Treatment of hidradenitis suppurativa using anti-BAFF-R antibodies

Abstract

This disclosure relates to methods, treatment regimens, uses, kits, and therapies for treating hidradenitis suppurativa by using molecules that inhibit B cell activator receptor (BAFF-R), such as anti-BAFF-R antibodies.

Description

[Technical Field]

[0001] This disclosure relates to methods, therapeutic regimens, uses, kits, and treatments for treating hidradenitis suppurativa, particularly in subjects requiring such treatment, including administering (in particular therapeutically effective doses) molecules that inhibit B-cell activator receptor (BAFF-R), such as anti-BAFF-R antibodies or their conjugate fragments, in particular ianarumab (collectively referred to as the Drugs of the Invention, which are interchangeable throughout this application), as well as related embodiments of the invention referred herein. [Background technology]

[0002] Hidradenitis suppurativa (HS), also known as "reverse acne" or "Verneuilh's disease," is a chronic, recurrent, and debilitating inflammatory skin condition that typically presents with deep, inflammatory, and painful lesions in areas of the body containing apocrine glands. The most common sites of occurrence are the axillae, groin, and anogenital region (Jemec 2012; Fimmel and Zouboulis 2010).

[0003] HS is currently considered an inflammatory disease of the hair follicles, sebaceous glands, and hair follicles, associated with an underlying immune system imbalance, occurring in genetically predisposed individuals (Kelly et al 2014). While HS is thought to be primarily caused by hair follicle obstruction, 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). The pathophysiology of HS remains largely unknown, but the benefits of tumor necrosis factor alpha (TNFα) blockade have been documented in more studies (Kimball et al 2016).

[0004] Evidence of the efficacy of anti-IL-1 therapy (Tzanetakou et al 2016) and IL-17A blockade (Thorlacius et al 2017, Schuch et al 2018, Giuseppe et al 2018, Jorgensen et al 2018) or anti-IL-23 therapy (Sharon et al 2012, Blok et al 2016) has also been found in fewer studies and / or case reports. More recently, investigative approaches using the oral PDE4 inhibitor apremilast (Weber et al 2017) or anti-complement 5a compounds (Kanni et al 2018) have been described.

[0005] This disease begins after puberty, and is more prevalent in women than men (3:1). Risk factors include obesity and smoking. Epidemiological prevalence estimates vary widely (0.03–4.3%; Jemec 2012, Jemec and Kimball 2015) and geographically differ, but a prevalence of approximately 0.1–1% is generally accepted by the scientific community (Garg et al 2018).

[0006] The clinical signs of HS are heterogeneous, but the disease tends to manifest as chronic, recurrent, deep, painful inflammatory skin lesions, primarily inflammatory nodules and abscesses that may lead to drainage and suppuration. The inflammatory lesions can become complicated during disease progression through sinus formation and fistula formation, and may result in hypertrophic scarring that may affect functional use.

[0007] HS is accompanied by pain, foul-smelling discharge from wounds, and scarring, and often has devastating psychosocial impacts. HS is an extremely debilitating disease with a strong negative impact on quality of life (QoL), and multiple studies have confirmed that its impact is greater than that seen in other skin diseases (Deckers and Kimball 2016). Patients with HS often experience depression, social isolation, impaired sexual health, and may have difficulty performing occupational duties (Esmann and Jemec 2011, Fimmel and Zouboulis 2010, Janse et al 2017).

[0008] HS is difficult to treat. European authorities first developed treatment guidelines in 2015, suggesting that patients should be offered adjuvant, pharmaceutical, and surgical treatments (Zouboulis et al 2015).

[0009] For mild cases, topical antibiotics can be used, but for moderate to severe HS, long-term, multiple-cycle systemic antimicrobial therapy using tetracycline or a combination of clindamycin and rifampicin (followed by maintenance with chronic antibiotic treatment for several months or years) is generally preferred (Bettoli et al 2016, Dessinioti et al 2016, Zouboulis et al 2015).

[0010] However, it is widely recognized that HS is not an infection but a chronic inflammatory state (Jemec 2012). Therefore, anti-inflammatory agents may be an alternative and perhaps more appropriate approach than antibiotics, or complement antibiotics. The result of chronic, recurrent, and poorly treated inflammation is irreversible fibrosis over time, which manifests as scars and canals or sinuses and often does not respond to medical therapy. When persistent anatomical changes occur, surgery is the only therapeutic option to reduce the volume of fibrotic tissue and improve functionality in the affected area of ​​skin (Andersen and Jemec 2017). One of the future treatment goals should be to reduce permanent scarring and avoid surgery, which can be achieved by preventing inflammatory lesions or may require specific treatments.

[0011] In 2015, adalimumab (Humira®), a recombinant human monoclonal immunoglobulin G1 (IgG1) antibody against soluble membrane-bound TNF-α, received regulatory approval for the treatment of moderate to severe hidradenitis suppurativa (HS). Adalimumab has demonstrated efficacy, with HiSCR (Hidradenitis Suppurativa Clinical Response) rates reported in Pioneer I and II studies being approximately 16% (41.8% adalimumab vs. 26% placebo) and 31% (58.9% adalimumab vs. 27.6% placebo), respectively (Kimball et al 2016). When captured with adalimumab labeling, adalimumab carries an increased safety risk of serious infections, including tuberculosis, invasive fungal infections, and other opportunistic infections. An increased incidence of malignancy has also been reported with adalimumab.

[0012] Therefore, there remains an unaddressed need for systemic therapies that effectively reduce inflammation while having a favorable safety profile for patients with moderate to severe HS. [Modes for carrying out the invention]

[0013] Although the etiology of HS is still not fully understood, this chronic skin disease is characterized by a large number of neutrophils, macrophages, and B / plasma cells in inflammatory 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). Van der Zee detected B cells and plasma cells in HS lesions, particularly in chronic lesions (as opposed to early stages), compared to surrounding and healthy skin. In some samples, lymphoid follicles with CD20+ B cells were detected in chronic lesions. In a recent study by Novartis (CJM112X2202) including subjects with moderate to severe HS, histological samples showed a large amount of B cell infiltration in the lesioned skin as well as several germinal centers in the lesioned tissue. In the same study, cell type features in gene expression data from skin biopsies, based on transcriptomics, showed not only clear B cell features but also macrophage features. Consistent with these findings, the European HS Foundation meeting in Rotterdam in 2018 reported on the abnormalities and upregulation of the circulating B cell subset in HS patients (Musilova J, 2018). It has recently been reported that BAFF (B cell activator) is abundant in HS lesions, particularly in nodules and abscesses, and that myeloid cells (neutrophils) are the main producers of BAFF (Sabat et al, 2023).

[0014] The present invention provides a potentially disease-modifying treatment for HS that exhibits good tolerability, is favorable to the subject, and results in a high response rate (which is maintained even after the end of the treatment period).

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

[0016] In one embodiment, the anti-BAFF-R antibody or binding fragment thereof comprises CDR-H1, CDR-H2, and CDR-H3 having the 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 the 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 binding fragment thereof comprises a VH having the amino acid sequence of SEQ ID NO: 3 and a 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, respectively.

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

[0020] B cell activator (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 acts via its receptor (BAFF-R), which is expressed on most B cells. The BAFF-R signaling pathway is heavily involved in the activation of B cell effector functions such as antibody production, isotype class switching, B cell proliferation, maturation, and survival (Mackay et al 2009).

[0021] The antigen specificity of ianarumab is directed towards the BAFF receptor, specifically BAFF-R (synonym: BR3), which is expressed on the surface of immature and mature B cells up to the lymphoblast stage. Therefore, pro and pre B cells that express CD20 but do not express BAFF-R are not expected to be affected by ianarumab. Thus, compared to existing B cell depletion anti-CD20 antibody therapies, ianarumab targets a narrower range of more differentiated B cells.

[0022] Ianarumab is a glycosylated (defucosylated) fully human IgG1 monoclonal antibody directed at BAFF-R expressed on the surface of B cells, thereby targeting B cells and their function through the following two mechanisms of action: Direct lysis and depletion of BAFF-R-expressing B cells by enhanced ADCC due to the fucose-deficient Fc (fragment crystallizable) region; and Blocking the BAFF receptor interferes with BAFF-mediated signaling for B cell maturation, proliferation, and survival (Bowman et al 2022).

[0023] In preclinical studies, ianarumab significantly enhanced NK cell-mediated ADCC against B cells and cytokine production, and was more potent in depleting B cells compared to approved anti-CD20 antibodies, including rituximab, obinutuzumab, and ofatumumab (McWilliams et al 2019).

[0024] Thanks to its dual activity, ianarumab can inhibit the pathogenic rebound mechanism driven by BAFF by combining rapid and potent B-cell depletion with continuous BAFF-R blockade (Genovese et al 2010, Furie et al 2011, Mariette 2012). Ianarumab demonstrated efficacy in primary Sjögren's syndrome (pSS) in a Phase II study (Bowman SJ, et al 2021).

[0025] Ianarumab has not yet been studied in HS. However, the use of Ianarumab in HS is supported by the following: Both B cells and plasma cells are present in HS lesions (Gudjonsson et al 2020). Recent studies have shown that increased BAFF expression correlates with the presence of lesional B cells and plasma cells in HS (Sabat 2022). • B cells and plasma cells are increased in lesional skin at baseline in adalimumab non-responders (Hambly, 2022, BioRxiv). • Autoantibodies correlate with the severity and duration of the disease. • Inhibition of the BAFF-R pathway has been demonstrated to be effective and safe in non-hematopoietic autoimmune diseases (BENLYSTA® package insert).

[0026] Clinical studies of ianarumab have demonstrated its efficacy in other autoimmune diseases.

[0027] Therefore, due to its dual mechanism of action, combining existing data with the data disclosed in this application, ianarumab is expected to demonstrate efficacy and safety in treating HS, particularly by addressing the limitations of the HS treatments described above through potent B-cell depletion and BAFF-R blockade.

[0028] Treatment of HS patients with anti-BAFF-R antibodies such as ianarumab, as disclosed herein, is an effective treatment that achieves a clinical response as assessed by, for example, the Simplified Hidradenitis Suppurative Clinical Response (HiSCR), the International Hidradenitis Suppurative Severity Score System (IHS4), the Hidradenitis Suppurative-Physician Comprehensive Assessment (HS-PGA) score and responder rate, the HS inflammatory disease count, or the SAHS Severity Assessment.

[0029] In one embodiment, an anti-BAFF-R antibody or a fragment thereof, particularly ianarumab, is administered to subjects who particularly require it, in doses 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.

[0030] In one embodiment, an antibody, particularly ianarumab, or a conjugated fragment thereof, is administered once every four weeks (q4w, monthly, + / - 3 days) to subjects who particularly need it.

[0031] In one embodiment, the antibody is ianarumab, which is administered subcutaneously at a dose of approximately 150 mg once every four weeks (q4w, monthly, + / - 3 days) to subjects who particularly need it.

[0032] In one embodiment, the antibody is ianarumab, which is administered subcutaneously at a dose of approximately 300 mg once every four weeks (q4w, monthly, + / - 3 days) to subjects who particularly need it.

[0033] In one embodiment, a molecule that inhibits B-cell activator receptor (BAFF-R), particularly an anti-BAFF-R antibody or its conjugate fragment, in particular ianarumab, is administered as monotherapy to a subject who specifically needs it. The subject receives no other treatment for HS during the period of treatment with the drug of the present invention.

[0034] In one embodiment, ianarumab is administered to a subject as monotherapy, where the subject has shown an inadequate response or has relapsed after a previous initial treatment regimen, and the initial treatment typically refers to first-line steroid therapy as standard treatment or a conventional HS drug.

[0035] In one embodiment, a molecule that inhibits B-cell activator receptor (BAFF-R), particularly an anti-BAFF-R antibody or its conjugate fragment, especially ianarumab, is administered to the subject after diagnosis of HS, at the time the subject receives initial treatment, or at the same time as the initiation of initial treatment.

[0036] In one embodiment, a molecule that inhibits B-cell activator receptor (BAFF-R), particularly an anti-BAFF-R antibody, or a conjugated fragment thereof, particularly ianarumab, is administered to a subject in combination with first-line treatment for the treatment of HS.

[0037] In one embodiment, the present invention provides a B-cell activator receptor (BAFF-R), particularly an anti-BAFF-R antibody, or a conjugated fragment thereof, particularly ianarumab, for use in combination with first-line treatment for the treatment of HS.

[0038] In one embodiment, initial treatment is or includes treatment with a standard of care (SOC) drug application, such as an antibiotic or biologic, which can be used to alleviate the signs and symptoms of HS.

[0039] In one embodiment, the initial treatment is a corticosteroid, preferably a glucocorticoid, preferably dexamethasone, preferably prednisone or prednisolone. The initial treatment with prednisone or prednisolone is administered according to the approved dose.

[0040] In one alternative embodiment, the initial treatment does not include rituximab. The subject never receives rituximab for at least one year or at least six months prior to treatment with the drug of the present invention.

[0041] In one embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of antibody for use according to a first embodiment and one or more pharmaceutically acceptable carriers.

[0042] In one embodiment, the route of administration is subcutaneous or intravenous administration of the antibody according to the first embodiment, or a combination of subcutaneous and intravenous administration.

[0043] The dosage may be approximately 3 mg to 10 mg of the active ingredient per kilogram of human subjects. This dosage can be administered weekly, every two weeks, or every four weeks.

[0044] In one embodiment, the dose is approximately 150 mg to 600 mg of the active ingredient. This dose can be administered weekly, every two weeks, or every four weeks.

[0045] In one embodiment, the dose is approximately 300 mg of the active ingredient. This dose can be administered weekly, every two weeks, or every four weeks.

[0046] In one preferred embodiment, the dose is 150 mg of the active ingredient. In another preferred embodiment, the dose is 300 mg of the active ingredient. In yet another preferred embodiment, the dose is 300 mg of the active ingredient and can be administered every four weeks.

[0047] In one embodiment, the antibody is administered through a loading dose and a maintenance dose. In one embodiment, the loading dose is administered by subcutaneous injection of a first dose, and the maintenance dose is administered by subcutaneous injection of a second dose. The first dose may be the same as or higher than the second dose.

[0048] HS patients can be selected according to one of the following criteria: - The patient has moderate to severe HS; - The patient is an adult; - The patient is a young man; - Prior to treatment with anti-BAFF-R antibody, the patient has an HS-PGA score of ≥3; - Prior to treatment with anti-BAFF-R antibody, the patient has at least three inflammatory lesions; or - Prior to treatment with anti-BAFF-R antibody, patients did not have extensive scarring as a result of HS (<10 fistulas).

[0049] In one embodiment, by the 16th week of treatment, the HS patient achieves a clinical response measured by at least one of the following: -Simplified HiSCR; - Reduction of HS erythema; -NRS30; - A decrease of ≤6 as measured by DLQI; and / or -Improvement of DLQI.

[0050] In one embodiment, by the 16th week of treatment, at least 40% of the patients achieve a clinical response as measured by a simplified HiSCR; or at least 25% of the patients achieve an NRS30 response; or less than 15% of the patients experience HS erythema.

[0051] In one embodiment, the patient receives the following treatment as early as one week after the first administration of anti-BAFF-R antibody: Rapid reduction of pain as measured by VAS or NRS, and Rapid decrease in CRP when measured using standard hsCRP measurement. It has at least one of the following.

[0052] In one embodiment, the patient achieves a sustained response three months after the end of treatment, as measured by the number of inflammatory lesions, HS clinical response (HiSCR), numerical rating scale (NRS), modified Sartorius HS score, hidradenitis suppurativa-physician comprehensive assessment (HS-PGA), or quality of life index for skin disease (DLQI).

[0053] In one embodiment, the patient achieves a sustained response, as measured by a simplified HiSCR (sHiSCR), three months after the end of treatment.

[0054] According to a second aspect, a method for treating HS in a human subject is provided, comprising administering a therapeutically effective dose of anti-BAFF-R antibody to the subject.

[0055] In one embodiment, the antibody is administered together with one or more pharmaceutically acceptable carriers.

[0056] In one embodiment, the antibody is administered subcutaneously, intravenously, or a combination of subcutaneously and intravenously.

[0057] In one embodiment, the antibody is administered at a dose of approximately 3 mg to 10 mg of the active ingredient per kilogram of human subject.

[0058] In one embodiment, the dose is approximately 3 mg of the active ingredient per kilogram of human subjects.

[0059] In one embodiment, the antibody is administered in an amount of approximately 150 mg to approximately 300 mg of the active ingredient, for example, as a dose of approximately 300 mg of the active ingredient.

[0060] In one preferred embodiment, the dose is 150 mg of the active ingredient. In another preferred embodiment, the dose is 300 mg of the active ingredient.

[0061] In one embodiment, the antibody is administered in loading doses and maintenance doses.

[0062] In one embodiment, a loading dose is administered via subcutaneous injection of a first dose, and a maintenance dose is administered via subcutaneous injection of a second dose.

[0063] The first dose may be the same as or higher than the second dose.

[0064] In carrying out some of the methods of treatment or use of the Disclosure, a therapeutically effective amount of a molecule that inhibits BAFF-R, particularly an anti-BAFF-R antibody, or a conjugated fragment thereof, is administered to a patient, e.g., a mammal (e.g., a human). It is understood that the methods disclosed provide treatment for HS patients using a molecule that inhibits BAFF-R, particularly an anti-BAFF-R antibody, or a conjugated fragment thereof, particularly ianarumab, but this does not preclude monotherapy if the patient is ultimately treated with a molecule that inhibits BAFF-R, particularly an anti-BAFF-R antibody, or a conjugated fragment thereof, particularly ianarumab. In fact, if a patient chooses treatment with a molecule that inhibits BAFF-R, particularly an anti-BAFF-R antibody, or a conjugated fragment thereof, particularly ianarumab, it may be administered alone or in combination with other agents and therapies according to the methods of the Disclosure.

[0065] It will be understood that regimen changes may be appropriate for certain HS patients, such as those who show an inadequate response to the BAFF-R inhibitory molecule used, particularly anti-BAFF-R antibodies or their conjugates, especially ianarumab. Therefore, administration of BAFF-R inhibitory molecules, particularly anti-BAFF-R antibodies or their conjugates (e.g., ianarumab), may be more frequent than monthly, for example, every other week or weekly.

[0066] For example, an appropriate regimen for ianarumab might be weekly doses for several weeks [e.g., doses in weeks 1 through 4, e.g., weeks 0, 1, 2, and 3] followed by a monthly maintenance regimen.

[0067] In another example, a suitable regimen for ianarumab would be weekly doses for several weeks (e.g., weeks 2 to 8, e.g., week 3, e.g., week 0, 1, and 2), followed by a bi-weekly maintenance regimen.

[0068] It should be understood that administration (for example, ianarumab) may be less frequent than monthly, for example, every 6 weeks, every 8 weeks (every 2 months), or 4 times a year (every 3 months).

[0069] Based on the severity of the disease, it will be understood that dose escalation may be appropriate for certain HS patients, such as those who show an inadequate response to the BAFF-R inhibitory molecule used, particularly anti-BAFF-R antibodies, or their conjugates, especially ianarumab. Therefore, subcutaneous (sc) doses may be greater than approximately 150 mg to 300 mg (sc), for example, 300 mg; similarly, intravenous (iv) doses may be greater than approximately 3 mg / kg, for example, 6 mg / kg, 9 mg / kg, 10 mg / kg. It will also be understood that dose reduction may be appropriate for certain HS patients, such as those who experience adverse events or adverse reactions to the BAFF-R inhibitory molecule, particularly anti-BAFF-R antibodies, or their conjugates, especially ianarumab. Therefore, the dosage of molecules that inhibit BAFF-R, particularly anti-BAFF-R antibodies, or their conjugate fragments, especially ianarumab, may be smaller than approximately 150 mg to 300 mg(sc), for example, approximately 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 175 mg, 200 mg, 250 mg, 300 mg, etc.

[0070] definition The following definitions, in addition to those already provided, serve to define the specific preferred meanings of features and terms used in the description and claims of the present invention, where one or more or all of the general terms may be replaced with specific meanings that result in particular embodiments of the invention.

[0071] The word “substantially” does not exclude “completely.” For example, a composition that “substantially does not contain” Y may not contain Y at all. Where necessary, the word “substantially” may be omitted from the definitions in this disclosure.

[0072] The term "includes" encompasses "contains" and "consists of," for example, a composition "includes" X may consist solely of X or may include some additional elements (e.g., X + Y).

[0073] AUC0-t represents the area under the plasma concentration-time curve from time 0 to time "t" (where t is the defined time after administration) [mass × time / volume].

[0074] AUCtx-ty represents the area under the plasma concentration-time curve from time "x" to time "y" (where "time x" and "time y" are defined time points after administration).

[0075] C max This is the maximum plasma concentration observed after drug administration [mass / volume].

[0076] C min This is the minimum plasma concentration observed after drug administration.

[0077] C トラフ This refers to the plasma concentration observed immediately before the start of the medication period or at the end of the medication interval.

[0078] T max This is the time [hours] it takes for a drug to reach its maximum concentration after administration.

[0079] The subscript ss indicates that the parameter is defined in a steady state.

[0080] Naturally occurring "antibodies" are glycoproteins containing at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain has a heavy chain variable region (V in this specification). H It consists of a heavy chain constant region (abbreviated as CH1, CH2, and CH3). Each light chain has a light chain variable region (V in this specification). L It consists of the (abbreviated as) and the light chain constant region. The light chain constant region consists of one domain, CL. Hand V L regions can be further subdivided into regions of high variability, termed complementarity determining regions (CDRs), interspersed within more conserved regions termed framework regions (FRs). Each V H and V L consists of three CDRs and four FRs arranged from the amino-terminus to the carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies can mediate the binding of the immunoglobulin 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, camelid antibodies, or chimeric antibodies. The antibodies can be of 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, most preferably IgG1.

[0081] Both light and heavy chains can be divided into regions of structural and functional homology. The terms "constant" and "variable" are used functionally. In this regard, it is to be understood that the variable domains of both the light (VL) chain portion and the heavy (VH) chain portion determine antigen recognition and specificity. Conversely, the constant domains of the light chain (CL) and the heavy chain (CH1, CH2, or CH3) confer important biological properties such as secretion, transplacental mobility, Fc receptor binding, complement binding, and the like. By convention, the numbering of the constant region domains increases as they become more distal from the antigen-binding site or amino-terminus of the antibody. The N-terminus is the variable region and the C-terminus is the constant region, and the CH3 and CL domains essentially comprise the carboxy-termini of the heavy and light chains, respectively.

[0082] The term "antigen-binding portion" (or simply "antigen portion") of an antibody, as used herein, refers to the full-length antibody or one or more fragments thereof, such as a protein that retains the ability to specifically bind to an antigen or epitope.

[0083] The "complementarity-determining region" ("CDR") is an amino acid sequence with a boundary determined using one of several well-known schemes, including those described by Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. 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). In IMGT, the CDR region of an antibody is defined as IMGT / DomainGap This can be determined using the Align program.

[0084] As used herein, the term “epitope” refers to any determinant that has the ability to bind to an immunoglobulin with high affinity. An epitope is a region of an antigen that is bound by an antibody that specifically targets that antigen, and if the antigen is a protein, it contains specific amino acids that come into direct contact with the antibody. Epitopes are most commonly found on proteins, but may also be found on other types of molecules, such as nucleic acids. Epitope determinants can include chemically active surface populations of molecules such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and may have specific three-dimensional structural properties and / or specific charge properties. Furthermore, the two domains of the Fv fragment, V L and V H These are encoded by other genes, but these are a single protein chain (where V L Region and V HThese can be linked using recombinant methods by synthetic linkers that allow the regions to pair up and behave as monovalent molecules (known as 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).

[0085] The expression “isolated antibody,” as used herein, refers to an antibody that substantially does not contain other antibodies having different antigen specificities. Furthermore, isolated antibodies may substantially not contain other cellular materials and / or chemicals. As used herein, the terms “monoclonal antibody” or “monoclonal antibody composition” refer to the preparation of an antibody molecule of single molecular composition. As used herein, the term “human antibody” is intended to include antibodies whose framework and CDR region have variable regions derived from human sequences. A “human antibody” does not need to be produced by a human, human tissue, or human cell. Human antibodies in this disclosure may contain amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro, by N-nucleotide addition at junctions in vivo during recombination of the antibody gene, or by somatic mutation in vivo).

[0086] "Identity" with respect to natural polypeptides and their functional derivatives is defined herein as the percentage of amino acid residues in a candidate sequence that are identical to the residues of the corresponding natural polypeptide after the sequence has been aligned as necessary and gaps introduced to obtain the greatest possible percentage identity, and no conservative substitutions are considered part of sequence identity. Neither N- or C-terminal extensions nor insertions are interpreted as reducing identity. Methods and computer programs for alignment are well known. Percent identity can be determined by standard alignment algorithms, e.g., the Basic Local Alignment Search Tool (BLAST) described by Altshul et al. ((1990) J.Mol.Biol., 215:403 410); the algorithm of Needleman et al. ((1970) J.Mol.Biol., 48:444 453); or the algorithm of Meyers et al. ((1988) Comput.Appl.Biosci., 4:11 17). The set of parameters can be a Blosum 62 score matrix with 12 gap penalties, 4 gap length penalties, and 5 frameshift gap penalties. Percent identity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17), which is incorporated into the ALIGN program (version 2.0), using a PAM120 weighted residue table, 12 gap length penalties, and 4 gap penalties.

[0087] "Amino acids" refers to all naturally occurring L-α-amino acids, including, for example, D-amino acids. The expression "amino acid sequence variant" refers to a molecule whose amino acid sequence differs somewhat from that of the sequence relating to the present disclosure. For example, an amino acid sequence variant of the antibody relating to the present disclosure of a particular sequence may still retain the ability to bind to human BAFF-R. Amino acid sequence variants include substitution variants (in which at least one amino acid residue in the polypeptide relating to the present disclosure is removed and another amino acid is inserted in the same position), insertion variants (in which one or more amino acids are inserted directly next to an amino acid at a particular position in the polypeptide relating to the present disclosure), and deletion variants (in which one or more amino acids are removed from the polypeptide relating to the present disclosure).

[0088] As used herein, the term "Fc region" refers to a polypeptide comprising at least a portion of the CH3, CH2, and hinge regions of the constant domain of an antibody.

[0089] 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 through weak non-covalent forces at numerous sites, and the more interactions there are, the stronger the affinity. As used herein, the term "high affinity" for an IgG antibody or a fragment thereof (e.g., a Fab fragment) refers to a 10% affinity for the target antigen. -8 M or less, 10 -9 M or less, or 10 -10 M, or 10 -11 M or less, or 10 -12 M or less, or 10 -13 K below M D This refers to antibodies that possess high affinity binding. However, high affinity binding may differ for other antibody isotypes. For example, high affinity binding for IgM isotypes is 10 -7 M or less or 10 -8 K below M D This refers to antibodies that possess [a certain characteristic].

[0090] The term “K assoc " or "K aWhen used herein, "K" is intended to refer to the association rate of a particular antibody-antigen interaction, whereas the term "K" is intended to refer to the association rate of a particular antibody-antigen interaction. dis " or "K d When used herein, "dissociation rate" is intended to refer to the dissociation rate of a particular antibody-antigen interaction.

[0091] The term “K D When used herein, " is K a K against d The ratio (i.e., K d / K a It is intended to refer to the dissociation constant obtained from ) and expressed as molar concentration (M). K for antibodies D The value can be determined using methods well established in the art. Antibody K D Methods for determining this include using surface plasmon resonance or biosensor systems such as the Biacore® system.

[0092] As used herein, the terms “ADCC” or “antibody-dependent cell-mediated cytotoxicity” activity refer to cell depletion activity. ADCC activity can be measured by ADCC assays well known to those skilled in the art.

[0093] In one embodiment, the term "no 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, when measured in a standard ADCC assay. "No ADCC activity" means that the antibody exhibits ADCC activity (specific cell lysis) of less than 1%.

[0094] As used herein, the term “binding fragment” refers to a portion of an anti-BAFF-R antibody capable of binding to a BAFF-R epitope, particularly an epitope involved in the binding of BAFF to BAFF-R, and / or negatively involved by allosteric binding, for example, influencing the activation of BAFF-R by BAFF. Binding of the 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.

[0095] Ianarumab heavy chain: SEQ ID NO: 1 [ka]

[0096] Ianalumab light chain: Sequence ID No. 2 [ka]

[0097] Variable domain of the heavy chain (VH) of ianarumab: Sequence ID 3 [ka]

[0098] Ianarumab light chain (VL) variable domain: Sequence ID No. 4 DIVLTQSPATLSLSPGERATLSCRASQFISSSYLSWYQQKPGQAPRLLIYGSSSRATGVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQLYSSPMTFGQGTKVEIKRT

[0099] Ianarumab includes the following complementarity-determining regions (CDRs): Heavy chain: HCDR1:GDSVSSNSAAWG Sequence ID 5 HCDR2:RIYYRSKWYNSYAVSVKS Sequence ID 6 HCDR3:YDWVPKIGVFDS Sequence ID 7 Light chain: LCDR1:RASQFISSSYLS Sequence ID 8 LCDR2:GSSSRAT Sequence ID 9 LCDR3:QQLYSSPMT Sequence ID 10

[0100] As used herein, the terms “inhibit,” “inhibit,” or “to inhibit” refer to the reduction or suppression of a given condition, symptom, disorder, or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0101] As used herein, the terms “to treat,” “to cure,” or “to treat” any disease or disorder mean, in one embodiment, restoring the disease or disorder (i.e., delaying, stopping, or reducing the onset or progression of at least one of the disease or its clinical symptoms). In another embodiment, “to treat,” “to cure,” or “to treat” means mitigating or restoring at least one physical parameter, including one that may not be recognizable by the patient / subject. In yet another embodiment, “to treat,” “to cure,” or “to treat” means modulating the disease or disorder physically (e.g., stabilizing recognizable symptoms), physiologically (e.g., stabilizing a physical parameter), or both. More specifically, the term “to treat” disease HS means treating inflammatory lesions in an HS patient (in terms of number or quality or by reducing their volume and size), and / or treating abscesses and inflammatory nodules, and / or draining fistulas in an HS patient, and / or reducing the amount of scarring, and / or mitigating functional limitations associated with scarring. Treating the disease HS also means alleviating pain, fatigue, and / or itching associated with HS, reducing pus discharge and odor associated with pus discharge, and / or improving the quality of life and / or reducing work-related impairment for HS patients.

[0102] As used herein, the term “prevention” means delaying the onset, onset, or progression of a disease or disorder. More specifically, the term “preventing” disease HS means preventing the appearance of HS erythema and / or new lesions, preventing scarring and the functional limitations associated with scarring, and / or preventing surgical intervention for functional limitations, particularly those related to HS.

[0103] As used herein, the term “subject” is used interchangeably with the term “patient” throughout this application; a subject or patient “needs” treatment if such subject / patient benefits from such treatment biologically, medically or in terms of quality of life.

[0104] When used herein, the terms “a,” “an,” “the,” and similar terms used in the context of the present invention (particularly in the context of the claims) should be interpreted as encompassing both singular and plural forms, unless otherwise shown herein or in a manner clearly inconsistent with the context.

[0105] As used herein, the term "about" includes a variation of ±10% or ±5% from a given value, unless otherwise defined.

[0106] The term "pharmaceutically acceptable" refers to a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient.

[0107] As used herein, the terms “administer” or “to administer” the subject compound mean to provide the compound of the present invention and its prodrug to a subject in need of treatment. “Combined” administration with one or more further therapeutic agents includes simultaneous (parallel) and sequential administrations in any order and via any route of administration. A single administration may be a single injection or multiple injections delivered together, depending on how much of the drug substance needs to be administered to achieve the therapeutic effect.

[0108] As used herein, “therapeutic dose” means the amount of anti-BAFF-R antibody or its antigen-binding fragment, e.g., ianarumab, that, when administered to a patient / subject (such as a human) in single or repeated doses, is effective in treating, preventing, preventing the onset of, curing, delaying, reducing the severity of, or restoring at least one symptom of a disorder or recurrent disorder, or in extending the patient’s survival beyond what would be expected in the absence of such treatment. When applied to an individual active ingredient administered alone (e.g., anti-BAFF-R antibody, e.g., ianarumab), the term refers to that ingredient alone. When applied to a combination, the term refers to the combined amount of active ingredients that produce a therapeutic effect, whether administered sequentially or simultaneously in the combination.

[0109] The term "treatment regimen" refers to a regimen used to treat a disease, such as a medication protocol used during the treatment of HS. A treatment regimen may include a loading regimen (or loading medication) followed by a maintenance regimen (or maintenance medication).

[0110] The terms “loading regimen” or “loading period” refer 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, processes, and regimens (e.g., methods for treating HS) utilize a loading regimen (or loading dose). In some cases, the loading period is the period until maximum efficacy is achieved. The general goal of a loading regimen is to provide a patient with a high level of medication during the initial period of a treatment regimen. A loading regimen may include administering a higher dose of medication than a physician would use during a maintenance regimen, or administering medication more frequently than a physician would administer during a maintenance regimen, or both. Dose escalation may be performed during or after a loading regimen.

[0111] The terms “maintenance regimen” or “maintenance period” refer to a treatment regimen (or part of a treatment regimen) used to maintain a patient’s condition during treatment for a disease, for example, to keep the patient in remission for an extended period (several months or several years) after a loading regimen or period. In some embodiments, the methods, uses, and regimens disclosed utilize a maintenance regimen. A maintenance regimen may be a continuous therapy (e.g., administering the drug at regular intervals, e.g., weekly, bi-weekly, or monthly (every four weeks), annually, etc.) or an intermittent therapy (e.g., intermittent treatment, intermittent therapy, treatment on relapse, or treatment when certain predetermined criteria are reached [e.g., pain, disease manifestation, etc.]). Dose escalation may be performed during a maintenance regimen.

[0112] The term "in combination with..." is understood to mean that two or more drugs are administered sequentially or simultaneously (this may be individual doses or fixed doses). Alternatively, the term "in combination with..." is understood to mean that two or more drugs are administered in a manner in which it is expected that effective therapeutic concentrations of these drugs will overlap in the patient's body for most of the duration. These two or more drugs may be administered independently, simultaneously, or separately, particularly within time intervals that allow these combination partners to exhibit a synergistic effect. As used herein, terms such as "simultaneous administration" or "combination administration" are intended to encompass the administration of selected combination partners to a single target (e.g., a patient) that requires them, and to include treatment regimens in which these drugs are not necessarily administered via the same route of administration or simultaneously. As another entity, drugs and treatment regimens administered to a patient simultaneously, in parallel, or sequentially without specific time constraints (where such administrations provide therapeutically effective levels of two compounds in the patient's body) will provide the beneficial effects of drug combinations in treating the conditions or disorders described herein.

[0113] The expression “means of administration” is used to refer to any available tools for systemically administering a drug to a patient, including, but not limited to, pre-filled syringes, vials and syringes, pen injectors, auto-injectors, intravenous infusion bags, pumps, patch pumps, etc. These tools may be used to enable a patient to self-administer the drug (i.e., administer the drug to themselves) or a physician to administer the drug.

[0114] All methods described herein may be carried out in any preferred order unless otherwise indicated herein or expressly refuted by the context. The use of any examples or illustrative words provided herein (e.g., "such as") is solely for the purpose of further clarifying the invention and does not impose any limitation on the scope of the invention as otherwise claimed. However, this may relate to preferred features.

[0115] Embodiments of the invention and their hierarchical interrelationships are also defined in the claims which should be considered to be incorporated herein.

[0116] 1. Pharmaceutical composition Therapeutic antibodies are typically formulated as an aqueous form ready for immediate administration or as a lyophilized product for reconstitution with a suitable diluent before administration. Anti-BAFF-R antibodies can be formulated as a lyophilized product or as an aqueous composition, for example, in a pre-filled syringe. The formulation is also called a drug formulation (DP).

[0117] A suitable formulation can provide an aqueous pharmaceutical composition or lyophilized product that can be reconstituted to give a solution with a high concentration of antibody active ingredient and a low level of antibody aggregation for delivery to a patient. The high concentration of antibody is useful because it reduces the amount of material that must be delivered to the patient. The reduced dosage volume minimizes the time required to deliver a given dose to the patient. The aqueous composition of the present invention containing a high concentration of anti-BAFF-R antibody is particularly suitable for subcutaneous administration.

[0118] Therefore, the present invention provides an aqueous pharmaceutical composition containing ianarumab that is suitable for administration to a subject, for example, subcutaneous administration.

[0119] Anti-BAFF-R antibodies can be used as pharmaceutical compositions when combined with pharmaceutically acceptable carriers. Such compositions may contain, in addition to anti-BAFF-R antibodies such as ianarumab, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The characteristics of the carrier depend on the route of administration. Pharmaceutical compositions for use in the disclosed methods may also contain additional therapeutic agents for the treatment of specific target disorders.

[0120] In one specific embodiment, the composition, also called the drug product (DP), has a pH of 6.0, and (i) 150 mg / mL ianarumab, (ii) 200-270 mM sucrose (as a stabilizer), (iii) 15-30 mM L-histidine (as a buffer), and (iv) 0.03%~0.06% polysorbate 20 (as a surfactant) It is a lyophilized formulation prepared from an aqueous formulation containing [the specified ingredient].

[0121] In another specific embodiment, the pharmaceutical composition, also called a drug product (DP), has a pH of 6.0, and (i) 150 mg / mL ianarumab, (ii) 220 mM sucrose (as a stabilizer), (iii) 20 mM L-histidine (as a buffer), and (iv) 0.04% polysorbate 20 (as a surfactant) It is an aqueous pharmaceutical composition containing [the specified ingredient].

[0122] 2. Combinations The present invention further relates to a combination of an anti-BAFF-R antibody, such as ianarumab, and one or more additional therapeutic agents for use in the treatment or prevention of HS in patients requiring such treatment and / or prevention.

[0123] These additional therapeutic agents may include topical treatments (creams [non-steroidal or steroidal], cleansers, disinfectants), systemic treatments (e.g., using biological agents, antibiotics, or chemical entities), disinfectants, photodynamic therapy, and surgical interventions (lasers, drainage or incision, excision).

[0124] Additional non-limiting therapeutic agents for use in combination with disclosed anti-BAFF-R antibodies, such as ianarumab, during the treatment of HS include IL-17 antagonists (ixekizumab, brodalumab, secukinumab, CJM112), as well as IL17A / F antagonists (such as bimekizumab) or IL17C antagonists (such as MOR106), tumor necrosis factor α (TNF-α) blockers (Enbrel® (etanercept), Humira® (adalimumab), Remicade® (infliximab), and Simponi® (golimumab), etc., interleukin 12 / 23 blockers (Stelara® (ustekinumab), tasocitinib, and briakinumab, etc.), IL-23 blockers (guselkumab, tildrakizumab, and risankizumab, etc.), p19 inhibitors, PDE4 inhibitors (apremilast or Otezla®, etc.), complement pathway inhibitors, for example, factor B inhibitors (e.g., compounds disclosed in International Publication No. 2015 / 009616, or 4-((2S,4S)-4-ethoxy-1-((5-methoxy- LNP023 (also known as 7-methyl)-1H-indole-4-yl)methyl)piperidine-2-yl)benzoic acid), C5a inhibitors (IFX-001, CCX168 (also known as Avacopan)), IL-1 antagonists (canakinumab, gevokizumab, lilonacept, anakinra, MaBp1 (XBiotech)), inflammasome inhibitors such as NLRP3 inhibitors and NLRP5 inhibitors, CXCR1 / 2 inhibitors, IL-18 antagonists, IL-6 antagonists, IL-36 antagonists, CD20 antagonists Examples include 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, antagonist antibodies), as well as broad-spectrum oral JAK inhibitors, or more specific TYK2 or JAK1, JAK2, or JAK3 inhibitors.

[0125] Additional HS agents for use in combination with the disclosed anti-BAFFR antibody during HS treatment include retinoids such as acitretin (e.g., Soriatane®) and isotretinoin, immunosuppressants (e.g., rapamycin, T-cell blockers [e.g., Amevive® (Alefacept) and Raptiva® (Ephalizumab)]), cyclosporine, methotrexate, mycophenolate mofetil, mycopheno (e.g., leflunomide, tacrolimus), hydroxyurea (e.g., Hydrea®), sulfasalazine, 6-thioguanine, fumarate (e.g., dimethyl fumarate and fumarate esters), azathioprine, colchicine, alitretinoin, steroids, corticosteroids, certolizumab, mometasone, rosiglitazone, pioglitazone, botulinum toxin, triamcinolone, IFX-1 (InflaRx), LY-3041658 (Eli Lilly), TE-2232 (Immunwork), NSAIDs, COX inhibitors, prescription narcotics, ketoprofen, codeine, gabapentin, pregabalin, gentanyl, antibiotics (topical, oral, IV) (e.g., clindamycin, rifampin, tetracycline, thalecycline, doxycycline, minocycline, rimecycline, trimethoprim-sulfamethoxazole, erythromycin, ceftriaxone, moxifloxacin, metronidazole) Examples include corticosteroids (for injection or oral use), used alone or in combination, antiandrogen / hormone therapies (oral contraceptives, spironolactone, finasteride, dutasteride, progesterone IUDs, cyproterone acetate, ethinylestradiol, gestodene, norgestimate, desogestrel, drospirenone, spironolactone), triamcinolone acetonide, MEDI8968, hydroxychloroquine, dapsone, metformin, adapalene, azelaic acid, and zinc.

[0126] The disclosed kits, methods, and preferred combinations for use include other biologics such as TNFα blockers, IL-17 or IL-23 and / or IL-1 and / or IL-18 blockers.

[0127] Examples of TNFα blockers for use in combination therapy include etanercept, adalimumab, infliximab, and golimumab. Examples of IL17 blockers include ixekizumab, brodalumab, secukinumab, or CJM112. Examples of IL23 blockers include guselkumab, tildrakizumab, and risankizumab. Examples of IL1 blockers include canakinumab, gevokizumab, lilonacept, anakinra, and MaBp1 (XBiotech).

[0128] 3. Route of administration Typically, antibodies or proteins are administered by injection, for example, intravenously, intraperitoneally, or subcutaneously. Methods for carrying out this administration are known to those skilled in the art. It is also possible to obtain compositions that can be administered topically or orally, or that may have the ability to penetrate mucous membranes. As will be understood by those skilled in the art, any means suitable for administration that is appropriate for the chosen specific route of administration can be used.

[0129] Possible routes of administration include parenteral administration (e.g., intravenous (IV or IV), intramuscular (IM), intradermal, subcutaneous (SC or SC), or infusion), oral and intrapulmonary administration (e.g., inhalation), nasal, transdermal (topical), transmucosal, and rectal administration. Liquids or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: sterile diluents, e.g., water for injection, saline solution, non-volatile oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents, e.g., benzyl alcohol or methylparaben; antioxidants, e.g., ascorbic acid or sodium bisulfite; chelating agents, e.g., ethylenediaminetetraacetic acid; buffers, e.g., acetic acid, citric acid, or phosphoric acid; and agents for adjusting tonicity, e.g., sodium chloride or dextrose. pH can be adjusted using an acid or base such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be sealed in glass or plastic ampoules, disposable syringes, or reusable vials.

[0130] The therapeutically effective dose can be administered, for example, according to a weekly dosing schedule or every two weeks (every other week), every three weeks, or every four weeks. In such embodiments, the therapeutically effective dose is generally within the dosing range (i.e., about 3 mg / kg to about 10 mg / kg, for example, about 3 mg / kg, for example, 9 mg / kg(IV), or about 150 mg or about 300 mg administered subcutaneously every week, every other week, or every four weeks).

[0131] The timing of medication is generally determined from the first dose of the active compound (e.g., ianarumab), which is also known as the "baseline." However, different healthcare providers use different nomenclature.

[0132] In particular, Week 0 may be considered Week 1 by a healthcare provider, while Day 0 may be considered Day 1 by a healthcare provider. Therefore, different physicians may refer to the same medication schedule as giving a certain dose on, for example, Week 3 / Day 21, Week 3 / Day 22, Week 4 / Day 21, or Week 4 / Day 22. For consistency, the first week of medication will be considered Week 0 in this specification, while the first day of medication will be considered Day 1. However, this naming convention is used merely for consistency and should not be interpreted as restrictive; that is, regardless of whether a physician refers to a particular week as "Week 1" or "Week 2," weekly medication is a provision for the weekly dose of an anti-BAFF-R antibody (e.g., ianarumab). It will be understood that a dose does not need to be provided at a precise time. For example, a dose scheduled for approximately day 29 could be delivered on, for example, day 24-34 or day 30, if it is delivered in the appropriate week.

[0133] As used herein, the expression “a container having a sufficient amount of anti-BAFF-R antibody to enable the delivery of [specified dose]” is used to mean that a given container (e.g., vial, pen, syringe) contains a certain volume of anti-BAFF-R antibody (e.g., as part of a pharmaceutical composition) that can be used to deliver the desired dose. For example, if the desired dose is 300 mg, a clinician may use 2 ml from a container containing an anti-BAFF-R antibody preparation at a concentration of 150 mg / ml, 1 ml from a container containing an anti-BAFF-R antibody preparation at a concentration of 300 mg / ml, 0.5 ml from a container containing an anti-BAFF-R antibody preparation at a concentration of 600 mg / ml, and so on. In each of these cases, these containers have a sufficient amount of anti-BAFF-R antibody to enable the delivery of the desired 300 mg dose.

[0134] As used herein, the expression “formulated in a dosage that enables delivery of [specified dose] via [route of administration]” is used to mean that a given pharmaceutical composition can be used to deliver a desired dose of anti-BAFF-R antibody, e.g., ianarumab, via a specified route of administration (e.g., sc or iv). For example, if the desired subcutaneous dose is 300 mg, a clinician may use 2 ml of an anti-BAFF-R antibody preparation having a concentration of 150 mg / ml, 1 ml of an anti-BAFF-R antibody preparation having a concentration of 300 mg / ml, 0.5 ml of an anti-BAFF-R antibody preparation having a concentration of 600 mg / ml, and so on. In each of these cases, these anti-BAFF-R antibody preparations are concentrated sufficiently high to enable subcutaneous delivery of the anti-BAFF-R antibody. Subcutaneous delivery typically requires delivery of a volume of less than about 2 ml, preferably less than about 1 ml. However, higher volumes can be delivered over time, for example, using a patch / pump mechanism.

[0135] Disclosed herein is the use of an anti-BAFF-R antibody (e.g., ianarumab) for the manufacture of a pharmaceutical product for the treatment of hidradenitis suppurativa in patients (wherein the pharmaceutical product is formulated to include a container, each container having a sufficient amount of anti-BAFF-R antibody to enable the delivery of at least about 75 mg, 150 mg, or 300 mg of anti-BAFF-R antibody or its antigen-binding fragment (e.g., ianarumab) per unit dose).

[0136] Disclosed herein is the use of an anti-CD40 antibody (e.g., ianarumab) for the manufacture of a pharmaceutical product for the treatment of hidradenitis suppurativa in patients (wherein the pharmaceutical product is formulated in doses that allow for systemic delivery (e.g., IV or SC delivery) of an anti-BAFF-R antibody or its antigen-binding fragment (e.g., ianarumab) of about 75 mg, about 150 mg, or about 300 mg per unit dose).

[0137] 4. Kit This disclosure also includes kits for treating patients with hidradenitis suppurativa (HS) with an anti-BAFF-R antibody or its antigen-binding fragment, e.g., ianarumab. Such kits include a pharmaceutical composition comprising an anti-BAFF-R antibody or its antigen-binding fragment, e.g., ianarumab or the anti-BAFF-R antibody (as described above), e.g., in liquid or lyophilized form. Furthermore, such kits may include means for administering the anti-BAFF-R antibody (e.g., syringes and vials, pre-filled syringes, pre-filled pens, patches / pumps) and instructions for use. The instructions may clarify that the anti-BAFF-R antibody (e.g., ianarumab) is to be provided to the patient as part of a specific drug regimen. These kits may also include additional therapeutic agents (as described above) for delivery in combination with an encapsulated anti-BAFF-R antibody, e.g., ianarumab, for the treatment of HS.

[0138] The expression “means of administration” is used to refer to any available tools for systemically administering a drug to a patient, including, but not limited to, pre-filled syringes, vials and syringes, pen injectors, auto-injectors, intravenous infusion bags, pumps, patches / pumps, etc. These tools may be used to enable a patient to self-administer the drug (i.e., administer the drug to themselves) or for a caregiver or physician to administer the drug.

[0139] Disclosed herein is a kit for the treatment of a patient having hidradenitis suppurativa, comprising: a) a pharmaceutical composition comprising a therapeutically effective amount of anti-BAFF-R antibody or its antigen-binding fragment; b) means for administering the anti-BAFF-R antibody or its antigen-binding fragment to a patient; and c) instructions for subcutaneously administering the anti-BAFF-R antibody or its antigen-binding fragment to a patient in need, at a dose of approximately 3 to approximately 10 mg of the active ingredient per kilogram of human subject, three times (once every other week), or at approximately 150 mg or approximately 300 mg weekly, every other week, or monthly.

[0140] In one specific embodiment, the use of a) a liquid pharmaceutical composition comprising an anti-BAFF-R antibody, a buffer, a stabilizer, and a solubilizer, and b) means for subcutaneously administering the anti-BAFF-R antibody to a patient having hidradenitis suppurativa, is provided for the manufacture of a pharmaceutical for the treatment of hidradenitis suppurativa, where the anti-BAFF-R antibody is administered intravenously to the patient in a dose of about 3 mg to about 10 mg.

[0141] In another specific embodiment, the use of a) a liquid pharmaceutical composition comprising an anti-BAFF-R antibody, a buffer, a stabilizer, and a solubilizer, and b) means for subcutaneously administering the anti-BAFF-R antibody to a patient having HS, is provided for the manufacture of a pharmaceutical for the treatment of HS, wherein the anti-BAFF-R antibody is administered subcutaneously to the patient in doses of about 150 mg of the active substance or about 300 mg of the active substance (weekly, bi-weekly, or monthly (every 4 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. .

[0142] 5.Hidradenitis suppurativa HS is a chronic inflammatory scarring condition affecting the intercutaneous tissue of the axillary, groin, submammary, genital anal, and perineal regions of the body. Three diagnostic criteria have been established for the diagnosis of HS: typical lesions (in the early first lesion, deep, painful nodules [without mouths] or in the second lesion, abscesses, draining sinuses, connected scars, and “tombstone” open comedones); typical tissue distribution (axillary, groin, genital, perineal and perianal regions, buttocks and submammary and intermammary regions); and chronicity and recurrence (Margesson and Danby (2014)). The physical severity of HS can be classified at baseline using Hurley's clinical staging, shown in Table 1 below.

[0143] [Table 1]

[0144] HS consists of follicular keratin plugs, tubular rupture, and a second inflammation. Patients initially experience blockage of the follicular tubules, which over time leads to tubular leakage and horizontal rupture into the dermis. If the follicular-pilolar sebaceous gland (FPSB) fails to repair, the follicular fragments stimulate three reactions that initiate the course of HS disease. The first is an inflammatory reaction triggered by the innate immune system, causing suppuration and tissue destruction, resulting in a foreign body reaction and extensive scarring. The second reaction leads to epithelial sinuses, which may arise from stem cells derived from FPSB units that survived the destruction caused by the inflammatory reaction. The third, invasive, proliferative, gelatinous masses consisting of a gel containing inflammatory cells, occur in most cases and are assumed to be precursors to the epithelial elements described above. (See Margesson and Danby (2014)). As used herein, the expression “delaying HS disease progression” means slowing the progression of any of the aspects of the course of HS disease described above, particularly the inflammatory response. In some embodiments of this disclosure, treatment with anti-BAFF-R antibodies delays HS disease progression.

[0145] Recurrences of HS in patients include the development of papules, pustules or inflammatory nodules, pain and itching, abscesses, suppuration, and any combination thereof. As used herein, “HS erythema” (etc.) is defined as an increase of at least 25% in the number of abscesses and inflammatory nodules (ANs), accompanied by a minimum increase of 2ANs compared to baseline.

[0146] In some embodiments of this disclosure, treatment with an anti-BAFF-R antibody according to the disclosed method prevents HS erythema, reduces the severity of HS erythema, and / or reduces the frequency of HS erythema. In some embodiments, when a population of HS patients is treated according to the disclosed method, less than 5%, less than 10%, less than 15%, or less than 20% experience erythema during the first 16 weeks of treatment.

[0147] As used herein, expressions such as "reducing the severity of HS erythema" mean reducing the intensity of HS erythema, for example, reducing the number and / or size of abscesses and / or inflammatory nodules, reducing the intensity of specific erythematous components (for example, reducing the number, size, and thickness of abscesses and / or inflammatory nodules, reducing the degree of skin irritation (itching, pain), etc.), and / or reducing the amount of time that the erythema (or its components) persists.

[0148] As used herein, expressions such as "reducing the frequency of HS erythema" mean reducing the incidence of HS erythema, for example, reducing the incidence of abscesses and / or inflammatory nodules. By reducing the frequency of HS erythema, patients experience fewer HS recurrences. The incidence of erythema can be assessed by observing patients over time to determine whether the prevalence of erythema has decreased.

[0149] As used herein, the expression "preventing HS erythema" means eliminating future HS erythema and / or erythematous components.

[0150] The effectiveness of HS treatment can be evaluated using various known methods and means for measuring the pathophysiology and / or clinical response of HS. Some examples include, for instance, Hurley's staging system, the Severity Assessment Scoring System (SAHS), the Sartorius score, the modified Sartorius score, the HS Comprehensive Physician Assessment (HS-PGA) score, visual analog scales (VAS) or numerical rating scales (NRS) for assessing skin-related pain, the Quality of Life Index (DLQI) for skin diseases, the HS Clinical Response (HiSCR) based on the sum of abscesses and inflammatory nodules, the simplified HiSCR, EuroQuol-5D (EQ5D), the Anxiety and Depression Scale in Etiology, the Resource Utilization Index, the Severity Assessment Index for Hidradenitis Suppurativa (HSSI), the Work Productivity Index (WPI), the BMI (Body Surface Area of ​​Inflammation), and the Anti-Acne Severity Index (AISI) (e.g., Deckers and Prens (2016) Drugs 76:215-229; Sartorius et al. (2009) Br.J. Dermatol 161:831-39; Chiricozzi et al. See al. (2015) Wounds 27(10):258-264). In some embodiments, the effectiveness of the methods of the present invention disclosed herein can be evaluated by the HS Comprehensive Physician Assessment (HS-PGA), Severity Assessment Scoring Score (SAHS), Numerical Rating Scale (NRS), Quality of Life Index for Skin Disease (DLQI), HS Clinical Response (HiSCR) based on the sum of abscesses and inflammatory nodules, and / or the simplified HiSCR. Preferably, the effectiveness of the HS treatment disclosed herein can be evaluated by the HS Clinical Response (HiSCR) based on the sum of abscesses and inflammatory nodules, and / or the simplified HiSCR.

[0151] In some embodiments, HS patients achieve HiSCR in response to HS treatment. In some embodiments, if a population of HS patients 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.

[0152] In other embodiments, the efficacy of the HS treatment disclosed herein can be measured by the difference between the proportion of responders in treated patients (i.e., patients achieving a HiSCR response to HS treatment with the compounds of the present invention) and the proportion of responders in placebo-treated patients up to week 16 of treatment. In some embodiments, this difference in the proportion of responders, as measured by HiSCR, is at least 15%, at least 25%, at least 30%, or at least 35%.

[0153] Preferred scoring systems for treatment response include HiSCR, Simplified HiSCR, NRS (especially NRS30), Severity Assessment Scoring System (SAHS), HS-PGA, Inflammatory Pathological Quantity (number of abscesses, inflammatory nodules and / or draining fistulas), and DLQI.

[0154] The HiSCR (High-Intensity Suppurative Reaction) is a measure of the clinical response to hidradenitis suppurativa (HS) treatment. The HiSCR response to treatment (compared to baseline) is defined as: 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 does not include abscess counts relative to baseline when assessing disease progression. In preferred embodiments, HS patients achieve a simplified HiSCR in response to HS treatment. In some embodiments, when a population of HS patients is treated according to the disclosed methods, at least 40%, at least 50%, at least 60%, or at least 70% achieve a simplified HiSCR by week 16 of treatment.

[0155] Pain can be assessed using a Numerical Rating Scale (NRS). In some embodiments, HS patients achieve an improvement in NRS in response to HS treatment. NRS 30 is defined as a reduction of at least 30% in pain and at least 1 unit from baseline in the Patient's Overall Assessment of Skin Pain (PGA) in patients with a baseline score of 3 or higher. In some embodiments, HS patients achieve NRS 30 in response to HS treatment. In some embodiments, if a population of HS patients is treated according to the disclosed method, at least 25%, at least 30%, at least 40%, at least 50%, or at least 60% achieve NRS 30 by the 16th week of treatment. In a preferred embodiment of this embodiment, if a population of HS patients is treated according to the disclosed method, at least 30% achieve NRS 30 by the 16th week 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 one week after the first dose.

[0156] 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 by the SAHS score, for which the following items are investigated: the number of affected areas (left axilla, right axilla, left subglandular, right subglandular, intermammary or chest, abdomen, pubic mound, left inguinal, right inguinal, genitals, perianal or perineal, left buttock, right buttock and other [e.g., neck, posterior auricle]), the number of inflammatory and / or painful lesions other than fistulas (ILOF), and the number of fistulas. These items, assessed by the physician, were completed by two items reported by the patient: the patient was asked about the number of new tumors or the number of existing tumors that had relapsed in the past four weeks, and was asked to rate the current severity (NRS) of pain in the most symptomatic lesions during a range of 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 cases of HS are defined by an SAHS score of 4 or less. Moderate HS is defined by a SAHS score of 5–8, and severe cases of HS are defined by a SAHS score of 9 or more.

[0157] In some embodiments, HS patients achieve an improvement in their SAHS score in response to HS treatment. In some embodiments, HS patients achieve a decrease of at least 1 point from baseline in their SAHS score in response to HS treatment. In other embodiments, HS patients achieve a decrease of at least 2 points or at least 3 points from baseline in their SAHS score in response to HS treatment. Preferably, the SAHS score was at least 4 at baseline before treatment with anti-BAFF-R antibody.

[0158] The DLQI is the most established measure of quality of life in dermatology. It consists of questions about the impact of skin disease on feelings and other aspects of daily living activities during the previous week. Each question is scored from 0 (not at all) to 3 (very much so). The maximum score is 30 points, where 0-1 is considered no impact on the patient's life, 2-5 is small, 6-10 is moderate, 11-20 is very large, and 21-30 is extremely large (see Finlay and Khan (1994) Clin Exp Dermatol 19:210-16). In some embodiments, HS patients achieve an improvement in DLQI in response to HS treatment.

[0159] In some embodiments, in response to treatment according to the claimed method, patients experience a rapid decrease in CRP, as measured by standard CRP measurement or high-sensitivity CRP (hsCRP) measurement, as early as one week after the first dose. As used herein, “C-reactive protein” and “CRP” refer to serum C-reactive protein, i.e., plasma protein commonly used as an indicator of the acute phase response to inflammation. The level of CRP in plasma can be expressed at any concentration (e.g., mg / dl, nmol / L). The level of CRP can be measured by various standard assay methods, such as radioimmunodiffusion, electroimmunoassay, immunoturbidimetric assay, ELISA, turbidimetric assay, fluorescence polarization immunoassay, and laser turbidimetric assay. Testing for CRP can be done using standard CRP tests or high-sensitivity CRP (hs-CRP) tests (i.e., high-sensitivity tests that allow for the measurement of low levels of CRP in a sample using laser turbidimetric assay). 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.

[0160] The Sartorius HS score (also known as the HS score or HSS) is assigned by counting the invasive areas, nodules, and sinuses in HS patients (Sartorius et al. (2003) Br J Dermatol 149:211-13). The modified Sartorius HS score is a revised version of the original HSS by making some simplifications to make it more practical to use, such as including fewer specific lesions in the score and changing the number of points given for each parameter (Sartorius et al. (2009)). In some embodiments, HS patients achieve an improvement in the modified Sartorius HS in response to HS treatment.

[0161] The HS Physician Comprehensive Assessment (HS-PGA) is a six-scale assessment scale (score range 0-5) based on the number of HS lesions (i.e., 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 2012;157:846-855). In some embodiments, HS patients achieve an improvement in the modified HS-PGA in response to HS treatment. In some embodiments, HS patients achieve a reduction of at least 2 points in their HS-PGA score from baseline in response to HS treatment. Preferably, the HS-PGA score was at least 3 at baseline before treatment with the anti-BAFF-R antibody.

[0162] In some embodiments, when a population of HS patients is treated 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 by week 16 (e.g., patients achieving HiSCR or simplified HiSCR by week 16) maintained their response three months after the end of treatment, or six months after the end of treatment, or twelve months after the end of treatment. In another embodiment of this embodiment, at least 40% or at least 50% of patients who responded to treatment by week 16 (e.g., patients achieving HiSCR or simplified HiSCR by week 16) maintained their response three months after the end of treatment. Preferably, at least 70% of patients who responded to treatment by week 16 (e.g., patients achieving HiSCR or simplified HiSCR by week 16) maintained their response three months after the end of treatment. As used herein, the term “sustained” means that the outcome or goal (e.g., pain relief, inflammation reduction) is substantially maintained over a given period of time.

[0163] Lesion-related pruritus can be assessed by patient surveys. Patients were asked to rate lesion-related pruritus on a scale of 0 (no pruritus) to 10 (likely more severe pruritus). In some embodiments, when a population of HS patients 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 a placebo group, the difference between the treated group and the placebo group is at least 3 points.

[0164] The odor caused by the discharge of pus from the lesions can be assessed by patient surveys. Patients were asked to rate the odor caused by the discharge of pus from the lesions on a scale of 1 (no odor), 2 (slight odor), 3 (moderate odor), and 4 (considerable odor). In some embodiments, when a population of HS patients is treated according to the disclosed method, the pruritus score improves by at least 1 point, preferably at least 2 points. Furthermore, when compared to the placebo group, the difference between the treated group and the placebo group is at least 1 point.

[0165] The impact of HS on the ability to complete work can be assessed by patient surveys. Patients were asked to rate the extent to which HS affected their ability to complete work on a scale of 1 (not at all), 2 (slightly), 3 (moderately), 4 (greatly), and 5 (completely unable to work). In some embodiments, when a group of HS patients is treated according to the disclosed method, their pruritus score improves by at least 1 point, preferably at least 2 points. Furthermore, when compared to a placebo group, the difference between the treated group and the placebo group is at least 1 point. [Examples]

[0166] To aid in understanding the present invention, the following embodiments are provided, which are also specific embodiments of the invention, but are not intended to limit the scope of the invention, nor should they be construed as limiting the scope of the invention.

[0167] Example 1. Reduction of B cells and autoantibodies in patients participating in a clinical trial for systemic lupus erythematosus (SLE). This is a double-blind, randomized, placebo-controlled, multicenter, two-arm study evaluating a 300 mg dose of ianarumab administered monthly via sc, compared to placebo, in patients with SLE receiving standard treatment. The dose regimen for this study is 300 mg (sc) of ianarumab once monthly for an 18-month treatment period.

[0168] Main selection criteria: At the time of screening, the patient must meet four or more of the eleven criteria for SLE established by the American College of Rheumatology in 1997. Patients diagnosed with SLE at least 6 months prior to screening. Elevated serum antibody titers of ANA at screening (≧1:80) in a pattern consistent with SLE diagnosis, including at least anti-double-stranded DNA (anti-dsDNA), anti-Ro (SSA), anti-La (SSB), anti-nuclear ribonucleoprotein (anti-RNP), or anti-Smith (anti-Sm). You are currently receiving treatment with corticosteroids and / or antimalarial drugs and / or thalidomide and / or other DMARDs, according to the following: If corticosteroids are the sole standard therapeutic agent: oral administration of ≤30 mg / day for a minimum of 8 weeks prior to randomization, and a stable dose for ≥2 weeks prior to randomization. If oral corticosteroids are not standard therapeutic drugs: Stable oral administration of prednisone or an equivalent at a stable dose of ≤30 mg / day for a minimum of 8 weeks prior to randomization, and ≥2 weeks prior to randomization. Treatment with an antimalarial drug and / or thalidomide at a stable dose for at least 12 weeks prior to screening and for ≥8 weeks prior to randomization, and / or one of the following DMARDs: methotrexate or imidazole derivatives (e.g., azathioprine, mizoribine) or mycophenolate derivatives (e.g., mycophenolate mofetil). Other combinations of DMARDs are not permitted. SLEDAI-2K score of ≥6 at screening The following BILAG-2004 scores were obtained during screening: - At least one "A" in the cutaneous mucosal domain or in the musculoskeletal domain or - One "B" in the cutaneous mucosa or musculoskeletal domain, and at least one "A" or "B" in the second domain. Weight of at least 40 kg at the time of screening

[0169] Main exclusion criteria: History of screenings performed before the screening -Within 12 weeks: iv High-dose corticosteroids, calcineurin inhibitors, or other oral DMARDs (excluding those listed in selection criterion 6) -Within 24 weeks: Cyclophosphamide, or biologics, e.g., intravenous Ig, plasma exchange therapy, anti-TNF-α mAb, CTLA4-Fc Ig (abatacept), or BAFF-targeted drugs (e.g., belimumab) - Any B-cell depletion therapy (e.g., anti-CD20 mAb, anti-CD22 mAb, anti-CD52 mAb) or TACI-Ig (atacicept) administered within 52 weeks prior to screening, and B-cell count <50 cells / μL at the time of screening. Presence of severe lupus renal disease defined by proteinuria exceeding 6 g / day or an equivalent spot urine protein / creatinine ratio, or by serum creatinine exceeding 2.5 mg / dL (221.05 μmol / L), or requiring immunosuppression induction or maintenance therapy exceeding the limits defined in the protocol.

[0170] Effectiveness evaluation: • SRI-4 (SLE responder index) • Visual Analog Scale for Comprehensive Physician Assessment (PhGA-VAS) • Comprehensive Patient Assessment (VAS) • Erythema rate based on BILAG-2004 score • Lupus Low Disease Activity State (LLDAS)

[0171] result: Under sustained prednisolone reduction (≤5 mg / day), the proportion of study patients achieving the composite primary endpoint of SRI-4 at week 28 was 42% higher with ianarumab than with placebo. Ianarumab also showed superiority over placebo in the incidence of moderate or severe erythema (45% vs. 73%, respectively) and time to first erythema (11.9 weeks vs. not reached median, respectively). At week 28, the differences between ianarumab and placebo were 50% for the proportion of patients achieving SRI-4 response, 34% for reduction in corticosteroid use, 43% for the primary composite endpoint of these two outcomes, 20% for lupus low disease activity status (LLDAS), and 31% for combined lupus assessment based on BILAG (BICLA). Ianarumab demonstrated good tolerability during the blinded 28-week treatment period, the open-label treatment period (weeks 28-52), and the subsequent safety follow-up period, without the detection of any new safety signals.

[0172] As part of this study, target cell analysis was performed by flow cytometry, and transcriptome profiling was conducted using total RNA obtained from whole blood with the Illumina Stranded Ribo-Zero Plus kit. Multivariate linear regression models were used to compare the treatment group and the placebo group over time to identify cellular markers, proteins, and genes specifically regulated by ianarumab.

[0173] Analysis of changes in cell subsets during ianarumab treatment demonstrated a potent and statistically significant decrease in total B cells. This was confirmed by changes in transitional B cells, naive B cells, and memory B cells, as well as CD27-high CD38-high antibody-producing cells and CD19-CD27-IgD-double-negative B cells, without a decrease in other lymphocyte subsets (CD4+ or CD8+ T cells, NK cells). Evaluation of SLE molecular drivers via blood transcriptomics, compared to healthy volunteers, confirmed disease features induced by type 1 interferon (IFN) and innate immune pathways, correlated with immunoglobulin genes. At week 28 during ianarumab treatment, potent declines in B cell-related genes were observed, accompanied by a significant decrease in IL-6 transcripts and modulation of the IFN gene signature (IFNGS). Extensive serum protein profiling revealed transcriptomics findings indicating a decrease in multiple B cell markers during ianarumab treatment. Importantly, the inventors observed that the SRI-4 response to ianarumab was equivalent to the reduction in SLEDAI associated with concomitant use, in both subjects with high and low IFNGS levels. Ianarumab treatment in SLE patients resulted in potent B-cell depletion, including autoantibody-producing subsets, as confirmed by transcriptomics and proteomics assessments. Early evidence suggests that patient responses to ianarumab were independent of IFNGS status, as clinically observed reductions in B-cell count and autoantibody levels were accompanied by reductions in IFNGS.

[0174] Conclusion: All these data indicate that ianarumab reduces autoantibodies and B cell counts in SLE patients. This effect is dose- and time-dependent. Elevated B cell counts play a significant role in the onset and progression of HS, and this is reduced by treatment with ianarumab.

[0175] Example 2. A randomized, subject- and investigator-blinded, placebo-controlled, multicenter study to evaluate the efficacy and safety of ianarumab in patients with moderate to severe hidradenitis suppurativa. Provided below are the details of the clinical trial design to demonstrate the efficacy of ianarumab.

[0176] In 12 clinical studies across multiple indications (rheumatoid arthritis, chronic lymphocytic leukemia, non-Hodgkin 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 various doses of ianarumab. In a phase 2b dose-ranging study in pSS, three doses of ianarumab administered monthly (q4w) (5 mg, 50 mg, and 300 mg) were investigated compared to placebo at week 24. Results from this dose-ranging study showed that ianarumab 300 mg (sc, q4w) had the greatest clinical efficacy compared to a lower dose (50 mg) (which achieved a similar level of circulating B cell depletion but failed to adequately maintain BAFF-R blockade).

[0177] The pharmacokinetic characteristics of ianarumab support a fixed dose for all patients (there was no evidence of a statistically significant impact of body size / weight on any PK parameter). In a phase 2b dose-range study in Sjögren's syndrome, the primary endpoint, ESSDAI, was highest at ianarumab 300 mg (q4w), and stimulated salivary flow showed greater improvement with ianarumab 300 mg (q4w) compared to lower doses.

[0178] Ianarumab 300 mg (q4w) provides significant B-cell depletion, suggesting maintenance of BAFF-R blockade based on biomarker results. Ianarumab 300 mg (q4w) has a favorable safety profile; there are no dose-related safety findings other than mostly mild local injection site reactions.

[0179] Patients with hidradenitis suppurativa tend to be heavier and have less exposure to therapeutic mAbs compared to patients with Sjögren's syndrome, which supports the idea that ianarumab 300 mg (q4w) should be tested in HS.

[0180] If necessary, mild to moderate local and systemic injection-related reactions may be treated at the discretion of the researcher, according to the symptoms and their severity (e.g., cooling, topical creams / gels, patches, paracetamol, antihistamines, etc.). It is recommended to alternate the administration site while avoiding any body area where a recent local reaction is present. If a research patient experiences a severe systemic or local injection-related reaction, treatment should be guided by general principles for treating the respective condition, including admission to the intensive care unit if necessary.

[0181] To ensure appropriate safety monitoring, subjects will be observed at the site of the initial injection for at least 4 hours after administration, or longer if necessary at the discretion of the researcher. As with any biologic therapy, patients should be observed for signs and symptoms of anaphylaxis, including urticaria, rash, dyspnea, hypotension, chest pain, elevated body temperature, and chills. Hypersensitivity reactions should be treated with antihistamines and glucocorticoids, and depending on the severity, these patients may require 100% oxygen, volume expansion, catecholamines, and transfer to an intensive care facility. Depending on the patient's condition, plasmapheresis may be considered to reduce the systemic concentration of ianarumab.

[0182] When evaluating patients suspected of having an infectious disease, it is recommended that the most sensitive tests (e.g., culture, PCR for direct pathogen detection) be used. 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 cause should be considered, and brain MRI and / or CSF testing should be performed as needed, in consultation with an infectious disease specialist where appropriate, and including cytological, biochemical, and microbiological analyses (e.g., herpesvirus, John Cunningham virus).

[0183] Ianarumab and its suitable placebo will be administered to subjects at the research center via two subcutaneous injections (2 x 1 mL) every four weeks during their scheduled medication visits. Except during epidemics or pandemics (e.g., the COVID-19 pandemic) that restrict or prevent in-facility research visits, outpatient medication should not be administered, and facility staff may arrange home visits to patients as permitted by local regulations to continue research treatment in accordance with the protocol.

[0184] Currently, only one drug (adalimumab) is approved for HS, and there is still a high medical need that remains unaddressed in HS. Furthermore, HS patients who do not respond to adalimumab have a greater abundance of lesional B cells and plasma cells compared to non-responders (Hamply 2023). In fact, plasma cells and B cells are predominantly present in lesional HS skin (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 in chronic lesions and around tubular structures, where tertiary lymphoid tissue-like structures are also observed (van Straalen et al 2022, Frew et al 2020). B cells and B cell signatures are present in HS (Frew et al 2020, Musilova 2020, Rumberger 2020), BCR activation has been demonstrated through the detection of pBTK and pSYK (Gudjonsson et al 2020, Rumberger 2020), and recently, autoantibodies correlated with disease severity and duration have been shown in HS patients (Macchiarella et al 2022). Little is known about the survival factors supporting the persistence of immune cells in HS lesions, but increased B cell activator (BAFF) expression has recently been demonstrated. In HS lesions, BAFF receptor expression is most prominent in B cells and plasma cells, and there is a strong correlation between BAFF expression and B cells and plasma cells (Sabat 2022). In summary, based on the aforementioned scientific rationale and the promising clinical efficacy observed in patients with primary Sjögren's syndrome, targeting the BAFF receptor with ianarumab in HS appears justifiable.

[0185] Blinding both subjects and researchers enables unbiased evaluation of subjective interpretations of disease frequency or overall HS-PGA score, as well as adverse events, in HS.

[0186] To evaluate the efficacy, safety, and tolerability of several active therapeutic compounds, including ianarumab, in patients with moderate to severe HS, a randomized, subject- and investigator-blinded, placebo-controlled, multicenter, parallel-group study will be conducted. A 16-week treatment period will be planned after approximately 4 weeks of screening, followed by approximately 12 weeks of safety follow-up. Participants will receive either ianarumab, 300 mg (two 1 mL injections) (sc) or its corresponding placebo (2 × 1 mL) (sc).

[0187] This study will include adult men and women aged 18–65 years presenting with moderate to severe HS with recurrent inflammatory lesions diagnosed for at least 12 months. Inclusion in this study requires having at least five inflammatory lesions. Baseline assessments may begin on day -7 to allow for completion of pre-treatment assessments on day -1. All baseline safety assessment results must be available before administration and meet eligibility criteria. Randomization will be conducted using a centralized, interactive automated response (IRT) system.

[0188] The primary clinical endpoint selected is a simplified HiSCR (Hidradenitis Suppurativa Clinical Response) after 16 weeks of treatment.

[0189] On day 113 (week 17), after safety and other assessments have been conducted, all subjects will enter a follow-up period in which they will not receive any medication. Subjects may receive previously prohibited drug therapies during this follow-up period if medically justifiable and no potential safety concerns have been identified (after discussion with the study sponsor).

[0190] Safety and efficacy evaluations will be conducted at follow-up visits on day 141 (week 21) and day 197 (week 29). Pharmacokinetic (PK) and pharmacodynamic (PD) data will be collected. Blinding of researchers and subjects will be maintained until the end of the study. A final visit will be held on day 197 (week 29) (this includes a final evaluation and subsequent release from the study).

[0191] Approximately 45 participants will be randomized to receive either the active ingredient (30 participants) or placebo (15 participants). On day 1, participants will receive 300 mg of ianarumab or a suitable placebo via subcutaneous injection (sc) administered by experienced on-site personnel. Clinical evaluations, as well as PK, PD, IG, biomarker, and safety evaluations will be conducted. Participants will be released from the facility on the same day after completion of all evaluations, provided that no safety concerns exist.

[0192] One to two hours before the first dose of the study treatment, study participants must receive premedication with 50 mg of prednison(lon) orally administered or equivalent. The purpose of corticosteroid premedication is to reduce the likelihood of cytokine release-related signs and symptoms associated with rapid depletion of circulating B cells. At the discretion of the researchers, in addition to prednison(lon), paracetamol (acetaminophen) (oral) in doses not exceeding 1000 mg, and / or oral second-generation antihistamines (e.g., loratadine) may be administered.

[0193] Following the initial administration of the research treatment, all participants must remain at the research facility / clinic for at least four hours to allow for safety monitoring for potential injection-related reactions. This monitoring will not be required at subsequent visits.

[0194] The primary objective is to demonstrate the preliminary efficacy of ianarumab treatment in HS subjects after 16 weeks of treatment, compared to placebo. A 12-week follow-up period is included after the 16-week treatment period to observe whether the persistence of the effect can be maintained or increased after 16 weeks of treatment.

[0195] We plan a 2:1 randomization based on the fact that subjects will be selected for exposure to the active ingredient while their exposure to the placebo will be limited.

[0196] This study includes multiple clinical endpoints to better assess the characteristics of these selected endpoints.

[0197] For this study, the simplified HiSCR (modified from Kimball 2014) was selected as the primary endpoint. Simplified HiSCR is defined as a 50% reduction in the total number of abscesses + inflammatory nodules without any increase in draining fistulas.

[0198] Inflammatory lesions in hidradenitis suppurativa (HS) are counted as individual lesions (inflammatory nodules, abscesses, and suppurative fistulas) within typical anatomical regions. In addition to counting, a comprehensive assessment scale (hidradenitis suppurativa-physician assessment or HS-PGA) and a composite score (hidradenitis suppurativa severity assessment score or SAHS) are used.

[0199] Outcomes reported by several patients, including the Quality of Life Index (DLQI) for skin diseases, will be used. Finally, from the perspective of the subjects, skin-related pain is the most significant symptom, and a Numerical Rating Scale (NRS) for pain will be included.

[0200] Additional information regarding clinical evaluation: HS-PGA (Hiradenitis Suppurativa - Physician-Comprehensive Assessment): This score is used for exploratory purposes to assess HS and was used and described in Kimball AB, Kerdel F, Adams D, et al (2012).

[0201] The SAHS score is a composite score (Hessam S, Scholl L, Sand M, et al (2018)) derived from collected information on inflammatory lesions, fistula count, and NRS pain. In addition, anatomical regions and new or relapsed existing tumors are collected in both cohorts.

[0202] Skin Pain - NRS (Numerical Rating Scale for Pain): The NRS for skin-related pain has been used in the adalimumab study (Kimball et al. (2016)) and is used because skin or HS-related pain is one of the most burdensome for patients (Matusiak et al. (2017)). HS-related pain is recorded as the average over the past 24 hours and as the worst condition (over the past 24 hours).

[0203] Outcomes reported by other patients (PROs) include aspects such as itching, fatigue, and impairment of work, as well as the Quality of Life Index (DLQI) and Quality of Life (QoL) tools for skin disease, using validated scores available in many countries and languages. This includes the Comprehensive Patient Assessment.

[0204] [Table 2]

[0205] [Table 3]

[0206] Main selection criteria • Men aged 18–65 years who have been clinically diagnosed with HS at least 12 months prior to screening. • A total of at least five inflammatory lesions, namely abscesses and / or inflammatory nodules, • At most 10 fistulas, • At least two anatomical regions must be involved in HS lesions. • Participants must have a minimum body weight of 50 kg (including fractional values).

[0207] Main exclusion criteria Use of the investigational drug at the time of screening, or within 30 days after registration, or within five times the second half-life of registration, or until the predicted pharmacodynamic effect returns to baseline (whichever is longer); or for a longer period if required by local regulations. • Randomization / Use of IL-12 and IL-23 blocking biological agents such as ustekinumab or guselkumab within the 6 months prior to the first treatment. • Use of B-cell targeting or B-cell depletion biological agents or similar products, such as rituximab or belirumab, within the past 12 months; for patients who received these drugs early, the B-cell count must be within the normal range. • Use of a bioimmunomodulatory agent other than those listed above (e.g., adalimumab, secukinumab, etanercept, infliximab, etc.) for 3 months prior to randomization / first treatment or 5 times its half-life (whichever is longer); • Use of rituximab or berilumab within the past 12 months; • Use of any systemic treatment for HS in the four weeks prior to randomization (e.g., retinoids or other immunomodulatory therapies, e.g., methotrexate, cyclosporine A, corticosteroids). • Use of cyclophosphamide within the past 6 months • Use of systemic antibiotics for HS in the week prior to randomization / first treatment If spironolactone or other antiandrogens (such as finasteride or cyproterone acetate) are used (for HS), only patients who have been using a stable dose for the past three weeks and are planned to continue using it for the duration of the study are eligible. • Randomization / surgical treatment for HS in the 4 weeks prior to the first treatment. Surgical treatment does not include occasional excisional biopsies. • Receiving any high-infusion corticosteroid bolus (>1 mg / kg) within the past 3 months

[0208] treatment The investigational drug, ianarumab, and its corresponding matched placebo will be prepared by Novartis and supplied to the research site as a double-blind pharmacotherapy kit. Storage requirements and detailed instructions regarding the management of research treatments, as well as target numbering, prescribing / dispensing, and adoption of research treatments, are outlined in the Site Operations Manual / Pharmacy Manual.

[0209] The target group will receive either ianarumab, 300 mg (two 1 mL injections or one 2 mL injection) (sc) or the corresponding placebo (sc).

[0210] Participants will be randomized in a 2:1 ratio to either the investigational treatment group or the corresponding placebo. The maximum treatment duration will not exceed 16 weeks.

[0211] If a skin infection or exacerbation of HS lesions occurs, researchers may choose to treat it with approved drug and non-drug therapies to avoid interruption of the study treatment. Examples include: Conservative and topical wound care and bandages, • Oral treatment with antibiotics (antibiotics should target the bacteria involved if known, and the treatment period should be no longer than two weeks).

[0212] For this trial, the use of specific rescue treatments is not planned. However, several standard of care (SOC) drug applications, such as antibiotics or biologics (Section 6.2.4), may be used to alleviate the signs and symptoms of HS. According to the European Guidelines (Zouboulis et al 2015), locally recurrent lesions can be treated with classical surgery or LASER techniques, while for extensively spread lesions, medical intervention as monotherapy or in combination with total excision is more appropriate. Medical interventions for HS may include antibiotics (clindamycin + rifampicin, tetracycline, etc.), acitretin, biologics (adalimumab, infliximab), hormone therapy, dapsone, and other biologics, such as IL-17A blockers.

[0213] If necessary, mild to moderate local and systemic injection-related reactions may be treated at the discretion of the researcher, according to the symptoms and their severity (e.g., cooling, topical creams / gels, patches, paracetamol, antihistamines, etc.). It is recommended to alternate the administration site while avoiding any body area where a recent local reaction is present. If a research patient experiences a severe systemic or local injection-related reaction, treatment should be guided by general principles for treating the respective condition, including admission to the intensive care unit if necessary.

[0214] To ensure appropriate safety monitoring, subjects will be observed at the site of the initial injection for at least 4 hours after administration, or longer if necessary at the discretion of the researcher. As with any biologic therapy, patients should be observed for signs and symptoms of anaphylaxis, including urticaria, rash, dyspnea, hypotension, chest pain, elevated body temperature, and chills. Hypersensitivity reactions should be treated with antihistamines and glucocorticoids, and depending on the severity, these patients may require 100% oxygen, volume expansion, catecholamines, and transfer to an intensive care facility. Depending on the patient's condition, plasmapheresis may be considered to reduce the systemic concentration of ianarumab.

[0215] When evaluating patients suspected of having an infectious disease, it is recommended that the most sensitive tests (e.g., culture, PCR for direct pathogen detection) be used. 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 cause should be considered, and brain MRI and / or CSF testing should be performed as needed, in consultation with an infectious disease specialist where appropriate, and including cytological, biochemical, and microbiological analyses (e.g., herpesvirus, John Cunningham virus).

[0216] List of embodiments 1. A method for treating or preventing hidradenitis suppurativa in a human subject requiring the treatment thereof, comprising administering a therapeutically effective amount of anti-BAFF-R antibody or a conjugated fragment thereof to the subject.

[0217] 1a. A method for treating hidradenitis suppurativa in a human subject having lesions associated with hidradenitis suppurativa, comprising the step of administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an amount of antibody effective in treating the symptoms of hidradenitis suppurativa in the subject: an anti-BAFF-R antibody or a conjugated fragment thereof.

[0218] 2. The method according to Embodiment 1 or 1a, wherein the anti-BAFF-R antibody or its conjugated fragment comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, and CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10.

[0219] 3. The therapeutic method according to Embodiment 1, 1a, or 2, wherein the anti-BAFF-R antibody or its conjugated 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.

[0220] 4. The method according to any 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.

[0221] 5. The method according to any of the above embodiments, wherein the anti-BAFF-R antibody or fragment thereof is ianarumab or a conjugated fragment thereof.

[0222] 6. The method according to any of the above embodiments, wherein the antibody is administered subcutaneously or intravenously, or a combination of subcutaneously and intravenously.

[0223] 7. The method according to any of the above embodiments, wherein the antibody is administered at a dose of approximately 3 mg to approximately 10 mg of the active ingredient per kilogram of human subject.

[0224] 8. The method according to Embodiment 7, wherein the dose is approximately 3 mg of the active ingredient per kilogram of human subjects.

[0225] 9. The method according to any of the above embodiments, wherein the antibody is administered in a dose of approximately 150 mg to approximately 400 mg of the active ingredient, for example, approximately 300 mg of the active ingredient.

[0226] 10. The method according to Embodiment 9, wherein the dose is 150 mg of the active ingredient or 300 mg of the active ingredient.

[0227] 11. The method according to any of the above embodiments, wherein the antibody is administered together with one or more pharmaceutically acceptable carriers.

[0228] 12. The above subject meets the following criteria: a) The subjects are those with moderate to severe HS; b) The subjects are adults; c) The target group is young people; d) Prior to treatment with anti-BAFF-R antibody, the subject has an HS-PGA score of ≥3; e) Prior to treatment with anti-BAFF-R antibody, the subject has at least three inflammatory lesions; or f) Prior to treatment with anti-BAFF-R antibody, subjects do not have extensive scarring as a result of HS (<10 fistulas). A method according to any of the above embodiments, selected according to one of the above.

[0229] 13. The subject described above, by the 16th week of treatment, has the following conditions: a) Simple HiSCR; b) Reduction in HS erythema; c) NRS30; d) A decrease of ≤6 as measured by DLQI; and / or e) Improvement of DLQI A method according to any of the above embodiments, which achieves a clinical response in at least one of the above.

[0230] 14. The method according to any of the above embodiments, wherein, when the method is used to treat a population of subjects suffering from moderate to severe HS, at least 40% of the subjects achieve a clinical response as assessed by a simplified HiSCR by the 16th week of treatment.

[0231] 15. The method according to any one of Embodiments 1 to 10, wherein, when the method is used to treat a population of subjects suffering from moderate to severe HS, at least 25% of the subjects achieve an NRS 30 response by the 16th week of treatment.

[0232] 16. The method according to any of the above embodiments, wherein, when the method is used to treat a population of subjects suffering from moderate to severe HS, less than 15% of the subjects experience HS erythema during 16 weeks of treatment.

[0233] 17. The method according to any of the above embodiments, wherein an anti-BAFF-R antibody or a conjugated fragment thereof is administered to a subject for at least 16 weeks.

[0234] 18. The subject is one of the following, as early as one week after the first dose of anti-BAFF-R antibody: a) Rapid pain relief as measured by VAS or NRS, and b) Rapid decrease in CRP when measured using a standard CRP test. The method according to any of the above embodiments, having at least one of the above.

[0235] 19. The method according to any of the above embodiments, which achieves sustained response three months after the end of treatment, when the subject is measured by inflammatory disease count, HiSCR, Numerical Rating Scale (NRS), Modified Sartorius HS score, Hidradenitis Suppurative Comprehensive Assessment (HS-PGA), or Quality of Life Index for Skin Disease (DLQI).

[0236] 20. The method according to Embodiment 19, which achieves sustained response three months after the end of treatment when the subject is measured by simplified HiSCR (sHiSCR).

[0237] 21. Use of a liquid pharmaceutical composition comprising an anti-BAFF-R antibody, a buffer, a stabilizer, and a solubilizer for the manufacture of a pharmaceutical for the treatment of hidradenitis suppurativa, and means for subcutaneous administration of the anti-BAFF-R antibody to a subject having hidradenitis suppurativa (wherein the anti-BAFF-R antibody is: It will be administered subcutaneously; and the anti-BAFF-R antibody or its conjugated fragment will each contain VH having the amino acid sequence of SEQ ID NO: 3 and VL having the amino acid sequence of SEQ ID NO: 4).

[0238] 22. Use of an anti-BAFF-R antibody or a conjugated 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 pharmaceutical product for treating a subject having hidradenitis suppurativa, which is prepared for administration according to any of the above embodiments.

[0239] 23. An anti-BAFF-R antibody or a conjugated fragment thereof for use in any of the methods described in Embodiments 1 to 20.

Claims

1. Anti-BAFF-R antibody or its conjugated fragment for use in the treatment of hidradenitis suppurativa in subjects requiring it.

2. An anti-BAFF-R antibody or its conjugated fragment for use according to claim 1, comprising CDR-H1, CDR-H2, and CDR-H3 having the 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 the amino acid sequences of SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO:

10.

3. An anti-BAFF-R antibody or its conjugated fragment for use according to claim 1 or 2, 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.

4. The anti-BAFF-R antibody for use according to any one of claims 1 to 3, comprising 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, respectively, or a conjugated fragment thereof.

5. An anti-BAFF-R antibody or a conjugated fragment thereof for use according to any one of claims 1 to 4, to be administered subcutaneously or intravenously, or a combination of subcutaneously and intravenously.

6. An anti-BAFF-R antibody or a conjugated fragment thereof for use according to any one of claims 1 to 5, to be administered in a therapeutically effective dose.

7. An anti-BAFF-R antibody or its conjugated fragment for use according to any one of claims 1 to 5, which is administered to human subjects at a dose of approximately 3 mg to approximately 10 mg of the active ingredient per kilogram.

8. The anti-BAFF-R antibody or its conjugated fragment for use according to claim 6, wherein the dose is approximately 6 mg of the active ingredient per kilogram of human subject.

9. An anti-BAFF-R antibody or its conjugated fragment for use according to any one of claims 1 to 5, which is administered in a dose of approximately 150 mg to approximately 600 mg of the active ingredient, for example, approximately 300 mg of the active ingredient.

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

11. The above-mentioned target is determined by the following criteria: a. The subject has moderate to severe HS; b. The subject is an adult; c. The subject is a young person; d. Prior to treatment with the anti-BAFF-R antibody or its conjugated fragment, the subject has an HS-PGA score of ≥3; e. Prior to treatment with the anti-BAFF-R antibody or its conjugated fragment, the subject has at least three inflammatory lesions; or f. Prior to treatment with the anti-BAFF-R antibody or its conjugate fragment, the subject does not have extensive scarring as a result of HS (<10 fistulas). An anti-BAFF-R antibody or a conjugated fragment thereof for use according to any one of claims 1 to 9, selected according to one of the following.

12. By the 16th week of treatment, the following are the cases of hidradenitis suppurativa: a. Simple HiSCR; b. Reduction in HS erythema; c. NRS30; d. A decrease of ≤6 when measured by DLQI; and / or e. Improving DLQI An anti-BAFF-R antibody or a conjugated fragment thereof for use according to any one of claims 1 to 10, which achieves a clinical response in at least one of the following:

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

14. The subject described above, as early as one week after the first administration of the anti-BAFF-R antibody or its conjugated fragment, exhibits the following: a. Rapid pain relief as measured by VAS or NRS, and b. Rapid decrease in CRP when measured using standard CRP measurement methods. An anti-BAFF-R antibody or a conjugated fragment thereof for use according to any one of claims 1 to 10, having at least one of the above.

15. An anti-BAFF-R antibody or its conjugated fragment for use according to any one of claims 1 to 10, which achieves sustained response three months after the end of treatment, when the subject is measured by inflammatory disease count, HiSCR (Hi-SCR), Numerical Rating Scale (NRS), Modified Sartorius HS score, Hidradenitis Suppurative Comprehensive Assessment (HS-PGA), or Quality of Life Index for Skin Diseases (DLQI).

16. An anti-BAFF-R antibody or its conjugated fragment for use according to any one of claims 1 to 10, which achieves sustained response three months after the end of treatment when the subject is measured by a simplified HiSCR (sHiSCR).

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

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