Biomarker-based treatment and diagnostic methods for IL-17-dependent conditions

Abstract

Methods for the treatment, monitoring, and diagnosis of IL-17-dependent conditions, including hidradenitis suppurativa, based on biomarkers are disclosed. These biomarkers include IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, and HGF. CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13, PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, EDAR, and combinations thereof may be selected. Kits for measuring biomarkers, diagnosing and treating IL-17-dependent conditions, and identifying superresponders are also disclosed.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 460,240 filed on April 18, 2023 and U.S. Provisional Application No. 63 / 460,230 filed on April 18, 2023, and the entire disclosure of each is hereby expressly incorporated by reference herein.

[0002] Incorporation by Reference to a Sequence Listing This application includes a sequence listing electronically submitted in XML file format, which is hereby incorporated by reference herein in its entirety. The XML copy was created on April 17, 2024, with the file name "P68859_SL.xml" and a size of 94,394 bytes.

Background Art

[0003] Biomarkers for various immune-mediated diseases have been disclosed. For example, WO2019 / 143585 discloses the detection of IL-19 in samples from patients with immune-related diseases such as psoriasis, atopic dermatitis, or diabetic neuropathy, and the treatment of such patients with an IL-19 antibody if IL-19 is detected above a reference level. As another example, WO2014 / 100312 discloses the proactive selection of psoriasis patients who are likely to benefit from treatment with an IL-23 antagonist based on the presence of one or more single nucleotide polymorphisms in the genome. WO2012 / 093254 relates to the use of lipocalin 2 (LCN2) as a biomarker and the use of an anti-IL-17A antibody to reduce LCN2 expression in an animal model of multiple sclerosis. However, there remains a need for more individualized treatment regimens, as well as the need to identify patients with immune-related disorders earlier, more accurately assess the severity of these disorders, particularly IL-17-dependent conditions, and more effectively manage disease progression and post-treatment relapses. Furthermore, there remains a need to identify specific patients and / or patient populations that respond positively to treatment with specific therapeutic agents from among patients who meet standard diagnostic criteria.

[0004] Historically, IL-17 was used to refer to what was later identified as a member of the cytokine IL-17 family. Therefore, those skilled in the art considered IL-17A to be the primary pro-inflammatory signaling agent driving IL-17 pathway-related immune conditions such as psoriasis, psoriatic arthritis, and axial spondyloarthropathy. Non-contagious inflammatory skin diseases characterized by elevated IL-17 activity are also referred to as type 3 diseases (Nakamura et al., Curr Rheumatol Rep. 23(5):31 (2021); Eyerich et al., J Eur Acad Dermatol). Venereol. 32(5):692-703 (2018); Annunziato et al., 135(3):626-35 (2015)). stop Over the years, it has been identified that several prevalent and burdensome chronic conditions, including the skin disease hidradenitis suppurativa (HS), follow this pattern. The first monoclonal antibody therapies developed to treat type 3 diseases were antibodies that specifically inhibited IL-17A, based on the conventional concept that this mediator is responsible for the main inflammatory activity.

[0005] The current concept of IL-17-driven inflammation in human diseases is based on the understanding that two members of the IL-17 cytokine family, IL-17A and IL-17F, bind to the IL-17 receptor, which consists of two receptor chains, IL-17RA and IL-17RC, and then form dimers that exert pro-inflammatory functions. Traditionally, it was thought that the pro-inflammatory potential and affinity for the RA / RC receptor decreased from IL-17A / A to IL-17A / F and then to IL-17F / F, but the amount of dimers present in a certain pathological state (e.g., I The presence of different types of receptors (e.g., RC / RC receptors) on relevant target cells that favor the biological activity of IL-17F (when IL-17F / F is more abundant than L-17A / A) suggests an important independent pro-inflammatory effect of IL-17F / F. In fact, cells that exclusively produce IL-17F have been identified, which are thought to be independent of mechanisms that control IL-17A-producing cells, such as stimulation by IL-23. IL-17F / F dimers are not inhibited by conventional IL-17A-blocking monoclonal antibody therapy.

[0006] Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by painful inflammatory lesions, which, if left untreated, can progress to irreversible tissue destruction, including the formation of tunnels and scars (Sabat et al., Nat Rev Dis Primers 6, 18 (2020); Navrazhina et al., J Allergy Clin Immunol 147, 2213-2224 (2021)). This disease can significantly impact quality of life and work. It has a significant impact on productivity (Merchant et al., Clin Exp Dermatol. 9:llae120 (2024)). Currently, there is a significant delay between the appearance of the first signs of HS and the initiation of diagnosis and appropriate treatment (Saunte et al., Br J Dermatol 173, 1546-1549 (2015); Garg et al., J Am Acad Dermatol 82, 366-376 (2020); Tsentemeidou et al., Australas J Dermatol (2024)). Because of the long period between the first appearance of HS signs and the confirmation of diagnosis and the initiation of appropriate treatment, many patients miss the opportunity for successful medical treatment. When the disease reaches the terminal stage and irreversible skin damage occurs, surgical intervention is the only option left. These are often major surgeries involving extensive excision or removal of affected tissue, increasing the patient's morbidity and limitations. Therefore, it is essential to identify patients with high inflammatory activity in HS and to initiate optimal anti-inflammatory treatment early to prevent irreversible tissue damage.

[0007] The main clinical inflammatory phenotypes used to assess the severity of the disease and determine appropriate HS treatment are (i) nodules, which are more superficial inflammatory lesions originating from inflamed hair follicles; (ii) abscesses, which correlate with deeper dermal lesions that develop after hair follicle rupture and the influx of inflammatory cells becomes more pronounced; and (iii) tunnels. These tunnels are deep dermal structures that can connect ruptured hair follicles and originate from them, and may reach the skin surface as openings. These tunnels usually undergo re-epithelialization and are the primary cause of inflammation, acting as the driving force of HS (active tunnels are filled with neutrophils and bacteria and often exude or "drain" foul-smelling pus to the skin surface). Tissue destruction secondary to inflammation of nodules, abscesses, tunnels and their surroundings leads to scarring. When patients reach the stage of extensive scarring or tunnel formation, extensive surgical intervention is often required, which can further aggravate the overall pathological and health condition.

[0008] In contrast to other, more superficial chronic inflammatory skin diseases (e.g., psoriasis and atopic dermatitis), the presence and severity of HS lesions, especially in the presence of tunnels, are largely unassessable by clinical visual inspection and examination alone. This remains a significant unresolved issue in the timely diagnosis of HS, the proper assessment of inflammatory disease activity, the selection and initiation of appropriate treatment, and the successful monitoring of treatment response and long-term management of HS. Furthermore, despite the identification of IL-17A and IL-17F as key mediators driving HS disease activity, particularly the release of chemoattractant cytokines that cause keratinocyte activation and the influx of neutrophils, T cells, and other inflammatory cells (these initiate, enhance, and sustain the inflammatory facets of HS) (Lima et al., Br J Dermatol. 174(3):514-21 (2016)), the management of HS and other IL-17-dependent conditions remains challenging. The need to identify biomarkers that enable improvement remains. There is also a need for early diagnosis, prediction of treatment response to existing therapies and / or similar drugs, and observation of long-term disease control. Furthermore, there is a need for more customized and effective treatments for inflammatory skin conditions. For diseases with hard-to-reach inflammatory sites, such as HS and psoriatic arthritis, the development of targeted therapies with enhanced tissue penetration is beneficial for delivering mechanisms of action that inhibit IL-17F and / or IL-17A. [Overview of the Initiative]

[0009] This specification discloses a method for treating IL-17-dependent conditions, the method comprising administering a pharmaceutical product comprising nanobodies® that inhibit IL-17A and / or IL-17F to a subject, wherein the subject is IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2R They have been identified as having elevated levels of one or more biomarkers selected from A, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, and CXCL13.

[0010] Furthermore, this specification also discloses a method for treating hidradenitis suppurativa (HS), the method comprising administering a pharmacopoeia comprising an IL-17A and / or IL-17F inhibitor to a subject, the subject being IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3 It has been identified as having elevated levels of one or more biomarkers selected from FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, and CXCL13. In embodiments, such a method is envisioned, where the IL-17A and / or IL-17F inhibitor comprises a nanobody.

[0011] Furthermore, the above-mentioned treatment method is disclosed, in which the nanobody is configured to specifically bind to IL-17A and IL-17F, and preferably the nanobody is sonerokimab (SLK).

[0012] Furthermore, the above treatment method is disclosed, in which the elevated level is compared to (i) the level present in non-lesional skin, preferably the skin surrounding the lesion, (ii) the level present in the peripheral blood of a healthy patient, or (iii) the level in the same subject before the initial treatment.

[0013] Furthermore, the above-mentioned treatment method is disclosed, in which the elevated level is compared to a reference value, the reference value being (i) the expression level of the biomarker from the corresponding body fluid or tissue sample obtained from a healthy subject, (ii) the average level of the biomarker expressed in the corresponding body fluid or tissue of multiple healthy subjects, or (iii) the average level of the biomarker expressed in healthy tissue, preferably healthy tissue from the same subject, more preferably in the skin around the lesion from the same subject.

[0014] Furthermore, the above treatment method is disclosed, which involves assembling the levels of one or more biomarkers from a tissue sample or body fluid, preferably a skin sample or peripheral blood sample, of a patient who has or is at risk of having an IL-17-dependent condition, prior to treatment. This includes doing [something].

[0015] Furthermore, the above treatment method is disclosed, wherein elevated levels of one or more biomarkers indicate that the patient has (i) an inflammatory skin disease, preferably an inflammatory skin disease affecting both the epidermis and dermis, more preferably an inflammatory skin disease involving hair follicle structures, even more preferably an inflammatory skin disease involving acne-like lesions, most preferably hidradenitis suppurativa (HS) such as moderate to severe HS, and / or (ii) a phenotype involving one or more drainage tunnels in the skin.

[0016] Furthermore, the above treatment methods have been disclosed, and the higher the level of one or more biomarkers, the greater the number of drainage tunnels present in the target.

[0017] Furthermore, the above treatment methods have been disclosed, and the subjects here are those clinically diagnosed with Hurley disease stage I, II, or III.

[0018] Furthermore, the above treatment methods have been disclosed, and the subjects here are those clinically diagnosed with mild HS, moderate HS, moderate to severe HS, severe HS, or juvenile HS.

[0019] Furthermore, the above treatment method has been disclosed, in which the subject either does not have a drainage tunnel or has at least one drainage tunnel.

[0020] Furthermore, the above-mentioned treatment method is disclosed, and the biomarker includes protein and / or mRNA biomarkers.

[0021] The above treatment methods have also been disclosed, where one or more biomarkers are IL6, PLA2G2A, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, C Selected from CL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, and CXCL13.

[0022] Furthermore, the above-mentioned treatment methods have also been disclosed, where one or more biomarkers are IL6, PLA2G2A, IL19, PI3, CST7, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3 Selected from FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, PDFGA, CXCR2, CCR6, and CXCL13.

[0023] Furthermore, the above-mentioned treatment method has also been disclosed, in which one or more biomarkers are selected from CSF3, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, and PDFGA.

[0024] Furthermore, the above-mentioned treatment method has also been disclosed, in which one or more biomarkers are selected from CCL20, CXCL8, CXCL1, IL17A, and IL17F.

[0025] Also disclosed herein is the use of an agent that selectively binds to IL-17A and / or IL-17F in a subject in which the level of at least one or more biomarkers of IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, and CXCL13 has been determined to be elevated compared to healthy controls. Preferably, the elevated levels are present in the skin and / or blood, and the uses according to the invention and any embodiments, any combinations, and / or any groups of biomarkers disclosed are applied as appropriate.

[0026] Also disclosed is the use as described above, where the elevated level of at least one biomarker is the level in a biological sample obtained from the subject, and the level of the corresponding at least biomarker in healthy controls is the level present in a biological sample not affected by an IL-17-dependent pathology, preferably an IL-17-dependent inflammatory skin disease, more preferably hidradenitis suppurativa (HS).

[0027] Also disclosed is the use as described above, where the biomarker is associated with an inflammatory skin disease, preferably an inflammatory skin disease affecting both the epidermis and dermis, more preferably an inflammatory skin disease involving the hair follicle structure, still more preferably an inflammatory skin disease involving acneiform lesions, and most preferably hidradenitis suppurativa (HS).

[0028] Also, the above-mentioned use is also disclosed, and the use is characterized by an increase in the mRNA level or protein level of at least one or more biomarkers selected from IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, and CXCL13, preferably at least one or more biomarkers selected from CCL20, CXCL8, CXCL1, IL17A and IL17F.

[0029] Also, the above-mentioned use is also disclosed, and the use is characterized in that the mRNA level or protein level of the diseased skin sample is increased as compared with the mRNA level or protein level of the non-diseased skin sample, respectively.

[0030] Also, the above-mentioned use is also disclosed, and the mRNA ratio or protein ratio of lesional IL-17F / non-lesional IL-17 is determined.

[0031] Also, the above-mentioned use is also disclosed, where the subject is identified as having an inflammatory skin disease, preferably an inflammatory skin disease affecting both the epidermis and the dermis, more preferably an inflammatory skin disease involving the hair follicle structure, even more preferably an inflammatory skin disease involving acne-like lesions, and most preferably hidradenitis suppurativa, and shows elevated levels of one or more biomarkers respectively.

[0032] Furthermore, the above-mentioned use is also disclosed, in which the subject is clinically diagnosed with Hurley disease stage I, II, or III.

[0033] Furthermore, the above-mentioned uses have also been disclosed, in which the release of IL-17A and / or IL-17F in Hurley's disease stages I, II, and / or III of hidradenitis suppurativa is inhibited by the drug.

[0034] Furthermore, the above-mentioned uses are also disclosed, where the drug is an IL-17A and / or IL-17F inhibitor.

[0035] Furthermore, the above-mentioned uses are also disclosed, in which inflammation and / or tissue destruction are inhibited.

[0036] Furthermore, the above-described uses are also disclosed, where the drug comprises an antibody, an antibody fragment, or a nanobody. In embodiments of such uses, the drug may also contain a nanobody, preferably sonerokimab or a derivative thereof.

[0037] Furthermore, the above-mentioned uses are also disclosed, where the drug is a nanobody, preferably sonerokimab or a derivative thereof, and the biomarker panel comprises a) CCL20, CXCL1, CXCL8, CXL1, IL17A, IL17F, IL19, LT01, CSF3, OSM, PLA2G2A, CST7 and / or PI3, b) IL17A, IL17F, CCL20, CXCL1 and / or CXCL8, c) IL17A, IL17F, CCL20 and / or CXCL8, d) LT01, IL17A, CSF3, OSM, PLA2G2A and / or CST7, e) CCL20, CXCL8, IL19 and PI3, or f) PI3 and IL19.

[0038] Furthermore, this specification also discloses methods for treating IL-17-dependent conditions, which include administering a pharmacopoeia comprising an IL-17A inhibitor and / or an IL-17F inhibitor to a subject identified as having reduced levels of one or more biomarkers selected from PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and EDAR.

[0039] Furthermore, methods for treating subjects identified as having reduced levels of one or more of the above-mentioned biomarkers are also disclosed, wherein the IL-17A inhibitor and / or IL-17F inhibitor comprises nanobodies.

[0040] Also disclosed are methods for treating subjects identified as having reduced levels of one or more of the above-mentioned biomarkers, wherein the nanobody is configured to specifically bind to IL-17A and IL-17F, and preferably the nanobody is sonerokimab (SLK).

[0041] Also disclosed are methods for treating subjects identified as having reduced levels of one or more of the above-mentioned biomarkers, where the reduced level is compared to (i) the level present in non-lesional skin, preferably peri-lesional skin, (ii) the level present in the peripheral blood of a healthy subject, or (iii) the level in the same subject before initial treatment.

[0042] Also disclosed are methods for treating subjects identified as having reduced levels of one or more of the above-mentioned biomarkers, where the reduced level is compared to a reference value, which is (i) the level of expression of the biomarker in the corresponding body fluid or tissue sample obtained from a healthy subject, (ii) the average level of the biomarker expressed in the corresponding body fluid or tissue of multiple healthy subjects, or (iii) the average level of the biomarker expressed in healthy tissue, preferably healthy tissue of the same subject, and more preferably in the skin around the lesion of the same subject.

[0043] Also disclosed is a method for treating subjects identified as having reduced levels of one or more of the above-mentioned biomarkers, the method comprising assaying the levels of one or more biomarkers in tissue samples or body fluids, preferably skin samples or peripheral blood samples, from subjects having or at risk of having an IL-17-dependent condition, prior to treatment.

[0044] Also disclosed are methods for treating subjects identified as having reduced levels of one or more biomarkers as described above, wherein the reduced levels of one or more biomarkers indicate that the patient has (i) an inflammatory skin disease, preferably an inflammatory skin disease affecting both the epidermis and dermis, more preferably an inflammatory skin disease involving hair follicle structures, even more preferably an inflammatory skin disease involving acne-like lesions, most preferably hidradenitis suppurativa (HS) such as moderate to severe HS, and / or (ii) a phenotype involving one or more drainage tunnels in the skin.

[0045] Furthermore, methods for treating subjects identified as having reduced levels of one or more of the above-mentioned biomarkers are disclosed, and the greater the reduced level of one or more biomarkers, the greater the number of drainage tunnels present in the subject.

[0046] Furthermore, methods for treating subjects identified as having reduced levels of one or more of the above-mentioned biomarkers are disclosed, where the subjects are clinically diagnosed with Hurley stage I, II, or III HS.

[0047] Furthermore, methods for treating subjects identified as having reduced levels of one or more of the above-mentioned biomarkers are disclosed, where the subjects are clinically diagnosed as having mild HS, moderate HS, moderate to severe HS, severe HS, or juvenile HS.

[0048] Also disclosed are methods for treating subjects identified as having reduced levels of one or more of the above-mentioned biomarkers, in which case the subject either does not have a drainage tunnel or the subject has at least one drainage tunnel.

[0049] Also disclosed are methods for treating subjects identified as having reduced levels of one or more of the above-mentioned biomarkers, wherein the biomarkers include protein and / or mRNA biomarkers.

[0050] Furthermore, this specification includes the low levels of PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and EDAR in the skin and / or blood. The use of agents that selectively bind to IL-17A and / or IL-17F in subjects in whom the level of at least one biomarker is determined to be reduced compared to healthy controls is also disclosed. Preferably, the reduced levels are present in the skin and / or blood.

[0051] Furthermore, this specification includes biological samples from subjects with a history of treatment for IL-17-dependent conditions, preferably hidradenitis suppurativa, such as IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, and CRELD. 2. A method for monitoring the treatment course or remission of an IL-17-dependent condition is disclosed, which includes assaying for one or more biomarkers selected from EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13, PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and EDAR.

[0052] Furthermore, the monitoring method described above has also been disclosed, in which the biomarkers include PI3 and IL19.

[0053] Furthermore, the monitoring methods described above are also disclosed, in which the normalization of the level of one or more biomarkers to the level of a healthy control indicates (i) remission of inflammation; (ii) tunnels still present in the subject but no longer active; and / or (iii) discontinuation of treatment.

[0054] Furthermore, this specification discloses a method for identifying subjects who have or are at risk of having hidradenitis suppurativa (HS), the method comprising determining the ratio of IL-17F / IL-17A protein or mRNA present in a tissue sample of the subject.

[0055] Furthermore, this specification includes the following samples from subjects that have or are at risk of HS: IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, A method for detecting hidradenitis suppurativa (HS) is disclosed, which includes assaying for elevated levels of one or more of the following: NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, and CXCL13, or for decreased levels of one or more of the following: PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and EDAR.

[0056] Furthermore, the above-mentioned detection method is also disclosed, in which each elevated or decreased level is compared to (i) the level present in non-lesional skin, preferably the skin surrounding the lesion, (ii) the level present in the peripheral blood of a healthy patient, or (iii) the level in the same subject before initial treatment.

[0057] Furthermore, the above-mentioned detection method is also disclosed, in which each elevated or decreased level is compared to a reference value, the reference value being (i) the expression level of the biomarker in the corresponding body fluid or tissue sample obtained from a healthy subject, (ii) the average level of the biomarker expressed in the corresponding body fluid or tissue of multiple healthy subjects, or (iii) the average level of the biomarker in healthy tissue, preferably healthy tissue from the same subject, more preferably in the skin around the lesion from the same subject.

[0058] Furthermore, the above-mentioned detection method is also disclosed, which involves assaying tissue samples or body fluids, preferably skin samples or peripheral blood samples, obtained from patients who have or are at risk of having HS.

[0059] Furthermore, this specification also discloses a method for treating subjects in which the assayed lesional IL-17F / non-lesional IL-17F protein ratio is 2 or greater, preferably 10 or greater, more preferably 2 to 50, and most preferably 10 to 30, the method comprising administering an effective dose of an agent configured to inhibit IL-17F present in the dermis of the inflammatory skin lesion of the subject.

[0060] Furthermore, this specification also discloses a method for treating subjects in which the assayed lesional IL-17F / non-lesional IL-17F mRNA ratio is 5 or greater, preferably 10 or greater, more preferably 5 to 500, and most preferably 10 to 300, the method comprising administering an effective dose of an agent configured to inhibit IL-17F present in the dermis of the inflammatory skin lesion of the subject.

[0061] Furthermore, this specification also discloses a method for treating hidradenitis suppurativa, which involves administering a pharmacopoeia comprising an IL-17A inhibitor and / or an IL-17F inhibitor to a subject, in which the subject has been identified as having elevated levels of one or more biomarkers selected from (a) LTO1, (b) CSF3, (c) OSM, (d) PLA2G2A, or (e) a combination of IL17A and TNC.

[0062] Furthermore, this specification discloses a method for identifying patients with hidradenitis suppurativa who are responsive to treatment with IL-17A inhibitory nanobodies and / or IL-17F inhibitory nanobodies, the method comprising assaying a biological sample from the patient for the presence of one or more biomarkers selected from (a) LTO1, (b) CSF3, (c) OSM, (d) PLA2G2A, or (e) a combination of IL17A and TNC, the presence of elevated levels of at least one, two, three or more biomarkers indicating that the patient is responsive to IL-17A inhibitory and / or IL-17F inhibitory nanobodies.

[0063] Such identification methods may include identifying patients who are super-responders.

[0064] Furthermore, this specification also discloses the identification method described above, and the identified patients are treated with IL-17A and / or IL-17F inhibitory nanobodies, preferably sonerokimab.

[0065] Furthermore, this specification also discloses the above identification method in which the nanobody contains sonerokimab.

[0066] Furthermore, this specification includes information on the risk of or need for treatment of IL-17-dependent conditions. A kit for identifying the target is also disclosed, and this kit includes IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRE Includes a reagent or reagent(s) for measuring one or more levels or expression selected from LD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13, PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, EDAR.

[0067] The kit described above may further include packaged components for collecting a biological sample from a subject, preferably a skin sample or a biological fluid sample, optionally the biological fluid sample being a blood sample.

[0068] The kits described above may include adhesive strips for collecting skin samples, or packaged components for collecting punch biopsies, microbiopsies, or surgical specimens.

[0069] Also disclosed herein is a kit for treating IL-17-dependent skin conditions, the kit comprising a pharmaceutical composition containing inhibitors of IL-17A and / or IL-17F, and IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR in a sample taken from a subject. Includes reagents for measuring the levels or expression of CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13, PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and / or EDAR. [Brief explanation of the drawing]

[0070] [Figure 1A]The pathogenesis and clinical localization of hidradenitis suppurativa (HS). Sebaceous glands (upper arrow in Figure 1A) secrete into hair follicles (also called follicular sebaceous units or FPSUs). HS affects hair follicles that also contain apocrine glands (lower arrow in Figure 1A). Both glands connect to the hair follicle in a microanatomical compartment called the infrafundibulum (region "B" in Figure 1B). Hyperkeratinization in this region (indicated by the arrow in Figure 1B) is considered an early pathophysiological event of HS, leading to obstruction and accumulation of glandular products in the affected hair follicle (Figure 1C). As a result, HS primarily affects body parts containing apocrine glands (Figure 1D). The photograph in Figure 1B is from https: / / plasticsurgerykey.com / the-folliculopilosebaceous-unit-the-normal-fpsu / ; Accessed June 2017; von Laffert M et al. Br J Dermatol 164:367-71, 2011. [Figure 1B]The pathogenesis and clinical localization of hidradenitis suppurativa (HS). Sebaceous glands (upper arrow in Figure 1A) secrete into hair follicles (also called follicular sebaceous units or FPSUs). HS affects hair follicles that also contain apocrine glands (lower arrow in Figure 1A). Both glands connect to the hair follicle in a microanatomical compartment called the infrafundibulum (region "B" in Figure 1B). Hyperkeratinization in this region (indicated by the arrow in Figure 1B) is considered an early pathophysiological event of HS, leading to obstruction and accumulation of glandular products in the affected hair follicle (Figure 1C). As a result, HS primarily affects body parts containing apocrine glands (Figure 1D). The photograph in Figure 1B is from https: / / plasticsurgerykey.com / the-folliculopilosebaceous-unit-the-normal-fpsu / ; Accessed June 2017; von Laffert M et al. Br J Dermatol 164:367-71, 2011. [Figure 1C]The pathogenesis and clinical localization of hidradenitis suppurativa (HS). Sebaceous glands (upper arrow in Figure 1A) secrete into hair follicles (also called follicular sebaceous units or FPSUs). HS affects hair follicles that also contain apocrine glands (lower arrow in Figure 1A). Both glands connect to the hair follicle in a microanatomical compartment called the infrafundibulum (region "B" in Figure 1B). Hyperkeratinization in this region (indicated by the arrow in Figure 1B) is considered an early pathophysiological event of HS, leading to obstruction and accumulation of glandular products in the affected hair follicle (Figure 1C). As a result, HS primarily affects body parts containing apocrine glands (Figure 1D). The photograph in Figure 1B is from https: / / plasticsurgerykey.com / the-folliculopilosebaceous-unit-the-normal-fpsu / ; Accessed June 2017; von Laffert M et al. Br J Dermatol 164:367-71, 2011. [Figure 1D]The pathogenesis and clinical localization of hidradenitis suppurativa (HS). Sebaceous glands (upper arrow in Figure 1A) secrete into hair follicles (also called follicular sebaceous units or FPSUs). HS affects hair follicles that also contain apocrine glands (lower arrow in Figure 1A). Both glands connect to the hair follicle in a microanatomical compartment called the infrafundibulum (region "B" in Figure 1B). Hyperkeratinization in this region (indicated by the arrow in Figure 1B) is considered an early pathophysiological event of HS, leading to obstruction and accumulation of glandular products in the affected hair follicle (Figure 1C). As a result, HS primarily affects body parts containing apocrine glands (Figure 1D). The photograph in Figure 1B is from https: / / plasticsurgerykey.com / the-folliculopilosebaceous-unit-the-normal-fpsu / ; Accessed June 2017; von Laffert M et al. Br J Dermatol 164:367-71, 2011. [Figure 2]Immune-mediated progression of HS. Hyperkeratosis and occlusion of hair follicles (clinical correlation: acne-like lesions), along with initial activation of the immune system (activation of antigen-presenting cells such as dendritic cells and macrophages) and neutrophil influx (clinical correlation: folliculitis and perifollicular inflammation), leads to changes in the local microbiome and hyperinfection of bacteria. Advanced folliculitis and rupture of hair follicles are accompanied by increased inflammation (influx and activation of lymphocytes such as T cells and neutrophils), leading to the formation of superficial nodules. A pathophysiological "vicious cycle" develops, where products released from immune cells such as IL-17A and IL-17F activate keratinocytes, which in turn release chemoattractant mediators such as CXCL1, CXCL8, and CCL20, further promoting the influx and activation of immune cells, resulting in the development of deep inflammatory lesions (clinical correlation: abscesses). Destruction of inflamed tissue and hair follicles leads to dermal scarring and tunnel formation. These tunnels may connect to ruptured hair follicles deep within the dermis, or they may connect to the skin surface. These tunnels epithelialize, likely due to the activation of stem cells in the outer root sheath of the hair follicle bulge region. Keratinocytes surrounding the tunnels respond to activation by IL-17A and IL-17F, attracting neutrophils into the tunnel lumen (clinical correlation: drainage tunnels), further enhancing inflammation in the deep dermis. Hurley stages primarily describe the presence of no tunnels (stage I), some tunnels (stage II), or numerous tunnels accompanied by scarring (stage III). Hurley stages II and III are typically used in clinical trials to define moderate to severe HS. [Figure 3]The "vicious cycle" of HS pathophysiology: Key cellular components and the central roles of IL-17A and IL-17F in the immune-mediated progression of HS. The interaction between immune cells and keratinocytes plays a crucial role in the onset and persistence of HS. IL-17A and IL-17F (released from various cellular sources including CD4+ and CD8+ T cells, γδ T cells, innate lymphoid group 3, and mucosa-associated invariant T cells (MAITs)) are major cytokines that activate keratinocytes in HS. Activated keratinocytes proliferate (e.g., upregulating Ki-67 and lipocalin-2) and produce chemokines that stimulate the influx of immune cells into HS lesions. For example, chemokines that stimulate the influx of immune cells include CXCL1 and CXCL8, which attract neutrophils, one of the most important immune cells involved in HS, and CCL20, which promotes the influx of more IL-17-producing T cells (Th17 cells). The influx of antigen-presenting cells (e.g., CD11c+ dendritic cells), T cells, and neutrophils via chemokines enhances skin inflammation and leads to the secretion of more IL-17A and IL-17F. [Figure 4] The clinical phenotypes of each stage of HS (which can occur simultaneously in the same patient) are as follows: Early HS is typically characterized by acne-like lesions and folliculitis, while more advanced HS presents with larger, more superficial lesions (nodules) or deeper inflammatory lesions (abscesses). Patients with chronic destructive HS often exhibit varying degrees of scarring and tunnel formation. Active (draining) tunnels that connect to the skin secrete pus (neutrophils originating from the tunnel lumen) onto the skin surface, which is one of the most burdensome aspects of HS for affected patients. [Figure 5A]Current concepts regarding the major events in the pathophysiology of chronic HS. Figure 5A. Immune cells are activated by antigen-presenting cells such as epidermal Langerhans cells and dermal dendritic cells. The main mediators released from activated immune cells such as T cells are IL-17A and IL-17F. Both cytokines work together to activate and proliferate keratinocytes (upregulation of the proliferation marker Ki-67 and formation of psoriasis-like epidermal hyperplasia) and also release chemoattractants such as CXCL1 and CXCL8. IL-17A and IL-17F also activate other pro-inflammatory pathways in keratinocytes, including pro-inflammatory secretion via autocrine release of IL-36 and IL-17C. CXCL1, CXCL8, and other chemokines induced in keratinocytes by IL-17A and IL-17F control the influx of inflammatory cells such as neutrophils and T cells into HS lesions. Keratinocytes surrounding newly epithelialized tunnels in the deep dermis become a de novo target for IL-17A and IL-17F, further promoting dermal inflammation and neutrophil influx into the tunnel lumen (in "efflux" tunnels). Image quoted from Navrazhina K, et al. J Allergy Clin Immunol 2021;147:2213-24. Figure 5B. Quantitative RT-PCR showed higher levels of IL-17A and IL-17F mRNA in the dermal compartment compared to the epidermal compartment in HS lesions, indicating maximum inflammatory activity around dermal tunnels. [Figure 5B]Current concepts regarding the major events in the pathophysiology of chronic HS. Figure 5A. Immune cells are activated by antigen-presenting cells such as epidermal Langerhans cells and dermal dendritic cells. The main mediators released from activated immune cells such as T cells are IL-17A and IL-17F. Both cytokines work together to activate and proliferate keratinocytes (upregulation of the proliferation marker Ki-67 and formation of psoriasis-like epidermal hyperplasia) and also release chemoattractants such as CXCL1 and CXCL8. IL-17A and IL-17F also activate other pro-inflammatory pathways in keratinocytes, including pro-inflammatory secretion via autocrine release of IL-36 and IL-17C. CXCL1, CXCL8, and other chemokines induced in keratinocytes by IL-17A and IL-17F control the influx of inflammatory cells such as neutrophils and T cells into HS lesions. Keratinocytes surrounding newly epithelialized tunnels in the deep dermis become a de novo target for IL-17A and IL-17F, further promoting dermal inflammation and neutrophil influx into the tunnel lumen (in "efflux" tunnels). Image quoted from Navrazhina K, et al. J Allergy Clin Immunol 2021;147:2213-24. Figure 5B. Quantitative RT-PCR showed higher levels of IL-17A and IL-17F mRNA in the dermal compartment compared to the epidermal compartment in HS lesions, indicating maximum inflammatory activity around dermal tunnels. [Figure 6]An experimental approach for identifying IL-17i-related HS biomarkers and characterizing specific target molecular properties. Punch biopsies of specific HS phenotypes (peri-lesion tissue, nodule-containing tissue, tunnel-containing tissue) were obtained from large surgical specimens of patients who underwent surgery for HS. Biopsies were first subjected to imaging studies (H&E staining to identify nodules and tunnels, multichannel immunofluorescence (IF) to characterize keratinocyte activation and immune cell infiltration, etc.) (see workflow(i)). Biopsies were then subjected to protein lysates and mRNA extraction, which were further subjected to multi-cytokine arrays or ELISA and bulkRNA-seq and quantitative RT-PCR analysis (see workflow(ii), (iii)). Finally, selected peri-lesion and tunnel-containing biopsies were tested for penetration and specific anti-inflammatory effects of IL-17 inhibitory (IL-17i) therapeutic molecules by gas-liquid interface organ culture (see workflow(iv)). Next, keratinocytes were exposed to different IL-17 dimers to test the specific pro-inflammatory effects of IL-17A and IL-17F (see Workflow (v)). Different IL-17i therapeutic molecules were added, and their specific inhibitory activity at different concentrations was evaluated (see Workflow (vi)). Separately, peripheral blood samples were collected from HS patients before and after treatment with IL-17 inhibitors (IL-17i), and peripheral blood samples were also collected from healthy controls in parallel. Further biomarkers for HS were identified using proteomics (Olink®) (see Workflow (vii)). [Figure 7]Experimental procedure for evaluating biomarkers in peripheral blood. Blood samples were collected from HS patients participating in the clinical trial (n=234) and age- and sex-matched healthy controls (n=50). Clinical trial samples collected at baseline and after 12 weeks of treatment with IL-17i or placebo were analyzed using the Proteomics Olink® platform, namely the Explore 384 Inflammation and 384 Cardiometabolic panels. Over 700 peripheral blood proteins were investigated. NPX (Normalized Protein eXpression) is an arbitrary unit using a Log2 scale, enabling the identification of protein level variations between different datasets. [Figure 8A] Validation of biopsy materials used to identify IL-17i-related HS biomarkers. Biopsies were examined by hematoxylin-eosin (H&E) staining and multichannel immunofluorescence staining. Microscopic analysis confirmed the presence of specific HS phenotypes (nodules and / or tunnels) in the obtained biopsies (Figures 8A and 8B). HS-specific keratinocyte activation (comparing Figure 3 and Figure 5A) was confirmed by upregulation of epithelial Ki-67 and lipocalin-2 expression (Figure 8C, above HS nodules). Tunnel activation (drainage) was confirmed by H&E staining and identification of MPO+ neutrophils in the tunnel lumen (Figure 8B). Typical immune cell influx (e.g., CD3+ T cells, CD11c+ dendritic cells; compare Figure 3 and Figure 5A) was recorded (Figure 8D shows the tissue surrounding the lesion, and Figure 8E shows the active nodule), and T cells containing IL-17A and / or IL-17F were present among the infiltrating immune cells (Figure 8F). [Figure 8B]Validation of biopsy materials used to identify IL-17i-related HS biomarkers. Biopsies were examined by hematoxylin-eosin (H&E) staining and multichannel immunofluorescence staining. Microscopic analysis confirmed the presence of specific HS phenotypes (nodules and / or tunnels) in the obtained biopsies (Figures 8A and 8B). HS-specific keratinocyte activation (comparing Figure 3 and Figure 5A) was confirmed by upregulation of epithelial Ki-67 and lipocalin-2 expression (Figure 8C, above HS nodules). Tunnel activation (drainage) was confirmed by H&E staining and identification of MPO+ neutrophils in the tunnel lumen (Figure 8B). Typical immune cell influx (e.g., CD3+ T cells, CD11c+ dendritic cells; compare Figure 3 and Figure 5A) was recorded (Figure 8D shows the tissue surrounding the lesion, and Figure 8E shows the active nodule), and T cells containing IL-17A and / or IL-17F were present among the infiltrating immune cells (Figure 8F). [Figure 8C] Validation of biopsy materials used to identify IL-17i-related HS biomarkers. Biopsies were examined by hematoxylin-eosin (H&E) staining and multichannel immunofluorescence staining. Microscopic analysis confirmed the presence of specific HS phenotypes (nodules and / or tunnels) in the obtained biopsies (Figures 8A and 8B). HS-specific keratinocyte activation (comparing Figure 3 and Figure 5A) was confirmed by upregulation of epithelial Ki-67 and lipocalin-2 expression (Figure 8C, above HS nodules). Tunnel activation (drainage) was confirmed by H&E staining and identification of MPO+ neutrophils in the tunnel lumen (Figure 8B). Typical immune cell influx (e.g., CD3+ T cells, CD11c+ dendritic cells; compare Figure 3 and Figure 5A) was recorded (Figure 8D shows the tissue surrounding the lesion, and Figure 8E shows the active nodule), and T cells containing IL-17A and / or IL-17F were present among the infiltrating immune cells (Figure 8F). [Figure 8D]Validation of biopsy materials used to identify IL-17i-related HS biomarkers. Biopsies were examined by hematoxylin-eosin (H&E) staining and multichannel immunofluorescence staining. Microscopic analysis confirmed the presence of specific HS phenotypes (nodules and / or tunnels) in the obtained biopsies (Figures 8A and 8B). HS-specific keratinocyte activation (comparing Figure 3 and Figure 5A) was confirmed by upregulation of epithelial Ki-67 and lipocalin-2 expression (Figure 8C, above HS nodules). Tunnel activation (drainage) was confirmed by H&E staining and identification of MPO+ neutrophils in the tunnel lumen (Figure 8B). Typical immune cell influx (e.g., CD3+ T cells, CD11c+ dendritic cells; compare Figure 3 and Figure 5A) was recorded (Figure 8D shows the tissue surrounding the lesion, and Figure 8E shows the active nodule), and T cells containing IL-17A and / or IL-17F were present among the infiltrating immune cells (Figure 8F). [Figure 8E] Validation of biopsy materials used to identify IL-17i-related HS biomarkers. Biopsies were examined by hematoxylin-eosin (H&E) staining and multichannel immunofluorescence staining. Microscopic analysis confirmed the presence of specific HS phenotypes (nodules and / or tunnels) in the obtained biopsies (Figures 8A and 8B). HS-specific keratinocyte activation (comparing Figure 3 and Figure 5A) was confirmed by upregulation of epithelial Ki-67 and lipocalin-2 expression (Figure 8C, above HS nodules). Tunnel activation (drainage) was confirmed by H&E staining and identification of MPO+ neutrophils in the tunnel lumen (Figure 8B). Typical immune cell influx (e.g., CD3+ T cells, CD11c+ dendritic cells; compare Figure 3 and Figure 5A) was recorded (Figure 8D shows the tissue surrounding the lesion, and Figure 8E shows the active nodule), and T cells containing IL-17A and / or IL-17F were present among the infiltrating immune cells (Figure 8F). [Figure 8F]Validation of biopsy materials used to identify IL-17i-related HS biomarkers. Biopsies were examined by hematoxylin-eosin (H&E) staining and multichannel immunofluorescence staining. Microscopic analysis confirmed the presence of specific HS phenotypes (nodules and / or tunnels) in the obtained biopsies (Figures 8A and 8B). HS-specific keratinocyte activation (comparing Figure 3 and Figure 5A) was confirmed by upregulation of epithelial Ki-67 and lipocalin-2 expression (Figure 8C, above HS nodules). Tunnel activation (drainage) was confirmed by H&E staining and identification of MPO+ neutrophils in the tunnel lumen (Figure 8B). Typical immune cell influx (e.g., CD3+ T cells, CD11c+ dendritic cells; compare Figure 3 and Figure 5A) was recorded (Figure 8D shows the tissue surrounding the lesion, and Figure 8E shows the active nodule), and T cells containing IL-17A and / or IL-17F were present among the infiltrating immune cells (Figure 8F). [Figure 9A] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9B]Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9C] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9D] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9E]Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9F] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9G] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9H]Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9I] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9J] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9K]Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9L] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9M] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9N]Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9O] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9P] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9Q]Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9R] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9S] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9T]Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9U] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 9V] Tissue and blood biomarkers related to HS disease and tunneling activity. mRNA: Figures 9A-9V. Mean ± SEM normalized biocounts (RNA-seq) of patient biopsies (n=4-5) in each skin compartment. Tissue proteins: Mean ± SEM of cytokine protein levels in lysate of peri-lesional and lesional HS punch biopsies (n=7). P-values ​​by Kruskal-Wallis test and unadjusted Dunn test. Peripheral blood proteins: Scatter plot of significant proteins associated with drainage tunnel count. P-values ​​by Kruskal-Wallis test and unadjusted Dunn test; ***P<0.001, **P<0.01, *P<0.05. [Figure 10]Tissue and blood biomarkers related to HS disease and tunneling activity. Upregulation of biomarkers in lesional tissue is not limited to the chemokines CCL20 and CXCL8, but extends to their receptors. mRNA: Mean ± SEM normalized metabiometric counts (RNA-seq) in each skin compartment of patient biopsies (4-5 / 7) for RNA-seq-eligible protein arrays. Protein: Mean ± SEM cytokine protein levels in lysate of peri-lesion and lesional HS punch biopsies (n=7). P values ​​by Kruskal-Wallis test and uncorrected Dunn test: ***P<0.001, **P<0.01, *P<0.05. [Figure 11] The nanobody sonerokimab (SLK) exhibits high affinity for IL-17A / A and similarly high affinity for IL-17F / F, in contrast to the antibody bimekizumab, which shows high affinity for IL-17A / A and low affinity for IL-17F / F. A surface plasmon resonance assay (SPR) compares the equilibrium dissociation constant (KD) between the IL-17A inhibitory antibody secukinumab, the IL-17A and IL-17F inhibitory antibody bimekizumab, and the IL-17A and IL-17F inhibitory nanobody sonerokimab. KD represents the concentration at which half of all binding sites are occupied (equilibrium state, i.e., when association and dissociation rate constants are equal). When comparing the KDs of two molecules, a lower KD indicates higher affinity. [Figure 12] Best-fit tetramer modeling of sonerokimab. This modeling shows that two IL-17 dimers and human serum albumin bind simultaneously, with the dimer containing IL-17F preferentially binding. [Figure 13] Sonerokimab inhibits the interaction between IL-17 dimers and their respective receptors with high activity. A protein-protein interaction assay between IL-17 dimers and IL-17 receptor chains showed a 100-fold difference in IC50 between sonerokimab and the IL-17A inhibitory antibody secukinumab, demonstrating that sonerokimab possesses superior inhibitory activity. [Figure 14]In a primate model of "human PsA," sonerokimab treatment resulted in higher IL-17 target binding activity in synovial fluid than IL-17A and IL-17F-binding antibodies. Arthritis was induced in n-50 female cynomolgus monkeys, and the treatment groups included sonerokimab, an IL-17A and IL-17F inhibitory nanobody, and IL-17A and IL-17F inhibitory mAbs. Binding activity to IL-17A (left bar graph) and IL-17F (right bar graph) was identified in the synovial fluid of affected animals 8 weeks after immunization (collagen-induced arthritis). Doses of nanobody and antibody treatment were corrected according to molecular size (sonerokimab 2.8 mg / kg, IL-17A / F mAb 10 mg / kg). Binding activity to IL-17A and IL-17F in the synovial fluid of nanobody-treated animals was significantly higher compared to antibody-treated animals, indicating preferential accumulation in inflamed joints. This difference was associated with a better clinical response (upper right panel). Evaluation joints for determining arthritis scores. Each scoring joint is shown in circles: major joints (upper panel), limb joints (middle panel), and hindlimb joints (lower panel). DIP: distal interphalangeal joint, PIP: proximal interphalangeal joint, MCP: metacarpophalangeal joint, MTP: metatarsophalangeal joint; 2 Exp IL-17A & IL-17F mAb (Novimmune); SLK = sonerokimab. [Figure 15A] Direct evidence of disease modification by IL-17i. Figure 15A. After 12 weeks of SLK administration, a significant number of patients achieved complete disappearance of the drainage tunnel (DT100), in contrast to placebo patients. After 24 weeks of treatment, the proportion of patients with complete disappearance of the drainage tunnel reached 49%. Figure 15B. Ultrasonography analysis in patients treated with IL-17i showed significant changes in the size and shape of the drainage tunnel (indicated by dashed lines). The dotted circles highlight the increased inflammatory blood flow characteristic of the tissue surrounding the HS tunnel. After 24 weeks of IL-17i treatment, inflammation around the drainage tunnel was significantly reduced, as is evident from the decrease in the size of the dotted circles. [Figure 15B]Direct evidence of disease modification by IL-17i. Figure 15A. After 12 weeks of SLK administration, a significant number of patients achieved complete disappearance of the drainage tunnel (DT100), in contrast to placebo patients. After 24 weeks of treatment, the proportion of patients with complete disappearance of the drainage tunnel reached 49%. Figure 15B. Ultrasonography analysis in patients treated with IL-17i showed significant changes in the size and shape of the drainage tunnel (indicated by dashed lines). The dotted circles highlight the increased inflammatory blood flow characteristic of the tissue surrounding the HS tunnel. After 24 weeks of IL-17i treatment, inflammation around the drainage tunnel was significantly reduced, as is evident from the decrease in the size of the dotted circles. [Figure 16] In HS lesions, IL-17F expression is significantly upregulated compared to peri-lesion tissue and is more abundant than IL-17A. IL-17A and IL-17F levels were measured by multi-cytokine arrays in biopsies from peri-lesion HS and defined HS lesions (nodules, tunnels). Compared to psoriasis (protein levels measured in dermal interstitial fluid using different methods; see Reference 1), the upregulation of IL-17F in lesional HS compared to peri-lesion HS was more pronounced than in lesional psoriasis compared to non-lesional psoriasis. Within HS lesions (nodules and tunnels), IL-17F was more abundant than IL-17A, with observed protein ratios of approximately 1.5–2.2. Mean ± SEM of cytokine protein expression levels in lysates of peri-lesion (PL) and lesional HS punch biopsies (n=7 independent patients, 2 technically repeated measures). Differences in IL-17F protein levels were significant between peripathological tissue and nodules and tunnels, respectively (Kruskal-Wallis test and unadjusted Dunn test, p<0.05). Reference 1 = Data from Kolbinger et al. J Allergy Clin Immunol 2017:139:923-932. The difference between pathological PsO and non-pathological (NL) PsO was not significant (p>0.05). [Figure 17]IL-17F, independently of IL-17A, potently activates human keratinocytes, releasing inflammatory mediators whose elevation is regulated by HS. IL-17F stimulates the production of CCL20, a major chemotactic for Th17 cells, and CXCL8, a major chemokine for neutrophils, in keratinocytes. mRNA data are shown as mean ± SEM from n=3 independent experiments after 6 hours of stimulation. CCL20 and CXCL8 gene expression are shown as multiplicative changes relative to TNF ("1") after normalization with GAPDH. [Figure 18] SLK exerts an enhanced inhibitory effect on keratinocytes activated by IL-17 dimers. Mean ± SEM percent inhibition rate of CCL20 and CXCL8 gene expression induced by IL-17 dimers and TNF stimulation. n=3 independent experiments. Primary normal human keratinocytes were treated in vitro for 6 hours with TNF and a selection of IL-17i concentrations, consisting of IL-17A / A, IL-17A / F, or IL-17F / F dimers. qRT-PCR was performed using GAPDH as the reference housekeeping gene. Mean values ​​from n=3 independent experiments. SLK is sonerokimab. [Figure 19] An experimental approach to investigate the specific inhibitory effect of IL-17i on the expression of IL-17-related biomarkers in HS organ cultures. To further examine the inhibitory effect observed with sonerokimab on the expression of IL-17-induced chemokines in human keratinocytes, biopsies from peripathic biopsies (control) and biopsies derived from defined HS phenotypes (nodules, tunnels) were cultured for 24 hours under gas-liquid interface conditions, either in the presence or absence of sonerokimab. Materials for quantitative analysis of tissue chemokine mRNA expression and protein levels in the culture supernatant were obtained. [Figure 20]Demonstration that IL-17 inhibitory nanobodies inhibit the release of IL-17i-related biomarkers in organ cultures of lesional HS. This figure shows the expression levels of CCL20 mRNA (left panel) and CXCL8 mRNA (right panel) in perivascular skin samples. Furthermore, it is shown that CCL20 and CXCL8 expression is upregulated in HS lesions including tunnels, and that treatment with IL-17i sonerokimab reduces their expression to levels comparable to those in perivascular HS samples. Relative expression levels (mean ± SEM) of CCL20 mRNA and CXCL8 mRNA were measured by qRT-PCR after 24 hours of ex vivo administration with SLK 10 μg / mL or vehicle buffer (VEH) in gas-liquid interface cultures of perivascular and tunnel biopsies from n=4 independent donors. The mean expression levels of HECT, UBA, and WWE domain-containing E3 ubiquitin protein ligase 1 (HUWEI1) and microtubule actin crosslinking factor 1 (MACF1) were used as housekeeping internal references. [Figure 21] Pharmacodynamic biomarkers: After treatment with IL-17i, levels of circulating biomarkers associated with HS activity normalized to levels seen in the healthy control population, indicating molecular remission (n=50). Significant downregulation of elaphin (left) and IL-19 (right) was observed from baseline to 12 weeks after sonerokimab treatment. HC represents healthy controls, SLK represents sonerokimab, and ADA represents adalimumab. Paired t-tests: ***P<0.001, **P<0.01, *P<0.05. [Figure 22]Biomarkers for identifying hyperresponsive hemoglobin (HS) to IL-17i: LOT1, IL-17A+TNC, G-CSF, OSM, PLA2G2A. SIDES (Subgroup Identification based on Differential Effect Search) analysis was employed as a segmentation method to determine treatment response within specific patient groups. Subgroups of patients with high biomarker expression levels showed improved clinical outcomes compared to unselected patients, as indicated by the delta relative to placebo in the HiSCR75 response. Application thresholds (NPX): LTO1>-0.4123; IL-17A>-0.8321; TNC>-0.0153; CSF3>-0.2455; OSM>-0.4974; PLA2G2A>0.6373; CST7>-0.628. [Modes for carrying out the invention]

[0071] Detailed explanation The specific details described herein are illustrative and intended to illustrate various embodiments, providing the most useful and easily understandable explanation of the principles and conceptual aspects of the methods and compositions described herein. In this regard, it is not intended to provide details beyond what is necessary for a basic understanding, but rather to clarify to those skilled in the art how some embodiments may actually be implemented.

[0072] The present invention will be described below with reference to more detailed embodiments. However, the present invention can be embodied in different forms and should not be construed as being limited to the embodiments described herein. Rather, these embodiments are provided so that the scope of this disclosure may be fully conveyed to those skilled in the art.

[0073] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art. The terms used herein are for the purpose of describing specific embodiments and are not intended to limit them. This is not a diagram. Where used herein and in the appended claims, the singular forms "a," "an," and "the" are intended to include the plural form unless the context clearly indicates otherwise. All publications, patent applications, patents, and other references referenced herein are expressly incorporated by reference in their entirety.

[0074] Unless otherwise indicated, the numerical parameters described in the following specification and the attached claims are approximations that may vary depending on the desired characteristics to be obtained, and are therefore modified by the term "approximately." At the very least, without attempting to limit the application of the doctrine of equivalents to the claims, each numerical parameter should be interpreted in light of the number of significant figures and the usual rounding approach.

[0075] While the numerical ranges and parameters representing a wide range are approximations, the numerical values ​​shown in the specific examples are reported as accurately as possible. However, any numerical value inherently contains a certain degree of error, which manifests as a standard deviation in each test measurement. All numerical ranges described herein include all narrow numerical ranges that fall within such a wide numerical range, even if such narrow numerical ranges are not explicitly described herein. The applicant also assumes that ranges are derived from the data points and explicit ranges disclosed herein.

[0076] definition As used herein, “treatment” and / or “procedure” and / or “to treat” means all methods or regimens that may slow, interrupt, stop, halt, prevent, or reverse the progression of the disorder described herein. However, these terms do not necessarily imply the complete elimination of all symptoms of the disorder being treated. Treatment includes, for example, the administration of a medicine for the treatment of a disease or condition in a subject who would benefit from a reduction in the activity of an elevated biomarker. Thus, treatment may include inhibiting the further progression of a disease, i.e., preventing its onset, and / or alleviating a disease, i.e., causing regression of the disease or disorder, or alleviating its symptoms or complications.

[0077] As used herein, “IL-17-dependent conditions” refers to diseases, disorders, or conditions mediated by IL-17, and may include autoimmune diseases, inflammatory diseases, or neurological diseases. The IL-17-dependent conditions intended herein preferentially include, but are not limited to, skin diseases, and include, for example, psoriasis, psoriatic arthritis, rheumatoid arthritis, and inflammatory skin diseases, including type III non-infectious inflammatory skin diseases. Type III diseases are defined by Th17 immunity and the presence of neutrophils in the skin, and include psoriasis (including pustular psoriasis, guttate psoriasis, and pityriasis rubra pilaris), acne and acne syndrome, hidradenitis suppurativa, and Cartesian folliculitis.

[0078] As used herein, “drainage tunnel” or “active tunnel” refers to a moderate to severe symptom of HS in which the epithelialized tissue forms one or more tunnel-like openings in the dermis, optionally communicating with the skin surface, and the openings are actively draining pus, i.e., containing pus that may be discharged to the skin surface.

[0079] As used herein, “healthy control” may refer to a determined level of one or more biomarkers in a non-affected biological sample containing one or more biomarkers. The biological sample may be isolated from the same subject affected by the disease in the sense of the present invention, but may also be isolated from a body part that does not exhibit signs or symptoms associated with the disease. Alternatively, the biological sample may correspond to a site where a patient affected by the disease exhibits characteristic symptoms. The tissue may be collected from another healthy subject. Methods for tissue sampling, blood sampling, RNA extraction, and protein isolation are well known to those skilled in the art. Examples of suitable methods are given herein.

[0080] A “derivative” of a polypeptide (e.g., a nanobody) disclosed herein may include one or more amino acid substitutions, additions, insertions, or deletions compared to a reference polypeptide, for example, 1, 2, 3, 4, 5, 6-20 or 21-50 amino acid substitutions, additions, insertions, or deletions. Alternatively, a “derivative” may have a predetermined degree of sequence identity with the reference polypeptide and / or include other amino acid substitutions, additions, insertions, or deletions described herein.

[0081] Biomarkers, combinations of biomarkers, and corresponding methods This section describes the identification of abnormally expressed biomarkers in peripheral blood and / or HS lesions that enable the assessment of immune disease activity, particularly HS and active tunneling in HS patients. It also describes how biomarkers can be used to monitor molecular immunological responses to IL-17 inhibitors and to identify patients who preferentially respond to IL-17 inhibitors such as sonerokimab (so-called super-responders). Biomarkers intended herein include “analytes” measured by the methods described herein and by the methods of the present invention. However, the biomarkers intended and disclosed herein may thus be used as functional biomarkers of the diseases and / or pathologies described herein.

[0082] In the context of this invention, whether one or more biomarkers or a panel / combination of biomarkers are most appropriate may vary depending on the subject, the stage of disease progression, and the individual phenotype. This specification provides appropriate biomarkers, including any combination of one, two, three, four, five, six, seven, eight, nine, ten, or more biomarkers.

[0083] In particular, elevated expression of the following biomarkers was observed in HS: IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FC AR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY 9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13.

[0084] On the other hand, the expression of the following biomarkers was decreased in HS: PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and EDAR.

[0085] Biomarkers used herein include any selected from Table 1, or wild-type proteins homologous to those disclosed in Table 1. Their isoforms and variants are also intended. For example, a sequence homologous to the amino acid sequence shown in SEQ ID NO: 1 may function as a biomarker for IL-17-dependent pathological conditions described herein, and may be a protein having the same amino acid sequence as the amino acid sequence shown in SEQ ID NO: 1, except that one or more amino acids are deleted, substituted, inserted, and / or added. In the case of substitution, insertion, or addition, one or more amino acids may be conservative substitutions or insertions. Conservative mutations by addition or substitution are also possible. In this specification, "one or more amino acids" means 1 to 50, preferably 1 to 20, more preferably 1 to 10, even more preferably 1 to 5, or 1 to 3 amino acids.

[0086] As a further example, proteins having an amino acid sequence homologous to the amino acid sequence shown in SEQ ID NO: 1 include proteins having an amino acid sequence that, in full form, has 60% or more identity with the amino acid sequence shown in SEQ ID NO: 1. These proteins include proteins having an amino acid sequence that, in full form, has 70% or more identity, preferably 80% or more, more preferably 90% or more, and even more preferably 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or more identity with the aforementioned amino acid sequence. The same applies to the remaining SEQ ID NOs: 2-73, other biomarkers intended herein, and nucleic acid sequences encoding such biomarkers or sequences.

[0087] "Sequence identity" refers to the proportion of identical nucleotides or amino acids shared between two sequences in a nucleotide or amino acid sequence. This proportion can be determined using optimal pairwise alignment, and can optionally be determined by conventional methods or commercially available algorithms.

[0088] Disclosed herein are methods for treating IL-17-dependent conditions, comprising pharmaceuticals containing IL-17A and / or IL-17F inhibitory nanobodies, such as IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, and CCL. A method comprising administering to a subject identified as having elevated levels selected from 23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13.

[0089] Also disclosed herein are methods for treating hidradenitis suppurativa (HS), including IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G The method comprises administering a pharmacopoeia containing an IL-17A and / or IL-17F inhibitor to a subject identified as having elevated levels of one or more selected from CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, and CXCL13.

[0090] Furthermore, in this specification, agents that selectively bind to IL-17A and / or IL-17F are defined as IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, and CD. It is also intended for use in subjects in whom at least one of the following biomarkers—79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13—is determined to be elevated compared to a healthy control, preferably with elevated levels present in the skin and / or blood.

[0091] Such methods and / or uses may involve assaying, prior to treatment, tissue or body fluid samples, preferably skin or peripheral blood samples, from patients who have or are at risk of having an IL-17-dependent condition for levels of one or more biomarkers.

[0092] The methods and / or uses described above are envisioned, where elevated levels of one or more biomarkers indicate that the patient has (i) an inflammatory skin disease, preferably an inflammatory skin disease affecting both the epidermis and dermis, more preferably an inflammatory skin disease involving hair follicle structures, even more preferably an inflammatory skin disease involving acne-like lesions, most preferably a moderate to severe hidradenitis suppurativa (HS), and / or (ii) a phenotype involving one or more drainage tunnels in the skin.

[0093] In the embodiment, the higher the level of one or more biomarkers, the greater the number of drainage tunnels present in the subject.

[0094] In this embodiment, the subject may be clinically diagnosed with hidradenitis suppurativa of stage I, II, or III of Hurley disease.

[0095] In this embodiment, the subject may be clinically diagnosed as having mild HS, moderate HS, moderate to severe HS, severe HS, or juvenile HS.

[0096] In some embodiments, the object may not have a drainage tunnel, or it may have at least one drainage tunnel.

[0097] The biomarkers disclosed herein may consist of or contain proteins. Alternatively, the biomarkers may consist of or contain mRNA. Both protein and mRNA biomarkers are conceivable.

[0098] As assumed herein, the elevated level of at least one biomarker may be the level present in the biological sample from the subject, and the corresponding level of at least one biomarker present in a healthy control may be representative of the level present in a biological sample that does not suffer from an IL-17-dependent condition, preferably an IL-17-dependent inflammatory skin disease, more preferably HS.

[0099] As assumed herein, the biomarkers may be associated with inflammatory skin diseases, preferably inflammatory skin diseases affecting both the epidermis and dermis, more preferably inflammatory skin diseases involving hair follicle structures, even more preferably inflammatory skin diseases involving acne-like lesions, and most preferably hidradenitis suppurativa (HS).

[0100] In a preferred embodiment, one or more biomarkers may be selected from the following combinations of biomarkers: IL6, PLA2G2A, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP 1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13.

[0101] In other preferred embodiments, one or more biomarkers may be selected from the following combinations of biomarkers: IL6, PLA2G2A, IL19, PI3, CST7, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SP ON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, PDFGA, CXCR2, CCR6, CXCL13.

[0102] In yet another preferred embodiment, one or more biomarkers may be selected from the following combinations of biomarkers: CSF3, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA.

[0103] The methods and uses described above may also be characterized by elevated mRNA levels or protein levels of at least one or more biomarkers selected from the following combinations of biomarkers: CCL20, CXCL8, CXCL1, IL17A, IL17F.

[0104] In embodiments, combinations or panels of biomarkers may be formed based on the physiological function of the biomarkers, for example, as disclosed in Table 1. In exemplary embodiments, those skilled in the art may determine that a panel of biomarkers involved in neutrophil activation or T cell activation may be advantageous. It is also conceivable that the neutrophil-activating biomarkers in Table 1 may be replaced with other biomarkers in Table 1 in any combination.

[0105] The methods and uses described above may also be characterized by elevated mRNA or protein levels in lesional skin samples compared to the respective mRNA or protein levels in non-lesional skin samples.

[0106] The above methods and uses are also conceivable if the subject has an inflammatory skin disease, preferably hidradenitis suppurativa, and has been identified to exhibit elevated levels of one or more biomarkers.

[0107] Furthermore, the methods and uses described above are also envisioned, in which the release of IL-17A and / or IL-17F is inhibited by the drug in hidradenitis suppurativa of Hurley stage I, II, and / or III.

[0108] The above methods and uses are also conceivable, provided the drug is an IL-17A inhibitor and / or an IL-17F inhibitor.

[0109] The above methods and uses are also conceivable when the drug contains antibodies, antibody fragments, or nanobodies.

[0110] In a preferred embodiment, the methods and / or uses described above are envisioned, where the drug is a nanobody, preferably sonerokimab or a derivative thereof, and the biomarker panel is envisioned to include a) CCL20, CXCL1, CXCL8, CXL1, IL17A, IL17F, IL19, LT01, CSF3, OSM, PLA2G2A, CST7 and / or PI3, b) IL17A, IL17F, CCL20, CXCL1 and / or CXCL8, c) IL17A, IL17F, CCL20 and / or CXCL8, d) LT01, IL17A+TNC, CSF3, OSM, PLA2G2A and / or CST7, e) CCL20, CXCL8, IL19 and PI3, or f) PI3 and IL19.

[0111] In embodiments, such methods and / or uses may further include comparing the expression level of at least one biomarker in a lesional skin sample of the subject with the expression level of at least one biomarker in a healthy skin sample of the subject, and determining that the subject has or is at risk of having HS if one or more biomarkers are elevated in the lesional skin sample compared with the healthy skin sample.

[0112] Furthermore, this specification also discloses a method for treating an IL-17-dependent condition, comprising administering a pharmaceutical agent comprising an IL-17A inhibitor and / or an IL-17F inhibitor to a subject identified as having reduced levels of one or more biomarkers selected from PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and EDAR.

[0113] Furthermore, this specification also envisions the use of agents that selectively bind to IL-17A and / or IL-17F in subjects determined to have reduced levels of at least one of the following biomarkers in the skin and / or blood compared to healthy controls, where preferably reduced levels are present in the skin and / or blood: PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and EDAR.

[0114] As described above, IL-17A and / or IL-17F inhibitors may include antibodies, antibody fragments, or nanobodies. In embodiments, the nanobodies are configured to bind specifically to IL-17A and IL-17F, and preferably the nanobodies are SLKs.

[0115] As described above, the reduced levels in the subjects can be compared to (i) levels present in non-lesional skin, preferably in the skin surrounding the lesion, (ii) levels present in the peripheral blood of healthy patients, or (iii) levels in the same subjects before initial treatment.

[0116] Alternatively, the reduced level may be compared to a reference value, which may be (i) the expression level of the biomarker from the corresponding body fluid or tissue sample obtained from a healthy subject, (ii) the average level of the biomarker expressed in the corresponding body fluid or tissue of multiple healthy subjects, or (iii) the average level of the biomarker expressed in healthy tissue, preferably healthy tissue of the same subject, more preferably the skin around the lesion of the same subject.

[0117] In embodiments, the above-described method involving the use of a reduced-expression biomarker may include assaying tissue or bodily fluid, preferably skin or peripheral blood, samples from patients with or at risk of having an IL-17-dependent condition for levels of one or more biomarkers prior to treatment.

[0118] In embodiments, a decrease in the level of one or more biomarkers may indicate that the subject has (i) an inflammatory skin disease, preferably an inflammatory skin disease affecting both the epidermis and dermis, more preferably an inflammatory skin disease involving hair follicle structures, even more preferably an inflammatory skin disease involving acne-like lesions, most preferably moderate to severe hidradenitis suppurativa (HS), and / or (ii) a phenotype involving one or more drainage tunnels in the skin.

[0119] In some embodiments, lower levels of one or more biomarkers may result in a greater number of drainage tunnels present in the target area.

[0120] Methods as described above, including the use of a biomarker with reduced expression, are also conceivable, wherein (i) the subject is clinically diagnosed with Hurley stage I, II, or III HS; (ii) the subject is clinically diagnosed with mild HS, moderate HS, moderate to severe HS, severe HS, or juvenile HS; (iii) the subject does not have a drainage tunnel and / or (iv) the subject has at least one drainage tunnel.

[0121] As described above, such methods and uses are envisioned, where the biomarkers include protein and / or mRNA biomarkers.

[0122] The therapeutic methods described herein may also include methods for treating subjects having an assayed lesional IL-17F / non-lesional IL-17F mRNA ratio of 5 or more, preferably 10 or more, more preferably 5 to 500, and most preferably 10 to 300. Herein, such methods may include administering to a subject an effective amount of an agent designed to inhibit IL-17F present in the dermis of the subject's inflammatory skin lesion.

[0123] Furthermore, this specification also envisions a method for treating hidradenitis suppurativa, comprising administering a pharmacopoeia comprising an IL-17A inhibitor and / or an IL-17F inhibitor to a subject identified as having elevated levels of one or more biomarkers selected from (a) LTO1, (b) CSF3, (c) OSM, (d) PLA2G2A, or (e) a combination of IL17A and TNC.

[0124] Diagnostic methods Furthermore, this specification intends to provide a diagnostic method and, for example, a method for detecting hidradenitis suppurativa (HS), wherein a sample from a subject having or at risk of having HS is identified as IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, One or more elevated levels of RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, and CXCL13, or PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and EDA This method involves assaying for a decreased level of one or more of the R values.

[0125] In the embodiments, each elevated or decreased level may be compared to (i) the level present in non-lesional skin, preferably peri-lesional skin, (ii) the level present in the peripheral blood of a healthy patient, or (iii) the level in the same subject before initial treatment.

[0126] In alternative embodiments, each elevated or decreased level may be compared to a reference value, where the reference value is (i) the level of biomarker expression from a corresponding fluid or tissue sample obtained from a healthy subject, (ii) the average level of biomarker expressed in the corresponding fluid or tissue of multiple healthy subjects, or (iii) the average level of biomarker expressed in healthy tissue, preferably healthy tissue from the same subject, more preferably the skin around a lesion from the same subject.

[0127] The diagnostic methods described above involve assaying tissue samples or bodily fluids, preferably skin samples or peripheral blood samples, from patients who have or are at risk of developing HS.

[0128] In one embodiment, the diagnostic method described above may include identifying subjects who have or are at risk of having HS by determining the ratio of IL-17F / IL-17A proteins or mRNA present in the tissue sample of interest.

[0129] Furthermore, this specification also envisions a method for indicating that a subject has or is at risk of having HS if the assayed lesional IL-17F / non-lesional IL-17F protein ratio is 2 or higher, preferably 10 or higher, more preferably 2 to 50, and most preferably 10 to 30.

[0130] Furthermore, this specification also envisions a diagnostic method in which a ratio of IL-17F / IL-17A protein of 1.5 or higher, preferably 1.5 to 3.0, and most preferably 1.5 to 2.2, indicates that a subject has or is at risk of having HS. In one embodiment, such a method may include obtaining a tissue sample from a subject and measuring the ratio of IL-17F / IL-17A mRNA in the obtained tissue sample.

[0131] Methods for identifying subjects that respond to treatment are also disclosed herein. For example, a method is conceived for identifying patients with hidradenitis suppurativa who respond to treatment with IL-17A and / or IL-17F inhibitory nanobodies, and this method comprises assaying a biological sample from the patient for one or more biomarkers selected from (a) LTO1, (b) CSF3, (c) OSM, (d) PLA2G2A, or (e) a combination of IL17A and TNC. The presence of elevated levels of at least one, two, three or more biomarkers indicates that the patient is a so-called superresponder, highly responsive to treatment with IL-17A and / or IL-17F inhibitory nanobodies.

[0132] In the embodiment of the identification method described above, the nanobody may include SLK.

[0133] Furthermore, this specification also discloses a method for identifying subjects who have or are at risk of having hidradenitis suppurativa (HS), which includes assaying the expression level of at least one biomarker selected from CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, and CSF3 in a tissue sample of the subject.

[0134] In one embodiment, this method may include assaying the expression level of at least one biomarker selected from CCL20, CXCL1, and / or CXCL8 in a tissue sample of interest.

[0135] In another embodiment, the biomarkers CCL20, CXCL8, CXCL1, IL17A, and / or IL17F may be sufficient and effective for identifying patients with HS or patients who respond highly to drugs for treating HS. For this purpose, those skilled in the art may consider using a biomarker panel including IL19, PI3, IL17A, IL17F, CCL7, and / or CCL3, a biomarker panel including LT01, IL17A, CSF3, OSM, PLA2G2A, and / or CST7, or any combination or different combinations of biomarkers within the aforementioned groups. In another embodiment, the combination of IL19 and PI3 may be sufficient. Those skilled in the art can freely combine biomarkers from Table 1 within the scope of the meaning of the present invention.

[0136] In another embodiment, it is appropriate and advantageous to use a biomarker panel of at least CCL20, CXCL8, CXCL1, IL17A, and / or IL17F for diagnosis and another biomarker panel for monitoring treatment over time. It will be obvious to those skilled in the art that biomarkers reflecting the course of the disease are not necessarily the same as those used for diagnosing subjects at risk of HS or for identifying superresponders.

[0137] In one embodiment, the expression levels of at least CCL20 and CXCL8 can be evaluated for the diagnosis of HS. In another embodiment, a combination of CCL20, CXCL8, and PI3 may be used for this purpose.

[0138] Also disclosed herein is a method for predicting the efficacy of a pharmaceutical agent in a subject having an IL-17-dependent skin condition, the method comprising: determining the level or expression of IL-17F protein in a lesional skin sample from the subject and the level or expression of IL-17F protein in a non-lesional skin sample from the subject, the pharmaceutical agent comprising an agent that inhibits IL-17F; a lesional IL-17F / non-lesional IL-17F protein ratio of 2 or more, preferably 10 or more, more preferably 2 to 50, most preferably 10 to 30, indicates that the pharmaceutical agent is effective in inhibiting or treating an IL-17-dependent skin condition in the subject; and the subject being human or a non-human animal.

[0139] This specification also discloses a method for predicting the efficacy of a pharmacopoeia in subjects having an IL-17-dependent skin condition, the method comprising determining the level or expression of IL-17F mRNA in lesional skin samples from the subject and the level or expression of IL-17F mRNA in non-lesional skin samples from the subject, wherein the pharmacopoeia comprises an agent that inhibits IL-17F; a lesional IL-17F / non-lesional IL-17F mRNA ratio of 5 or higher, preferably 10 or higher, more preferably 5 to 500, and most preferably 10 to 300 indicates that the pharmacopoeia is effective in inhibiting or treating the IL-17-dependent skin condition in the subject; and the subject may be human or a non-human animal.

[0140] In one embodiment, the method envisioned herein involves IL-17-dependent skin conditions, specifically hidradenitis suppurativa.

[0141] In one embodiment, the method may further include administering a drug to a subject.

[0142] Furthermore, disclosed herein is a method for predicting the efficacy of a drug in subjects with IL-17-dependent skin conditions, the method being used to predict the efficacy of a group of subjects before the initial treatment period with the drug. This involves determining the levels or expression of IL-17F and IL-17A present in a tissue sample; where the pharmaceutical agent includes an agent that inhibits IL-17F; an IL-17F / IL-17A ratio of 1.5 or higher, preferably 1.5 to 3.0, most preferably 1.5 to 2.2, indicates that the pharmaceutical agent is effective in inhibiting or treating the IL-17-dependent skin condition of the subject; and the subject is human or non-human animal.

[0143] In one embodiment, the IL-17-dependent skin condition may be hidradenitis suppurativa.

[0144] In one embodiment, this method may further include administering a drug to a subject.

[0145] In one embodiment, the method intended herein involves an initial treatment period of at least one week, at least two weeks, at least four weeks, at least eight weeks, at least twelve weeks, at least eighteen weeks, or at least twenty-four weeks.

[0146] Monitoring of the course, remission, and treatment needs of IL-17-dependent conditions. This specification aims to obtain biological samples from subjects previously treated for IL-17-dependent diseases, preferably hidradenitis suppurativa, including IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF A method for monitoring the treatment course or remission of an IL-17-dependent condition, comprising assaying one or more biomarkers selected from CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13, PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and EDAR.

[0147] In one embodiment, the biomarker may include PI3 and IL19.

[0148] In the methods of monitoring the course of treatment or remission described above, normalization of the level of one or more biomarkers to the level of a healthy control indicates (i) remission of inflammation, (ii) that tunnels present in the subject are still present but inactive, and / or (iii) the need to discontinue treatment.

[0149] As disclosed herein, the method may preferably involve monitoring the treatment course or remission of an inflammatory skin disease, preferably an inflammatory skin disease affecting both the epidermis and dermis, more preferably an inflammatory skin disease related to hair follicle structures, even more preferably an inflammatory skin disease related to acne-like lesions, most preferably hidradenitis suppurativa.

[0150] Furthermore, as disclosed herein, the method may include a step of determining, before assaying biological samples from subjects previously treated for IL-17-dependent conditions, whether the mRNA and / or protein levels of one or more biomarkers in biological samples from subjects suffering from IL-17-dependent conditions are elevated compared to healthy levels of the same or multiple biomarker mRNA and / or protein in healthy or unaffected biological samples. The method may further or alternatively include at least one biomarker from subjects suffering from IL-17-dependent conditions. The procedure may include a step of determining the mRNA and / or protein levels of one or more biomarkers in one other biological sample, where at least one other biological sample is obtained after the initiation of treatment.

[0151] In the embodiment, a subject previously treated for an IL-17-dependent condition is treated with an IL-17A and / or IL-17F inhibitory nanobody, preferably sonerokimab or a derivative thereof.

[0152] In embodiments, the above method is envisioned to include determining the mRNA and / or protein levels of one or more biomarkers in at least one other biological sample one day, two days, three days or more, one week, two weeks or more, and twelve weeks after the initial treatment, respectively.

[0153] Another method envisioned herein includes administering an IL-17 inhibitor to a subject identified by one or more of the biomarkers disclosed herein for a total of four weeks or more, preferably no more than 24 weeks, followed by a treatment hiatus of more than two weeks, and then resuming treatment if one or more symptoms of the IL-17-dependent condition recur or if the expression of one or more biomarkers becomes abnormal again. In one embodiment, administration may be resumed if the subject's HiSCR score falls below a certain threshold. Alternatively, administration may be resumed if the subject's International Hidradenitis Severity Score (IHS4) falls below a certain threshold. In one embodiment, restarting treatment may involve administering an effective dose of the inhibitor in conjunction with restarting either a new induction dosing scheme or a maintenance dosing schedule.

[0154] In one embodiment, a patient responding to treatment may have a HiSCR score of 75-90, preferably a HiSCR score of 90 or higher (e.g., 90-100 or 91-100). Alternatively, in one embodiment, a patient responding to treatment may have an IHS4 score of 75-90, preferably a IHS4 score of 90 or higher (e.g., 90-100 or 91-100). Such scores may be achieved after a treatment period of 4 weeks or longer, 8 weeks or longer, 10 weeks or longer, 12 weeks or longer, 14 weeks or longer, 16 weeks or longer, 18 weeks or longer, 20 weeks or longer, or 24 weeks. In such embodiments, subjects responding to treatment may have or be at risk of having hidradenitis suppurativa, and may have withdrawn from prior treatment with an IL-17 inhibitor more than 4 weeks, more than 8 weeks, more than 10 weeks, more than 12 weeks, more than 14 weeks, more than 16 weeks, more than 18 weeks, more than 20 weeks, or 24 weeks after that.

[0155] Evaluation and / or measurement of elevated or decreased levels of biomarkers Methods for measuring or evaluating biomarkers disclosed herein are not particularly limited and may include one or more of the following methods: (i) measuring protein levels in peripheral blood; (ii) measuring mRNA or circulating DNA from peripheral blood cells; (iii) analyzing surface markers on peripheral cells (e.g., in the case of cytokine receptors or receptors for other mediators); (iv) in (v) Analysis of intracellular markers in peripheral cells by situ techniques (e.g., flow cytometry), (v) all of the measurements described in (i) to (iv) in other body fluids including but not limited to CSF, breast milk, amniotic fluid, urine, saliva, and serous fluid, (vi) measurement of protein levels in tissue or tissue-derived cells, (vii) including tissue or cells collected with adhesive attached to the skin surface, (viii) measurement of RNA in tissue (e.g., quantitative RT-PCR or bulk RNA sequencing), or measurement of RNA in tissue-derived cells (e.g., single-cell RNA sequencing), (ix) including measurement of RNA in tissue or cells collected with adhesive attached to the skin surface, (x) single nucleotide polymorphisms, insertions Measurement of changes in the quantity or function of biomarkers induced by genetic mutations, including but not limited to insertions, deletions, copy number variations, translocations, and inversions, and / or changes in the quantity or function of biomarkers induced by epigenetic modifications, including but not limited to changes in (xi) histones, DNA methylation, and / or non-coding RNA.

[0156] The expression level or expression amount of one or more biomarkers can be determined in vitro, for example, from an in vitro sample or from an ex vivo sample. Subsequently, following the in vitro determination, the IL-17 inhibitor intended herein can be administered to the subject in vivo.

[0157] In the methods and uses envisioned herein, elevated levels can be compared to: (i) levels present in non-lesional skin, preferably peri-lesional skin; (ii) levels present in the peripheral blood of a healthy patient; or (iii) levels in the same subject prior to initial treatment.

[0158] In the methods and uses envisioned herein, elevated levels may be compared to a reference value, where the reference value is (i) the level of biomarker expression from a corresponding body fluid or tissue sample obtained from a healthy subject, (ii) the average level of biomarker expressed in the corresponding body fluid or tissue of multiple healthy subjects, or (iii) the average level of biomarker expressed in healthy tissue, preferably healthy tissue of the same subject, more preferably in the skin surrounding a lesion of the same subject.

[0159] In a preferred embodiment, elevated levels of mRNA biomarkers determined in an affected biological sample can be compared to mRNA levels of the same biomarker determined in a non-affected biological sample (= healthy level). The biological samples may come from the same subject affected by the disease according to the present invention, but may be obtained from different body parts (healthy and diseased areas), or the healthy control may be obtained from a biological sample from another subject not affected by the disease according to the present invention. The affected biological sample may be obtained from diseased skin or blood, and the non-affected biological sample may be obtained from non-pathogenic skin or blood, preferably peripathic skin, of the same or a different subject.

[0160] In this disclosure, the term “increased” may refer to an increase in the level of a particular biomarker compared to, for example, a reference value (e.g., a healthy control). The degree of increase may be, for example, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%, or at least 100%, or a multiple of at least 100%.

[0161] In this disclosure, the term “reduced” may refer to a decrease in the level of a particular biomarker compared to, for example, a reference value (e.g., a healthy control). The degree of reduction may be, for example, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%, or at least 100%, or a multiple of at least 100%.

[0162] The “elevated” or “decreased” levels of one or more biomarkers as used herein also refer to healthy controls (e.g., reference values, or healthy tissue of the same / different subject). The level may be evaluated based on a multiple change in the level present in a biological sample compared to the level present in the blood. For example, an "elevated" level of a biomarker as defined herein may represent a multiple increase of 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 20, 30, 40, 50, or at least 50 times, or at least 100 times, or a multiple of those multiples, compared to a healthy control. As another example, the “reduced” levels of a hypothetical biomarker may represent reductions of 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 20, 30, 40, 50, or at least 50 times, or at least 100 times, or multiples thereof, compared to a healthy control.

[0163] mRNA and / or protein levels can be determined for biopsy, tissue, or peripheral blood samples. mRNA or protein levels may be based on the overall levels of mRNA or protein across multiple samples. Alternatively, mRNA or protein levels may be based on a specific category of samples (e.g., peripheral blood, HS lesions, or nodules) or a sample from a single individual. Furthermore, since some biomarkers may be regulated at the transcriptional and / or translational levels, monitoring both protein and mRNA levels can sometimes be beneficial.

[0164] subject In this disclosure, the term “Subject,” or similar terms such as “Patient,” or “Individual,” may refer to a person receiving a drug, or to an individual from whom a biological sample has been taken for the evaluation of a biomarker. The subject is, for example, a mammal, preferably a human. Humans are not limited to any disease state, weight, age, or sex. For example, the subject may be an adolescent (i.e., a person 12–17 years of age), juvenile, young (e.g., 1–11 years, 2–10 years, 3–9 years, or 6–12 years of age), or infant (e.g., an infant at least 6 months of age). The subject may have, or be at risk of developing, a disease, disorder, or condition that would benefit from the measurement and / or treatment of the biomarkers disclosed herein. Alternatively, the subject may include, without limitation, animals such as livestock (cattle, sheep, pigs, goats, horses, donkeys, mules, buffaloes, oxen, llamas, alpacas, camels, etc.) or non-human animals (such as dogs and cats, etc.).

[0165] This disclosure identifies subjects who constitute a new patient population that may be treated, for example, with an IL-17 inhibitor, and whose disease progression or remission can be monitored based on the expression levels (e.g., against a healthy control or appropriate reference value) of one or more biomarkers (one or more) present in a biological sample, or who have at least one, two, three, four, five, six, seven, eight, nine, ten, fifteen, twenty or more of the biomarkers listed in Table 1, or who have at least one, two, three, four, five, six, seven, eight, nine, ten, fifteen, twenty or more of them.

[0166] The subjects may have any of the IL-17-dependent conditions disclosed herein, or may be at risk of having such conditions.

[0167] In this embodiment, the subjects may be clinically diagnosed with Hurley disease stage I, II, or III.

[0168] In this embodiment, the subjects may be clinically diagnosed with mild HS, moderate HS, moderate to severe HS, severe HS, or juvenile HS.

[0169] Biological samples As used herein, “sample” or “biological sample” refers to a sample derived from the subject. Non-limited sources of samples include blood, plasma, serum, cerebrospinal fluid, lymph, biopsy aspirates, ascites, fluid extracts, solid or soft tissue, skin, external sections of the respiratory, intestinal and genitourinary tracts, tears, saliva, breast milk, tumors, organs, cell cultures and / or cell culture components. Samples may be collected by means of syringe, adhesive strip, punch biopsy, microbiopsy, surgical excision, etc.

[0170] In one embodiment, the biological sample includes a biopsy sample, tissue, and peripheral blood. In one embodiment, the tissue sample may be a sample of skin cells obtained via a biopsy, microbiopsy, or adhesive strip configured to obtain skin cells from a subject.

[0171] Biological samples (including skin samples from these areas) may be intended from the axilla, buttock, perianal and gluteal region, groin, and breast. Samples may be obtained from lesional tissue (e.g., abscesses, nodules, or tunnels in subjects with or suspected of having HS) or from healthy tissue or tissue with a healthy phenotype.

[0172] IL-17F as a target in IL-17-dependent pathology IL-17F is a unique target in hidradenitis suppurativa (HS), psoriasis (PsO), and other inflammatory skin diseases. For example, IL-17F is specifically upregulated in skin and joint inflammation. In fact, IL-17F is more upregulated in HS than in PsO and is more abundant than IL-17A in overall HS lesions. Furthermore, IL-17F has the ability to activate KC independently of IL-17A. Therefore, inhibitors of IL-17F, and / or inhibitors that block IL-17F with at least the same efficiency as IL-17A, are likely to be more effective in the treatment of HS, PsO, and other inflammatory skin diseases.

[0173] IL-17 inhibitors The IL-17 inhibitors envisioned herein are not particularly limited and may include antibodies, antibody fragments, or nanobodies. IL-17 inhibitors may be capable of modulating, for example, blocking, inhibiting, reducing, antagonizing, neutralizing, or otherwise interfering with the production of pro-inflammatory cytokines and / or chemokines mediated by IL-17, i.e., IL-17A and / or IL-17F.

[0174] The IL-17 inhibitors intended herein can specifically bind to IL-17F, IL-17F homodimers, IL-17A, IL-17A homodimers, or the IL-17A / IL-17F complex, which is a heterodimer.

[0175] In this specification, the term “antibody” may refer to an immunoglobulin molecule and an immunoglobulin (Ig) molecule that includes an immunoactive portion, i.e., an antigen-binding site that specifically binds to an antigen (immune response). For example, an antibody may be thought to react with one or more antigenic determinants of a desired antigen, but not with other polypeptides, or to bind with a much lower affinity.

[0176] Antibodies include polyclonal, monoclonal, chimeric, dAb (domain antibody), single-chain, Fab, Fab', F(ab')2 fragment, and scFv. Antibodies that combine elements or one or more of the structures or characteristics of the aforementioned antibody types are also being considered.

[0177] The basic structural units of antibodies are known to those skilled in the art. Each antibody contains a tetramer consisting of two "light" chains (each about 25 kDa) and two "heavy" chains (each about 50-70 kDa). The amino-terminus of each chain contains a variable region of about 100-110 or more amino acids, primarily responsible for antigen recognition. The carboxyl-terminus of each chain defines the constant region. Human antibody molecules can belong to one of the classes IgG, IgM, IgA, IgE, and IgD, which differ from each other in the properties of the heavy chains present in the molecule. In humans, the light chains can be κ or λ chains.

[0178] As used herein, the term “monoclonal antibody” (mAb) may refer to a single antibody species or molecule, or to a group of antibody molecules that contain only one species of antibody molecule, each consisting of a unique light chain gene product and a unique heavy chain gene product. The complementarity-determining region (CDR) of a monoclonal antibody is identical across all molecules in the group.

[0179] As used herein, the terms “nanobody” and “VHH single-domain antibody” are synonymous and can be used interchangeably. A VHH single-domain antibody contains an immunoglobulin single variable domain (ISV). An immunoglobulin single variable domain is (i) an amino acid sequence that contains an immunoglobulin fold or can form an immunoglobulin fold (i.e., by folding) under suitable conditions (e.g., physiological conditions), i.e., forms an immunoglobulin variable domain (e.g., a VH, VL, or VHH domain), and (ii) an amino acid sequence that forms (or can form under such suitable conditions) an immunoglobulin variable domain that has functional antigen-binding activity (in the sense that it does not require interaction with another immunoglobulin variable domain (e.g., VH-VL interaction) to form a functional antigen-binding site). Preferred examples of nanobodies or immunoglobulin single variable domains suitable for use in the present invention include VHH such as humanized VHH, camelid VH such as camelid human VH, dAbs, and (single) domain antibodies. As intended herein, a nanobody may contain or consist of a single ISV or VHH domain, or, as intended herein, a nanobody may contain or consist of multiple ISV or VHH domains, thereby including embodiments such as VHH multidomain antibodies. Antibodies and antibody fragments combined with ISVs, VHH structures, or nanobodies are also envisioned.

[0180] In a preferred embodiment, the IL-17 inhibitor may be selected from bimekizumab, secukinumab, ixekizumab, brodalumab, netakimab, or izokivep.

[0181] In a preferred embodiment, the IL-17 inhibitor is an IL-17A and / or IL-17F inhibitor and may include a Fab, a VHH single-domain antibody, or an scFv (single-chain Fv fragment) having an ISV.

[0182] In one embodiment, the nanobodies may have a mass of 35-45 kDa. Due to the small size of the nanobodies inhibitor, a tissue / serum ratio 10 times higher than that of conventional mAbs is possible.

[0183] In one embodiment, the nanobodies may be designed to specifically bind to IL-17A and IL-17F.

[0184] The nanobody may include a region that specifically binds to IL-17F, a region that specifically binds to human serum albumin, and a region that specifically binds to IL-17A / F.

[0185] In this embodiment, the nanobody may bind to IL-17F / F dimers to at least the same extent as it binds to IL-17A / A dimers.

[0186] In this embodiment, the nanobody has an affinity for IL-17A / A, IL-17A / F, and IL-17F / F dimers of 0.037 nM or less, preferably 0.004 nM or less, as measured by surface plasmon resonance.

[0187] In embodiments, the nanobody is sonerokimab (SLK) or a derivative thereof. Sonerokimab is a nanobody that inhibits IL-17A and IL-17F and has an enhanced ability to penetrate and accumulate in inflammatory sites in deep, hard-to-access tissue structures, such as inflammatory and fibrotic HS lesions in the dermis.

[0188] Modeling of sonerokimab's PK and molecular PD from subcutaneous administration to tissue penetration demonstrates that the unique advantages of nanobody technology stem from its small size, enhanced absorption after sc. administration, and tissue penetration capacity. This is expected to enable disease control at lower trough levels with lower doses or longer injection intervals compared to mAbs, resulting in an improved benefit-risk ratio.

[0189] Management method In this specification, the term “administer” means to provide a pharmacopoeia to a subject. The method or route of administration is not particularly limited and may be, for example, subcutaneous, intravenous, intraperitoneal, intramuscular, or transdermal. In preferred embodiments, administration is systemic (e.g., by injection). Subcutaneous injection is also intended. Subcutaneous injection may include subcutaneous injection of a pre-filled syringe, an autoinjector, or a reconstituted lyophilized powder.

[0190] An "effective" or "therapeutably effective" amount of a drug is generally administered. An effective dose refers to the amount (dosage, duration of administration, method of administration) necessary to achieve the desired therapeutic outcome. The effective dose of a drug may vary depending on factors such as the patient's disease state, age, sex, weight, and the drug's ability to induce the desired response in the patient. An effective dose may also refer to the amount of a drug in which the toxic or adverse effects outweigh the therapeutic benefits.

[0191] Also disclosed herein is a method for treating a subject having or at risk of suppurative hidradenitis, comprising administering an effective dose of an agent configured to inhibit IL-17F present in the dermis of the subject's inflammatory skin lesions, the effective dose being the same amount required to effectively treat psoriasis with the same agent.

[0192] In one embodiment, this method may involve administering an effective dose to a subject having an assayed pathological IL-17F / non-pathological IL-17F protein ratio of 2 or more, preferably 10 or more, more preferably 2 to 50, and most preferably 10 to 30.

[0193] In one embodiment, this method may involve administering an effective dose to a subject having an assayed pathological IL-17F / non-pathological IL-17 mRNA ratio of 5 or more, preferably 10 or more, more preferably 5 to 500, and most preferably 10 to 300.

[0194] In one embodiment, a drug configured to inhibit IL-17F may include an antibody, an antibody fragment, or a nanobody. In one embodiment, the drug may include a nanobody having a mass of 35-45 kDa.

[0195] kit Kits are intended for the diagnosis of IL-17-dependent conditions, identification of super-responders, and / or simply for measuring biomarkers.

[0196] For example, the kit intended herein is for identifying subjects at risk of or in need of treatment for IL-17-dependent conditions, and this kit includes IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SER Includes one or more reagents for measuring the level or expression of one or more of the following: PINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13, PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and EDAR.

[0197] In one embodiment, the kit may further include packaged components for collecting biological samples from a subject, preferably blood samples or other bodily fluid samples. In certain embodiments, the kit may include adhesive strips for collecting skin samples or packaged components for collecting punch biopsies, microbiopsies, or surgical specimens.

[0198] This specification also envisions a kit for treating IL-17-dependent skin conditions, wherein the kit comprises a pharmaceutical composition containing inhibitors of IL-17A and / or IL-17F, as well as IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, in samples taken from subjects. The reagent may include one or more reagents for measuring the level or expression of one or more of the following: RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13, PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and / or EDAR.

[0199] In this disclosure, “Kit” may refer to the materials necessary to perform an evaluation, including sample collection and safe disposal. For example, a kit may include adhesive strips used to collect skin samples. It may also include materials for collecting bodily fluids such as blood and, if necessary, separating the blood into components such as plasma and red blood cells. Such materials may include, for example, syringes and sponges. A kit may also include materials such as reagents (buffers, blocking agents, etc.) and assay cartridges. A kit may also include instructions for sample collection and testing.

[0200] Alternatively, the kit may contain the materials necessary for administering the medication. Such kits may include medications in the form of tablets, creams, medicinal foods or beverages, or injectable liquid medications. The kit may also include pre-filled administration devices (e.g., syringes or pens) containing the medication. Furthermore, the kit may include materials and instructions for the safe disposal of the administration devices.

[0201] Also disclosed herein is a kit for identifying subjects at risk of or in need of treatment with IL-17F inhibitors, which may include adhesive strips configured for collecting test skin samples, reagents for measuring the level or expression of IL-17F, and optionally reagents for measuring the level or expression of IL-17A.

[0202] Also disclosed herein is a kit for treating IL-17-dependent skin conditions, the kit comprising a pharmaceutical composition, a reagent for measuring the level or expression of IL17F in a sample taken from a subject, and optionally a reagent for measuring the level or expression of IL17A in a sample taken from a subject, the pharmaceutical composition comprising an IL-17F inhibitor.

[0203] Also disclosed herein is a kit for identifying subjects at risk of or in need of treatment with IL-17F inhibitors, the kit comprising an adhesive strip configured for collecting a test skin sample, a reagent for measuring the level or expression of IL-17F, and optionally a reagent for measuring the level or expression of IL-17A.

[0204] Also disclosed herein is a kit for treating IL-17-dependent skin conditions, the kit comprising a pharmaceutical composition, a reagent for measuring the level or expression of IL-17F in a sample taken from a subject, and optionally a reagent for measuring the level or expression of IL-17A in a sample taken from a subject, the pharmaceutical composition comprising an IL-17F inhibitor.

[0205] In one embodiment, the kit contemplated herein is a kit in which the sample taken from a subject to measure the level of IL-17F is a sample of skin cells, and the kit further comprises an adhesive piece configured to obtain a sample of skin cells from a subject.

[0206] In one embodiment, the kit intended herein is one in which the IL-17-dependent skin condition is hidradenitis suppurativa.

[0207] Also disclosed herein is a kit for identifying subjects at risk of having HS or in need of treatment with IL-17A and / or IL-17F inhibitors, the kit comprising an adhesive strip configured to obtain a test skin sample, and at least one reagent for measuring the level or expression of at least one biomarker in the sample taken from the subject, the biomarker comprising one or more of CCL20, CXCL1, CXCL8, CCL2, CCL3, CCL4, CCL5, CCL7, PDFGAA, or CSF3.

[0208] Also disclosed herein is a kit for treating IL-17-dependent skin conditions, the kit comprising a pharmaceutical composition and a reagent for measuring the level or expression of at least one biomarker in a sample taken from a subject, the pharmaceutical composition comprising an inhibitor of IL-17A and / or IL-17F, the biomarker comprising one or more of CCL20, CXCL1, CXCL8, CCL2, CCL3, CCL4, CCL5, CCL7, PDFGAA, or CSF3.

[0209] In one embodiment, the above-described kit is intended, where the sample taken from the subject is a sample of skin cells, and the kit may further include an adhesive piece configured to obtain a sample of skin cells from the subject.

[0210] In one embodiment, the above-described kit is intended, where the IL-17-dependent skin condition is hidradenitis suppurativa. [Examples]

[0211] Example 1 Inflammatory activity based on the expression of IL-17A and IL-17F was observed to occur most vigorously around dermal tunnels in HS. Quantitative RT-PCR was performed on HS samples from the dermis and epidermis, as well as healthy controls. Higher levels of IL-17A and IL-17F mRNA were observed in the dermal compartments compared to the epidermal compartments of HS lesions. This result indicates that maximum inflammatory activity occurs around the dermal tunnels. See Figure 5B.

[0212] Example 2 Identification of IL-17i-related hemoglobin biomarkers and characterization of specific target molecular properties. Punch biopsies were taken from large surgical specimens of patients diagnosed with and who underwent surgery for HS (disease severity, Hurley II-III) to identify specific HS phenotypes (peri-lesional tissue, nodule-containing tissue, tunnel-containing tissue). Biopsies were first subjected to imaging studies (e.g., H&E staining to identify nodules and tunnels, multichannel immunofluorescence (IF) to characterize keratinocyte activation and immune cell infiltration (Figure 6--workflow (i); see also Figures 8A-8F)). Subsequently, biopsies were subjected to protein lysis and mRNA extraction, and further analyzed by multicytokine arrays or ELISA, bulk RNA sequencing, and quantitative RT-PCR analysis (Figure 6--workflow (ii) and (iii); see also Table 1).

[0213] Selected biopsies containing tunnels around lesions were used for gas-liquid interface organ culture to test the permeability and specific anti-inflammatory effects of IL-17 inhibitor (IL-17i) therapeutic molecules (Figure 6--workflow (iv); see also Figures 19 and 20).

[0214] Next, KC was exposed to different IL-17 dimers to test the specific pro-inflammatory effects of IL-17A and IL-17F (Figure 6 -- Workflow (v)). Different IL-17i therapeutic molecules were added, and their specific inhibitory activity at different concentrations was evaluated (Figure 6 -- Workflow (vi); see also Figures 17 and 18).

[0215] Finally, peripheral blood samples were collected from HS patients before and after treatment with IL-17 inhibitors (IL-17i), as well as from healthy controls. Proteomics (Olink®) was used to identify biomarkers for HS (see Figure 6--workflow (vii); Figures 7, 21, 22, and Table 1). In particular, a total of 502 serum samples from 233 HS subjects were analyzed using the Olink® Explore platform, specifically the Olink® Explore 384 Cardiometabolic and Olink® Explore 384 Inflammation panels. This platform covers over 700 proteins associated with inflammation and / or metabolic disorders. The Olink® Explore platform uses proximity expansion assay (PEA) technology in combination with next-generation sequencing (NGS) readout techniques. PEA technology is dual-recognition immune. This is an epidemic assay in which matched antibody pairs with unique DNA tags (PEA probes) bind to protein targets. Upon binding to the target, the bound oligonucleotides approach and hybridize. The newly generated oligonucleotide sequences are subsequently amplified by PCR and measured by NGS. Quality control (QC) and data normalization were performed using internal and external controls.

[0216] In particular, elevated expression of the following biomarkers was observed in HS: IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FC AR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13. Furthermore, decreased expression of the following biomarkers was observed in HS: PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, EDAR. The identified biomarkers and their associated information are summarized in Table 1.

[0217] [Table 1-1]

[0218] [Table 1-2]

[0219] [Table 1-3]

[0220] [Table 1-4]

[0221] [Table 1-5]

[0222] Table 1-6

[0223] Table 1-7

[0224] Table 1-8

[0225] Table 1-9

[0226] Table 1-10

[0227] Table 1-11

[0228] Table 1-12

[0229] Table 1-13

[0230] Table 1-14

[0231] Table 1-15

[0232] [Table 1-16]

[0233] [Table 1-17]

[0234] [Table 1-18]

[0235] [Table 1-19]

[0236] As further shown in Table 1, the results of the above studies and tests confirmed that biomarker levels in the peripheral blood of HS patients were significantly elevated compared to healthy controls (HC). The number and diversity of these biomarkers reflect the marked inflammatory activity and complexity of HS. Here, a paired t-test was employed with FDR < 0.05 set as the significance cutoff.

[0237] Regression analysis was also performed to establish a correlation between biomarker levels and the number of drainage tunnels. The slope values ​​in Table 1 correspond to the coefficient values, with larger absolute values ​​indicating a stronger correlation. In particular, a high number of drainage tunnels was associated with high levels of 58 types of biomarkers. Furthermore, a high number of drainage tunnels was also correlated with a decrease in the levels of the following 8 types of biomarkers. The identified molecules were: PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and EDAR. These findings highlight the active role of drainage tunnels in the pathophysiology of HS and position them as a crucial contributing factor to HS pathology.

[0238] Furthermore, molecular signatures of drainage tunnel biomarkers in peripheral blood, as well as additional HS mediators, HS pathways, and HS receptor biomarkers, were explored within tissues from HS drainage tunnels and evaluated at mRNA and protein levels compared to peripathological tissue and inflammatory nodules using RNA-seq, cytokine arrays, and ELISA. In HS skin tissue, high expression of biomarkers was observed in drainage tunnels compared to peripathological skin and inflammatory nodules.

[0239] In addition to timely diagnosis of HS, the identification of a biomarker panel with functional relevance for (i) assessment of inflammatory disease activity such as tunnel count correlation, (ii) selection and initiation of appropriate treatment, and (iii) monitoring of treatment response and long-term treatment management was unexpected.

[0240] Example 3 Normalization of elastin and IL-19 (circulating biomarker) levels to levels seen in healthy control groups after treatment. Following 12 weeks of treatment with the IL-17 inhibitor SLK, levels of two circulating biomarkers associated with HS activity normalized to levels observed in the healthy control group (n=50). This result demonstrates molecular remission in HS patients and confirms the value of these biomarkers in the diagnosis and monitoring of HS. See Figure 21 and Table 2.

[0241] [Table 2]

[0242] Example 4 Biomarkers for identifying HS superresponders "Subgroup Identification by Differential Effect Search (SIDES) analysis" (Lipkovich et al., Stat Med. 30(21):2601-21 (2011)) was adopted as a partitioning method to determine treatment response within a specific patient population. A subgroup of patients with higher biomarker expression levels showed improvement in clinical outcomes with 120 mg sonelokimab, which was demonstrated by the delta with placebo in the HiSCR75 response compared to randomly selected patients. The applied thresholds (NPX): LOT1 > -0.4123; IL-17A > -0.8321; TNC > -0.0153; CSF3 > -0.2455; OSM > -0.4974; PLA2G2A > 0.6373; CST7 > -0.628. Thus, it was unexpectedly revealed that a) LOT1, b) the combination of IL17A and TNC, c) G-CSF, d) OSM, and e) PLA2G2A could identify HS superresponders to IL-17 inhibitors, respectively. See Figure 22 and Table 3.

[0243] Many of the biomarkers listed in Table 1 reflect pathways involved in the pathophysiology of HS, such as neutrophil activation and degradation, angiogenesis and neurogenesis, innate immunity, activation of T cells, especially Th17 cells, activation of B cells, epithelial regeneration, organization of the extracellular matrix, activation of keratinocytes, extravasation of immune cells, and activation of NK cells and CD8+ cells. However, other biomarkers are not involved in inflammatory conditions including HS. For example LOT1 (also called PLAGL1 or ZAC1; see Table 3) is a zinc finger-type nuclear transcription factor known to play a role in controlling cell proliferation. Associated diseases include growth retardation, neonatal diabetes, and various types of cancer (Abdollahi, J Cell Physiol. 2007 Jan; 210(1):16-25), but the role of this biomarker in inflammatory diseases including HS has not been reported so far. Furthermore, the roles of CST7, COL4A1, NRCAM, HYOU1, and SDC1 in HS have not been reported so far.

[0244] Table 3

Claims

1. A method for treating IL-17-dependent conditions, This includes administering to a pharmaceutical product containing IL-17A and / or IL-17F inhibitory nanobodies (registered trademark), The target is IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, O SM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CS A method of identification by having elevated levels of one or more biomarkers selected from F1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13.

2. A method for treating hidradenitis suppurativa (HS), This includes administering a pharmaceutical product containing an IL-17A inhibitor and / or an IL-17F inhibitor to the target population. The target is IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, O SM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CS A method of identification by having elevated levels of one or more biomarkers selected from F1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13.

3. The method according to claim 2, wherein the IL-17A inhibitor and / or IL-17F inhibitor comprises a nanobody.

4. The method according to claim 1 or 3, wherein the nanobody is configured to specifically bind to IL-17A and IL-17F, and preferably the nanobody is sonerokimab (SLK).

5. The method according to any one of claims 1 to 4, wherein the elevated level is compared to (i) a level present in non-lesional skin, preferably peri-lesional skin, (ii) a level present in the peripheral blood of a healthy patient, or (iii) a level in the same subject before initial treatment.

6. The aforementioned elevated level was compared to the reference value. The method according to any one of claims 1 to 4, wherein the reference value is (i) the biomarker expression level from a corresponding body fluid or tissue sample obtained from a healthy subject, (ii) the average level of the biomarker expressed in the corresponding body fluid or tissue of a plurality of healthy subjects, or (iii) the average level of the biomarker expressed in healthy tissue, preferably healthy tissue of the same subject, more preferably in the skin surrounding a lesion of the same subject.

7. The method according to any one of claims 1 to 6, comprising assaying, prior to treatment, a tissue sample or body fluid, preferably a skin or peripheral blood sample, from a patient having or at risk of having an IL-17-dependent condition for the level of one or more biomarkers.

8. The method according to any one of claims 1 to 7, wherein the elevated level of one or more biomarkers indicates that the patient has (i) an inflammatory skin disease, preferably an inflammatory skin disease affecting both the epidermis and dermis, more preferably an inflammatory skin disease involving hair follicle structures, even more preferably an inflammatory skin disease involving acne-like lesions, particularly preferably hidradenitis suppurativa (HS) such as moderate to severe HS, and / or (ii) a phenotype involving one or more drainage tunnels in the skin.

9. The method according to any one of claims 1 to 8, wherein the number of drainage tunnels present in the subject increases as the level of one or more biomarkers increases.

10. The method according to any one of claims 1 to 6, wherein the subject is clinically diagnosed with Hurley Stage I, II, or III HS.

11. The method according to any one of claims 1 to 6, wherein the subject is clinically diagnosed with mild HS, moderate HS, moderate to severe HS, severe HS, or juvenile HS.

12. The method according to any one of claims 1 to 6, wherein the object does not have a drainage tunnel.

13. The method according to any one of claims 1 to 6, wherein the object has at least one drainage tunnel.

14. The method according to any one of claims 1 to 12, wherein the biomarker comprises a protein and / or mRNA biomarker.

15. One or more of the above biomarkers are IL6, PLA2G2A, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SE The method according to any one of claims 1 to 14, selected from RPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13.

16. The one or more of the above biomarkers include IL6, PLA2G2A, IL19, PI3, CST7, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, and C. CL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TI From MP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, PDFGA, CXCR2, CCR6, CXCL13 The method according to any one of claims 1 to 14, as selected.

17. The method according to any one of claims 1 to 14, wherein the one or more biomarkers are selected from CSF3, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, and PDFGA.

18. The method according to any one of claims 1 to 14, wherein the one or more biomarkers are selected from CCL20, CXCL8, CXCL1, IL17A, and IL17F.

19. Use of a drug that selectively binds to IL-17A and / or IL-17F in a subject determined to have elevated levels of at least one of the following biomarkers compared to a healthy control: Preferably, the elevated level is present in the skin and / or blood, and the use is: IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1 , SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN , SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, and CXCL13.

20. The elevated level of the at least one biomarker is the level present in the biological sample from the subject. The use according to claim 19, wherein the level of at least the corresponding biomarker present in the healthy control is representative of the level present in a biological sample that is not affected by an IL-17-dependent condition, preferably an IL-17-dependent inflammatory skin disease, more preferably hidradenitis suppurativa (HS).

21. The use according to claim 19, wherein the biomarker is associated with inflammatory skin diseases, preferably inflammatory skin diseases affecting both the epidermis and dermis, more preferably inflammatory skin diseases involving hair follicle structures, even more preferably inflammatory skin diseases involving acne-like lesions, and most preferably hidradenitis suppurativa (HS).

22. The use according to any one of claims 19 to 21, characterized in that the mRNA level or protein level of at least one or more biomarkers selected from CCL20, CXCL8, CXCL1, IL17A, and IL17F is elevated.

23. The use according to any one of claims 19 to 22, characterized in that the mRNA level or protein level of the lesioned skin sample is elevated compared to the mRNA level or protein level of the non-lesioned skin sample, respectively.

24. The use according to any one of claims 19 to 23, wherein the pathological IL-17F / non-pathological IL-17 mRNA ratio or protein ratio is determined.

25. The aforementioned subject is an inflammatory skin disease, preferably an inflammatory skin disease affecting both the epidermis and dermis, more preferably an inflammatory skin disease involving the hair follicle structure, and even more preferably an acne-like lesion. The use according to any one of claims 19 to 24, relating to an inflammatory skin disease, most preferably hidradenitis suppurativa, which is identified by exhibiting elevated levels of one or more biomarkers.

26. The use according to any one of claims 19 to 25, wherein the subject is clinically diagnosed with Hurley stage I, II, or III HS.

27. The use according to any one of claims 19 to 26, wherein the release of IL-17A and / or IL-17F in hidradenitis suppurativa of stage I, II and / or III of Hurley disease is inhibited by the agent.

28. The use according to any one of claims 19 to 27, wherein the drug is an IL-17A inhibitor and / or an IL-17F inhibitor.

29. The use according to any one of claims 19 to 28, wherein inflammation and / or tissue destruction is suppressed.

30. The use according to any one of claims 19 to 29, wherein the drug comprises an antibody, an antibody fragment, or a nanobody.

31. The use according to claim 30, wherein the drug comprises a nanobody.

32. The drug is a nanobody, preferably sonerokimab or a derivative thereof. The use according to any one of claims 19 to 21, wherein the biomarker panel comprises a) CCL20, CXCL1, CXCL8, CXL1, IL17A, IL17F, IL19, LT01, CSF3, OSM, PLA2G2A, CST7 and / or PI3, b) IL17A, IL17F, CCL20, CXCL1 and / or CXCL8, c) IL17A, IL17F, CCL20 and / or CXCL8, d) LT01, IL17A, CSF3, OSM, PLA2G2A and / or CST7, e) CCL20, CXCL8, IL19 and PI3, or f) PI3 and IL19.

33. A method for treating IL-17-dependent conditions, This includes administering a pharmaceutical product containing an IL-17A inhibitor and / or an IL-17F inhibitor to the target population. A method wherein the subject is identified as having reduced levels of one or more biomarkers selected from PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and EDAR.

34. The method according to claim 33, wherein the IL-17A inhibitor and / or IL-17F inhibitor comprises a nanobody.

35. The method according to claim 33 or 34, wherein the nanobody is configured to specifically bind to IL-17A and IL-17F, and preferably the nanobody is sonerokimab (SLK).

36. The method according to any one of claims 33 to 35, wherein the reduced level is compared to (i) a level present in non-lesional skin, preferably peri-lesional skin, (ii) a level present in the peripheral blood of a healthy patient, or (iii) a level in the same subject before initial treatment.

37. The aforementioned decreased level was compared to the reference value. The method according to any one of claims 33 to 35, wherein the reference value is (i) the expression level of a biomarker from a corresponding body fluid or tissue sample obtained from a healthy subject, (ii) the average level of a biomarker expressed in the corresponding body fluid or tissue of a plurality of healthy subjects, or (iii) the average level of a biomarker expressed in healthy tissue, preferably healthy tissue of the same subject, more preferably in the skin surrounding a lesion of the same subject.

38. The method according to any one of claims 33 to 37, comprising assaying, prior to treatment, a tissue sample or body fluid, preferably a skin sample or peripheral blood sample, from a patient having or at risk of having an IL-17-dependent condition for the level of one or more biomarkers.

39. The method according to any one of claims 33 to 38, wherein the reduced level of one or more of the biomarkers indicates that the patient has (i) an inflammatory skin disease, preferably an inflammatory skin disease affecting both the epidermis and dermis, more preferably an inflammatory skin disease involving hair follicle structures, even more preferably an inflammatory skin disease involving acne-like lesions, most preferably hidradenitis suppurativa (HS) such as moderate to severe HS, and / or (ii) a phenotype involving one or more drainage tunnels in the skin.

40. The method according to any one of claims 33 to 39, wherein the lower the level of one or more biomarkers, the greater the number of drainage tunnels present in the subject.

41. The method according to any one of claims 33 to 40, wherein the subject is clinically diagnosed with Hurley stage I, II, or III HS.

42. The method according to any one of claims 33 to 41, wherein the subject is clinically diagnosed with mild HS, moderate HS, moderate to severe HS, severe HS, or juvenile HS.

43. The method according to any one of claims 33 to 42, wherein the object does not have a drainage tunnel.

44. The method according to any one of claims 33 to 43, wherein the object has at least one drainage tunnel.

45. The method according to any one of claims 33 to 44, wherein the biomarker comprises a protein and / or mRNA biomarker.

46. The use of a drug that selectively binds to IL-17A and / or IL-17F in a subject who is determined to have reduced levels of at least one of the following biomarkers in the skin and / or blood compared to a healthy control, Preferably, the reduced level is present in the skin and / or blood, and the use: PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and EDAR.

47. A method for monitoring the treatment course or remission of an IL-17-dependent condition, Biological samples from subjects previously treated for IL-17-dependent conditions, preferably hidradenitis suppurativa, are used to identify IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​and NM. A method comprising assaying for one or more biomarkers selected from E3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13, PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, EDAR.

48. The method according to claim 47, wherein the biomarkers include PI3 and IL19.

49. The method according to claim 47 or 48, wherein normalization of the level of one or more of the biomarkers to the level of a healthy control indicates (i) remission of inflammation, (ii) that tunnels present in the subject are still present but no longer active, and / or (iii) discontinuation of treatment.

50. A method for identifying subjects who have or are at risk of having hidradenitis suppurativa (HS), A method comprising determining the ratio of IL-17F / IL-17A protein or mRNA present in the aforementioned tissue sample.

51. A method for detecting hidradenitis suppurativa (HS), Samples from subjects that have or are at risk of having HS include IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EF A method comprising assaying for elevated levels of one or more of EMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, and CXCL13; or for decreased levels of one or more of PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and EDAR.

52. The method according to claim 51, wherein each of the elevated or decreased levels is compared to (i) a level present in non-lesional skin, preferably peri-lesional skin, (ii) a level present in the peripheral blood of a healthy patient, or (iii) a level in the same subject before initial treatment.

53. Each of the aforementioned increased or decreased levels is compared to a reference value. The method according to claim 51, wherein the reference value is (i) the biomarker expression level from a corresponding body fluid or tissue sample obtained from a healthy subject, (ii) the average level of the biomarker expressed in the corresponding body fluid or tissue of a plurality of healthy subjects, or (iii) the average level of the biomarker expressed in healthy tissue, preferably healthy tissue of the same subject, more preferably in the skin surrounding a lesion of the same subject.

54. The method according to any one of claims 51 to 53, comprising assaying a tissue sample or body fluid, preferably a skin sample or peripheral blood sample, from a patient who has or is at risk of developing HS.

55. A method for treating subjects whose assayed pathological IL-17F / non-pathological IL-17F protein ratio is 2 or higher, preferably 10 or higher, more preferably 2 to 50, and most preferably 10 to 30, A method comprising administering an effective amount of a drug configured to inhibit IL-17F present in the dermis of the inflammatory skin lesion of the subject.

56. A method for treating a subject whose assayed pathological IL-17F / non-pathological IL-17F mRNA ratio is 5 or higher, preferably 10 or higher, more preferably 5 to 500, and most preferably 10 to 300, A method comprising administering an effective amount of a drug configured to inhibit IL-17F present in the dermis of the inflammatory skin lesion of the subject.

57. A method for treating hidradenitis suppurativa, comprising administering a pharmaceutical product containing an IL-17A inhibitor and / or an IL-17F inhibitor to the target, A method wherein the subject has been identified as having elevated levels of one or more biomarkers selected from (a) LTO1, (b) CSF3, (c) OSM, (d) PLA2G2A, or (e) a combination of IL17A and TNC.

58. A method for identifying patients with hidradenitis suppurativa who are responsive to treatment with IL-17A and / or IL-17F inhibitory nanobodies, The assay involves testing a biological sample from the patient for the presence of one or more biomarkers selected from (a) LTO1, (b) CSF3, (c) OSM, (d) PLA2G2A, or (e) a combination of IL17A and TNC. A method in which the presence of elevated levels of at least one, two, three or more of the biomarkers indicates that a patient is responsive to treatment with IL-17A and / or IL-17F inhibitory nanobodies.

59. The method according to claim 58, comprising identifying a patient who is a super-responder.

60. The method according to claim 58 or 59, wherein the identified patient is treated with an IL-17A and / or IL-17F inhibitory nanobody, preferably sonerokimab.

61. The method according to any one of claims 58 to 60, wherein the nanobody comprises sonerokimab.

62. A kit for identifying individuals at risk of IL-17-dependent conditions or those requiring treatment for such conditions, IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CLEC4G, CSF1, HGF, CRELD2, EFEMP A kit comprising reagents for measuring the level or expression of one or more of the following:

1. LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13, PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, EDAR.

63. The kit according to claim 62, further comprising packaged components for obtaining a biological sample from a subject, preferably a skin sample or a biological fluid sample, wherein the biological fluid sample is optionally a blood sample.

64. The kit according to claim 62 or 63, comprising an adhesive strip for collecting a skin sample, or a packaged component for collecting a punch biopsy, microbiopsy, or surgical specimen.

65. A kit for treating IL-17-dependent skin conditions, A pharmaceutical composition comprising an inhibitor of IL-17A and / or IL-17F, and IL6, PLA2G2A, IL19, PI3, CST7, IL17A, IL17F, GH1, MZB1, IL1B, IFNG, TNC, CXCL9, SLAMF7, VEGFA, IL17C, SLAMF1, SDC1, OSM, LBP, REG3A, CD79B, COL4A1, CLEC4D, VWF, IL5RA, CSF3, TGFA, IL2RA, ITIH3, FCAR, CCL23, NRCAM, RETN, SERPINA11, CL A kit comprising reagents for measuring the level or expression of EC4G, CSF1, HGF, CRELD2, EFEMP1, LTBR, ​​NME3, CKAP4, CD276, SPON2, GGH, TIMP1, LY9, MCFD2, TCN2, QPCT, HYOU1, TNSFSF13B, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CXCL1, CXCL8, PDFGA, CXCR2, CCR6, CXCL13, PCDH1, BOC, MEPE, ADAM23, THOP1, IL1RL2, RCOR1, and / or EDAR.

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