WO2014182655A1 - Dosage - Google Patents

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Publication number
WO2014182655A1
WO2014182655A1 PCT/US2014/036900 US2014036900W WO2014182655A1 WO 2014182655 A1 WO2014182655 A1 WO 2014182655A1 US 2014036900 W US2014036900 W US 2014036900W WO 2014182655 A1 WO2014182655 A1 WO 2014182655A1
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WO
WIPO (PCT)
Prior art keywords
skin
production
pro
human skin
test compound
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PCT/US2014/036900
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English (en)
Inventor
Javier Cote-Sierra
Susan Smith
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Stiefel Laboratories, Inc.
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Application filed by Stiefel Laboratories, Inc. filed Critical Stiefel Laboratories, Inc.
Publication of WO2014182655A1 publication Critical patent/WO2014182655A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/20—Dermatological disorders
    • G01N2800/205—Scaling palpular diseases, e.g. psoriasis, pytiriasis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to an assay for assessing the production of proinflammatory cytokines in human skin, and for assessing the effect of test compounds such production.
  • Psoriasis is an autoimmune skin disease. It is chronic and recurrent, and characterized by marked inflammatory changes in epidermis and dermis, as well as hyperproliferation of keratinocytes. It is estimated that approximately 2-3% of the human population is affected by psoriasis.
  • Various methods of treating psoriasis are known, including topical, phototherapeutic, and systemic medications.
  • psoriasis Several types of psoriasis are recognized, including plaque psoriasis, nail psoriasis, scalp psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, and psoriatic arthritis. Diagnosis of psoriasis may be accomplished by physical examination of the individual, or examination of a skin biopsy. The severity of psoriasis varies among individuals, and the course of the disease may fluctuate. No cure is presently recognized for psoriasis.
  • Rodent models of autoimmune skin diseases do not completely recapitulate human pathology. There remains a need to develop assays capable of screening compounds and agents for their effects on autoimmune skin diseases in human skin.
  • Figure 1 is a schematic of one aspect of the tissue-based assay described herein.
  • Skin resident T cells are activated by exposure to Thl7 polarizing conditions, leading to production of IL-17 and IL-22.
  • RORyt retinoic acid-receptor-related orphan receptor gamma T
  • Stat3 signal transducer and activator of transcription 3
  • TCR T Cell Receptor.
  • Figure 2A depicts the transwell, liquid-air interface design of the present ex vivo skin assay.
  • Figure 2B is a timeline for an ex vivo experiment, where D-l is the day the skin tissue is received.
  • Figure 3A graphs the production of IL17a mRNA transcripts by skin-resident T cells following activation (under three different conditions) in the present ex vivo skin assay. Expression values are relative to that on Day 0 (arbitrarily deemed to be a value of "1").
  • Each data point represents the average expression value of duplicate cultures from a single skin donor.
  • Figure 3B graphs the production of IL22 mRNA transcripts by skin-resident T cells following activation (under three different conditions) in the present ex vivo skin assay. Expression values are relative to that on Day 0 (arbitrarily deemed to be a value of "1").
  • Each data point represents the average expression value of duplicate cultures from a single skin donor.
  • Figure 5 is a timeline schematic for an experiment to test compounds for the ability to inhibit expression of pro-inflammatory cytokines.
  • Test compounds may be added to the liquid medium or applied topically in an appropriate vehicle.
  • Figure 6A graphs IL17a mRNA levels at 48 hours for human skin samples using the present ex vivo assay system and four different media.
  • Medium base medium without any activators or test compound.
  • the other three culture conditions included pre- treatment for three days with a test compound before TH17 activation on Day 0 using Thl7 medium.
  • DMSO medium containing DMSO as a vehicle control;
  • Dig(Sal) medium containing Digoxin-21-Salicylidene as test compound;
  • Compound A medium containing a small molecule compound as test compound.
  • Figure 6B graphs IL-17F mRNA levels at 48 hours for human skin using the present ex vivo assay system. Conditions were as described for Figure 6A.
  • Figure 7A graphs IL17a mRNA levels at 48 hours for human skin samples using the present ex vivo assay system and four different media. Four different conditions were tested.
  • Medium base medium without any activators or test compound.
  • Veh medium containing vehicle as a control for test compounds;
  • Compound B small molecule test compound;
  • Compound A small molecule test compound.
  • Figure 7B graphs IL17F mRNA levels at 48 hours for human skin samples using the present ex vivo assay system. Four conditions were tested, as described for Figure 7A.
  • the invention provides a method of screening a compound for the ability to modulate pro-inflammatory cytokine production in human skin, using a liquid-air interface culture of human skin, exposing the skin to a test compound, exposing the skin to a Thl7 activating condition, measuring the production of proinflammatory cytokines, and comparing the production of pro-inflammatory cytokines to that produced in the absence of the test compound.
  • a further aspect of the invention is a method of screening a compound for use as a treatment for psoriasis, by providing a liquid-air interface culture of human skin, exposing the skin to a test compound, exposing the skin to a Thl7 activating condition, measuring the production of pro-inflammatory cytokines, and comparing the production of pro-inflammatory cytokines to that produced in the absence of test compound, where a reduction in the production of pro-inflammatory cytokines indicates the compound is useful as a treatment for psoriasis.
  • Psoriasis has been described as mediated by T cells producing interferon gamma (IFNy) and Tumor Necrosis Factor alpha (TNFa).
  • IFNy interferon gamma
  • TNFa Tumor Necrosis Factor alpha
  • Psoriatic skin lesions have been reported to have increased gene and protein expression of IL-23, IL-21, IL-22 and IL-17 (Boniface et al., Clin. Exp. Immunol. 150:407 (2007)). Elevated IL-17 and IL-22 production has been reported in psoriatic skin.
  • the inflammatory cell infiltrate consists not only of T cells but also of effector cells of innate immunity, including neutrophils, macrophages, and plasmocytoid DCs and CDllc+ DCs, which produce various inflammatory mediators such as cytokines and adhesion molecules.
  • Thl7 cells play a role in immunological activation in psoriasis.
  • Thl7 cells are a subset of CD4 T helper cells characterized by production of interleukin-17, particularly IL-17A and IL-17F, and interleukin 22 (IL-22).
  • IL-17A and IL-22 both enhance the innate immune response of tissue fibroblast and epithelial cells; however, their functions do not overlap completely.
  • IL-22 induces proliferation of keratinocytes and augments healing responses, whereas IL-17A induces much stronger proinflammatory effects and more recruitment of neutrophils.
  • I L-23/IL-17 pathway plays a critical role in the pathogenesis of human psoriasis, as improvement in clinical scores has been associated with reduction of Thl7 responses.
  • tissue-based assay suitable for use in evaluating therapeutics, including topically-delivered therapeutics, for the ability to modulate expression of pro-inflammatory cytokines.
  • the present tissue- based assay is suitable for use with human skin.
  • Naive I cells upon activation, differentiate into cytokine-expressing effector T he!per ceils such as Thl, Th2, and Thl7. Differentiation of T cells into Thl7 ce!is has been reported as driven by IGF- beta and IL6 (Bettelli et aL, Mature 441:235-238 (2006); Veidhoen et aL, immunity 24 :179-89 (2006).
  • T cells are activated under Thl7- polarizing conditions to mimic T cell-mediated immune responses within human skin.
  • Resident T cells are activated in situ in freshly excised healthy human skin, resulting in Thl7-associated cytokine production, including production of IL-17 and IL-22.
  • IL-17 production is highly dependent on the transcription factor RORg.
  • the present assay was validated using a specific small molecule inhibitor of RORg.
  • Pretreatment of ex vivo human skin cultures with RORg inhibitor decreased activation- induced H17a and H17f transcript expression.
  • topical and systemic drugs that inhibit the production of IL- 17 in the skin represent possible therapies against psoriasis.
  • tissue-based assay using ex vivo human skin to mimic in vivo T cell-mediated inflammatory processes and cytokine production.
  • This tissue-based assay is used to evaluate test compounds and biological agents as potential therapeutics for the treatment of inflammatory skin diseases, such as psoriasis, based on suppression of induced pro-inflammatory cytokine production.
  • inflammatory skin diseases such as psoriasis
  • Thl7 mediated diseases are Thl7 mediated diseases.
  • a further aspect of the present invention is a method of screening compounds and biological agents to identify those able to suppress the production of proinflammatory cytokines.
  • the method comprises providing a liquid-air interface culture of human skin; exposing said skin to both a test compound and Thl7-polarizing conditions, and assessing the effect of said test compound on the transcription or production of proinflammatory cytokines in the skin tissue.
  • the test compound is administered to the cultured skin tissue prior to exposing the skin tissue to the Thl7- polarizing conditions.
  • the cytokine assessed is IL17a and/or IL17f, and the production of mRNA transcripts is measured.
  • the effect of the test compound on cytokine production or transcription is compared to cytokine production in a control assay lacking test compound.
  • the test compound is delivered topically.
  • Test compounds identified as able to suppress Th-17 induced pro-inflammatory cytokine production are identified as potential anti-psoriasis medicaments.
  • Suitable small molecule test compounds include but are not limited to inhibitors of RORy and RORyt (a specific isoform of RORg).
  • the invention further relates to a method for preventing, treating, or ameliorating a medical condition caused by increased production of pro-inflammatory cytokines, including Thl7- induced IL17 production, comprising administering to a mammalian subject a therapeutically effective amount of a compound identified by the present assay as an inhibitor of pro-inflammatory cytokine production, including a compound identified as an inhibitor of Thl7-induced IL17 production.
  • Administration of such a compound may be by topical administration.
  • the compound is an inhibitor of RORyt and the medical condition is psoriasis.
  • modulate or “modulates” refer to an increase or decrease in the amount, quality or effect of a particular activity.
  • 'biological agents means complex biological molecules such as antibodies, monoclonal antibodies, proteins, polypeptides and nucleotides.
  • plaque psoriasis includes plaque psoriasis, nail psoriasis, scalp psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, and psoriatic arthritis.
  • a 'treatment' for, or a 'method of treating', a medical condition refers to a method of reducing, ameliorating or delaying the signs, symptoms, or progression of that medical condition.
  • 'treatment' does not imply a cure.
  • a treatment need not be effective in every member of a population, e.g., a population of patients with psoriasis, to have clinical utility, as is recognized in the medical and pharmaceutical arts.
  • Thl7 activating conditions refer to tissue culture conditions which result in the differentiation of naive T cells resident in the tissue into effector Th 17 helper cells.
  • 'Thl7 activation' is used interchangeably with the term 'Thl7 stimulation'.
  • 'subjects' and/or 'patients' includes human subjects and patients.
  • Various routes of administering a therapeutic compound to a subject are known in the art, including but not limited to topical, intradermal, intramuscular,
  • topical application consists of or comprises application to the cutis or external integument of a subject, such as application to the epidermis of skin, including application to psoriatic lesions.
  • Appropriate vehicles and pharmaceutical carriers for use in topical application are known in the art.
  • compositions comprise a therapeutically effective amount of a compound or agent, and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for example
  • “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
  • An 'effective amount' of the compound or agent for treatment of a disease or condition can be determined by standard clinical techniques.
  • Skin culture Healthy human skin obtained from elective abdominoplasty surgery underwent minimal processing (removal of sub-dermal fat and sectioning to fit 10 mm transwells), and was then cultured in transwells at the interface of air and a liquid culture medium (liquid-air interface culture). See Figure 2A showing the transwell configuration.
  • Skin was cultured in the upper chamber of a 0.4 urn PCF membrane transwell (Millicell #PIHP01250).
  • the medium used on day -1 was Cornification medium + hydrocortisone (final concentration of 0.4 ug/ml). From day 0 and onward, medium used was Cornification medium without hydrocortisone.
  • Cornification medium is: equal parts F12 and Dulbecco's Modified Eagle's Medium (DMEM) containing 4 mM L-glutamine, 5 ug/ml Insulin, 5 ug/ml Transferrin, 0.02 nM Triiodothyromine, 100 uM Ethanolamine, 100 uM Phosphorylethanolamine, 180 uM Adenine, 52.6 nM Selenium, 1.88 uM CaCI2, 2% FBS.
  • DMEM Dulbecco's Modified Eagle's Medium
  • Activation of skin cell cultures After at least one day of resting (undisturbed culturing on the starting mediumj, skin-resident T cells in the human skin cultures were activated under various conditions.
  • Thl7-polarizing conditions were achieved using cornification media (without hydrocortisone) containing: Cluster of Differentiation 3 (CD3) 1 ug/ml (BD Pharmingen); Cluster of Differentiation 28 (CD28) 2 ug/ml (R&D Systems); anti-l nterferon gamma (IFNg) mAb 1 ug/ml (R&D Systems); anti-interleukin 4 (IL4) mAb 1 ug/ml (R&D Systems); interleukin-6 (I L6) 10 ng/ml (R&D Systems); interleukin-lbeta (ILlb) 10 ng/ml (R&D Systems); Transforming Growth Factor beta (TGFb) 1 ng/ml (R&D Systems); and interleukin 21 (I L21) 10 ng/ml (R&D Systems).
  • CD3 Cluster of Differentiation 3
  • CD28 Cluster of Differentiation 28
  • R&D Systems anti-l nter
  • T cell stimulation was maintained by a daily refresh of medium (where refresh refers to complete replacement of the medium by aspiration of the medium and delivery of 1 ml of the replacement medium.
  • TCR medium or 'TCR only conditions' refers to cornification medium containing CD3 1 ug/ml (BD Pharmingen) and CD28 2 ug/ml (R&D Systems).
  • Recombinant human IL-17 and I L-22 medium refers to cornification medium containing 10 ng/ml of I L-17a and lOng/m l of I L-22 human recombinant proteins (from R&D Systems).
  • cytokine expression Following culture as described above, levels of pro-inflammatory cytokine transcript expression were measured. Skin samples were harvested from duplicate wells (2 wells per condition) each day over the time course of the experiment. Each skin sample was cut in half; one piece was used for histology and the other for qPCR. This scheme is depicted in Figure 2B, where D-l (D negative one) represents the day the skin tissue is received for culture; Thl7-polarizing conditions are established on Day 0; and samples are harvested for qPCR at DO (for baseline measurements), Dl, D2, D3, D4, D5 and D6.
  • qRT-PCR Transcriptase Polymerase Chain Reaction
  • H&E Hematoxylin/Eosin staining as is known in the art.
  • FIGS 3 and 4 provide results obtained using skin cultures as described in the Materials and Methods, above.
  • RNA transcripts for pro-inflammatory cytokines IL17a and IL-22 were found to be produced at significant levels within 24 hours of T cell activation; see Figures 3A and 3B, where values given are relative to expression at day 0 (before activation, arbitrarily set to an value of 1).
  • Figure 3A shows the relative expression of IL17a (and Figure 3B shows relative expression of IL22) at Day 0, Dl, D2, D3, D4, and D6 (no Day 5 measurement was taken in order to reduce the experiment size) produced by skin-resident T cells in human skin samples activated as described above under: Thl7 conditions (uppermost graphed line), TCR only (middle graphed line), or recombinant IL-17a/IL22 (lower graphed line).
  • Interleukin expression was normalized to beta-actin as is known in the art.
  • Figure 4 demonstrates that, after several days of culture, the induced proinflammatory cytokine expression led to ballooning degeneration of the skin. Tissue integrity was assessed by Hematoxylin/Eosin staining at each of three time-points (Day 1,
  • test compounds were: Dimethyl Sulfoxide (DMSO; vehicle control), Digoxin-21-Salicylidene in DMSO Dig/sal; positive control) or Compound A in DMSO vehicle; where final
  • Medium base medium (cornification medium without additions, refreshed similar to the other media).
  • the other three culture conditions included pre-treatment for three days with one of the test
  • the digoxin derivative Digoxin-21-Salicylidene
  • Thl7-polarizing medium was added (also including test compound), and then skin cultures were left untouched (no further refreshment of medium) for 48 hours (until Day 2). At Day 2, samples were harvested for qPCR and histology. See
  • Figure 6A graphs IL17a mRNA levels at Day 2, relative to expression in the medium-only sample.
  • Figure 6B graphs IL-17F mRNA levels at Day 2, relative to expression in the medium-only sample.
  • Use of Dig(sal) was shown to suppress levels of both IL17a mRNA and IL17f mRNA relative to the vehicle (DMSO) control.
  • Compound A was also shown to suppress levels of both IL17a mRNA and IL17f mRNA relative to the vehicle (DMSO) control. Compound A was also shown to be approximately as potent as the Dig/Sal inhibitor in suppressing IL-17a and IL17f production relative to vehicle control.
  • each data point is the average of triplicate wells +/- SEM from the same skin donor.
  • the data are representative of four independent experiments run on four different skin donors and yielding similar results.
  • Test Compounds A (1%) and B (1%) were each dissolved in a simple ethanolic formulation of 60% EtOH: 40% H20 and applied 0.13 mg per cm 2 to the epidermis (air-interface) of the ex vivo human skin cultures for four days (D-3, D-2, D-l and DO).
  • a vehicle control ethanolic formulation without test compound
  • a medium-only no test compound, no Thl7 activation
  • Figure 7A graphs the relative expression of IL17a mRNA
  • Figure 7B graphs the relative expression of IL17f mRNA, measured at D2. It is shown that topical application of test Compound A inhibits H17a and Ill7f transcript expression from skin-resident T cells. Data shown is the average +/- SEM of triplicate wells from a single skin donor. These data are representative of three independent experiments run on three different skin donors yielding similar results.
  • T cells can be activated in situ in healthy skin cultures, and that pre-treatment with small molecule test compounds result in significant cytokine inhibition when applied either in the medium or topically.

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Abstract

La présente invention a trait à un dosage pour évaluer la production de cytokines pro-inflammatoires de la peau humaine, et pour évaluer l'effet de composés d'essai sur ladite production.
PCT/US2014/036900 2013-05-06 2014-05-06 Dosage WO2014182655A1 (fr)

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US61/819,718 2013-05-06

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3071508A1 (fr) * 2017-09-26 2019-03-29 Genoskin Modele ex vivo de peau humaine inflammee et ses utilisations pour le criblage de composes anti-inflammatoires
WO2020186010A1 (fr) 2019-03-12 2020-09-17 Epm Group, Inc. Compositions d'ester d'acide cannabinoïde et leurs utilisations

Citations (2)

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US5962477A (en) * 1994-04-12 1999-10-05 Adolor Corporation Screening methods for cytokine inhibitors
US20130035333A1 (en) * 2010-02-23 2013-02-07 The Regents Of The University Of California Use of cinnabarinic acid as a modulator of immune responses in autoimmune disorders

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US5962477A (en) * 1994-04-12 1999-10-05 Adolor Corporation Screening methods for cytokine inhibitors
US20130035333A1 (en) * 2010-02-23 2013-02-07 The Regents Of The University Of California Use of cinnabarinic acid as a modulator of immune responses in autoimmune disorders

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Title
BONIFACE ET AL.: "A role for T cell -derived interleukin 22 in psoriatic skin inflammation", CLINICAL AND EXPERIMENTAL IMMUNOLOGY, vol. 150, no. 3, December 2007 (2007-12-01), pages 407 - 415 *
HARPER ET AL.: "Th17 Cytokines Stimulate CCL20 Expression in Keratinocytes In Vitro and In Vivo: Implications for Psoriasis Pathogenesis", JOURNAL OF INVESTIGATIVE DERMATOLOGY, vol. 129, no. 9, 19 March 2009 (2009-03-19), pages 2175 - 2183 *
PRUNIERAS ET AL.: "Methods for Cultivation of Keratinocytes with an Air-Liquid Interface", THE JOURNAL OF INVESTIGATIVE DERMATOLOGY, vol. 81, no. 1, July 1983 (1983-07-01), pages 28S - 33S *
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3071508A1 (fr) * 2017-09-26 2019-03-29 Genoskin Modele ex vivo de peau humaine inflammee et ses utilisations pour le criblage de composes anti-inflammatoires
WO2019063122A1 (fr) 2017-09-26 2019-04-04 Genoskin Modele ex vivo de peau humaine inflammee et ses utilisations pour le criblage de composes anti-inflammatoires
JP2020535402A (ja) * 2017-09-26 2020-12-03 ゲノスキン 炎症ヒト皮膚のｅｘ ｖｉｖｏモデルおよび抗炎症化合物のスクリーニングのためのその使用
JP7199427B2 (ja) 2017-09-26 2023-01-05 ゲノスキン 炎症ヒト皮膚のｅｘ ｖｉｖｏモデルおよび抗炎症化合物のスクリーニングのためのその使用
WO2020186010A1 (fr) 2019-03-12 2020-09-17 Epm Group, Inc. Compositions d'ester d'acide cannabinoïde et leurs utilisations

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