered to a subject (especially a subject in need) at a dose of about 150 to about 450 mg, or about 200 to about 350 mg. Preferably, the dose is about 150 mg to about 300 mg. More preferably, the dose is about 300 mg.

[0037] In one embodiment, an antibody (especially ilmeniteb) or a binding fragment thereof is administered to a subject (especially a subject in need) every 4 weeks (q4w, monthly, + / - 3 days).

[0038] In one embodiment, the antibody is ilmeniteb, wherein ilmeniteb is administered subcutaneously to subjects (especially those in need) at a dose of approximately 150 mg every four weeks (q4w, monthly, + / - 3 days).

[0039] In one embodiment, the antibody is ilmeniteb, wherein ilmeniteb is administered subcutaneously to the subject (especially the subject in need) at a dose of approximately 300 mg every four weeks (q4w, monthly, + / - 3 days).

[0040] In one embodiment, a molecule that inhibits B-cell activating factor receptor (BAFF-R), particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly ilmenite, is administered to a subject (especially a subject in need) as a monotherapy. During the period of treatment with the medicament of the present invention, the subject did not receive any other treatment for HS.

[0041] In one embodiment, ilmeniteb is administered as a monotherapy to a subject who has experienced inadequate response or relapse following an initial prior treatment regimen, typically first-line steroid therapy or conventional HS medication (as standard care).

[0042] In one embodiment, a molecule that inhibits the B-cell activating factor receptor (BAFF-R), particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly ilimibe, is administered to a subject, wherein the subject receives initial treatment after being diagnosed with HS, or the molecule is administered at the same time as the start of initial treatment.

[0043] In one embodiment, a molecule that inhibits the B-cell activating factor receptor (BAFF-R), particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly ilmeniteb in combination with initial treatment, is administered to a subject for the treatment of HS.

[0044] In one embodiment, the present invention provides B-cell activating factor receptor (BAFF-R), particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly ilmeniteb, for use in combination with initial treatment to treat HS.

[0045] In one embodiment, initial treatment is or includes treatment with standard care (SOC) medications, which can be used to relieve the signs and symptoms of HS, such as antibiotics or biologics.

[0046] In one embodiment, the initial treatment is a corticosteroid, preferably a glucocorticoid, preferably dexamethasone, and more preferably prednisone or prednisolone. Initial treatment with prednisone or prednisolone is administered according to the approved dosage.

[0047] In an alternative embodiment, the initial treatment did not include rituximab. The subject had never received rituximab or had not received rituximab for at least one year or at least 6 months prior to treatment with the drug of the present invention.

[0048] In one embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of an antibody for use according to the first aspect and one or more pharmaceutically acceptable carriers.

[0049] In one embodiment, the administration route is subcutaneous or intravenous, or a combination of subcutaneous or intravenous administration of the antibody according to the first aspect.

[0050] The dosage can be from about 3 mg to about 10 mg of active ingredient per kilogram of human subject. The dosage can be given once a week, once every two weeks, or once every four weeks.

[0051] In one embodiment, the dosage is from about 150 mg to about 600 mg of the active ingredient. The dosage can be given once a week, once every two weeks, or once every four weeks.

[0052] In one embodiment, the dose is approximately 300 mg of the active ingredient. The dose may be administered once weekly, once every two weeks, or once every four weeks.

[0053] In one preferred embodiment, the dosage is 150 mg of the active ingredient. In another preferred embodiment, the dosage is 300 mg of the active ingredient. In yet another preferred embodiment, the dosage is 300 mg of the active ingredient and can be administered every four weeks.

[0054] In one embodiment, the antibody is administered via loading and maintenance administration. In one embodiment, loading is administered via subcutaneous injection of a first dose, and maintenance is administered via subcutaneous injection of a second dose. The first dose may be the same as or higher than the second dose.

[0055] Patients with HS can choose based on one of the following criteria:

[0056] - The patient has moderate to severe HS;

[0057] -The patient is an adult;

[0058] -The patient is a teenager;

[0059] - Prior to treatment with anti-BAFF-R antibody, the patient's HS-PGA score was ≥ 3;

[0060] - Prior to treatment with anti-BAFF-R antibodies, the patient had at least 3 inflammatory lesions; or

[0061] - Prior to treatment with anti-BAFF-R antibody, the patient did not have extensive scarring due to HS (< 10 fistulas).

[0062] In one embodiment, by week 16 of treatment, HS patients achieve a clinical response as measured by at least one of the following:

[0063] - Simplified HiSCR;

[0064] -Redness and swelling in HS have decreased;

[0065] -NRS30;

[0066] - Reduction ≤ 6 as measured by DLQI; and / or

[0067] - Improvements to DLQI.

[0068] In one embodiment, by week 16 of treatment, at least 40% of the patients achieved a clinical response as measured by a simplified HiSCR; or at least 25% of the patients achieved an NRS30 response; or less than 15% of the patients experienced HS redness.

[0069] In one embodiment, the patient has at least one of the following as early as one week after the first dose of the anti-BAFF-R antibody:

[0070] - Pain is rapidly relieved as measured by VAS or NRS, and

[0071] - CRP levels decreased rapidly when measured using the standard hsCRP assay.

[0072] In one embodiment, patients achieve sustained response 3 months after the end of treatment, as measured by inflammatory lesion count, HS clinical response (HiSCR), numerical rating scale (NRS), modified Sartorius HS score, hidradenitis suppurativa-physician overall assessment (HS-PGA), or dermatology quality of life index (DLQI).

[0073] In one embodiment, the patient achieves a sustained response 3 months after the end of treatment, as measured by a simplified HiSCR (sHiSCR).

[0074] According to the second aspect, a method for treating HS in a human subject is provided, the method comprising administering a therapeutically effective dose of antiBAFF-R antibody to the subject.

[0075] In one embodiment, the antibody is administered together with one or more pharmaceutically acceptable carriers.

[0076] In one embodiment, the antibody is administered subcutaneously or intravenously, or a combination of subcutaneous or intravenous administration.

[0077] In one embodiment, the antibody is administered at a dose of about 3 mg to about 10 mg of active ingredient per kilogram of human subject.

[0078] In one embodiment, the dosage is approximately 3 mg of active ingredient per kilogram of human subject.

[0079] In one embodiment, the antibody is administered at a dose of about 150 mg to about 300 mg of the active ingredient (e.g., 300 mg of the active ingredient).

[0080] In one preferred embodiment, the dosage is 150 mg of the active ingredient. In another preferred embodiment, the dosage is 300 mg of the active ingredient.

[0081] In one embodiment, the antibody is administered via loading and maintenance dosing.

[0082] In one embodiment, loading administration is administered via subcutaneous injection of a first dose, and maintenance administration is administered via subcutaneous injection of a second dose.

[0083] The first dose may be the same as or higher than the second dose.

[0084] In practicing some of the treatment methods or uses disclosed herein, a therapeutically effective amount of a BAFF-R-inhibiting molecule, particularly an anti-BAFF-R antibody or a binding fragment thereof, is administered to a patient, such as a mammal (e.g., a human). While it should be understood that the disclosed methods provide for the treatment of HS patients with BAFF-R-inhibiting molecules, particularly anti-BAFF-R antibodies or a binding fragment thereof, particularly imicumab, this does not preclude that if a patient is ultimately treated with a BAFF-R-inhibiting molecule, particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly imicumab, it must be monotherapy. In fact, if a patient is selected for treatment with a BAFF-R-inhibiting molecule, particularly an anti-BAFF-R antibody or a binding fragment thereof, particularly imicumab, it can be administered alone or in combination with other agents and therapies according to the methods disclosed herein.

[0085] It should be understood that regimen changes may be applicable to certain HS patients, such as those who do not respond adequately to treatment with molecules that inhibit BAFF-R, particularly anti-BAFF-R antibodies or their binding fragments, especially ilimibe. Therefore, administration of molecules that inhibit BAFF-R, particularly anti-BAFF-R antibodies or their binding fragments (e.g., ilimibe), may be more frequent than monthly dosing, such as every two weeks or weekly.

[0086] For example, an appropriate regimen for illuminumab could be once weekly for several weeks [e.g., 1 to 4 weeks, such as administration in weeks 0, 1, 2 and 3], followed by a monthly maintenance regimen.

[0087] In another instance, the appropriate regimen for illuminumab is once weekly for several weeks (e.g., 2 to 8 weeks, such as 3 weeks, e.g., dosing at week 0, week 1, week 2), followed by a maintenance regimen every two weeks.

[0088] It should also be understood that administration (e.g. for ilimiba) may not be as frequent as once a month, such as every 6 weeks, every 8 weeks (every two months), or every quarter (every three months).

[0089] It should be understood that, based on disease severity, dose escalation may be appropriate for certain HS patients, such as those who have not responded adequately to treatment with molecules that inhibit BAFF-R, particularly anti-BAFF-R antibodies or their binding fragments, especially imatinib. Therefore, subcutaneous (sc) doses may be greater than about 150 mg to about 300 mg sc, e.g., about 300 mg; similarly, intravenous (iv) doses may be greater than about 3 mg / kg, e.g., about 6 mg / kg, 9 mg / kg, 10 mg / kg, etc. It should also be understood that dose reduction may be appropriate for certain HS patients, such as those who have experienced adverse events or adverse responses to treatment with molecules that inhibit BAFF-R, particularly anti-BAFF-R antibodies or their binding fragments, especially imatinib. Therefore, the dose of molecules that inhibit BAFF-R, especially anti-BAFF-R antibodies or their binding fragments, especially ilmenite, can be less than about 150 mg to about 300 mg sc, for example about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, etc.

[0090] definition

[0091] In addition to other definitions already provided, the following definitions are used to define the specific, preferred meanings of the features and language used in the specification and claims of this invention, wherein any one or more or all more general terms may be replaced with specific meanings to produce specific inventive embodiments.

[0092] The word “substantially” does not exclude “completely”; for example, a composition that is “substantially free of” Y can be completely free of Y. The word “substantially” may be omitted from the definition in this disclosure if necessary.

[0093] The term “comprising” encompasses both “including” and “consisting of”, for example, a composition that “comprising” X may consist of only X or may include other components, such as X + Y.

[0094] AUC0-t represents the area under the plasma concentration-time curve from time zero to time 't', where t is the determined time point after administration [mass x time / volume].

[0095] AUCtx-ty represents the area under the plasma concentration-time curve from time 'x' to time 'y', where 'time x' and 'time y' are time points defined after administration.

[0096] C max It is the maximum plasma concentration [mass / volume] observed after drug administration.

[0097] C min It is the lowest plasma concentration observed after drug administration.

[0098] C 谷 It is the plasma concentration observed exactly before or at the end of the dosing interval.

[0099] T max It is the time [time] for a drug to reach its maximum concentration after administration.

[0100] ss (subscript) indicates that the parameter is defined in a stable state.

[0101] Naturally occurring "antibodies" are glycoproteins comprising at least two heavy (H) chains and two light (L) chains linked together by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region consists of three domains (CH1, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region. The light chain constant region consists of one domain, CL. The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant regions of these antibodies can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. The term "antibody" includes, for example, monoclonal antibodies, human antibodies, humanized antibodies, camel antibodies, or synthetic antibodies. These antibodies can belong to any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass, preferably IgG and most preferably IgG1.

[0102] Both the light and heavy chains are divided into structural homology regions and functional homology regions. The terms "constant" and "variable" are used functionally. In this respect, it should be understood that the variable domains of both the light chain (VL) and heavy chain (VH) portions determine antigen recognition and specificity. Conversely, the constant domains of the light chain (CL) and heavy chain (CH1, CH2, or CH3) confer important biological properties such as secretion, transplacental mobility, Fc receptor binding, and complement binding. By convention, the farther the constant domain is from the antibody's antigen-binding site or N-terminus, the higher its number. The N-terminus is the variable region, and the C-terminus is the constant region; the CH3 and CL domains actually contain the carboxyl terms of the heavy and light chains, respectively.

[0103] As used herein, the term “antigen-binding portion” (or simply “antigen portion”) of an antibody refers to a full-length antibody or one or more fragments of an antibody, such as a protein, that retain the ability to specifically bind to an antigen or epitope.

[0104] A complementarity-determining region (“CDR”) is an amino acid sequence with defined boundaries using one of many well-known schemes, including those described in the following literature: Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD (“Kabat” numbering scheme); Al-Lazikani et al., (1997) JMB 273, 927-948 (“Chothia” numbering scheme); and ImMunoGenTics (IMGT) numbering (Lefranc, M.-P., The Immunologist, 7, 132-136 (1999); Lefranc, M.-P. et al., Dev. Comp. Immunol.). 27,55-77 (2003) (“IMGT” numbering scheme). Under IMGT, the CDR region of an antibody can be determined using the IMGT / DomainGap Align procedure.

[0105] As used herein, the term "epitope" refers to any determinant that binds to immunoglobulins with high affinity. An epitope is a region of an antigen that an antibody specifically targets binds to, and when the antigen is a protein, the epitope comprises a specific amino acid that directly contacts the antibody. In most cases, epitopes are located on proteins, but in some cases, they can be located on other types of molecules, such as nucleic acids. Epitope determinants can include chemically active surface groups of a molecule, such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and can have specific three-dimensional structural features and / or specific charge features. Furthermore, although the two domains VL and VH of the Fv fragment are encoded by separate genes, these two domains can be linked together using recombination methods through synthetic linkers that enable them to form a single protein chain, where the VL and VH regions pair to form a monovalent molecule (called a single-stranded Fv (scFv); see, for example, Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc. Natl. Acad. Sci. 85:5879-5883).

[0106] As used herein, the phrase "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigen specificities. Furthermore, isolated antibodies may be substantially free of other cellular material and / or chemicals. As used herein, the terms "monoclonal antibody" or "monoclonal antibody composition" refer to formulations of antibody molecules having a single molecular composition. As used herein, the term "human antibody" is intended to include antibodies having variable regions having both a framework region and a CDR region derived from human-derived sequences. "Human antibodies" need not be produced by humans, human tissues, or human cells. Human antibodies of this disclosure may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro, N-nucleotide addition at the in vivo linker during antibody gene recombination, or somatic mutations in vivo).

[0107] The “identity” of natural polypeptides and their functional derivatives is defined in this paper as the percentage of amino acid residues in a candidate sequence that are identical to those of the corresponding natural polypeptide residues, after sequence alignment and the introduction of vacancies (if necessary) to achieve the maximum percentage of identity, and without regard to any conserved substitutions as part of sequence identity. N-terminal or C-terminal extensions and insertions should not be interpreted as reducing identity. The methods and computer programs used for alignment are well known. Percentage identity can be determined by standard alignment algorithms, such as the Basic Local Alignment Search Tool (BLAST) described by Altshul et al. ((1990) J. Mol. Biol. [Journal of Molecular Biology], 215: 403 410); the algorithm of Needleman et al. ((1970) J. Mol. Biol. [Journal of Molecular Biology], 48: 444 453); or the algorithm of Meyers et al. ((1988) Comput. Appl. Biosci. [Computer Applications in Biological Sciences], 4: 11 17). A set of parameters can be a Blosum 62 scoring matrix with a vacancy penalty of 12, a vacancy extension penalty of 4, and a frameshift vacancy penalty of 5. Alternatively, the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17), which is already integrated into the ALIGN program (version 2.0), can be used to determine the percentage identity between two amino acid or nucleotide sequences using a PAM120 weighted residue table, a vacancy length penalty of 12, and a vacancy penalty of 4.

[0108] "One or more amino acids" refers to, for example, all naturally occurring L-α-amino acids and includes D-amino acids. The phrase "amino acid sequence variant" refers to a molecule that has some differences in its amino acid sequence compared to the sequence according to this disclosure. Amino acid sequence variants of antibodies according to this disclosure (e.g., specified sequences) still retain the ability to bind human BAFF-R. Amino acid sequence variants include substitution variants (those variants that remove at least one amino acid residue and insert a different amino acid at the same position in the polypeptide according to this disclosure), insertion variants (those variants that insert one or more amino acids immediately adjacent to an amino acid at a specific position in the polypeptide according to this disclosure), and deletion variants (those variants that remove one or more amino acids from the polypeptide according to this disclosure).

[0109] As used herein, the term "Fc region" refers to at least a portion of the hinge region of an antibody, which includes the CH3, CH2, and constant structural domains.

[0110] As used herein, the term "affinity" refers to the strength of the interaction between an antibody and an antigen at a single antigenic site. Within each antigenic site, the variable region of the antibody "arm" interacts with the antigen at many sites via weak non-covalent forces; the more interactions, the stronger the affinity. As used herein, the term "high affinity" for IgG antibodies or fragments thereof (e.g., Fab fragments) refers to an affinity of 10 for the target antigen. -8 M or smaller, 10 -9 M or smaller, or 10 -10 M, or 10 -11 M or smaller, or 10 -12 M or smaller, or 10 -13 M or smaller K D The antibody is known as the IgM antibody. However, high-affinity binding can vary for other antibody isotypes. For example, high-affinity binding for the IgM isotype refers to binding with a 10-1... -7 M or smaller, or 10 -8 M or smaller K D Antibodies.

[0111] As used in this article, the term "K" assoc "or "K a "Intended to refer to the binding rate of a specific antibody-antigen interaction, rather than the term "K" as used herein." dis "or "K d "This refers to the dissociation rate of a specific antibody-antigen interaction."

[0112] As used in this article, the term "K" D "This refers to the dissociation constant, which is obtained from K." d With K a The ratio (i.e., K) d / K a The Kc of the antibody is expressed as a molar concentration (M). The Kc of the antibody can be determined using methods well-established in the art. D Value. K value used to determine antibodies. D The method involves using surface plasmon resonance or using biosensor systems such as the Biacore® system.

[0113] As used herein, the term “ADCC” or “antibody-dependent cytotoxic” activity refers to cell depletion activity. ADCC activity can be measured by ADCC assays as well known to those skilled in the art.

[0114] In one embodiment, the term "no ADCC activity or low ADCC activity" means that the antibody exhibits ADCC activity of less than 50% specific cell lysis (e.g., less than 10% specific cell lysis), as measured in a standard ADCC assay. No ADCC activity means that the antibody exhibits less than 1% ADCC activity (specific cell lysis).

[0115] As used herein, the term "binding fragment" refers to a portion of an anti-BAFF-R antibody capable of binding to BAFF-R epitopes, particularly epitopes involved in the binding of BAFF to BAFF-R and / or negatively (e.g., through allosteric binding) affecting BAFF's activation of BAFF-R. Binding of an antibody (or its binding fragment) to BAFF-R reduces the formation of the BAFF / BAFF-R complex and / or reduces the activation of BAFF-R.

[0116] Illumab heavy chain SEQ ID NO: 1

[0117] QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWGWIRQSPGRGLEWLGRIYYRSKWYNSYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARYDWVPKIGVFDS WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0118] Ilimumab light chain: SEQ ID NO: 2

[0119] DIVLTQSPATLSLSPGERATLSCRASQFISSSYLSWYQQKPGQAPRLLIYGSSSRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQLYSSPMTFGQGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0120] Ilimumab heavy chain variable domain (VH) SEQ ID NO: 3

[0121] QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWGWIRQSPGRGLEWLGRIYYRSKWYNSYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARYDWVPKIGVFDSWGQGTLVTVSS

[0122] Ilimumab light chain variable domain (VL) SEQ ID NO: 4

[0123] DIVLTQSPATLSLSPGERATLSCRASQFISSSYLSWYQQKPGQAPRLLIYGSSSRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQLYSSPMTFGQGTKVEIKRT

[0124] Ilimumab includes the following complementary determinant region (CDR):

[0125] Heavy chain:

[0126]

[0127] Light chain:

[0128]

[0129] As used herein, the term “inhibit (inhibition or inhibiting)” means the reduction or suppression of a given condition, symptom or disorder, or disease, or a significant reduction in baseline activity of a biological activity or process.

[0130] As used herein, the term "treat, treating, or treatment" for any disease or disorder, in one embodiment, means improving the disease or disorder (i.e., slowing or halting or reducing the development or progression of the disease or at least one of its clinical symptoms). In another embodiment, "treat, treating, or treatment" means reducing or improving at least one bodily parameter, including those that cannot be discerned by the patient / subject. In yet another embodiment, "treat, treating, or treatment" means modulating the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of bodily parameters), or both. More specifically, the term "treat" for disease HS means treating inflammatory lesions in a patient with HS (in terms of quantity or quality, or reducing their volume and size), and / or treating abscesses and inflammatory nodules and / or draining fistulas in a patient with HS, and / or reducing the amount of scar formation and / or alleviating functional limitations associated with scar formation. Treatment of HS also includes alleviating HS-related pain, fatigue and / or itching, reducing purulent discharge and odor associated with purulent discharge, and / or improving the quality of life and / or reducing work impairment in patients with HS.

[0131] As used herein, the term “prevention” refers to delaying the onset, development, or progression of a disease or disorder. More specifically, the term “preventing” in the context of HS refers to preventing HS lumps and / or the appearance of new lesions; preventing scar formation and preventing functional limitations associated with scar formation; and / or, in particular, preventing surgical interventions for HS.

[0132] As used herein, the term “subject” and the term “patient” are used interchangeably throughout this application. A subject or patient is “in need of” treatment if the subject or patient would benefit biologically, medically, or in terms of quality of life from the treatment.

[0133] As used herein, the terms “a / an”, “the”, and similar terms used in the context of this invention (especially in the context of the claims) should be interpreted to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context.

[0134] As used herein, unless otherwise defined, the term “about” includes a variation of a given value by ±10% or ±5%.

[0135] The term "pharmaceutical acceptable" refers to a non-toxic material that does not interfere with the effectiveness of the bioactivity of one or more active ingredients.

[0136] As used herein, the term "administration / administering" of a subject compound refers to providing the compound of the invention and its prodrug to a subject requiring treatment. Administration in combination with one or more other therapeutic agents includes simultaneous (parallel) and consecutive administration in any order and via any route of administration. A single administration may be a single injection or multiple injections delivered in combination, depending on the amount of pharmaceutical substance required to achieve a therapeutic effect.

[0137] As used herein, "therapeutic effective amount" refers to the amount by which an anti-BAFF-R antibody or its antigen-binding fragment (e.g., ilmenbab) effectively treats, prevents, or prevents the onset of at least one symptom of a disorder or relapsing disorder when administered to a patient / subject (e.g., human) in a single or multiple doses, thereby curing, delaying, reducing, improving, or prolonging the patient's survival beyond what would have been expected in the absence of such treatment. Two or more drugs may be administered independently at the same time or separately at time intervals. When applied to a single active ingredient (e.g., an anti-BAFF-R antibody, such as ilmenbab) administered alone, the term refers to that single ingredient. When applied to a combination, the term refers to the combined amount of active ingredients that produce a therapeutic effect (whether administered sequentially or in combination).

[0138] The phrase "treatment regimen" refers to a regimen used to treat a disease, such as a dosing regimen used during the treatment of HS. A treatment regimen may include a loading regimen (or loading administration) followed by a maintenance regimen (or maintenance administration).

[0139] The phrase "loading regimen" or "loading period" refers to a treatment regimen (or part of a treatment regimen) used for the initial treatment of a disease. In some embodiments, the disclosed methods, uses, kits, procedures, and regimens (e.g., methods for treating HS) employ a loading regimen (or loading dosing). In some cases, the loading period is the time period until maximum efficacy is achieved. The overall goal of a loading regimen is to provide the patient with a high level of the drug at the initial stage of the treatment regimen. A loading regimen may include administering a higher dose of the drug than a physician would use during a maintenance regimen, administering the drug more frequently than a physician would administer the drug during a maintenance regimen, or both. Dosage escalation may occur during or after the loading regimen.

[0140] The phrase "maintenance regimen" or "maintenance period" refers to a treatment regimen (or part of a treatment regimen) used to maintain a patient's remission during disease treatment, such as keeping the patient in remission for an extended period (months or years) after a loading regimen or loading period. In some embodiments, the disclosed methods, uses, and regimens employ a maintenance regimen. Maintenance regimens may be continuous therapy (e.g., administration of medication at regular intervals, such as weekly, every two weeks, or monthly (every four weeks), annually, etc.) or intermittent therapy (e.g., treatment interruption, intermittent treatment, treatment upon relapse, or treatment following the achievement of specific predetermined criteria [e.g., pain, disease presentation, etc.]). Dosage escalation may occur during the maintenance regimen.

[0141] The term “in combination with” should be understood as the subsequent or simultaneous administration of two or more drugs at a single dose or at a fixed dose. Alternatively, the term “in combination with” should be understood as the administration of two or more drugs in such a manner that the effective therapeutic concentrations of the drugs are expected to overlap for the majority of the time period in the patient. Two or more drugs may be administered independently at the same time or separately at time intervals, especially where these time intervals allow the combination couple to exhibit synergistic (e.g., co-administration) effects. As used herein, the terms “co-administered” or “combined administration” are intended to cover the administration of a selected combination couple to a single subject (e.g., a patient) in need, and are intended to include treatment regimens in which the agents are not necessarily administered via the same route of administration or simultaneously. Simultaneous, parallel, or sequential administration of drugs as separate entities to a patient without specific time constraints, wherein such administration provides therapeutically effective levels of both compounds in the patient, and the treatment regimen will provide the beneficial effect of the drug combination in treating the condition or disorder described herein.

[0142] The phrase “administration device” is used to refer to any available instrument for the systemic administration of medication to a patient, including but not limited to pre-filled syringes, vials and syringes, injection pens, auto-injectors, intravenous drip sets and bags, pumps, patch pumps, etc. With the use of such items, a patient may administer the medication themselves (i.e., administer the medication on their own behalf) or a physician may administer the medication.

[0143] Unless otherwise indicated herein or otherwise obviously contradicted by the context, all methods described herein can be performed in any suitable order. The use of any and all instances or exemplary language (e.g., "as") provided herein is intended only to better illustrate the invention and not to limit the scope of the otherwise claimed invention. However, it may relate to preferred features.

[0144] The embodiments of the invention and their hierarchical relationships are also defined in the claims and are considered to be included herein.

[0145] 1. Pharmaceutical composition

[0146] Therapeutic antibodies are typically formulated in aqueous form for administration or as lyophilized products to be reconstituted with a suitable diluent prior to administration. Anti-BAFF-R antibodies can be formulated as lyophilized products or as aqueous compositions, for example, in pre-filled syringes. This formulation is also known as a pharmaceutical product (DP).

[0147] Suitable formulations can provide aqueous pharmaceutical compositions or lyophilized products that can be reconstituted to provide a solution with a high concentration of the antibody active ingredient and a low level of antibody aggregation for delivery to a patient. The high antibody concentration is useful because it reduces the amount of substance that must be delivered to the patient. The reduced dosing volume minimizes the time required to deliver a fixed dose to the patient. The aqueous compositions of the present invention with a high concentration of anti-BAFF-R antibody are particularly suitable for subcutaneous administration.

[0148] Therefore, the present invention provides an aqueous pharmaceutical composition suitable for administration in subjects (e.g., for subcutaneous administration), the aqueous pharmaceutical composition comprising ilmenite.

[0149] Anti-BAFF-R antibodies can be used as pharmaceutical compositions when combined with pharmaceutically acceptable carriers. In addition to anti-BAFF-R antibodies (such as illuminumab), such compositions may also contain carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The characteristics of the carrier will depend on the route of administration. Pharmaceutical compositions used in the disclosed methods may also contain additional therapeutic agents for treating specific targeting disorders.

[0150] In one particular embodiment, the composition (also referred to as the pharmaceutical product (DP)) is a lyophilized formulation prepared from an aqueous preparation with a pH of 6.0, and comprises:

[0151] (i) 150 mg / mL illuminumab

[0152] (ii) 200-270 mM sucrose as a stabilizer.

[0153] (iii) 15-30 mM L-histidine as a buffer, and

[0154] (iv) 0.03%-0.06% polysorbate 20 as a surfactant.

[0155] In another specific embodiment, the pharmaceutical composition (also referred to as the pharmaceutical product (DP)) is an aqueous pharmaceutical composition with a pH of 6.0 and comprises:

[0156] (i) 150 mg / mL illuminumab

[0157] (ii) 220 mM sucrose as a stabilizer,

[0158] (iii) 20 mM L-histidine as a buffer, and

[0159] (iv) 0.04% polysorbate 20 as a surfactant.

[0160] 2. Combination

[0161] The present invention further relates to a combination of an anti-BAFF-R antibody (such as ilmenbab) with one or more other therapeutic agents for the treatment or prevention of HS in patients requiring such treatment and / or prevention.

[0162] Other therapeutic agents of this kind may include topical treatments (creams [nonsteroidal or steroidal], lotions, antiseptics), systemic treatments (e.g., with biological products, antibiotics or chemical entities), antiseptics, photodynamic therapy and surgical interventions (laser, drainage or incision, excision).

[0163] During HS treatment, other non-restricted therapeutic agents that can be used in combination with disclosed anti-BAFF-R antibodies (such as ilimibe) include IL-17 antagonists (ixekizumab, brodalumab, secukinumab, CJM112), as well as IL-17A / F antagonists (such as bimekizumab) or IL-17C antagonists (such as MOR106), tumor necrosis factor-α (TNF-α) blockers (such as Enbrel® (etanercept) or Humira® (adalimumab)). Remicade® (infliximab) and Simponi® (golimumab), interleukin-12 / 23 blockers (e.g., Stelara® (ustekinumab), tofacitinib, and briakinumab), IL-23 blockers (e.g., guselkumab, tildrakizumab, and risankizumab), p19 inhibitors, PDE4 inhibitors (e.g., apremilast or Otezla®), complement pathway inhibitors (e.g., Factor B inhibitors (e.g., compounds disclosed in WO2015 / 009616 or LNP023 (also known as 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl)-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid), C5a inhibitors (IFX-001, CCX168 (also known as Avacopan)), IL-1 antagonists (canakinumab, gevokizumab, rilonacept, anakinra, MaBp1 (X Biotech Inc.)). Biotech's inflammasome inhibitors (e.g., NLRP3 and NLRP5 inhibitors), CXCR1 / 2 inhibitors, IL-18 antagonists, IL-6 antagonists, IL-36 antagonists, CD20 antagonists, CTLA4 antagonists, IL-8 antagonists, B-cell depletion agents (especially CD20 antagonists such as rituximab, as well as CD40 antagonists and LTA4H inhibitors), IL-21 antagonists, IL-22 antagonists, VEGF antagonists, CXCL antagonists, MMP antagonists, and defensin antagonists (e.g., receptor decoys, antagonistic antibodies, etc.), as well as broad-spectrum oral JAK inhibitors or more specifically TYK2 or JAK1, JAK2, or JAK3 inhibitors.

[0164] During HS treatment, other HS agents used in combination with the disclosed anti-BAFFR antibody include retinoids (e.g., acitretin, retariatin, soriatane). ® and isotretinoin), immune system inhibitors (such as rapamycin, T-cell blockers [such as Amevive® (alefacept) and Raptiva® [efalizumab]]), cyclosporine, methotrexate, mycophenolate mofetil, mycophenolic acid, leflunomide, tacrolimus, etc.), hydroxyurea (such as Hydrea®), sulfasalazine, 6-thioguanine, fumarates (such as dimethyl fumarate and fumarate), imidazothiopurine, colchicine, cis-retinoids, steroids, corticosteroids, certolizumab, mometasone, rosiglitazone, pioglitazone, crystalline botulinum toxin, fluoxyprednisolone, IFX-1 (InflaRx), LY-3041658 (Ellilly, Inc.) Lilly), TE-2232 (Immunwork), NSAIDs, COX inhibitors, prescription anesthetics, ketoprofen, codeine, gabapentin, pregabalin, fentanyl, antibiotics (topical, oral, intravenous) (e.g., clindamycin, rifampin, tetracycline, sarrocycline, doxycycline, minocycline, lysine tetracycline, trimethoprim-sulfamethoxazole, erythromycin, ceftriaxone, moxifloxacin, metronidazole, alone or in combination), corticosteroids (injectable or oral), anti-androgen / hormone therapy (oral contraceptives, spironolactone, finasteride, dutasteride, progesterone IUD, cyproheptadine acetate, ethinylestradiol, gestrinone, norgestrel, desogestrel, drospirenone, spironolactone), promethazine, MEDI 8968, hydroxychloroquine, dapoxetine, metformin, adapalene, azelaic acid, and zinc.

[0165] Preferred combinations for use in the disclosed kits, methods and uses include other biological products, such as TNFα blockers, IL-17 or IL23 and / or IL1 and / or IL18 blockers.

[0166] Examples of TNFα blockers used in combination include etanercept, adalimumab, infliximab, and golimumab. Examples of IL17 blockers include exegizilumab, blorucumab, secukinumab, or CJM112. Examples of IL23 blockers include gusecucumab, tetragicucumab, and lizangicucumab. Examples of IL1 blockers include canaginumab, glibenclamide, linacin, anakinrexate, and MaBp1 (X Biotech).

[0167] 3. Application route

[0168] Antibodies or proteins are typically administered, for example, via intravenous, intraperitoneal, or subcutaneous injection. Methods for achieving this administration are known to those skilled in the art. Compositions that can be administered topically or orally, or those capable of transmucosal delivery, are also available. As will be understood by those skilled in the art, any suitable method of administration, such as that appropriate for a particular chosen route of administration, may be used.

[0169] Examples of possible routes of administration include parenteral (e.g., intravenous (IV or IV), intramuscular (IM), intradermal, subcutaneous (SC or SC), or infusion), oral and pulmonary (e.g., inhalation), nasal, transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may include the following components: sterile diluents such as water for injection, saline solution, fixative oil, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate, or phosphate; and reagents for adjusting osmotic pressure such as sodium chloride or glucose. The pH may be adjusted with an acid or base (e.g., hydrochloric acid or sodium hydroxide). Parenteral preparations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0170] The therapeutically effective dose may be administered, for example, according to a weekly dosing regimen, or once every two weeks, once every three weeks, or once every four weeks. In such embodiments, the therapeutically effective dose typically falls within the dosing range (i.e., about 3 mg / kg to about 10 mg / kg, such as about 3 mg / kg, for example 9 mg / kg IV, or about 150 mg or about 300 mg subcutaneously weekly, every two weeks, or every four weeks).

[0171] The timing of administration is typically measured from the day of the first dose of the active compound (e.g., ilmenbab), which is also known as the “baseline.” However, different healthcare providers use different naming conventions.

[0172] It is worth noting that some healthcare providers may refer to week 0 as week 1, and others may refer to day 0 as day 1. Therefore, it is possible that different physicians will specify the dosage, for example, during week 3 / day 21, week 3 / day 22, week 4 / day 21, and week 4 / day 22, referring to the same dosing schedule. For consistency, the first week of dosing will be referred to herein as week 0, and the first day of dosing as day 1. However, those skilled in the art will understand that this naming convention is for consistency only and should not be construed as limiting the provision that weekly dosing means providing a weekly dose of the anti-BAFF-R antibody (e.g., ilmenbab), regardless of whether the physician refers to a particular week as "week 1" or "week 2". It should be understood that it is not necessary to provide the dosage at precise time points; for example, a dose scheduled for approximately day 29 may be provided, for example, between day 24 and day 34 (e.g., day 30), as long as it is provided within the appropriate week.

[0173] As used herein, the phrase “a container containing a sufficient amount of anti-BAFF-R antibody to allow delivery of [the specified dose]” means that a given container (e.g., a vial, pen, syringe) already contains a volume of anti-BAFF-R antibody that can be used to deliver the desired dose (e.g., as part of a pharmaceutical composition). For example, if the required dose is 300 mg, a clinician might use 2 ml from a container containing an anti-BAFF-R antibody formulation at a concentration of 150 mg / ml, 1 ml from a container containing an anti-BAFF-R antibody formulation at a concentration of 300 mg / ml, 0.5 ml from a container containing an anti-BAFF-R antibody formulation at a concentration of 600 mg / ml, and so on. In each such case, these containers contain a sufficient amount of anti-BAFF-R antibody to allow delivery of the required 300 mg dose.

[0174] As used herein, the phrase “formulated in a dose that allows delivery of the specified dose via [route of administration]” indicates that a given pharmaceutical composition is suitable for delivering the desired dose of an anti-BAFF-R antibody (e.g., ilumab) via a specified route of administration (e.g., sc or iv). For example, if the desired subcutaneous dose is 300 mg, a clinician could use 2 ml of an anti-BAFF-R antibody formulation at a concentration of 150 mg / ml, 1 ml of an anti-BAFF-R antibody formulation at a concentration of 300 mg / ml, 0.5 ml of an anti-BAFF-R antibody formulation at a concentration of 600 mg / ml, etc. In each such case, the concentration of these anti-BAFF-R antibody formulations is sufficient to allow subcutaneous delivery of the anti-BAFF-R antibody. Subcutaneous delivery typically requires delivering a volume of less than about 2 ml, preferably about 1 ml or less. However, higher volumes can be delivered over time using, for example, patch / pump mechanisms.

[0175] This article discloses the use of anti-BAFF-R antibodies (e.g., ilmenba) in the manufacture of a medicament for treating patients with hidradenitis suppurativa, wherein the medicament is formulated into a container, each container having a sufficient amount of anti-BAFF-R antibody to allow delivery of at least about 75 mg, 150 mg, or 300 mg of anti-BAFF-R antibody or its antigen-binding fragment (e.g., ilmenba) per unit dose.

[0176] This article discloses the use of anti-BAFF-R antibodies (e.g., ilmenba) in the manufacture of a medicament for the treatment of patients with hidradenitis suppurativa, wherein the medicament is formulated in a dose to allow systemic delivery (e.g., intravenous or subcutaneous) of about 75 mg, about 150 mg, or 300 mg of the anti-BAFF-R antibody or its antigen-binding fragment (e.g., ilmenba) per unit dose (e.g., intravenous or subcutaneous delivery).

[0177] 4. Reagent kit

[0178] This disclosure also covers kits for treating patients with hidradenitis suppurativa (HS) with an anti-BAFF-R antibody or its antigen-binding fragment (e.g., imatinib). Such kits contain an anti-BAFF-R antibody or its antigen-binding fragment (e.g., imatinib) (e.g., in liquid or lyophilized form) or a pharmaceutical composition containing an anti-BAFF-R antibody (as described above). Additionally, such kits may contain a device for administering the anti-BAFF-R antibody (e.g., syringe and vial, pre-filled syringe, pre-filled pen, patch / pump) and instructions for use. The instructions may disclose that the anti-BAFF-R antibody (e.g., imatinib) is provided to the patient as part of a specific dosing regimen. These kits may also contain additional therapeutic agents (as described above) for treating HS, such as for delivery in combination with the contained anti-BAFF-R antibody (e.g., imatinib).

[0179] The phrase “administration device” is used to refer to any available instrument for the systemic administration of medication to a patient, including but not limited to pre-filled syringes, vials and syringes, injection pens, auto-injectors, intravenous drip sets and bags, pumps, patches / pumps, etc. Using these items, patients may administer medication themselves (i.e., self-administer medication) or it may be administered by a caregiver or physician.

[0180] This article discloses kits for treating patients with hidradenitis suppurativa, the kits comprising: a) a pharmaceutical composition comprising a therapeutically effective amount of an anti-BAFF-R antibody or an antigen-binding fragment thereof; b) a device for administering the anti-BAFF-R antibody or an antigen-binding fragment thereof to a patient; and c) instructions for use that provide for subcutaneous administration of the anti-BAFF-R antibody or an antigen-binding fragment thereof to a patient in need at a dose of about 3 to about 10 mg of active ingredient per kilogram of human subject three times, once every week, or at a dose of about 150 mg or about 300 mg, once weekly, once every two weeks or once monthly.

[0181] In one particular embodiment, the use of a) a liquid pharmaceutical composition comprising an anti-BAFF-R antibody, a buffer, a stabilizer, and a solubilizer, and b) an apparatus for subcutaneously administering the anti-BAFF-R antibody to a patient suffering from hidradenitis suppurativa for the manufacture of a medicament for the treatment of hidradenitis suppurativa, wherein the anti-BAFF-R antibody is administered intravenously to the patient at a dose of about 3 mg to about 10 mg.

[0182] In another specific embodiment, a) a liquid pharmaceutical composition comprising an anti-BAFF-R antibody, a buffer, a stabilizer, and a solubilizer is provided, and b) an apparatus for subcutaneously administering the anti-BAFF-R antibody to a patient suffering from HS for the manufacture of a medicament for treating HS, wherein the anti-BAFF-R antibody is administered subcutaneously to the patient at a dose of about 150 mg of active substance or about 300 mg of active substance (once weekly, once every two weeks, or once monthly (once every four weeks)), wherein the anti-BAFF-R antibody comprises VH having the amino acid sequence of SEQ ID NO: 3 and VL having the amino acid sequence of SEQ ID NO: 4.

[0183] 5. Suppurative hidradenitis

[0184] HS is a chronic, inflammatory, scarring condition that primarily affects the axillary, groin, submammary, genital, anal, and perineal areas of the body. Three diagnostic criteria can be used to diagnose HS: typical lesions (deep, painful nodular [blind] furuncles in early primary lesions, or abscesses, sinus drainages, bridging scars, and “tombstone” open comedones in secondary lesions); typical distribution (axillary, groin, genital, perineal, and perianal regions, buttocks, and submammary and inframammary regions); and chronic and recurrent (Margesson and Danby (2014)). The physical extent of HS can be classified at baseline using Hurley’s clinical staging, as shown in Table 1 below:

[0185]

[0186] Table 1: Hurley stage of HS. In fact, patients with Hurley stage III may have exhausted stage III disease but still have active stage I or II lesions.

[0187] HS consists of follicular blockage, duct rupture, and secondary inflammation. Patients initially experience follicular duct blockage, which over time leads to duct leakage and horizontal rupture into the dermis. When follicular-pillar sebaceous gland (FPSB) repair fails, follicular fragmentation stimulates three responses, thus initiating the HS course. The first is an inflammatory response triggered by the innate immune system, causing suppuration and tissue destruction, leading to a foreign body reaction and extensive scarring. The second response results in epithelialized sinus tracts, which may develop from stem cells derived from the FPSB unit that survived the destruction caused by the inflammatory response. The third, in most cases, produces an invasive proliferative gel material composed of a gel containing inflammatory cells and presumably a precursor to the aforementioned epithelialized elements (see Margesson and Danby (2014)). As used herein, the phrase “slowing the progression of HS” refers to reducing the rate of progression of any aspect of the aforementioned HS course, particularly the inflammatory response. In some embodiments disclosed herein, treatment with an anti-BAFF-R antibody slowed the progression of HS.

[0188] Recurrence of HS in patients includes the development of papules, pustules or inflammatory nodules, pain and itching, abscesses, drainage, and any combination thereof. As used herein, “HS red mass” (etc.) is defined as an increase of at least 25% in the abscess and inflammatory nodule count (AN) relative to baseline, with a minimum increase of two ANs.

[0189] In some embodiments of this disclosure, treatment with anti-BAFF-R antibodies according to the disclosed methods prevents HS erythema, reduces the severity of HS erythema, and / or reduces the frequency of HS erythema. In some embodiments, when treating a HS patient population according to the disclosed methods, less than 5%, less than 10%, less than 15%, or less than 20% experience erythema during the first 16 weeks of treatment.

[0190] As used herein, phrases such as “reduce the severity of HS erythema” indicate a reduction in the intensity of HS erythema, such as reducing the number and / or size of abscesses and / or inflammatory nodules, reducing the intensity of specific erythema components (e.g., reducing the number, size, thickness, etc. of abscesses and / or inflammatory nodules, reducing the degree of skin irritation (itching, pain), etc.), and / or reducing the duration of erythema (or its components).

[0191] As used in this article, phrases such as "reducing the frequency of HS lumps" indicate a reduction in the incidence of HS lumps, for example, a reduction in the incidence of abscesses and / or inflammatory nodules. By reducing the frequency of HS lumps, patients will experience fewer HS recurrences. The incidence of lumps can be assessed by monitoring patients over time to determine whether the prevalence of lumps has decreased.

[0192] As used herein, the phrase “preventing HS erythema” means eliminating future HS erythema and / or erythema components.

[0193] The effectiveness of HS treatment can be assessed using a variety of known methods and tools for measuring HS disease status and / or HS clinical response. Some examples include, for instance, the Hurley staging system, the Severity Assessment Scoring System (SAHS), the Sartorius score, the modified Sartorius score, the HS Physician Global Assessment (HS-PGA) score, the Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) for assessing skin-related pain, the Dermatology Quality of Life Index (DLQI), the HS Clinical Response Based on the Sum of Abscesses and Inflammatory Nodules (HiSCR), the simplified HiSCR, the EuroQuol-5D (EQ5D), the Hospital Anxiety and Depression Scale, healthcare resource utilization, the Severity Index of Hidradenitis Suppurative (HSSI), the Work Performance Index (WPI), the Inflamed Body Surface Area (BSA), the Acne Inverse Severity Index (AISI), etc. (see, for example, Deckers and Prens (2016) Drugs 76:215-229; Sartorius et al. (2009) Br. J. Dermatol [British Journal of Dermatology]). 161:831-39; Chiricozzi et al. (2015) Wounds 27(10):258-264). In some embodiments, the effectiveness of the methods of the present invention disclosed herein can be assessed by: HS Physician Global Assessment (HS-PGA), Severity Assessment Score (SAHS), Numerical Rating Scale (NRS), Dermatology Quality of Life Index (DLQI), HS Clinical Response (HiSCR) based on the sum of abscesses and inflammatory nodules, and / or a simplified HiSCR. Preferably, the effectiveness of HS treatment as disclosed herein can be assessed by: HS Clinical Response (HiSCR) based on the sum of abscesses and inflammatory nodules, and / or a simplified HiSCR.

[0194] In some embodiments, HS patients achieve HiSCR in response to HS treatment. In some embodiments, when the HS patient population is treated according to the disclosed method, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% achieve HiSCR by week 16 of treatment.

[0195] In other embodiments, the effectiveness of the HS treatment disclosed herein can be measured by the difference between the response rate in treated patients (i.e., patients who achieved a HiSCR response to HS treatment with the compounds of the present invention) and the response rate in patients treated with placebo by week 16 of treatment. In some embodiments, such as as measured by HiSCR, the difference in responder ratio is at least 15%, at least 25%, at least 30%, or at least 35%.

[0196] Preferred scoring systems for treatment response include HiSCR, Simplified HiSCR, NRS (especially NRS30), Severity Assessment Scoring System (SAHS), HS-PGA, inflammatory lesion count (abscess, inflammatory nodule and / or draining fistula count), and DLQI.

[0197] The Hidradenitis Suppuratus Clinical Response (HiSCR) is a measure of the clinical response to treatment of HS. A HiSCR response to treatment (compared to baseline) is defined as follows: 1) a reduction of at least 50% in abscesses and inflammatory nodules; 2) no increase in the number of abscesses; and 3) no increase in the number of draining fistulas. As used herein, “simplified HiSCR” or “sHiSCR” refers to a modified HiSCR that excludes abscess counts relative to baseline when assessing disease progression. In a preferred embodiment, the HS patient response to HS treatment achieves a simplified HiSCR. In some embodiments, when the HS patient population is treated according to the disclosed methods, a simplified HiSCR is achieved in at least 40%, at least 50%, at least 60%, or at least 70% of patients by week 16 of treatment.

[0198] Pain can be assessed using a digital rating scale (NRS). In some embodiments, HS patients respond to HS treatment and achieve an improved NRS. NRS30 is defined as a reduction of at least 30% and at least 1 unit in pain on the Patient Overall Assessment (PGA) of skin pain compared to baseline in patients with a baseline score of 3 or higher. In some embodiments, HS patients respond to HS treatment and achieve NRS30. In some embodiments, when treating a population of HS patients according to the disclosed method, at least 25%, at least 30%, at least 40%, at least 50%, or at least 60% achieve NRS30 by week 16 of treatment. In a preferred aspect of this embodiment, when treating a population of HS patients according to the disclosed method, at least 30% achieve NRS30 by week 16 of treatment. In some embodiments, in response to treatment according to the claimed method, patients experience a rapid reduction in pain as measured by VAS or NRS as early as 1 week after initial administration.

[0199] The Severity Assessment Scoring System (SAHS) was described by Hessam S, Scholl L, Sand M, et al. (2018). The severity of HS can be assessed using the SAHS score, for which the following items were investigated: the number of affected areas (left axilla, right axilla, left submammary, right submammary, intermammary or chest, abdomen, mons pubis, left groin, right groin, genitals, perianal or perineum, left gluteal muscles, right gluteal muscles, and others [e.g., neck, behind the ear]), the number of inflammatory and / or painful lesions other than fistulas (ILOF), and the number of fistulas. These physician-scored items were completed using two patient-reported items: asking the patient about the number of new boils or existing boils that had erupted in the past 4 weeks, and assessing the current pain severity (NRS) of the most symptomatic lesion during daily activities (e.g., sitting, moving, or working) on ​​a numerical rating scale. The SAHS score is a composite score of all the information collected above. Mild HS is defined as an SAHS score of 4 or lower. Moderate HS is defined as an SAHS score of 5 to 8, while severe HS is defined as an SAHS score of 9 or higher.

[0200] In some embodiments, HS patients achieve an improved SAHS score in response to HS treatment. In some embodiments, in response to HS treatment, the HS patient's SAHS score achieves a reduction of at least one point compared to baseline. In other embodiments, in response to HS treatment, the HS patient's SAHS score achieves a reduction of at least two points or at least three points compared to baseline. Preferably, the SAHS score was at least 4 at baseline prior to treatment with the anti-BAFF-R antibody.

[0201] The DLQI is the most established quality-of-life assessment tool for dermatology. It consists of questions about the impact of the skin condition on various aspects of sensation and daily living activities over the past week. Each question is scored from 0 (no impact at all) to 3 (very high). The highest score is a total of 30 points, where 0-1 is considered no impact, 2-5 is considered minor impact, 6-10 is considered moderate impact, 11-20 is considered significant impact, and 21-30 is considered extremely impactful on the patient's life. (See Finlay and Khan (1994) Clin Exp Dermatol [Clinical Experimental Dermatology] 19:210-16). In some embodiments, patients with HS respond to HS treatment to achieve an improved DLQI.

[0202] In some embodiments, in response to treatment according to the claimed method, as early as one week after initial administration, the patient experiences a rapid decrease in CRP as measured by a standard CRP assay or a high-sensitivity CRP (hsCRP) assay. As used herein, “C-reactive protein” and “CRP” refer to serum C-reactive protein, a plasma protein commonly used as an indicator of the acute phase response to inflammation. Plasma CRP levels can be given at any concentration, such as mg / dL, nmol / L. CRP levels can be measured by a variety of standard assays, such as radioimmunodiffusion, electroimmunoassay, immunoturbidimetry, ELISA, turbidimetry, fluorescence polarization immunoassay, and laser turbidimetry. CRP testing can be performed using a standard CRP assay or a high-sensitivity CRP (hs-CRP) assay (i.e., a high-sensitivity assay capable of measuring low levels of CRP in a sample using laser turbidimetry). Kits for detecting CRP levels can be purchased from various companies, such as Calbiotech, Inc., Cayman Chemical, Roche Diagnostics Corporation, Abazyme, DADE Behring, Abnova Corporation, Aniara Corporation, Bio-Quant Inc., and Siemens Healthcare Diagnostics.

[0203] The Sartorius HS score (also known as the HS score or HSS) is derived by counting the affected areas, nodules, and sinus tracts in patients with HS (Sartorius et al. (2003) Br J Dermatol [British Journal of Dermatology] 149:211-13). The modified Sartorius HS score is a revision of the original HSS, with some simplifications to make it more practical, such as including fewer specific lesions in the score and varying the score for each parameter (Sartorius et al. (2009)). In some embodiments, the modified Sartorius HS is achieved in response to HS treatment in HS patients.

[0204] The HS Physician Overall Assessment (HS-PGA) is a six-level assessment scale (scoring range 0-5) based on the number of HS lesions (abscesses, draining fistulas, inflammatory nodules, and non-inflammatory nodules). (Kimball AB, Kerdel F, Adams D et al. Adalimumab for the treatment of moderate to severe hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med [Annals of Internal Medicine] 2012; 157: 846-855). In some embodiments, an improved HS-PGA is achieved in HS patients responding to HS treatment. In some embodiments, a response to HS treatment results in a reduction of at least 2 points in the HS-PGA score compared to baseline. Preferably, the HS-PGA score was at least 3 at baseline prior to treatment with anti-BAFF-R antibody.

[0205] In some embodiments, when treating the HS patient population according to the disclosed method, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of patients who responded to treatment at week 16 (e.g., patients who achieved HiSCR or simplified HiSCR at week 16) had a sustained response 3 months, 6 months, or 12 months after the end of treatment. In another aspect of this embodiment, at least 40% or at least 50% of patients who responded to treatment at week 16 (e.g., patients who achieved HiSCR or simplified HiSCR at week 16) had a sustained response 3 months after the end of treatment. Preferably, at least 70% of patients who responded to treatment at week 16 (e.g., patients who achieved HiSCR or simplified HiSCR at week 16) had a sustained response 3 months after the end of treatment. As used herein, the term "sustainable" means substantially maintaining the outcome or goal (e.g., pain reduction, inflammation reduction) over a given period of time.

[0206] Lesion-related pruritus can be assessed through a patient survey. Patients are asked to rate lesion-related pruritus on a scale of 0 (no pruritus) to 10 (worse, possibly pruritus). In some embodiments, when the HS patient population is treated according to the disclosed method, the pruritus score improves by at least 2 points, preferably at least 3 points. Furthermore, when compared to the placebo group, the difference between the treatment group and the placebo group is at least 3 points.

[0207] Odor caused by lesion drainage can be assessed through a patient survey. Patients are asked to rate the odor caused by lesion drainage on a scale of 1 (no odor), 2 (minor odor), 3 (moderate odor), to 4 (major odor). In some embodiments, when the HS patient population is treated according to the disclosed method, the pruritus score improves by at least 1 point, preferably at least 2 points. Furthermore, when compared with the placebo group, the difference between the treatment group and the placebo group is at least 1 point.

[0208] The impact of HS on work performance can be assessed through a patient survey. Patients are asked to rate the degree to which HS affects their ability to perform work on a scale of 1 (nothing at all), 2 (somewhat), 3 (moderate), 4 (significantly), to 5 (unable to perform any work). In some embodiments, when the HS patient population is treated according to the disclosed method, the pruritus score improves by at least 1 point, preferably at least 2 points. Furthermore, when compared with the placebo group, the difference between the treatment group and the placebo group is at least 1 point. Example

[0209] The following examples are illustrated to aid in understanding the invention, and although they are specific embodiments of the invention, they are not intended to and should not be construed as limiting its scope in any way.

[0210] Example 1. Decreased B cells and autoantibodies in patients participating in a systemic lupus erythematosus (SLE) trial.

[0211] This study was a double-blind, randomized, placebo-controlled, multicenter, two-arm trial in SLE patients receiving standard care to evaluate 300 mg ilmenolumab administered monthly subcutaneously (SC) as a substitute for placebo. The dosing regimen was 300 mg SC ilmenolumab monthly for 18 months.

[0212] Key selection criteria:

[0213] During screening, candidates must meet at least 4 of the 11 criteria for SLE classification defined by the American College of Rheumatology in 1997.

[0214] Patients diagnosed with SLE for at least 6 months prior to screening

[0215] In a pattern consistent with SLE diagnosis, elevated serum titers are observed upon ANA screening (≥ 1:80), including at least anti-double-stranded DNA (anti-ds DNA), anti-Ro (SSA), anti-La (SSB), anti-ribonucleoprotein (anti-RNP), or anti-Smith (anti-Sm).

[0216] Currently receiving treatment with corticosteroids and / or antimalarial drugs and / or thalidomide and / or other DMARDs according to the following criteria:

[0217] In cases where corticosteroids are the single standard of care medication: oral doses ≤30 mg / day for at least 8 weeks prior to randomization, and at a stable dose for ≥2 weeks prior to randomization.

[0218] When oral corticosteroids are not used as the sole standard of care: a stable oral dose of prednisone or an equivalent drug ≤ 30 mg / day for at least 8 weeks prior to randomization, and a stable dose for ≥ 2 weeks prior to randomization.

[0219] For at least 12 weeks prior to screening, the patient must have received antimalarial treatment and / or thalidomide treatment and / or one of the following DMARDs: methotrexate or imidazole derivatives (e.g., azathioprine, imidazole ribine) or mycophenolic acid derivatives (e.g., mycophenolate mofetil), and be at a stable dose for ≥8 weeks prior to randomization.

[0220] During screening, a SLEDAI-2K score ≥ 6 is required, and combinations with other DMARDs are not permitted.

[0221] During the screening process, BILAG-2004 scored as follows:

[0222] - At least one "A" in either the mucosal skin area or the musculoskeletal area.

[0223] or

[0224] - There is one "B" in either the mucosal skin area or the musculoskeletal area, and at least one "A" or "B" in the second area.

[0225] During screening, the weight must be at least 40 kg.

[0226] Key exclusion criteria:

[0227] Prior to screening, the patient had a history of receiving the following medications:

[0228] - Within 12 weeks: IV high-dose corticosteroids, calcineurin inhibitors, or other oral DMARDs, except as listed in inclusion criterion 6.

[0229] - Within 24 weeks: Cyclophosphamide or biologics such as intravenous Ig, plasma ablation, anti-TNF-α mAb, CTLA4-Fc Ig (abatacept) or BAFF-targeting agents (e.g., belimumab).

[0230] - Administer any B-cell depletion therapy (e.g., anti-CD20 mAb, anti-CD22 mAb, anti-CD52 mAb) or TACI-Ig (abatacept) within 52 weeks prior to screening, and have a B-cell count < 50 cells / μL at screening.

[0231] Patients with severe lupus nephropathy, defined as proteinuria greater than 6 g / day or using the equivalent value of random urine protein to creatinine ratio, or serum creatinine greater than 2.5 mg / dL (221.05 µmol / L), or requiring immunosuppressive induction or maintenance therapy beyond the limits specified in the protocol.

[0232] Efficacy evaluation:

[0233] •SRI-4 (SLE Respondent Index)

[0234] • Physician Global Assessment Visual Analogue Scale (PhGA-VAS)

[0235] • Patient Global Assessment (VAS)

[0236] • The rate of sudden increase in BILAG-2004 scores

[0237] • Low disease activity status of lupus (LLDAS)

[0238] result:

[0239] With sustained prednisolone dose reduction ≤ 5 mg / day, the proportion of patients achieving the composite primary endpoint SRI-4 at week 28 was 42% higher in the ilimiba group than in the placebo group. Ilimumab also outperformed placebo for the incidence of moderate or severe sudden exacerbations (45% vs. 73%, respectively) and the time to first sudden exacerbation (not reaching median vs. 11.9 weeks, respectively). At week 28, the differences between ilimiba and placebo were: 50% of patients achieving SRI-4 response, 34% with reduced corticosteroid use, 43% for the primary composite endpoint of these two outcomes, 20% for low disease activity status of lupus (LLDAS), and 31% for combined lupus assessment based on BILAG (BICLA). Ilimumab was well tolerated during the 28-week blinded treatment period and the open-label treatment period (weeks 28 to 52) and subsequent safety follow-up, with no new safety signals detected.

[0240] As part of this trial, targeted cell analysis was performed by flow cytometry, and transcriptomic profiling was conducted using total RNA obtained from whole blood via the Illumina Stranded Ribo-Zero Plus kit. Multivariate linear regression models were used to compare the treatment and placebo groups over time to identify differentially regulated cellular markers, proteins, and genes by illuminumab.

[0241] Analysis of cell subset changes following iricumab treatment revealed a strong and statistically significant reduction in total B cells, confirmed by changes in transitional B cells, naive B cells, memory B cells, CD27highCD38high antibody-producing cells, and CD19+CD27-IgD double-negative B cells, while other lymphocyte subsets (CD4+ or CD8+ T cells, NK cells) were not reduced. Assessment of SLE molecular drivers by blood transcriptomics (compared to healthy volunteers) confirmed a disease profile driven by interferon type 1 (IFN) and innate immune pathways, associated with immunoglobulin genes. A strong reduction in B cell-related genes was observed at week 28 following iricumab treatment, accompanied by a significant reduction in IL6 transcripts and regulation of IFN gene signatures (IFNGS). Extensive serum proteomic analysis confirmed the transcriptomics findings, showing a reduction in multiple B cell markers following iricumab treatment. Importantly, we observed comparable SRI-4 responses to imatinib in subjects with high and low INGS, accompanied by a reduction in SLEDAI. Iimatinib treatment in SLE patients resulted in severe B-cell exhaustion, including autoantibody-producing subsets, as confirmed by transcriptomic and proteomic assessments. Preliminary evidence suggests that the clinically observed reduction in B-cell counts and autoantibody levels is associated with decreased INGS, therefore, patient response to imatinib is independent of INGS status.

[0242] Conclusion: All these data indicate that imatinib reduces autoantibodies and B-cell counts in SLE patients. This effect is dose- and time-dependent. Elevated B-cell counts play a crucial role in the development and progression of HS, and these B-cell counts are reduced by treatment with imatinib.

[0243] Example 2. A randomized, double-blind, placebo-controlled, multicenter study to evaluate Illinois. Efficacy and safety of monoclonal antibodies in patients with moderate to severe hidradenitis suppurativa

[0244] The following provides a detailed clinical trial design to demonstrate the efficacy of ilimibe.

[0245] In 12 clinical studies covering multiple indications (rheumatoid arthritis, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, Sjögren's syndrome, multiple sclerosis, pemphigus vulgaris, idiopathic pulmonary fibrosis, systemic lupus erythematosus, autoimmune hepatitis, and lupus nephritis), many subjects have been exposed to different doses of imatinib. A phase 2b dose-range study for pSS explored three doses of imatinib (5 mg, 50 mg, and 300 mg) administered monthly (q4w) and compared with placebo at week 24. The results of this dose-range study indicated that imatinib 300 mg sc q4w was associated with maximum clinical efficacy compared to the lower dose (50 mg), which, while achieving similar levels of circulating B-cell depletion, lacked sustained BAFF-R blockade.

[0246] The pharmacokinetic properties of ilimibe support a fixed dose for all patients (there is no evidence that body size / weight has a statistically significant effect on any PK parameter). In the phase 2b dose-range study of Sjögren's syndrome, the primary endpoint ESSDAI was maximized at ilimibe 300 mg q4w, and ilimibe 300 mg q4w also showed a greater improvement in salivary flow stimulation compared to lower doses.

[0247] Ilimumab 300 mg q4w provides deep B-cell depletion, with sustained BAFF-R blockade based on biomarker results. Ilimumab 300 mg q4w has a favorable safety profile; apart from most minor local injection site reactions, no dose-related safety observations were observed.

[0248] Patients with hidradenitis suppurativa are heavier than those with Sjögren's syndrome and tend to have lower therapeutic mAb exposures compared to other patient categories, which supports testing illuminumab 300 mg q4w in HS.

[0249] If necessary, mild to moderate local and systemic injection-related reactions may be managed according to their symptoms and severity (e.g., cooling, topical creams / gels, patches, acetaminophen, antihistamines, etc.), at the investigator's discretion. Alternating application sites is recommended, avoiding any body area where a local reaction has recently occurred. If a study patient experiences a severe systemic or local injection-related reaction, they should be managed according to the general principles for treating the corresponding condition, including admission to the intensive care unit (if necessary).

[0250] Subjects will be monitored at the injection site for at least 4 hours after the first injection, or longer if necessary, at the investigator's discretion, to ensure adequate safety monitoring. As with any biological therapy, patients should be monitored for signs and symptoms of allergic reactions, including urticaria, rash, dyspnea, hypotension, chest pain, fever, and chills. Hypersensitivity reactions should be treated with antihistamines and corticosteroids, and depending on the severity, these patients may require 100% oxygen, fluid resuscitation, catecholamines, and transfer to an intensive care unit. Plasma ablation may be considered to reduce systemic iricumab concentrations, depending on the patient's condition.

[0251] When evaluating patients suspected of having an infection, it is recommended to use the most sensitive detection method (e.g., culture, PCR for direct pathogen detection). If a patient is evaluated for unexpected neurological or psychiatric symptoms (e.g., cognitive impairment, behavioral changes, visual disturbances, or any other neurological signs and symptoms), an infectious disease specialist should be consulted as appropriate to consider an infectious cause, and brain MRI and / or CSF examination should be performed as needed, including cytological, biochemical, and microbiological analyses (e.g., herpesvirus, John Cunningham virus).

[0252] During subject dosing visits at research centers, ilimibab and its matched placebo will be administered to subjects twice every four weeks via subcutaneous injection (2 × 1 mL). Dosing should not be administered on an outpatient basis, except during epidemics or pandemics that restrict or prevent research visits at research centers (e.g., the COVID-19 pandemic). Research center staff may be arranged to visit patients at their homes to continue study treatment as permitted by local regulations.

[0253] Currently, only one drug (adalimumab) is approved for HS, indicating a significant unmet medical need in HS. Furthermore, in HS patients who do not respond to adalimumab, B cells and plasma cells are enriched at the lesion site compared to non-responders (Hamply 2023). Indeed, plasma cells and B cells are dominant in the skin at the lesion site of HS (Shah 2017, Altman and Criswell 2021, Gudjonsson et al. 2020, Frew et al. 2020, Musilova 2020). In particular, B cells appear to be more prominent around chronic lesions and tunnel structures, where tertiary lymphoid structures are also found (vanStraalen et al. 2022, Frew et al. 2020). B cells and B cell characteristics are present in HS (Frew et al. 2020, Musilova 2020, Rumberger 2020), BCR activation has been demonstrated by detecting pBTK and pSYK (Gudjonsson et al. 2020, Rumberger 2020), and autoantibodies correlated with disease severity and duration have recently been demonstrated in HS patients (Macchiarella et al. 2022). Little is known about survival factors supporting the persistence of immune cells in HS lesions, but increased expression of B cell activating factor (BAFF) has recently been confirmed. BAFF receptor expression is most pronounced in B cells and plasma cells in HS lesions, and there is a strong correlation between BAFF expression and B cell and plasma cell expression (Sabat 2022). In summary, based on the above scientific principles and the promising clinical efficacy observed in patients with primary Sjögren's syndrome, targeting the BAFF receptor with illuminumab in HS appears reasonable.

[0254] Double-blinding of subjects and investigators allows for unbiased assessment of subjective readings, such as the lesion count of HS or the overall HS-PGA score, as well as adverse events.

[0255] A randomized, double-blind, placebo-controlled, multicenter, parallel-group study was conducted to evaluate the efficacy, safety, and tolerability of several active therapeutic compounds, such as ilimibab, in subjects with moderate to severe HS. After a screening period of approximately 4 weeks, the planned treatment period was 16 weeks, followed by approximately 12 weeks of safety follow-up. Subjects were given 300 mg ilimibab (two 1 mL injections subcutaneously) or their corresponding placebo (2 × 1 mL subcutaneously).

[0256] This study included adult men and women aged 18 to 65 years who presented with a diagnosis of moderate to severe hepatic sclerosis (HS) with recurrent inflammatory lesions lasting at least 12 months. To be included in the study, participants had at least five inflammatory lesions. Baseline assessment could begin on day -7 to allow assessment to be completed on day -1 prior to day 1 of treatment. All baseline safety assessments had to be available before dosing and meeting eligibility criteria. Randomization was performed using a centralized interactive response (IRT) system.

[0257] After 16 weeks of treatment, the primary clinical endpoint was the simplified HiSCR (Histoplasma purpura clinical response).

[0258] On day 113 (week 17), after safety and other assessments, all participants entered the follow-up period without any medication administration. During this follow-up period, participants may receive previously prohibited medications if medically justifiable and no potential safety risks have been identified (after discussion with the sponsor).

[0259] Safety and efficacy assessments were conducted during follow-up at day 141 (week 21) and day 197 (week 29). Pharmacokinetic (PK) and pharmacodynamic (PD) parameters were collected. Double-blinding was maintained for both investigators and subjects until the end of the study. Follow-up ended on day 197 (week 29), which included completing study evaluations and then disengaging from the study.

[0260] Approximately 45 participants were randomized, with 30 in the active drug group and 15 in the placebo group. On Day 1, a single dose of 300 mg ilmenite or a matched placebo was administered subcutaneously (SC) by a trained field staff. Clinical evaluations, as well as assessments for pharmacokinetics (PK), drug-promoting activities (PD), immunoglobulin (IG), biomarkers, and safety, were performed. Participants were discharged from the field on the same day after all evaluations were completed, provided there were no safety concerns.

[0261] One to two hours prior to the first administration of study treatment, study participants must receive a pre-treatment dose of 50 mg prednisone (or equivalent) orally. The purpose of the corticosteroid pre-treatment is to alleviate signs and symptoms associated with the potential release of cytokines that may be related to rapid depletion of circulating B cells. In addition to prednisone (or equivalent), at the investigator's discretion, acetaminophen (paracetamol) at a dose not exceeding 1000 mg po and / or an oral second-generation antihistamine (e.g., loratadine) may also be administered.

[0262] Following the initial administration of the study treatment, all participants must remain at the study site / physician's office for at least 4 hours for safety monitoring to detect potential injection-related reactions. Such monitoring is not required at subsequent visits.

[0263] The primary objective was to demonstrate the preliminary efficacy of ilimibe treatment compared to placebo in HS subjects after 16 weeks of treatment. A 12-week follow-up period was conducted after the 16-week treatment period to observe whether the sustainability or improvement of this effect after 16 weeks of treatment could be observed.

[0264] Based on this fact, a 2:1 randomization is planned to facilitate exposure to the active drug while limiting subjects’ exposure to the placebo.

[0265] The study included multiple clinical endpoints to better assess the characteristics of these selected endpoints:

[0266] For this study, a simplified HiSCR (modified from Kimball 2014) was chosen as the primary endpoint. The simplified HiSCR was defined as a 50% reduction in the total number of abscesses plus inflammatory nodules, without an increase in draining fistulas.

[0267] Inflammatory lesions of HS will be counted as single lesions (inflammatory nodules, abscesses, and draining fistulas) in typical anatomical areas. In addition to counting, a holistic assessment scale (Hyperpigmentation Severity Assessment or HS-PGA) and a comprehensive score (Hyperpigmentation Severity Assessment or SAHS) will be used.

[0268] Several patient-reported outcomes will be used, including the Dermatology Quality of Life Index (DLQI). Finally, from the participants' perspective, skin-related pain is the most important symptom, therefore a numerical rating scale for pain (NRS) will be included.

[0269] Additional information regarding clinical evaluation:

[0270] HS-PGA (Hidradenitis suppurativa-Physician Holistic Assessment): This score will be used as an exploratory target for assessing HS and is used and described in Kimball AB, Kerdel F, Adams D et al. (2012).

[0271] The SAHS score is a composite score (Hessam S, Scholl L, Sand M et al. (2018)) and will be derived from collected inflammatory lesion counts, fistula counts, and NRS pain information. Additionally, anatomical areas and new or present-with-redness boils will be collected from both cohorts.

[0272] Skin pain - NRS (Numerical Rating Scale for Pain): The NRS for skin-related pain was used in the adalimumab study (Kimball et al. (2016)) and was used for pain associated with skin or HS (which is one of the biggest burdens on patients (Matusiak et al. (2017))). Pain associated with HS was recorded as the mean and worst time values ​​(within the most recent 24 hours).

[0273] Other patient-reported outcomes (PROs) will include aspects of itching, fatigue, and work disruption, as well as the Dermatology Quality of Life Index (DLQI) and the Dermatology-Related Quality of Life (QoL) tool (with validated scores available in many countries and languages). It includes a holistic patient assessment.

[0274]

[0275] Key selection criteria

[0276] • Male and female subjects aged 18 to 65 years who were clinically diagnosed with HS at least 12 months prior to screening.

[0277] • A total of at least 5 inflammatory lesions, namely abscesses and / or inflammatory nodules, and

[0278] • No more than 10 fistulas, and

[0279] • HS lesions must involve at least two anatomical regions.

[0280] • The minimum weight of the subject must be 50 kg (inclusive).

[0281] Key Exclusion Criteria

[0282] • Use the investigational drug at screening, or within 30 days of registration, or within 5 half-lives of registration, or until the desired pharmacodynamic effect returns to baseline (whichever is longer); or if local regulations require a longer period.

[0283] • Use IL12 and IL23 blocking biologics (such as uterogensumab or gusecubitumab) during the last 6 months before randomization / first treatment.

[0284] • Use of B-cell targeted or B-cell depleting biologics or analogues, such as rituximab or belimumab, within 12 months; for patients who received these drugs earlier, B-cell counts must be within the normal range.

[0285] • Use other biological immunomodulators (e.g., adalimumab, secukinumab, etanercept, infliximab, etc.) 3 months or 5 half-lives (whichever is longer) before randomization / first treatment.

[0286] • Use rituximab or belimumab within 12 months;

[0287] • Use any systemic treatment for HS (e.g., retinoids or other immunomodulatory therapies such as methotrexate, cyclosporine A, or corticosteroids) during the last 4 weeks prior to randomization.

[0288] • Use of cyclophosphamide within the last 6 months

[0289] • Administer systemic antibiotics to treat HS during the last week prior to randomization / initial treatment.

[0290] • If spironolactone or other anti-androgens (finasteride, cyprolin, etc.) are used (for HS), only patients with stable doses over the past 3 months and who plan to continue during the study are eligible.

[0291] • Surgical treatment of HS should be performed within the last 4 weeks prior to randomization / initial treatment. Surgical treatment does not include incidental excisional biopsy.

[0292] • Received any high-injection corticosteroid bolus (> 1 mg / kg) within 3 months.

[0293] treat

[0294] The investigational drug ilimibe and its corresponding matched placebo were manufactured by Novartis and delivered to the study site in the form of a double-blind drug kit. Detailed information regarding the storage and administration requirements of the investigational treatment, as well as instructions for subject numbering, prescription / allocation, and administration of the investigational treatment, is outlined in the Site Operations Manual / Pharmacy Manual.

[0295] Subjects will receive 300 mg ilmenite (two 1 mL injections or one 2 mL injection) subcutaneously or as a placebo subcutaneously.

[0296] Subjects will be randomized in a 2:1 ratio to the study treatment group or the corresponding placebo group. The maximum treatment duration will not exceed 16 weeks.

[0297] If a skin infection or worsening of HS lesions occurs, researchers may choose to treat it with permitted pharmacological and non-pharmacological therapies to prevent subjects from discontinuing treatment in the study. Examples include:

[0298] • Conservative treatment, local wound care and dressings

[0299] • Oral antibiotic treatment: If the causative agent is known, targeted medication should be used, and the duration should not exceed 2 weeks.

[0300] This trial does not plan to use specific rescue drugs. However, several standard of care (SOC) medications, such as antibiotics or biologics, can be used to alleviate the signs and symptoms of HS (Section 6.2.4). According to European guidelines (Zouboulis et al. 2015), locally recurrent lesions can be treated with classic surgery or the LASER technique, while drug therapy (as a monotherapy or in combination with radical surgery) is more suitable for extensively spreading lesions. Drug therapy for HS may include antibiotics (such as clindamycin plus rifampin, tetracyclines), acitretin, biologics (adalimumab, infliximab), hormone therapy, dapsone, and other biologics such as IL-17A blockers.

[0301] If necessary, mild to moderate local and systemic injection-related reactions may be managed according to their symptoms and severity (e.g., cooling, topical creams / gels, patches, acetaminophen, antihistamines, etc.), at the investigator's discretion. Alternating application sites is recommended, avoiding any body area where a local reaction has recently occurred. If a study patient experiences a severe systemic or local injection-related reaction, they should be managed according to the general principles for treating the corresponding condition, including admission to the intensive care unit (if necessary).

[0302] Subjects will be monitored at the injection site for at least 4 hours after the first injection, or longer if necessary, at the investigator's discretion, to ensure adequate safety monitoring. As with any biological therapy, patients should be monitored for signs and symptoms of allergic reactions, including urticaria, rash, dyspnea, hypotension, chest pain, fever, and chills. Hypersensitivity reactions should be treated with antihistamines and corticosteroids, and depending on the severity, these patients may require 100% oxygen, fluid resuscitation, catecholamines, and transfer to an intensive care unit. Plasma ablation may be considered to reduce systemic iricumab concentrations, depending on the patient's condition.

[0303] When evaluating patients suspected of having an infection, it is recommended to use the most sensitive detection method (e.g., culture, PCR for direct pathogen detection). If a patient is evaluated for unexpected neurological or psychiatric symptoms (e.g., cognitive impairment, behavioral changes, visual disturbances, or any other neurological signs and symptoms), an infectious disease specialist should be consulted as appropriate to consider an infectious cause, and brain MRI and / or CSF examination should be performed as needed, including cytological, biochemical, and microbiological analyses (e.g., herpesvirus, JC virus). Listed Examples

[0304] 1. A method for treating or preventing hidradenitis suppurativa in a human subject, the method comprising administering to the subject a therapeutically effective amount of an anti-BAFF-R antibody or a conjugate fragment thereof.

[0305] 1a. A method for treating hidradenitis suppurativa in a human subject with lesions associated with hidradenitis suppurativa, the method comprising the step of administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of an anti-BAFF-R antibody or a binding fragment thereof that is effective in treating the symptoms of hidradenitis suppurativa in the subject.

[0306] 2. The method according to Example 1 or 1a, wherein the anti-BAFF-R antibody or its binding fragment comprises CDR-H1, CDR-H2 and CDR-H3 having amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6 and SEQ ID NO: 7 respectively, and CDR-L1, CDR-L2 and CDR-L3 having amino acid sequences of SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10 respectively.

[0307] 3. The treatment method according to Example 1, 1a or 2, wherein the anti-BAFF-R antibody or its binding fragment comprises VH having the amino acid sequence of SEQ ID NO: 3 and VL having the amino acid sequence of SEQ ID NO: 4, respectively.

[0308] 4. The method according to any one of the above embodiments, wherein the anti-BAFF-R antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 1 and a light chain having the amino acid sequence of SEQ ID NO: 2.

[0309] 5. The method according to any one of the above embodiments, wherein the anti-BAFF-R antibody or a fragment thereof is ilmeniteb or a binding fragment thereof.

[0310] 6. The method according to any one of the above embodiments, wherein the antibody is administered subcutaneously or intravenously, or a combination of subcutaneously or intravenously.

[0311] 7. The method according to any one of the above embodiments, wherein the antibody is administered at a dose of about 3 mg to about 10 mg of active ingredient per kilogram of human subject.

[0312] 8. The method according to Example 7, wherein the dose is about 3 mg of active ingredient per kilogram of human subject.

[0313] 9. The method according to any one of the above embodiments, wherein the antibody is administered at a dose of about 150 mg to about 400 mg of active ingredient, such as about 300 mg of active ingredient.

[0314] 10. The method according to Example 9, wherein the dose is 150 mg of active ingredient or 300 mg of active ingredient.

[0315] 11. The method according to any one of the above embodiments, wherein the antibody is administered together with one or more pharmaceutically acceptable carriers.

[0316] 12. The method according to any one of the above embodiments, wherein the subject is selected according to one of the following criteria:

[0317] a) The subjects suffered from moderate to severe HS;

[0318] b) The subjects were adults;

[0319] c) The subjects were adolescents;

[0320] d) Prior to treatment with the anti-BAFF-R antibody, the subject's HS-PGA score was ≥ 3;

[0321] e) Prior to treatment with the anti-BAFF-R antibody, the subject had at least three inflammatory lesions; or

[0322] f) Prior to treatment with the anti-BAFF-R antibody, the subject did not have extensive scarring (< 10 fistulas) due to HS.

[0323] 13. The method according to any one of the above embodiments, wherein by week 16 of treatment, the subject achieves a clinical response in at least one of the following:

[0324] a) Simplified HiSCR;

[0325] b) The redness and swelling of HS decreased;

[0326] c) NRS30;

[0327] d) A reduction ≤ 6 as measured by DLQI; and / or

[0328] e) Improvement of DLQI.

[0329] 14. The method according to any one of the above embodiments, wherein when the method is used to treat a subject population with moderate to severe HS, at least 40% of the subjects achieve a clinical response by the simplified HiSCR assessment by week 16 of treatment;

[0330] 15. The method according to any one of Examples 1 to 10, wherein when the method is used to treat a subject population with moderate to severe HS, at least 25% of the subjects achieve an NRS30 response by week 16 of treatment.

[0331] 16. The method according to any one of the above embodiments, wherein when the method is used to treat a subject population with moderate to severe HS, less than 15% of the subjects experience HS redness and swelling during the 16-week treatment period.

[0332] 17. The method according to any one of the above embodiments, wherein the anti-BAFF-R antibody or its binding fragment is administered to the subject for at least 16 weeks.

[0333] 18. The method according to any one of the above embodiments, wherein the subject has at least one of the following conditions as early as one week after the first dose of the anti-BAFF-R antibody:

[0334] a) Pain, as measured by VAS or NRS, rapidly subsides.

[0335] b) CRP levels decreased rapidly when measured using the standard CRP assay.

[0336] 19. The method according to any one of the above embodiments, wherein the subject achieves a sustained response 3 months after the end of treatment, as measured by inflammatory lesion count, hidradenitis suppurativa clinical response (HiSCR), numerical rating scale (NRS), modified Sartorius HS score, hidradenitis suppurativa-physician overall assessment (HS-PGA) or dermatology quality of life index (DLQI).

[0337] 20. The method according to Example 19, wherein the subject achieves a sustained response 3 months after the end of treatment, as measured by a simplified HiSCR (sHiSCR).

[0338] 21. The use of a liquid pharmaceutical composition comprising an anti-BAFF-R antibody, a buffer, a stabilizer, and a solubilizer, and an apparatus for subcutaneously administering said anti-BAFF-R antibody to a subject suffering from hidradenitis suppurativa, for the manufacture of a medicament for treating hidradenitis suppurativa, wherein said anti-BAFF-R antibody:

[0339] Subcutaneous administration; and wherein the anti-BAFF-R antibody or its binding fragment comprises VH having the amino acid sequence of SEQ ID NO: 3 and VL having the amino acid sequence of SEQ ID NO: 4, respectively.

[0340] 22. Use of an anti-BAFF-R antibody or a binding fragment thereof comprising VH having the amino acid sequence of SEQ ID NO: 3 and VL having the amino acid sequence of SEQ ID NO: 4, respectively, for the manufacture of a medicament for treating a subject suffering from hidradenitis suppurativa, wherein the medicament is prepared for administration according to any of the above embodiments.

[0341] 23. An anti-BAFF-R antibody or a binding fragment thereof for use in any of the methods according to Examples 1-20.

Claims

1. An anti-BAFF-R antibody or a binding fragment thereof for use in treating hidradenitis suppurativa in a subject in need.

2. The anti-BAFF-R antibody or its binding fragment according to claim 1, wherein the anti-BAFF-R antibody or its binding fragment comprises CDR-H1, CDR-H2 and CDR-H3 having amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6 and SEQ ID NO: 7 respectively, and CDR-L1, CDR-L2 and CDR-L3 having amino acid sequences of SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10 respectively.

3. The anti-BAFF-R antibody or its binding fragment according to claim 1 or 2, wherein the anti-BAFF-R antibody or its binding fragment comprises VH having the amino acid sequence of SEQ ID NO: 3 and VL having the amino acid sequence of SEQ ID NO: 4, respectively.

4. The anti-BAFF-R antibody or its binding fragment according to any one of claims 1 to 3, wherein the anti-BAFF-R antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO:1 and a light chain having the amino acid sequence of SEQ ID NO:

2.

5. The anti-BAFF-R antibody or its binding fragment thereof according to any one of claims 1 to 4, wherein the anti-BAFF-R antibody or its binding fragment thereof is administered subcutaneously or intravenously, or in combination, subcutaneously or intravenously.

6. The anti-BAFF-R antibody or its binding fragment according to any one of claims 1 to 5, wherein the anti-BAFF-R antibody or its fragment is administered at a therapeutically effective dose.

7. The anti-BAFF-R antibody or its binding fragment thereof according to any one of claims 1 to 5, wherein the anti-BAFF-R antibody or its binding fragment thereof is administered at a dose of about 3 mg to about 10 mg active ingredient per kilogram of human subject.

8. The anti-BAFF-R antibody or its binding fragment as described in claim 6, wherein the dose is about 6 mg of active ingredient per kilogram of human subject.

9. The anti-BAFF-R antibody or its binding fragment thereof for use according to any one of claims 1 to 5, wherein the anti-BAFF-R antibody or its binding fragment thereof is administered at a dose of about 150 mg to about 600 mg of the active ingredient, such as about 300 mg of the active ingredient.

10. The anti-BAFF-R antibody or its binding fragment according to claim 8, wherein the dose is 150 mg of active ingredient or 300 mg of active ingredient.

11. The anti-BAFF-R antibody or its binding fragment according to any one of claims 1 to 9, wherein the subject is selected according to one of the following criteria: a. The subject had moderate to severe HS; b. The subjects were adults; c. The subjects were adolescents; d. Prior to treatment with the anti-BAFF-R antibody or its binding fragment, the subject's HS-PGA score was ≥ 3; e. Prior to treatment with the anti-BAFF-R antibody or its binding fragment, the subject had at least three inflammatory lesions; or f. Prior to treatment with the anti-BAFF-R antibody or its binding fragment, the subject did not have extensive scarring (< 10 fistulas) due to HS.

12. The anti-BAFF-R antibody or its binding fragment according to any one of claims 1 to 10, wherein by week 16 of treatment, the subject with hidradenitis suppurativa achieves a clinical response in at least one of the following: a. Simplified HiSCR; b. The redness and swelling in HS have decreased; c.NRS30; d. Reduction ≤ 6 as measured by DLQI; and / or e.DLQI improvements.

13. The anti-BAFF-R antibody or its binding fragment according to any one of claims 1 to 10, wherein by week 16 of treatment, at least 40% of the subjects achieve a clinical response as measured by simplified HiSCR; or at least 25% of the subjects achieve an NRS30 response; or less than 15% of the subjects experience HS redness.

14. The anti-BAFF-R antibody or its binding fragment according to any one of claims 1 to 10, wherein the subject has at least one of the following conditions most recently, one week after the first dose of the anti-BAFF-R antibody or its binding fragment: a. Pain rapidly reduced as measured by VAS or NRS, and b. CRP levels measured using the standard CRP assay decrease rapidly.

15. The anti-BAFF-R antibody or its binding fragment as claimed in any one of claims 1 to 10, wherein the subject achieves a sustained response 3 months after the end of treatment, as measured by inflammatory lesion count, Hidradenitis Suppurative Clinical Response (HiSCR), Numerical Rating Scale (NRS), Modified Sartorius HS score, Hidradenitis Suppurative Physician Global Assessment (HS-PGA), or Dermatology Quality of Life Index (DLQI).

16. The anti-BAFF-R antibody or its binding fragment thereof as claimed in any one of claims 1 to 10, wherein the subject achieves a sustained response 3 months after the end of treatment, as measured by a simplified HiSCR (sHiSCR).

17. A pharmaceutical composition comprising a therapeutically effective amount of an anti-BAFF-R antibody or a binding fragment thereof as claimed in any one of claims 1 to 16, and one or more pharmaceutically acceptable carriers.

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