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WO2021050563A1 - Traitement par anticorps pour le tissu lésionnel de l'hidradénite suppurée - Google Patents

Traitement par anticorps pour le tissu lésionnel de l'hidradénite suppurée Download PDF

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Publication number
WO2021050563A1
WO2021050563A1 PCT/US2020/049964 US2020049964W WO2021050563A1 WO 2021050563 A1 WO2021050563 A1 WO 2021050563A1 US 2020049964 W US2020049964 W US 2020049964W WO 2021050563 A1 WO2021050563 A1 WO 2021050563A1
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WIPO (PCT)
Prior art keywords
brodalumab
individual
receptor agonist
administered
hidradenitis suppurativa
Prior art date
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PCT/US2020/049964
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English (en)
Inventor
James Krueger
John Frew
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The Rockefeller University
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Publication of WO2021050563A1 publication Critical patent/WO2021050563A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • Hidradenitis Suppurativa is a cutaneous disease characterized by psoriasiform
  • IL-Ib IL-17A .
  • Dermal tracks are more associated with late-stage (Hurley 2/3) and have been considered to arise from tissue damage resulting from a primary process of
  • the present disclosure provides methods for treating an individual diagnosed with HS by administering to the individual an agonist of the IL-17 receptor, a non-limiting example of which comprises brodalumab.
  • the method is based at least in part on the following discoveries.
  • Interleukin 17C is a cytokine produced by epithelial cells, (including keratinocytes) in response to multiple stimuli 1 including IL-17 A, IL-17F, TNF-alpha, bacterial stimuli and toll-like receptor agonists. When produced in keratinocytes, it mediates the production of numerous inflammatory molecules, including IL-1B, IL-8, CXCL1, and IL- 36y. These mechanisms contribute to the feed-forward inflammatory cascades described in psoriasis and atopic dermatitis (AD).
  • AD atopic dermatitis
  • IL-17C has feedback upon Thl7 cells leading to further elevation in IL-17A and IL-17F in a pro-inflammatory positive amplification loop in both Psoriasis and AD.
  • Previous investigations have identified IL-17A and IL-17F as elevated in HS lesional tissue 4 , associated with the epidermal psoriasiform patterning in HS lesional skin, in line with changes seen in psoriasis and chronic AD.
  • epithelial derived cytokines such as IL-17C
  • the present disclosure provides the first identification of IL-17C as present in lesional tissue of HS.
  • IL-17C may contribute to the upregulation of other keratinocyte derived cytokines and inflammatory mediators including IL-36y, IL-32, CXCL1, CXCL8 and LCN2.
  • IL-36y is elevated in HS 4 and is highly upregulated in other pustular disorders including generalized pustular psoriasis (GPP) 5 .
  • GPP generalized pustular psoriasis
  • brodalumab a commercially-available, anti-IL-17 antibody used to treat plaque psoriasis, as a treatment for HS.
  • brodalumab can block IL-17A, IL-17F, and IL-17C, and thus it is expected that brodalumab will be an effective treatment option for patients with HS, based on newly discovered overlap in the pathways driving plaque psoriasis and HS.
  • the present disclosure demonstrates that weekly administration of brodalumab improves patient outcomes in HS patients with draining tunnels.
  • Figure 1 shows A) Interleukin 17C (IL-17C) localizes to the keratinocytes of psoriasiform epidermal hyperplasia in Hidradenitis Suppurativa by immunohistochemistry (Fig. 1A) with increased IL-17C in suprabasal and granular layer of HS lesional skin. Healthy skin has a pigmented basal layer (Fig. 1 A). Diffuse dermal and epidermal staining is indicative of IL-17C protein diffusing into the surrounding dermis and epidermis at levels comparable with psoriasis. B) mRNA levels of IL-17C are significantly elevated in lesional, perilesional and unaffected skin compared with healthy controls (Fig.
  • IL-17A and IL-17F are provided (Fig. IB) for comparison.
  • IL17-A, IL17-C, and IL17-F the order of the bars from left to right is: Healthy Volunteer, Unaffected, Perilesional, Lesional, and Psoriasis.
  • Figure 2 is an illustration showing epithelialized dermal tracts are active contributors to inflammation in Hidradenitis Suppurativa.
  • Figure 3 shows (a) clinical photography of multiple sinus tracts, diffuse inflammation, fibrosis and active draining tracts on the right buttock with indication of the site of lesional (L), perilesional (PL) and unaffected (U) biopsy sites (b) Ultrasound demonstrating hyperechoic epidermis (*) with a hair follicle evident (White arrow) above a parallel hyperechoic structure (black arrow) histologically consistent with an epithelialized dermal tract/tunnel. Color doppler ultrasound (c) identifies a hypoechoic inflammatory nidus (**) with active vascularity (black arrows) in adjacent tissue.
  • Figure 4 shows Hemotoxin and Eosin staining of Healthy volunteer, HS lesional skin and the lesional dermal tract/tunnel alongside immunohistochemical staining of Loricrin, Langerin, Neutrophil Elastase and CD 11c. (Provided Scale 10pm). Histology and IHC indicate pronounced psoriasiform epidermal hyperplasia in the overlying epidermis as well as epidermis-like structure lining the dermal tunnels and tracts with comparable expression of pro-inflammatory mediators.
  • Figure 5 shows Hemotoxin and Eosin staining of Healthy volunteer, HS lesional skin and the lesional dermal tract/tunnel alongside immunohistochemical staining of CXCL1, CXCL8, IL-17C and IL-36y. (Provided Scale IOmih)
  • Figure 6 shows Hemotoxin and Eosin staining of Healthy volunteer, HS lesional skin and the lesional dermal tract/tunnel alongside immunohistochemical staining of S100A7, Filaggrin, Lipocalin 2 and Keratin 16. (Provided Scale 1 Opm)
  • Figure 7 shows Hemotoxin and Eosin staining of Healthy volunteer, HS lesional skin and the lesional dermal tract/tunnel alongside immunohistochemical staining of ki-67, c-kit, Melan-A and Trichohyalin. (Provided Scale 1 Opm)
  • Figure 8 shows Hemotoxin and Eosin staining of Healthy volunteer, HS lesional skin and the lesional dermal tract/tunnel alongside immunohistochemical staining of CD 138,
  • CD 163 and CD3 Provided Scale 10pm
  • Figure 9 shows A) Clinical Improvements with the use of weekly subcutaneous brodalumab therapy. Significant reduction in pain, edema and purulent drainage of tunnels was noted in participants treated with weekly brodalumab. Reduction in diffuse edema resulted in a dimpled appearance of the surrounding tissue, with widening of tunnel ostia due to a reduction in the surrounding inflammation, with subsequent healing with post- inflammatory pigmentation.
  • B Clinical Outcomes with Weekly Brodalumab Therapy: All participants achieved HiSCR by Week 4 of therapy which was maintained through to Week 24. 50% participants also achieved complete (100%) reduction in disease activity as measured by HiSCR and AN Count.
  • the present disclosure provides data identifying previously undescribed cytokines (IL- 17C, IL-17F) as central mediators of neutrophil trafficking in HS dermal tracts. Given limited understanding of the mechanisms of disease activity, this presents concept-changing and paradigm shifting views of the HS disease, from one where dermal tracts are a product of fibrosis to one where they are active mediators of inflammation. This disclosure also described newly discovered mechanistic pathways which parallel with psoriasis in the development of the Infiltrative Proliferative Gelatinous Mass (IPGM) and luminal biofilm formation through transepithelial neutrophil trafficking. We also demonstrate the clinical utility of identifying epithelialized dermal tracts through non-invasive imaging modalities and histological correlates.
  • IPGM Infiltrative Proliferative Gelatinous Mass
  • epidermal hyperplasia in HS has a psoriasis-like pattern set of “feed-forward” 6 molecular mediators that promote neutrophilic infiltration; and even more importantly, that dermal sinus tracts in HS are stratified, hyperplastic epithelial structures with cellular and molecular features of psoriatic inflammation including up- regulation of an IL-17A, IL-17F, IL-17C, IL-36, and CXCL1 cytokine axis that could drive transepithelial trafficking of neutrophils into duct lumens. This results in constant purulent drainage as well as the infiltrative proliferative gelatinous mass
  • IPGM neutrophil net-osis
  • the present disclosure provides a method for treatment and/or prophylaxis of HS by administering an effective amount of an IL-17 receptor agonist to the individual.
  • an IL-17 receptor agonist comprises an IL-17 receptor binding partner that specifically binds to human IL-17 receptor A, and inhibits the binding of IL-17A to said IL-17 receptor A.
  • use of such an agent also blocks the function of IL17-F, and IL-17C cytokines simultaneously.
  • the IL-17 receptor agonist comprises brodalumab, or a derivative thereof.
  • brodalumab has been described for treating non-HS disorders, such as psoriasis (U.S. patents 7,833,527 and 10,208,122), plaque psoriasis (U.S. patent 8,435,518), psoriatic arthritis (U.S. patent 8,790,648), and COPD (U.S. patent 9,096,673).
  • non-HS disorders such as psoriasis (U.S. patents 7,833,527 and 10,208,122), plaque psoriasis (U.S. patent 8,435,518), psoriatic arthritis (U.S. patent 8,790,648), and COPD (U.S. patent 9,096,673).
  • the disclosure thus comprises administering an IL-17 receptor agonist, such as brodalumab, or a derivative thereof, to an individual who has been diagnosed with HS.
  • an IL-17 receptor agonist such as brodalumab, or a derivative thereof
  • the disclosure includes the proviso that the individual has not been previously treated, and/or is not undergoing at the time of the presently described treatment, with brodalumab or any other IL-17 receptor agonist, for any of psoriasis, plaque psoriasis, psoriatic arthritis, inflammatory bowel disease, spondyloarthropathies, or COPD.
  • an IL-17 receptor agonist used in the methods of this disclosure comprise antibodies or antigen binding fragments thereof that have a light chain variable domain sequence comprising the following sequence:
  • Glu lie Val Met Thr Gin Ser Pro Ala Thr Leu Ser Val Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gin Ser Val Ser Ser Ser Asn Leu Ala Trp Phe Gin Gin Lys Pro Gly Gin Ala Pro Arg Pro Leu lie Tyr Asp Ala Ser Thr Arg Ala Thr Gly Val Pro Ala Arg Phe Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gin Gin Tyr Asp Asn Trp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu He Lys (SEQ ID NO:l) and a heavy chain variable domain sequence comprising the following sequence:
  • the disclosure comprises use of an antibody or an antigen binding fragment thereof comprising a light chain CDR1 comprising the sequence Arg Ala Ser Gin Ser Val Ser Ser Ser Asn Leu Ala (SEQ ID NO:3), a light chain CDR2 comprising the sequence Asp Ala Ser Thr Arg Ala Thr (SEQ ID NO:4), a light chain CDR3 comprising the sequence Gin Gin Tyr Asp Asn Trp Pro Leu Thr (SEQ ID NO:5), and a heavy chain CDR1 comprising the sequence Arg Tyr Gly He Ser (SEQ ID NO:6), a heavy chain CDR2 comprising the sequence Trp He Ser Thr Tyr Ser Gly Asn Thr Asn Tyr Ala Gin Lys Leu Gin (SEQ ID NO:7), and a heavy chain CDR3 comprising the sequence Arg Gin Leu Tyr Phe Asp Tyr (SEQ ID NO:8).
  • a light chain CDR1 comprising the sequence Arg Ala Ser Gin Ser Val Ser Ser Ser Asn Leu Ala
  • amino acid sequences having from 80-99% similarity, inclusive, and including ranges of numbers there between, with the sequences provided here are included in the invention.
  • an “antibody” it does not necessarily mean a single antibody molecule.
  • administering an antibody includes administering a plurality of the same antibodies.
  • a composition comprising an “antibody” can comprise a plurality of the same antibodies.
  • Antibodies of this disclosure can be modified to improve certain biological properties of the antibody, e.g., to improve stability, to modify effector functions, to improve or prevent interaction with cell-mediated immunity and transfer across tissues (placenta, blood-brain barrier, blood-testes barrier), and for improved recycling, half-life and other effects, such as manufacturability and delivery.
  • an antibody of this disclosure can be modified by using techniques known in the art, such as those described in Buchanan, et ah, Engineering a therapeutic IgG molecule to address cysteinylation, aggregation and enhance thermal stability and expression mAbs 5:2, 255-262; March/ April 2013, and in Zalevsky J. et ah, (2010) Nature Biotechnology, Vol. 28, No.2, pl57-159, and Ko, S-Y, et ah, (2014) Nature, Vol. 514, p642- 647, and Horton, H. et ah, Cancer Res 2008; 68: (19), October 1, 2008, from which the descriptions are incorporated herein by reference.
  • an antibody modification increases in vivo half-life of the antibody (e.g. LS mutations), or alters the ability of the antibody to bind to Fc receptors (e.g. GRLR mutations).
  • an antibody modification comprises a change of G to R, L to R, M to L, or N to S, or any combination thereof.
  • any antibody described herein comprises a modified heavy chain, a modified light chain, a modified constant region, or a combination thereof, thus rendering them distinct from antibodies produced by humans.
  • the modification is made in a hypervariable region, and/or in a framework region (FR).
  • mutations to an antibody described herein comprise modifications relative to the antibodies originally produced in humans. Such modifications include but are not necessarily limited to the heavy chain to increase the antibody half-life.
  • Antibodies of this disclosure can be provided as intact immunoglobulins, or as fragments of immunoglobulins, including but not necessarily limited to antigen-binding (Fab) fragments, Fab' fragments, (Fab')2 fragments, Fd (N-terminal part of the heavy chain) fragments, Fv fragments (the two variable domains), dAb fragments, single domain fragments or single monomeric variable antibody domains, isolated CDR regions, single chain variable fragment (scFv).
  • Fab antigen-binding
  • Antibodies of this disclosure can be provided in pharmaceutical formulations. It is considered that administering a DNA or RNA vaccine encoding any protein (including peptides and polypeptides) antigen described herein is also a method of delivering such peptide antigens to an individual, provided the DNA and RNA are expressed in the individual. Methods of delivering DNA and RNAs encoding proteins are known in the art and can be adapted to deliver the protein antigens, given the benefit of the present disclosure. Similarly, the antibodies of this disclosure can be administered as DNA molecules encoding for such antibodies using any suitable expression vector(s), or as RNA molecules encoding the antibodies.
  • compositions containing antibodies or viral antigens can be prepared by mixing them with pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers include solvents, dispersion media, isotonic agents and the like.
  • the carrier can be liquid, semi-solid, e.g. pastes, or solid carriers.
  • a pharmaceutical/vaccine formulation exhibits an improved activity relative to a control, such as antibodies that are delivered without adding additional agents, or a particular added agent improves the activity of the antibodies.
  • the formulation can contain more than one antibody type or antigen, and thus mixtures of antibodies, and mixtures of antigens, and combinations thereof as described herein can be included.
  • These components can be combined with a carrier in any suitable manner, e.g., by admixture, solution, suspension, emulsification, encapsulation, absorption and the like, and can be made in formulations such as tablets, capsules, powder (including lyophilized powder), syrup, suspensions that are suitable for injections, ingestions, infusion, or the like. Sustained-release preparations can also be prepared.
  • a therapeutic amount of an antibody disclosed herein is administered to a subject in need thereof.
  • the term “therapeutically effective amount” means the dose required to effect a reduction in disease manifestation, or its symptoms.
  • the dosage of an antibody depends on the disease state and other clinical factors, such as weight and condition of the subject, the subject's response to the therapy, the type of formulations and the route of administration.
  • the precise dosage to be therapeutically effective and non detrimental can be determined by those skilled in the art.
  • a suitable dose of an antibody for the administration to adult humans parenterally is in the range of about 0.1 to 20 mg/kg of patient body weight per day, once a week, or even once a month, with the typical initial range used being in the range of about 2 to 10 mg/kg. Since the antibodies will eventually be cleared from the bloodstream, re-administration may be required.
  • implantation or injection of the antibodies provided in a controlled release matrix can be employed.
  • the individual is treated in intervals subcutaneously with brodalumab.
  • a weekly subcutaneous administration is used.
  • the individual is treated with about 210mg administered subcutaneously every week for between 4 and 24 weeks, including all days and intervals of days there between.
  • the individual can be monitored during and after such treatment periods, and the brodalumab administration regimen can be adjusted accordingly.
  • HS Clinical Response (HiSCR) at can be monitored, and can include a determination of abscesses, and inflammatory nodule counts, and the like.
  • weekly treatment with brodalumab produces an improved HiSCR in patients with draining tunnels, relative to HiSCR for patients without draining tunnels, and/or relative to relative to HiSCR for which bi-weekly administration is used, such as in patients with draining tunnels.
  • Draining tunnels in HS patients can be identified by those skilled in the art. In general, draining tunnels, also referred to a sinus tracts, connect different areas of HS outbreaks in the skin. Draining tunnels are thus the described sinus tracts from which a liquid biological fluid is secreted.
  • an individual to whom a composition of this disclosure is administered exhibits draining tunnels, and weekly brodalumab administration unexpectedly improves the HS symptoms of such patients, relative to bi-weekly administration.
  • any result obtained using a method described herein can be compared to any suitable reference, such as a known value, or a control sample or control value, suitable examples of which will be apparent to those skilled in the art, given the benefit of this disclosure.
  • performance of a method of this disclosure results in any of reduced pain, edema, or purulent drainage of tunnels.
  • performing a method of this disclosure results in an improvement in one or more signs or symptoms of HS.
  • performance of a method of the disclosure results in a reduction in clinical disease activity as assessed using the Hidradenitis Suppurativa Clinical Response (HiSCR) and/or International Hidradenitis Suppurativa Severity Scoring System (IHS4), including but not limited to scoring metrics, patient-rated visual analogue scales of pain, itch and disease severity.
  • performing a weekly administration results in an improvement of any of the foregoing traits of HS relative to a control.
  • performing a once a week dosing provides improved results in patients with draining tunnels relative to a twice a week dosing of the patients.
  • the disclosure provides for a reduction in dermal post-capillary venules and inflammatory infiltrates.
  • performing a method of the disclosure results in a reduction of edema and exophytic nodules at the ostia of tunnels.
  • the method results in an IHS4 category change or a two category change in IHS4.
  • a score of 3 or lower signifies mild HS
  • a score of 4-10 signifies moderate HS
  • a score of 11 or higher signifies severe HS.
  • an improvement from weekly dosing is achieved in patients with draining tunnels within the first 4-12 weeks of EW dosing.
  • EW dosing results in cyclical disease suppression and disease recurrence during the treatment period.
  • the antibodies are administered subcutaneously.
  • the disclosure also includes administration by standard routes, including oral, transdermal, topical and parenteral (e.g., intravenous, intraperitoneal, intradermal, subcutaneous or intramuscular).
  • the antibodies can be introduced into the body, by injection or by surgical implantation or attachment such that a significant amount of an antibody is able to enter blood stream in a controlled release fashion.
  • antibodies described herein are incorporated into one or more prophylactic compositions or devices.
  • a composition and/or device comprises a polymeric matrix that may be formed as a gel, and comprises at least one of hydrophilic polymers, hydrophobic polymers, poly(acrylic acids) (PAA), poly(lactic acids) (PLA), carageenans, polystyrene sulfonate, polyamides, polyethylene oxides, cellulose, poly(vinylpyrrolidone) (PVP), poly(vinyl alcohol) (PVA), chitosan, poly(ethylacrylate), methylmethacrylate, chlorotrimethyl ammonium methylmethacrylate, hydroxyapatite, pectin, porcine gastric mucin, poly(sebacic acid) (PSA), hydroxypropyl methylcellulose (HPMC), cellulose acetate phthalate (CAP), magnesium stearate (MS), polyethylene glycol, gum-based polymers and variants thereof, poly (D,L)-lactide (PDLL), polyvinyl
  • the disclosure comprises including antibodies in micro- or nano-particles formed from any suitable biocompatible material, including but not necessarily limited to poly(lactic-co-glycolic acid) (PLGA). Liposomal and microsomal compositions are also included.
  • a gel of this disclosure comprises a carbomer, methylparaben, propylparaben, propylene glycol, sodium carboxymethylcellulose, sorbic acid, dimethicone, a sorbitol solution, or a combination thereof.
  • a gel of this disclosure comprises one or a combination of benzoic acid, BHA, mineral oil, peglicol 5 oleate, pegoxol 7 stearate, and purified water, and can include any combination of these compositions.
  • Figure 3 provides clinical (Fig. 3 a) and doppler ultrasound (using GE Next-Gen LOGIQ with L10-2220Mhz probe) images (Fig. 3b-c) of HS from a patient with Stage 3 disease and quantification of key inflammatory cytokine mRNAs done in parallel on control skin, HS lesions, and psoriasis vulgaris lesional skin (Fig.3). All data and sample collections were performed in line with a protocol approved by the Rockefeller University Institutional Review Board (IRB).
  • IRB Rockefeller University Institutional Review Board
  • IL-17C and IL-36y tract staining was highly positive (Fig. 3) in the dermal tracts. This was suggestive of a “pseudo-psoriasiform” pattern of the epithelialized tracts compared with overlying epidermis.
  • CXCL1 staining highlighted a discemable CXCL1 gradient from the dermo-epidermal junction of the tract to the tunnel lumen.
  • CXCL8 was also positive throughout the epithelialized tract although a gradient was less clear than the overlying epidermis (Fig. 5).
  • C-kit highlighted melanocytes and epidermal Langerhans cells (confirmed with Langerin staining) within the epithelialized tracts (Fig. 7).
  • Dermal dendritic cells and mast cells throughout dermal tissues were also highlighted by c-kit.
  • Melan-A confirmed the presence of melanocytes in the basal epidermal layer of the tracts in comparable density to the overlying epidermis.
  • Neutrophil Elastase and CD1 lc stained the dense neutrophilic infiltrate of the superficial dermis with comparable staining surrounding the deep tracts (Fig. 4).
  • T cells, Macrophages and Plasma cells were identified in the vasculature and in the dermal interstitium by CD3, CD 168 and CD138 respectively (Fig. 8).
  • nest of neutrophils reminiscent of pustular psoriasis were seen.
  • Evidence of diffuse extracellular filamentous chromatin-histone scaffolds adorned with neutrophil granular proteins consistent with NETosis (Neutrophil Extracellular Traps) were seen (Fig. 4).
  • epithelialized dermal structures may participate in active inflammation and contribute to disease activity.
  • epithelialized tracts recapitulate the morphology and function of the overlying epidermis and demonstrate “pseudo-psoriasiform” patterning suggest that a similar “feed
  • HS dermal tracts may be at play in HS dermal tracts.
  • melanocytes and trichohyalin demonstrate tracts have features of both overlying epidermis and follicular outer root sheath, which does not settle the outstanding question of the origin of the dermal tracts.
  • Quantification of IL-17 subtypes has not previously been undertaken in lesional HS tissue, and the identification of IL-17A, C and F isoforms at comparable levels with psoriasis.
  • the comparable levels of IL-36 isoforms with psoriasis also suggests a similarity in the epithelial driven mechanisms of inflammation in epithelialized dermal tracts in Hurley Stage 3 disease.
  • brodalumab is an IL-17RA antagonist used in every 2 weeks (E2W) in HS.
  • E2W IL-17RA antagonist used in every 2 weeks
  • Brodalumab E2W demonstrated high clinical efficacy (10/10 HiSCR at Weekl2), however participants with draining tunnels were observed to demonstrate cyclical response (rapid reduction in acute symptoms, with slow re-emergence of tunnel drainage and pain). The present Example addresses this cyclical response.
  • the IHS4 is known in the art (see, for example, Zouboulis et al., Development and validation of the International Hidradenitis Suppurativa Severity Score System (IHS4), a novel dynamic scoring system to assess HS severity. Br J Dermatol 2017; 177(5): 1401-1409, the entire disclosure of which is incorporated herein by reference).
  • BDI Beck Depression Inventory and PHQ-9: Physical Health Questionnaire-9.

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Abstract

L'invention concerne des méthodes de traitement de l'hidradénite suppurée (HS). Les méthodes comprennent l'administration à un patient HS d'un agoniste du récepteur de IL-17. Un agoniste représentatif du récepteur de IL-17 est le brodalumab. La posologie hebdomadaire de brodalumab améliore l'HS chez des patients ayant des tunnels de drainage. Dans des modes de réalisation, l'agoniste du récepteur de IL-17 comprend un partenaire de liaison au récepteur de IL -17 qui se lie spécifiquement au récepteur A de IL -17 humain, et inhibe la liaison d'EL-17A audit récepteur A de IL-17.
PCT/US2020/049964 2019-09-09 2020-09-09 Traitement par anticorps pour le tissu lésionnel de l'hidradénite suppurée WO2021050563A1 (fr)

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