WO2022016509A1 - Procédé de criblage de médicament et utilisation de médicament dans le traitement du psoriasis - Google Patents

Procédé de criblage de médicament et utilisation de médicament dans le traitement du psoriasis Download PDF

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WO2022016509A1
WO2022016509A1 PCT/CN2020/104453 CN2020104453W WO2022016509A1 WO 2022016509 A1 WO2022016509 A1 WO 2022016509A1 CN 2020104453 W CN2020104453 W CN 2020104453W WO 2022016509 A1 WO2022016509 A1 WO 2022016509A1
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drug
interferon
interleukin
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阎忠扬
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P21/00—Preparation of peptides or proteins
    • C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present disclosure generally relates to the technical field of psoriasis (psoriasis, psoriasis) treatment. Specifically, the present disclosure relates to a drug screening method for screening a drug for treating psoriasis from a plurality of candidate drugs, and a method for treating psoriasis using the therapeutic drug.
  • Psoriasis is a chronic inflammatory skin disease mediated by immunity. It is generally believed that psoriasis is related to immune dysfunction and genetics. However, other factors such as seasonal changes, stress, viruses, bacteria, metabolic disorders, drug-induced , trauma and diet, etc., are also considered to have the possibility of inducing psoriasis.
  • the typical symptoms of psoriasis are the appearance of lumpy skin abnormalities on the surface of the patient's skin, with redness, itching and scaling in the affected area.
  • the prevalence of psoriasis is known to be about 2-4%, women and men are equally affected, and the prevalence is higher in adults (about 0.91%) than children (about 0-2.1%). -8.5%).
  • psoriasis Current treatments for psoriasis include topical therapy, phototherapy, photochemotherapy, or systemic therapy.
  • drugs such as steroids (Steroid), calcipotriol (Calcipotriol), anthralin (Anthralin), or tar (Coal tar) are used locally on the affected area.
  • Phototherapy uses ultraviolet rays to irradiate the skin of patients. It is currently the first-line treatment for psoriasis. However, patients often need to go to a treatment center with phototherapy equipment for treatment, which is troublesome, and ultraviolet rays also have the potential to cause cancer.
  • photochemotherapy refers to the combined therapy of oral psoralen and ultraviolet irradiation with a wavelength of 320-400 nm.
  • biological agents that can treat psoriasis eg, therapeutic antibodies
  • Cyclosporine Cyclosporine
  • Methotrexate Methrexate
  • Tretinoin retinoic acid
  • the purpose of the present disclosure is to provide a drug screening method, so as to select a therapeutic drug suitable for an individual psoriasis patient from a plurality of candidate drugs, so as to treat the psoriasis condition of the patient.
  • one aspect of this disclosure is directed to a method of screening a therapeutic drug from a plurality(s) of drug candidates, wherein the therapeutic drug is used to An individual suffering from psoriasis is treated. The method includes:
  • PBMC peripheral blood mononuclear cell
  • step (b) activating the peripheral blood mononuclear cells of step (a) with a stimulus, so that the cells produce interferon- ⁇ (interferon-gamma, IFN- ⁇ ) and interleukin-13 (interleukin-13, IL-13);
  • step (c) administering the plurality of drug candidates respectively to the activated peripheral blood mononuclear cells of step (b);
  • step (d) respectively detecting the expression levels of the interferon- ⁇ and the interleukin-13 in the peripheral blood mononuclear cells of step (c);
  • step (e) based on the expression levels of the interferon- ⁇ and the interleukin-13 detected in step (d), screen out the therapeutic drug from the plurality of candidate drugs, wherein the therapeutic drug has an effect on the interferon- ⁇
  • the expression level has the highest inhibitory ability, or the ratio of the interferon- ⁇ expression level to the interleukin-13 expression level is the smallest.
  • the therapeutic drug reduces the expression of the interferon- ⁇ by at least 1% after administration of the candidate drug compared to before administration of the candidate drug. According to another embodiment of the present disclosure, the therapeutic drug reduces the expression of interferon- ⁇ and interleukin-13 by at least 1% after administration of the candidate drug compared to before administration of the candidate drug ratio.
  • the stimulator is a Gram-positive bacteria (Gram-positive bacteria), a Gram-negative bacteria (Gram-negative bacteria), or lipopolysaccharide (LPS).
  • Gram-positive bacteria Gram-positive bacteria
  • Gram-negative bacteria Gram-negative bacteria
  • lipopolysaccharide LPS
  • the gram-positive bacterium Streptococcus pyogenes.
  • the Gram-negative bacteria is Escherichia coli.
  • each of the plurality of drug candidates is selected from the group consisting of: Acitretin, alefacept, Anthralin (Allium phenol), Acitretin Apremilast, Betamethasone, Calcipotriene, Calcipotriol, Calcitriol, Clobetasol, Coal tar , Cyclosporine, Dithranol, Etanercept, Fluocinolone, Hydrocortisone, Infliximab, Methotrexate , Pimecrolimus, Tacrolimus, Tazarotene, Tretinoin, ALX-0761, BCD-085, Bimekizumab, Boda Brodalumab, CJM112, CNTO 6785, COVA322, Ixekizumab, LY3114062, MSB0010841, NI-1401, Perakizumab, Remtolumab, RG7624 , Secukinumab, Vunakizum
  • the plurality of drug candidates are composed of: adalimumab, golimumab, guselkumab, ixelizumab, secukinumab, and ustekinumab. composition.
  • Another aspect of the present disclosure pertains to a method for treating an individual suffering from psoriasis.
  • the method includes:
  • step (1b) activating the peripheral blood mononuclear cells of step (1a) with a stimulus, so that the cells produce interferon- ⁇ and interleukin-13;
  • the therapeutic drug is screened from the plurality of candidate drugs, wherein the therapeutic drug has an effect on the interferon- ⁇ .
  • the expression level has the highest inhibitory ability, or the ratio of the interferon- ⁇ expression level to the interleukin-13 expression level is the smallest;
  • the therapeutic drug reduces the expression of the interferon- ⁇ by at least 1% after administration of the candidate drug compared to before administration of the candidate drug. According to another embodiment of the present disclosure, the therapeutic drug reduces the expression of interferon- ⁇ and interleukin-13 by at least 1% after administration of the candidate drug compared to before administration of the candidate drug ratio.
  • the irritant is a gram-positive bacteria, a gram-negative bacteria, or a lipopolysaccharide.
  • the Gram-positive bacteria are Streptococcus pyogenes.
  • the Gram-negative bacteria is Escherichia coli.
  • each of the plurality of drug candidates is selected from: acitretin, afacept, anthralin, apremilast, betamethasone, calcipotriene , Calcipotriol, Calcitriol, Beclotasol, Tar, Cyclosporine, Dithranol, Etanercept, Fluocinolone, Hydrocortisone, Infliximab, Methotrexate, Pimecrolimus Division, Tacrolimus, Tazarotene, Retinoic Acid, ALX-0761, BCD-085, Pestrolizumab, Bodalumab, CJM112, CNTO 6785, COVA322, Ixelizumab, LY3114062, MSB0010841, NI-1401, perelizumab, rendolizumab, RG7624, secukinumab, vonazumab, blaculumab, guselkumab
  • the plurality of drug candidates are composed of: adalimumab, golimumab, guselkumab, ixelizumab, secukinumab, and ustekinumab composed.
  • an individual suitable for use in the methods of the present disclosure to treat psoriasis is a human.
  • FIG. 1 is a photographic diagram obtained according to an embodiment of the present disclosure, illustrating the screening of a therapeutic drug adalimumab using the method of the present disclosure.
  • the changes in the appearance of the lesions of the patients before and after treatment in which the panels A, C, and E are before adalimumab treatment, while the panels B, D, and F are after adalimumab treatment;
  • At least one of A, B and C means only A, only B, only C, both A and B, both B and C, and both C, and A, B, and C.
  • treatment may refer to a curative or palliative measure.
  • treatment refers to the administration or administration of an effective amount of a therapeutic agent of the present disclosure to a subject, the therapeutic agent being screened using the screening methods of the present disclosure, and
  • the individual is suffering from psoriasis, suffering from symptoms associated with psoriasis, a disease or disorder of psoriasis whereby partial or complete alleviate, ameliorate, relieve, Delay onset, inhibit progression, reduce severity, and/or reduce the incidence of one or more symptoms or features of psoriasis.
  • activate refers to the use of a specific substance (eg, streptococcus) to stimulate a living body or living cell (eg, peripheral blood mononuclear cells), so that the living body or Live cells induce a corresponding immune response (for example, secrete related inflammatory cytokines, such as: interferon-gamma, interleukin-13, interleukin-6, interleukin-8, interleukin-12, or interleukin-17, etc.).
  • a specific substance eg, streptococcus
  • a living body or living cell eg, peripheral blood mononuclear cells
  • a corresponding immune response for example, secrete related inflammatory cytokines, such as: interferon-gamma, interleukin-13, interleukin-6, interleukin-8, interleukin-12, or interleukin-17, etc.
  • administered As used herein, the terms “administered,” “administering,” or “administration” are used interchangeably herein and refer to the direct contact of a target (eg, peripheral blood mononuclear cells) with a specific substance (eg, the present disclosure). The act of administering a specific substance (eg, a therapeutic drug of the present disclosure) to an individual (eg, a human). For example, a drug candidate of the present disclosure is directly added to a culture dish containing peripheral blood mononuclear cells for co-cultivation for a period of time.
  • a target eg, peripheral blood mononuclear cells
  • a specific substance eg, the present disclosure
  • an individual eg, a human
  • a drug candidate of the present disclosure is directly added to a culture dish containing peripheral blood mononuclear cells for co-cultivation for a period of time.
  • a therapeutic agent of the present disclosure when administered to an individual, it is meant via oral, intracranial, intraspinal, intrathecal, intramedullary, intracerebral, intracerebroventricular, intravenous, intraarterial, intracardiac, intradermal, subcutaneous , transdermal, intraperitoneal, or intramuscular routes to administer the therapeutic agents of the present disclosure to the individual in need thereof.
  • an effective amount refers to an amount effective, in the dosage and for the time period necessary, to achieve the desired therapeutic effect of the treatment of the therapeutic agents of the present disclosure (eg, for the treatment of psoriasis). ) dosage.
  • an effective amount also means that the therapeutic benefits of a component of a drug outweigh the toxic or detrimental effects of that component.
  • An effective amount of an agent does not necessarily cure the disease or disorder, but delays, retards or prevents the onset of the disease or disorder, or alleviates the symptoms associated with the disease or disorder.
  • An effective amount can be divided into one, two or more doses and administered one, two or more times over a specified period in the appropriate dosage form.
  • the specific effective amount depends on a variety of factors, for example, the condition to be treated, the physiological condition of the individual (eg, the individual's weight, age, or sex), the species being treated, the duration of treatment, concurrent therapy (if any) words), and the specific dosage form used, and the structure of the compound or its derivatives.
  • An effective amount may be expressed in any suitable manner.
  • an effective amount of an agent can be expressed as the total weight of the drug (eg, grams, milligrams, or micrograms), or as a ratio of the weight of the drug to body weight (eg, milligrams per kilogram of body weight (mg/kg, mg/kg) Kg)).
  • an effective amount of an agent can be expressed in terms of concentration, e.g., molar concentration, mass concentration, volume concentration, molality, molar fraction ( mole fraction), mass fraction and mixing ratio.
  • concentration e.g., molar concentration, mass concentration, volume concentration, molality, molar fraction ( mole fraction), mass fraction and mixing ratio.
  • Appropriate doses range from 0.01 mg to 100.0 mg per kilogram of body weight.
  • a wide range of adjustments in the desired dosage are also contemplated, depending upon the different compositions and the different efficacies resulting from the different routes of administration. For example, oral administration is expected to require higher doses than intravenous injection.
  • the dosage can be adjusted according to rules of thumb.
  • HEDs human equivalent doses
  • drugs eg, therapeutic drugs of the present disclosure
  • FDA US Food and Drug Administration
  • the terms “subject” or “patient” are used interchangeably to refer to an animal, including humans, that can be treated with a therapeutic agent of the present disclosure, wherein the therapeutic agent refers to Those screened by the screening method of the present disclosure. Unless one of the genders is specified, the terms “individual” and “patient” refer to both males and females. Accordingly, the terms “individual” and “patient” include any mammal that would benefit from treatment with the therapeutic agents of the present disclosure.
  • Examples of “individuals” and “patients” that can be treated with therapeutic agents of the present disclosure include, but are not limited to, humans, rats, mice, guinea pigs, monkeys, pigs, goats, cows, horses, dogs, cats, Birds and Chickens.
  • the individual is a mouse.
  • the individual is a human.
  • pharmaceutically acceptable refers to molecular entities and compositions that are "generally regarded as safe", eg, that are physiologically tolerable and that are Usually, there is no allergic reaction or similar adverse reaction, such as nausea, dizziness, etc.
  • pharmaceutically acceptable as used herein means approved by a regulatory agency of the federal or state government or listed in the US Pharmacopeia or other generally recognized pharmacopeia for use in animals, particularly is for humans.
  • the purpose of the present disclosure is to provide a method for screening a drug suitable for the treatment of psoriasis from a plurality of candidate drugs, and the method can screen a psoriasis drug suitable for the patient according to the different constitutions of individual psoriasis patients, so as to Improve the efficacy and safety of psoriasis treatment, and reduce the waste of medical resources.
  • one aspect of the present disclosure relates to a method for screening a drug, wherein a therapeutic drug is selected from a plurality of candidate drugs, wherein the therapeutic drug is used to treat psoriasis in an individual, comprising:
  • PBMC peripheral blood mononuclear cell
  • step (b) activating the peripheral blood mononuclear cells of step (a) with a stimulus to make the cells produce interferon- ⁇ (IFN- ⁇ ) and interleukin-13 (IL-13);
  • step (c) administering the plurality of drug candidates respectively to the activated peripheral blood mononuclear cells of step (b);
  • step (d) respectively detecting the expression levels of the interferon- ⁇ and the interleukin-13 in the peripheral blood mononuclear cells of step (c);
  • step (e) based on the expression levels of the interferon- ⁇ and the interleukin-13 detected in step (d), screen out the therapeutic drug from the plurality of candidate drugs, wherein the therapeutic drug has an expression of the interferon- ⁇
  • the expression level has the highest inhibitory ability, or the ratio of the interferon- ⁇ expression to the interleukin-13 expression has the highest inhibitory ability.
  • step (a) a whole blood sample is collected from a patient suffering from psoriasis, and peripheral blood mononuclear cells are isolated from the whole blood sample.
  • the obtained peripheral blood mononuclear cells are treated with a stimulus for a period of time (eg, 16 to 72 hours, such as: 16, 18, 24, 36, 48, 60 or 72 hours; preferably, 24 hours hours), so that the peripheral blood mononuclear cells are activated by the stimulation of the streptococcus and secrete interferon-gamma, interleukin-13, and other inflammatory cytokines (for example, interleukin-6, interleukin-8, interleukin-12, or interleukin-17, etc.) (step (b)).
  • a stimulus for a period of time eg, 16 to 72 hours, such as: 16, 18, 24, 36, 48, 60 or 72 hours; preferably, 24 hours hours
  • the irritant is a gram-positive bacteria, a gram-negative bacteria, or a lipopolysaccharide.
  • Exemplary Gram-positive bacteria include, but are not limited to, Bacillus (eg, Bacillus cereus, Bacillus thuringiensis, Bacillus anthracis); Listeria (Listeria) (eg, Listeria monocytogenes); Staphylococcus (eg, Staphylococcus aureus, Staphylococcus albus, Staphylococcus citrate ( Staphylococcus citreus); Streptococcus (described below), Enterococcus (described below); and Clostridium (eg, Clostridium botulinum, Clostridium butyricum) (Clostridium butyricum), Clostridium difficile, Clostridium perfringens, Clostridium tetani).
  • the Gram-positive bacteria are Streptococcus.
  • the Streptococcus is Group A Streptococcus, eg, Streptococcus pyogenes.
  • the Streptococcus is Group B Streptococcus, eg, Streptococcus agalactiae.
  • the Streptococcus is Group C Streptococcus, eg, Streptococcus equi, Streptococcus zooepidemicus, and Streptococcus nuisides.
  • the Streptococcus is Group D Streptococcus (now reclassified as Enterococcus), eg, Enterococcus faecalis, Enterococcus faecium, Enterococcus durans, and Enterococcus avium.
  • the streptococcus is Group F Streptococcus, eg, Streptococcus anginosus (or Streptococcus milleri), Streptococcus intermedius, and Streptococcus constellation.
  • the Streptococcus is Group G Streptococcus, eg, Streptococcus nasus, Streptococcus canis, and Streptococcus zeta.
  • the Streptococcus is Group H Streptococcus, e.g., Streptococcus sanguis.
  • Other unclassified streptococci may also be suitable for use in the methods of the present disclosure, as long as the streptococcus can achieve the purpose of activating peripheral blood mononuclear cells to secrete inflammatory cytokines.
  • streptococci suitable for use in the methods of the present disclosure include, but are not limited to, S. Streptococcus gordonii, Streptococcus intermedius, Streptococcus lentus, Streptococcus mutans, Streptococcus seals, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus sialae, Streptococcus sanguis, Streptococcus suis, or Streptococcus zooepidemicus.
  • the Streptococcus is type A Streptococcus, eg, Streptococcus pyogenes.
  • the stimulator is a Gram-negative bacteria, including, but not limited to, Acinetobacter (eg, Acinetobacter baumannii), calcium acetate Acinetobacter calocoaceticus, Acinetobacter lwoffi); Bdellovibrio (eg, Bdellovibrio bacteriovorus); Enterobacter (eg, carcinogenic intestinal tract) Enterobacter cancerogenous, Enterobacter cloacae, Enterobacter cowanii, Enterobacter gergoviae, Enterobacter taylorae); Escherichia (eg, large intestine Escherichia coli); Haemophilus (eg, Haemophilus ducreyi, Haemophilus influenzae); Helicobacter (eg, Helicobacter pylori); Klebsiella (eg, Klebsiella oxytoca, Klebsiella pneumoniae); Legionella (eg, Veterans Legionella pneumophila); Moraxella (
  • step (b) after the peripheral blood mononuclear cells are co-cultured with Streptococcus for a period of time (eg, 24 hours), the culture supernatant of the cells is collected to analyze that the cells are activated to secrete inflammatory cells hormone situation.
  • the expression of inflammatory cytokines can be detected by various analytical methods well known to those skilled in the art, for example, enzyme linked immunosorbent assay (ELISA) (eg, multiplex assay ( multiplex assay), radioimmunoassay (RIA), immunofluorescence (IFA), Western blot (WB), immunoblotting (IB), immunoprecipitation (immunoprecipitation) , IP), or flow cytometry and other analytical methods.
  • ELISA enzyme linked immunosorbent assay
  • ELISA enzyme linked immunosorbent assay
  • ELISA enzyme linked immunosorbent assay
  • RIA radioimmunoassay
  • IFA immunofluorescence
  • WB Western blot
  • IB immuno
  • peripheral blood mononuclear cells activated by Streptococcus to express the expression of inflammatory cytokines can be detected.
  • the activated peripheral blood mononuclear cells can be collected, and the expression level of inflammatory cytokines can be detected by analyzing the gene expression level.
  • the analysis methods for analyzing gene expression levels are well known to those skilled in the art, including, but not limited to, genome-wide expression profiling using expressed sequence tag (EST) analysis using expression sequence tag (EST) analysis.
  • RNA sequencing for example, reverse transcription-PCR (RT-PCR), real-time RT-PCR or qRT-PCR), digital polymerase chain reaction (digital-PCR or dPCR), touchdown PCR (touchdown PCR), nested PCR (nested PCR), multiplex PCR (multiplex PCR), recovery condition PCR (reconditioning PCR), etc.); two-dimensional PCR Gel electrophoresis (two-dimensional gel electrophoresis, 2-D electrophoresis); tissue array (tissue array); immunohistochemistry (immunochemistry, IHC) staining, etc.
  • RT-PCR reverse transcription-PCR
  • qRT-PCR real-time RT-PCR or qRT- PCR
  • digital polymerase chain reaction digital polymerase chain reaction
  • touchdown PCR touchdown PCR
  • nested PCR nested PCR
  • multiplex PCR multiplex PCR
  • recovery condition PCR recovery condition PCR
  • the plurality of drug candidates is tested using the activated peripheral blood mononuclear cells (step (c)).
  • the specific step is to administer the drug candidates to be tested to the activated peripheral blood mononuclear cells, respectively, so that the activated peripheral blood mononuclear cells and the drug candidates to be tested are co-cultured for a period of time (for example, 16 to 72 hours, such as: 16, 18, 24, 36, 48, 60 or 72 hours; preferably, treatment for 24 hours) (step (c)).
  • a period of time for example, 16 to 72 hours, such as: 16, 18, 24, 36, 48, 60 or 72 hours; preferably, treatment for 24 hours
  • For the specific concentration of the candidate drug administered to the cells reference may be made to the serum trough concentration under steady state recommended in the relevant pharmacokinetics section in the copy list of each candidate drug.
  • adalimumab Use 4 ⁇ g/ml; golimumab Use 0.5 ⁇ g/ml; guselkumab Use 1.2 ⁇ g/mL; icelizumab Use 3.5 ⁇ g/ml; secukinumab Use 34 ⁇ g/ml; ustekinumab Use 0.25 ⁇ g/ml.
  • the plurality of candidate drugs may be current drugs for treating psoriasis, or potential drugs under development for treating psoriasis.
  • the plurality of drug candidates comprises acitretin, afacept, anthralin, apremilast, betamethasone, calcipotriene, calcipotriol, ossification Triol, beclothazol, tar, cyclosporine, dithranol, etanercept, fluocinolone, hydrocortisone, infliximab, methotrexate, pimecrolimus, tacrolimus, Zarotene, Retinoic Acid, ALX-0761, BCD-085, Pestrolizumab, Bodalumab, CJM112, CNTO 6785, COVA322, Ixelizumab, LY3114062, MSB0010841, NI-1401, Pella Zizumab, rendolizumab
  • step (d) after the treatment of the specific drug candidate, the culture supernatant of the cells or the cells are collected respectively, and the expression of inflammatory cytokines caused by the influence of the drug on the cells is analyzed by the above analysis method Changes, especially changes in the expression levels of interferon- ⁇ , interleukin-13, and other inflammatory cytokines (eg, interleukin-6, interleukin-8, interleukin-12, or interleukin-17, etc.).
  • interferon- ⁇ interleukin-13
  • other inflammatory cytokines eg, interleukin-6, interleukin-8, interleukin-12, or interleukin-17, etc.
  • step (e) a therapeutic drug is screened from the plurality of candidate drugs by using the changes in the expression levels of interferon- ⁇ and interleukin-13 detected in step (d).
  • the change in the expression levels of interferon- ⁇ and interleukin-13 refers to the expression levels of interferon- ⁇ and interleukin-13 in step (b) (that is, before the specific drug candidate is administered), and step (d). ) in the expression levels of interferon- ⁇ and interleukin-13 (ie, after administration of a specific drug candidate).
  • formula (I) is the formula for calculating the rate of change of the expression of interferon- ⁇
  • formula (II) is the rate of change in the ratio of the expression of interferon- ⁇ to the expression of interleukin-13. formula.
  • the therapeutic drug is selected from the plurality of candidate drugs with the highest inhibitory ability on the expression of interferon- ⁇ (according to formula (I) ) Calculation result), or select the drug with the highest inhibitory ability (or make the ratio reach the minimum) (according to the calculation result of formula (II)) Drug.
  • adalimumab and ustekinumab are treated with peripheral blood mononuclear cells of a specific psoriasis patient, wherein the administration of adalimumab can reduce the expression of interferon- ⁇ in cells by approximately 9.4%, and administration of ustekinumab can reduce the expression of interferon- ⁇ in cells by about 12.8%; in this example, ustekinumab was selected to treat the psoriasis patient.
  • the peripheral blood mononuclear cells of a specific psoriasis patient are treated with exelizumab and ustekinumab, wherein the administration of exelizumab can increase the expression level of interferon- ⁇ in the cells
  • the ratio of interleukin-13 expression to interleukin-13 expression increased by about 4.2%, while the administration of ustekinumab reduced the ratio of interferon- ⁇ expression to interleukin-13 expression in cells by about 5.9%; in this example , is to choose ustekinumab to treat this psoriasis patient.
  • a drug candidate can reduce the expression of interferon-gamma by at least 1% (eg, reduce 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%) , 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3 %, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3%, 6.4%, 6.5%, 6.6% , 6.7%, 6.8%, 6.9%, 7.0%, 7.1%, 7.
  • the drug candidate can be screened as a therapeutic drug. More preferably, if a drug candidate can reduce the expression of interferon- ⁇ by about 1 to 10%, the drug candidate can be screened as a therapeutic drug. In a specific embodiment, the drug candidate can reduce the expression of interferon- ⁇ by about 4.1%, 4.6%, 8.0%, 9.4%, 12.8%, 13.5%, 13.9%, and 16.9%, respectively.
  • a drug candidate can reduce the ratio of interferon-gamma expression to interleukin-13 expression by at least 1% (eg, a reduction of 1.0%, 1.1%, 1.2%, 1.3%) %, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6% , 4.7%, 4.8%, 4.9%, 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 5.6%, 5.7%, 5.8%, 5.9%, 6.0%, 6.1%, 6.2%, 6.3 %, 6.4%, 6.5%, 6.6%
  • a candidate drug can reduce the ratio of interferon- ⁇ expression to interleukin-13 expression by about 1 to 30%, the candidate drug can be screened as a therapeutic drug. More preferably, if a candidate drug can reduce the ratio of interferon- ⁇ expression to interleukin-13 expression by about 1 to 10%, the candidate drug can be screened as a therapeutic drug. In a specific embodiment, the drug candidate can reduce the ratio of interferon- ⁇ expression to interleukin-13 expression by about 1.1%, 4.3%, 4.6%, 5.9%, 9.2%, and 27.1%, respectively.
  • Another aspect of the present disclosure pertains to a method for treating psoriasis in an individual comprising:
  • step (1b) activating the peripheral blood mononuclear cells of step (1a) with a stimulus, so that the cells produce interferon- ⁇ and interleukin-13;
  • the therapeutic drug is screened from the plurality of candidate drugs, wherein the therapeutic drug has an effect on the interferon- ⁇ .
  • the expression level has the highest inhibitory ability, or the ratio of the interferon- ⁇ expression level to the interleukin-13 expression level has the highest inhibitory ability;
  • the steps of screening the therapeutic drugs are the same as the screening methods of the present disclosure.
  • the steps of screening the therapeutic drugs are the same as the screening methods of the present disclosure.
  • steps (1a) to (1e) are the same as the screening methods of the present disclosure.
  • Step (2) is to administer the therapeutic drug screened out in step (1) to the individual, which can be administered to the individual through oral, intravenous, intradermal, subcutaneous, transdermal, topical smearing, or intramuscular routes.
  • the present disclosure provides pharmaceutical compositions. According to certain embodiments of the present disclosure, an effective amount of a therapeutic drug is administered to the individual via intravenous injection to achieve the therapeutic purpose.
  • the subject is a mammal including humans, rats, mice, guinea pigs, monkeys, pigs, goats, cows, horses, dogs, cats, birds and chickens.
  • the individual is a human.
  • PASI Psoriasis Area Severity Index
  • the evaluation method of the PASI covers the evaluation of the psoriasis area (Area) and the psoriasis severity (Severity), as shown in Table 1 and Table 2, and after evaluating the psoriasis area and the psoriasis severity, the obtained numerical value is calculated by the following formula.
  • PASI 0.1 ⁇ (E h + I h + D h) ⁇ A h + 0.3 ⁇ (E t + I t + D t) ⁇ A t + 0.2 ⁇ (E u + I u + D u) ⁇ A u +0.4 ⁇ (E l +I l +D l ) ⁇ A l ; Parts: head (h), trunk (t), upper limbs (u), lower limbs (l).
  • the PASI after treatment can be improved by at least 3 points or more compared to the PASI before treatment, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 points.
  • peripheral blood 16 ml of peripheral blood (whole blood) from patients with psoriasis was collected into a cell preparation tube (CPT). Next, the blood was centrifuged at 1700 ⁇ g for 15 minutes, and peripheral blood mononuclear cells were then aspirated with a 3 ml pipette. Afterwards, cells were washed with phosphate buffered saline (PBS) and cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% antibiotics. Cells were cultured at 37°C in an incubator containing 5% carbon dioxide.
  • PBS phosphate buffered saline
  • FBS fetal bovine serum
  • peripheral blood mononuclear cells the concentration of peripheral blood mononuclear cells and the bacterial solution of Streptococcus pyogenes (Streptococcus pyogenes) McFarland 2 (McFarland 2) solution and different biological agents
  • McFarland 2 McFarland 2
  • cell supernatants were collected for analysis of inflammatory hormones (including interferon-gamma, interleukin-13, and other inflammatory cytokines (eg, interleukin-6, interleukin-8, interleukin-12, or interleukin-12). -17 etc.)) concentration.
  • inflammatory hormones including interferon-gamma, interleukin-13, and other inflammatory cytokines (eg, interleukin-6, interleukin-8, interleukin-12, or interleukin-12).
  • concentrations of the candidate biologics tested in this study were referenced to the trough serum concentrations at steady state disclosed in the pharmacokinetics section of each biologics copy.
  • the specific concentrations used are as follows: Adalimumab Use 4 ⁇ g/ml; golimumab Use 0.5 ⁇ g/ml; guselkumab Use 1.2 ⁇ g/mL; icelizumab Use 3.5 ⁇ g/ml; secukinumab Use 34 ⁇ g/ml; ustekinumab Use 0.25 ⁇ g/ml.
  • this study developed the use of the expression changes of inflammatory cytokines or the ratio of inflammatory cytokines produced by peripheral blood monocytes before and after administration as a medication index to evaluate whether the patient is suitable for a specific therapy.
  • the relationship between changes in PASI and changes in the expression of inflammatory cytokines (ie, ratios or differences) in different patients before and after receiving a specific biological agent was analyzed.
  • the change of PASI before and after treatment refers to the change of PASI value of individual patients before and after receiving individual biological agents
  • the change of interferon- ⁇ before and after administration refers to the measurement of peripheral blood of the patient.
  • Monocytes were tested in vitro for changes in interferon-gamma before and after drug administration for individual biologics using the methods of drug screening described in this disclosure.
  • the calculation method of the difference value is: after treatment-before treatment; and the calculation method of the change ratio is: [(after treatment-before treatment)/before treatment] ⁇ 100%.
  • the calculation method of the difference is: after administration-before administration; and the calculation method of the change ratio is: [(after administration-before administration)/before administration] ⁇ 100 %.
  • the present example further analyzes the relationship between PASI and interferon- ⁇ changes before and after treatment by statistical analysis, and is summarized in Table 4. Based on the results in Table 4 above, it can be seen that the reduction ratio of PASI before and after treatment with different biological agents is significantly related to the reduction ratio or the difference of the patient's interferon- ⁇ , and the difference of PASI reduction is related to the patient's interferon-gamma. Both the rate of decline or the difference in decline in ⁇ were significantly correlated. Accordingly, the changes in the expression of interferon- ⁇ before and after treatment (whether it is the decreasing ratio or the decreasing difference) can be used as a medication index for psoriasis patients.
  • the change in PASI before and after treatment refers to the change in PASI values recorded by individual patients before and after receiving individual biological agents; Nuclear cells were tested in vitro for changes in interleukin-6 before and after drug administration for individual biologics using the methods of drug screening described in this disclosure.
  • the calculation method of the difference value is: after treatment-before treatment; and the calculation method of the change ratio is: [(after treatment-before treatment)/before treatment] ⁇ 100%.
  • the calculation method of the difference is: after administration-before administration; and the calculation method of the change ratio is: [(after administration-before administration)/before administration] ⁇ 100% .
  • the change in PASI before and after treatment refers to the change in PASI values recorded by individual patients before and after receiving individual biological agents; Nuclear cells were tested in vitro for changes in interleukin-8 before and after drug administration for individual biologics using the methods of drug screening described in this disclosure.
  • the calculation method of the difference value is: after treatment-before treatment; and the calculation method of the change ratio is: [(after treatment-before treatment)/before treatment] ⁇ 100%.
  • the calculation method of the difference is: after administration-before administration; and the calculation method of the change ratio is: [(after administration-before administration)/before administration] ⁇ 100% .
  • the change in PASI before and after treatment refers to the change in PASI values recorded by individual patients before and after receiving individual biological agents; Nuclear cells were tested in vitro for changes in interleukin-12 before and after drug administration for individual biologics using the methods of drug screening described in this disclosure.
  • the calculation method of the difference value is: after treatment-before treatment; and the calculation method of the change ratio is: [(after treatment-before treatment)/before treatment] ⁇ 100%.
  • the calculation method of the difference is: after administration-before administration; and the calculation method of the change ratio is: [(after administration-before administration)/before administration] ⁇ 100% .
  • Table 11 to Table 12 show the relationship between changes in PASI before and after treatment and changes in interleukin-17 before and after administration and related statistical analysis.
  • the change in PASI before and after treatment refers to the change in PASI values recorded by individual patients before and after receiving individual biological agents; Nuclear cells were tested in vitro for changes in interleukin-17 before and after drug administration for individual biologics using the methods of drug screening described in this disclosure.
  • the calculation method of the difference value is: after treatment-before treatment; and the calculation method of the change ratio is: [(after treatment-before treatment)/before treatment] ⁇ 100%.
  • the calculation method of the difference is: after administration-before administration; and the calculation method of the change ratio is: [(after administration-before administration)/before administration] ⁇ 100% .
  • this example proves that before and after the treatment of different biological preparations, interferon- ⁇ will produce a change in the expression of decreased (whether it is a decrease rate or a decrease in the difference), so the decreased expression of interferon- ⁇ can be used as a psoriasis disease. patient medication indicators.
  • Example 2 The relationship between the change in PASI before and after treatment and the change in the ratio of interferon- ⁇ /interleukin-13
  • the relationship between the PASI change and the expression change (ie, change ratio or difference) of the ratio of inflammatory cytokines in different patients before and after treatment with a specific biological agent was analyzed.
  • the relationship between the change in PASI before and after treatment and the change in the ratio of interferon- ⁇ /interleukin-13 before and after administration and related statistical analysis are shown in Table 13 to Table 14.
  • the change in PASI before and after treatment refers to the change in the PASI value of individual patients before and after receiving individual biological agents; and the change in the ratio of interferon- ⁇ /interleukin-13 before and after administration refers to, Peripheral blood mononuclear cells from the patient were taken, and the changes in the ratio of interferon- ⁇ /interleukin-13 before and after drug administration obtained from individual biologics were tested in vitro by the method for screening drugs described in the present disclosure. quantity.
  • the calculation method of the difference is: after treatment-before treatment; and the calculation method of the change ratio is: [(after treatment-before treatment)/before treatment] ⁇ 100%.
  • the calculation method of the difference is: obtained after administration (interferon- ⁇ /interleukin-13 ratio) - obtained before administration (interferon-13 ratio)
  • the ratio of IL- ⁇ /IL-13); and the calculation method of the change ratio is as shown in the above formula (II).
  • this example further analyzes the relationship between PASI and the ratio of interferon- ⁇ /interleukin-13 before and after treatment, and is summarized in Table 14. Based on the results in Table 14 above, it can be seen that the reduction ratio of PASI before and after treatment with different biological agents is significantly related to the reduction ratio or the difference of the ratio of interferon- ⁇ /interleukin-13 in the patient, but the difference of PASI reduction is related to the There was no significant correlation between the ratio of declines or the difference in declines in the interferon-gamma/interleukin-13 ratio of patients. Accordingly, the expression change of the ratio of interferon- ⁇ /interleukin-13 before and after treatment (whether it is the decreasing ratio or the decreasing difference) can be used as a medication index for psoriasis patients.
  • Example 1 Based on the results of Example 1 and Example 2, it was confirmed that the decrease in the expression of interferon- ⁇ and the ratio of interferon- ⁇ /interleukin-13 before and after treatment can be used as an indicator of medication for psoriasis patients. Therefore, this example Therefore, the feasibility of the in vitro drug screening method was evaluated, that is, the cell screening platform of the present invention was used in vitro to screen out the drug suitable for the patient from which the cell was derived, and then the screened drug was administered to the patient.
  • the treatment results of a psoriasis patient ie, patient C in Examples 1 and 2 admitted to an outpatient clinic of the present embodiment, the patient was initially treated with After six months of treatment, no significant improvement was found, the psoriasis lesions were red, visually thick, and there was a lot of scaling up close (Panel A (back) and Panel C (back of the thigh) in Figure 1). side), E panel (back of the calf (partial))).
  • the peripheral blood mononuclear cells of the patient are used to carry out the drug screening method of the present invention, and the drug that can produce the best curative effect on the patient is screened out for treatment.
  • the drug screening method of the present invention firstly evaluates the changes in the expression levels of inflammatory cytokines secreted by cells in vitro (for example, the ratio of interferon- ⁇ expression reduction, or interferon- ⁇ expression level/interleukin-13 expression level)
  • the ratio of decreasing ratio as the basis for the drug of the source individual of the cell, can indeed achieve the purpose of significantly improving the efficacy of the drug, and has the benefit of requesting invention patent protection.

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Abstract

L'invention concerne un procédé de criblage d'un médicament thérapeutique destiné au traitement d'un individu souffrant de psoriasis. L'invention concerne également une méthode de traitement du psoriasis au moyen du médicament thérapeutique mentionné ci-dessus pour traiter un individu souffrant de psoriasis.
PCT/CN2020/104453 2020-07-24 2020-07-24 Procédé de criblage de médicament et utilisation de médicament dans le traitement du psoriasis Ceased WO2022016509A1 (fr)

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Citations (2)

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CN1052608A (zh) * 1989-12-20 1991-07-03 先灵公司 干扰素-γ抑制剂BCRF1蛋白质
CN102212505A (zh) * 2010-04-08 2011-10-12 长春藤生命科学股份有限公司 免疫杀手细胞及其制造方法,包含其的医药组成物及套组

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