WO2020037714A1 - Application de protéines mutantes trail dans la préparation de médicaments pour le traitement de l'acné et préparation associée - Google Patents

Application de protéines mutantes trail dans la préparation de médicaments pour le traitement de l'acné et préparation associée Download PDF

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WO2020037714A1
WO2020037714A1 PCT/CN2018/104064 CN2018104064W WO2020037714A1 WO 2020037714 A1 WO2020037714 A1 WO 2020037714A1 CN 2018104064 W CN2018104064 W CN 2018104064W WO 2020037714 A1 WO2020037714 A1 WO 2020037714A1
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trail
preparation
acne
mutant
treatment
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PCT/CN2018/104064
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Chinese (zh)
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陈守春
闫娟
徐琦
胡海洋
魏利佳
黄先洲
丁奕
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成都华创生物技术有限公司
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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
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61P17/10—Anti-acne agents

Definitions

  • the invention relates to the technical field of medicines, in particular to the application of a variety of TRAIL mutants with different structures in the preparation of a medicine for treating acne and a preparation thereof.
  • Acne is a chronic inflammatory skin disease of the hair follicle sebaceous glands. It is a common and frequently-occurring disease in dermatology, especially in adolescent men and women. According to domestic surveys, about 85% of individuals in the 12 to 15-year-old age group developed disease at different times. It is reported abroad that the incidence of acne in adolescence reaches 90.6% in women and 100% in men. Acne affects adolescents more psychologically and socially than asthma and epilepsy. In view of the widespread epidemic of acne, and the disease is mainly on the face, acne, pimples, cysts, and even individual patients form keloids, damage people's faces, bring pain and annoyance, and affect the quality of life of patients.
  • Topical retinoids commonly used today include first-generation retinoids such as 0.025% to 0.1% all-trans retinoid creams or gels, isotretinoin gels, and third-generation retinoids. Drugs such as adapalene gel and tazarotene. Due to the chronic course of acne and the clinical characteristics of easy recurrence, no matter what level of acne there is, there is no one-size-fits-all cure.
  • the main pathological changes of acne are: (1) Excessive secretion of sebaceous glands; (2) Excessive keratinization and desquamation of the funnel of the hair follicle, resulting in blackheads; (3) Propionibacterium acnes migrates into the hair follicle; (4) Inflammatory immune response.
  • Tumor necrosis factor-related apoptosis-inducing ligand is a member of the Tumor necrosis factor (TNF) superfamily, and its gene sequences were obtained in 1995 by Wiley et al. And Independently cloned in 1996 by Pitti et al., which named it apoptin 2 ligand (Apo2 Ligand, Apo2L). Subsequent research confirmed that Apo2L and TRAIL are essentially the same protein, so it is customarily called Apo2L / TRAIL.
  • TRAIL The function of TRAIL is firstly as a regulator of organisms' innate or adaptive immunity, and secondly, it plays an anti-tumor role as immune surveillance in the exogenous apoptosis pathway of cells.
  • the biggest advantage of TRAIL is that it can selectively induce apoptosis in a variety of tumor cells with little toxicity to normal cells.
  • Research data show that Apo2L / TRAIL is effective for human tumor cell lines of various origins, including colon (rectal) cancer, lung cancer, breast cancer, prostate cancer, pancreatic cancer, kidney cancer, central nervous system tumor, Thyroid cancer, lymphoma, leukemia, and multiple myeloma can all induce apoptosis.
  • Isotretinoin is the only drug approved by the FDA to change the condition of acne.
  • 13-cisRA isotretinoin
  • 13-cisRA induces key genes in adipocytes involved in apoptosis.
  • Treatment with recombinant human TRAIL (rhTRAIL) protein alone increased TUNEL-positive staining of SEB-1 adipocytes, while TRAIL siRNA significantly reduced the percentage of TUNEL-positive SEB-1 adipocytes responding to 13-cisRA treatment.
  • TRAIL expression in acne patients' skin increased after 1 week of isotretinoin treatment, and TRAIL expression was limited to sebaceous glands.
  • TRAIL protein does not increase its response to 13-cisRA in normal human epidermal keratinogenesis, and rhTRAIL does not induce keratinocyte apoptosis.
  • Experimental studies have shown that TRAIL is the key to the specific apoptosis of 13-cis RA lipid cells.
  • B.C. Melnik proposed the following hypothesis based on existing research. This hypothesis considers acne to be a PI3K-AKt-MTORC1-driven sebaceous glands follicle hyperproliferative disease with impaired TRAIL-mediated death signals. Previous experiments have shown that the anti-acne agent isotretinoin can enhance TRAIL-induced death signals, thereby adjusting the disordered balance of sebaceous hair follicle survival and death signals in acne vulgaris. It is hypothesized that TRAIL is a potentially critical factor in the pathogenesis of acne. TRAIL not only stops the pro-survival signal of acne fat cells, but also participates in late epidermal differentiation by inducing total protein and type I transglutaminase. TRAIL-induced Caspase activation induces degradation of the key transcription factor P63, which regulates epidermal proliferation and differentiation.
  • rhTRAIL can induce the apoptosis of sebaceous gland cells SEB-1 in vitro, there are still insurmountable obstacles for rhTRAIL in the treatment of acne.
  • the reasons are as follows: (1) The existing immortalized sebaceous gland cells (including SEB-1 and SZ95 cells) are all SV40 large T antigen gene transfected cells, which cannot completely represent the sebaceous gland cells in the natural growth state. Immortalized sebaceous gland cell culture Models considered inappropriate for key features of acne pathogenesis. (2) The role of rhTRAIL in inducing apoptosis of SEB-1 cells is weak.
  • rhTRAIL cannot directly affect the sebaceous glands and hair follicles through the epidermis, so it cannot play a role in practical applications.
  • Active rhTRAIL is a non-covalently bound trimer form, a positively charged basic protein, and the skin surface is an acidic environment with a pH of 5 to 6, and the protein has poor stability in this condition.
  • rhTRAIL has a short biological half-life, and its effect depends strictly on its binding to the cell surface receptors DR4 and DR5. The above deficiencies and shortcomings determine that rhTRAIL still has huge obstacles in the treatment of acne alone.
  • this application extends the structure, preparation method, and tumor drug use of the five patented TRAIL mutants that were originally patented, and uses the above mutant proteins for the treatment of acne Of drugs. Because, first of all, the above five TRAIL mutants have higher biological activity in vitro and in vivo than wild-type rhTRAIL, have stronger affinity with DR4 / DR5 receptors on the cell surface, and can aggregate and redistribute on the cell membrane surface, which is conducive to their exertion. effect.
  • the above-mentioned protein mutants all have cell membrane penetrating function, which is helpful to overcome the cell and tissue barriers, and can act on the structure of the sebaceous glands and hair follicles of the dermis and play a role in inhibiting the function of the sebaceous gland cells.
  • the physicochemical properties of the above-mentioned proteins are more stable, and the half-life of biological metabolism is longer, which is more conducive to the function.
  • the present application provides the application of a TRAIL mutant in the preparation of a medicine for treating acne.
  • the TRAIL mutant is: TRAIL transmembrane peptide-like mutant protein TRAIL-Mu3 (WO2015103894A1), and TRAIL-MuR5 (WO2016138618A1), TRAIL-MuR6 (WO2016138625A1), and TRAIL transmembrane peptide fusion protein TRAIL-MuR5S4TR ( WO2017066962A1) and TRAIL-MuR6S4TR (WO2017066963A1) and other five TRAIL mutants.
  • the above-mentioned TRAIL mutant can inhibit the proliferation and induce apoptosis of primary cultured sebaceous gland cells in vitro, and its inhibitory activity is much stronger than that of wild-type rhTRAIL and the positive control drug isotretinoin.
  • the application also provides a formulation comprising a TRAIL mutant and a pharmaceutically acceptable excipient.
  • formulations are in the form of creams, ointments, gels, sprays, masks, etc., and the present application simultaneously optimizes and perfects the preparation process of the related formulations.
  • the mass percentage content of the TRAIL mutant in the preparation is 0.1% to 1.0%.
  • the mass percentage content of the TRAIL mutant in the preparation is 0.25% to 0.5%.
  • the formulation is suitable for administration to a patient twice a day.
  • This application provides the application of a TRAIL mutant in the preparation of a medicine for treating acne.
  • Experimental results show that the TRAIL mutant can inhibit the proliferation and induce apoptosis of primary cultured sebaceous gland cells in vitro, and its inhibitory activity is much stronger than that of wild-type rhTRAIL and the positive control drug isotretinoin;
  • Different acne animal models have obvious effects of inhibiting and alleviating acne, and have better therapeutic effect than compound isotretinoin cream in no less than 30 cases of acne human trials.
  • TRAIL-Mu3 5g Allantoin 10g Vitamin E 20g Vaseline 125g Monoglycerol fatty acid ester 25g glycerin 62.5ml Propylene glycol 62.5ml Sodium dodecyl sulfate 10g Stearyl alcohol 90g Hydroxyphenethyl 1g purified water Right amount production 1000g
  • TRAIL-Mu3 or TRAIL-MuR5S4TR to an appropriate amount of purified water and save it for future use. Add the water phase to the oil phase and stir rapidly (rotation speed 900r / min) for 15min. When the temperature drops to 20 ° C, add TRAIL-Mu3 or TRAIL-MuR5S4 solution, stir quickly (rotation speed 900r / min) for 15min. to make.
  • TRAIL-Mu3 creams and TRAIL-MuR5S4TR creams (10 g / branch) were prepared respectively, and the effective ingredient content was 0.5%.
  • Carbomer is mixed with polysorbate 80 and 300 ml of purified water.
  • Sodium hydroxide is dissolved in 100 ml of purified water and added to the top liquid to mix well. After dissolving nipagin in ethanol, slowly add and mix, then add propylene glycol. Stir well.
  • Example 3 Inhibitory effect of 5 proteins including TRAIL-Mu3 and MuR5S4TR on the growth of human cultured sebaceous gland cells
  • Sebaceous gland cells were isolated from normal human scalp tissue in patients undergoing dermatological surgery. Fresh specimens of normal human head skin were washed once with PBS and 70% alcohol, and placed in Medium (add 2% fetal calf serum, antibiotic mixture). The subcutaneous fat was removed, and the skin was cut into a size of 0.5 cm ⁇ 0.5 cm. Add neutral protease and place in a refrigerator at 4 ° C overnight. The epidermal layer was peeled off under a visual microscope, and more than 15 sebaceous glands were separated with tweezers and placed in a cell culture dish with a collagen coating (6 cm diameter, inside the dish The culture medium is about 1.25ml), and cultured in a 5% CO 2 incubator at 37 ° C. The culture medium is replaced once every 2 to 3 days. After the cells are full, passaging or TRAIL-Mu3 and TRAIL-MuR5S4TR proliferation inhibition activity detection .
  • connection plate take human sebaceous gland cells in logarithmic growth phase, digest cells in culture flask with 0.25% trypsin, dilute cells with Sebomed basic culture solution, configure as a single cell suspension, and mix well After adjusting the cell concentration to 5 ⁇ 10 5 / ml, inoculate 100ul per well into a 96-well plate, and place it in a 37 ° C, 5% CO 2 saturated humidity incubator to culture.
  • Isotretinoin and five TRAIL proteins such as TRAIL-Mu3 and MuR5S4TR can inhibit the growth of sebaceous gland cells, and the inhibitory activity of the five TRAIL proteins is stronger than isotretinoin.
  • Preliminary mechanism studies have shown that the above-mentioned samples inhibit the growth of sebaceous gland cells by inducing apoptosis of sebaceous gland cells.
  • the blank control group (group 1) was not administered, and the remaining 56 rabbits were randomly divided into 7 groups, which were group 2 (isoretinoin A cream) and group 3 (TRAIL-Mu3 cream low). Dose group, active ingredient content 0.25%), group 4 (TRAIL-Mu3 cream medium dose group, 0.5%), group 5 (TRAIL-Mu3 cream high dose group, 1%), group 6 (MuR5S4TR cream low dose Group, 0.25%), group 7 (MuR5S4TR cream medium-dose group, 0.5%), group 8 (MuR5S4TR cream high-dose group), respectively, the above medicine was coated with the above drug 0.25g / times, 2 times / d, 2 consecutive weeks.
  • Symptom improvement includes thinning of the epidermis, reduction of keratin in the hair follicle, and recovery of the funnel of the hair follicle.
  • Isotretinoin cream, TRAIL-Mu3 cream in each dose group, and MuR5S4TR cream in each dose group can significantly improve the symptoms and pathological changes of experimental acne models in rabbit ears.
  • TRAIL-Mu3 cream and MuR5S4TR cream The high-dose group was significantly better than the isotretinoin cream group.
  • Clinical Dermatology The diagnostic criteria of the cases were referred to "Clinical Dermatology", that is, the skin lesions were whiteheads, blackheads, inflammatory pimples, and pimples. Some nodules, cysts, and scars were visible. There were no conscious symptoms or local tenderness. Excessive secretion of facial oils and enlarged pores occur on the face, especially the forehead, cheeks, nose, and jaw, followed by the chest and back. More common in young men and women, various skin lesions can exist at the same time.
  • treatment group 1 and treatment group 2 A total of 90 cases were collected and randomly divided into two treatment groups (treatment group 1 and treatment group 2) and control group, of which 30 cases were in the treatment group, aged 18 to 39 years, and the course of disease was 4 to 58 months; 2 cases were treated in the treatment group 30 , Aged 19 to 37 years, with a course of 4 to 56 months; 30 patients in the control group, aged 19 to 38 years, with a course of 3 to 50 months. There were no significant differences in age, gender, disease status, and comprehensive classification of the three groups (P> 0.05).
  • Treatment groups 1 and 2 were given 0.5% of TRAIL-MuR5S4 and TRTRAIL-Mu3 creams twice a day, respectively. After the face was fully cleansed, apply the affected area, thickly to prevent short-term drying, and wipe away; the control group was given 0.1% Vitamin A acid cream, twice daily, the same usage as the treatment group, the course of treatment is 4 weeks.
  • the scores of the skin lesions before and after treatment were recorded in detail in the form of a table in one, two, three, four, five, one, two, three, and four weeks.
  • Efficacy Index Calculate the total score before and after treatment, and then use the following formula to calculate.
  • Efficacy Index (Total Points Before Treatment-Total Points After Treatment) / Total Points Before Treatment ⁇ 100%
  • Effective rate (number of cured cases + number of significant cases + number of effective cases) / total number of cases ⁇ 100%
  • the method divides the hair-prone areas into 6 areas: area I (forehead): 2; area II (right cheek): 2; area III (left cheek): 2; IV Area (nose) 1; area V (mandible): 1; area VI (chest or back): 3, values are scores for different areas.
  • the severity of skin lesions was divided into 5 grades, and each grade was scored according to the degree of skin lesions. No skin lesions: 0; acne: 1; pimples: 2; pustules: 3; nodules, cysts: 4.
  • Total score First, multiply the score of the most severe skin lesion type in each zone with the score of the zone factor to obtain each score. The sum of the scores of the 6 zones is the total score of the patient.
  • TRAIL-Mu3 and TRAIL-MuR5S4TR creams have a good therapeutic effect on acne, and their effects are better than that of compound isotretinoin cream.
  • the diagnostic criteria refer to "Clinical Dermatology", that is, skin lesions manifested as whiteheads, blackheads, inflammatory pimples, pimples, some nodules, cysts, scar formation can be seen, no conscious symptoms or local tenderness. It is accompanied by excessive secretion of facial oils and enlarged pores. It occurs on the face, especially the forehead, cheeks, nose, and jaw, followed by the chest and back. More common in young men and women, various skin lesions can exist at the same time.
  • treatment group 1 and treatment group 2 A total of 93 cases were collected and randomly divided into two treatment groups (treatment group 1 and treatment group 2) and control group, of which 32 cases were in the treatment group, aged 16-35 years, and the course was 6-47 months; 31 cases were in the treatment group 2 , Aged 17-37 years, with a course of 6-45 months; 30 patients in the control group, aged 19-36 years, with a course of 3-40 months. There were no significant differences in age, gender, disease status, and comprehensive classification of the three groups (P> 0.05).
  • the treatment group 1 and the treatment group 2 were given 0.25% of TRAIL-MuR5S4 and TRTRAIL-Mu3 gels twice a day. After the face was cleansed, the affected area was applied, thickly to prevent short-term drying, and wiped off. The control group was given 0.1%. Compound isotretinoin acid gel was used twice a day in the same way as the treatment group, and the course of treatment was 4 weeks.
  • the scores of the skin lesions before and after treatment were recorded in detail in the form of a table in one, two, three, four, five, one, two, three, and four weeks.
  • Efficacy Index Calculate the total score before and after treatment, and then use the following formula to calculate.
  • Efficacy Index (Total Points Before Treatment-Total Points After Treatment) / Total Points Before Treatment ⁇ 100%
  • Effective rate (number of cured cases + number of significant cases + number of effective cases) / total number of cases ⁇ 100%
  • the method divides the hair-prone areas into 6 areas: area I (forehead): 2; area II (right cheek): 2; area III (left cheek): 2; IV Area (nose) 1; area V (mandible): 1; area VI (chest or back): 3, values are scores for different areas.
  • the severity of skin lesions was divided into 5 grades, and each grade was scored according to the degree of skin lesions. No skin lesions: 0; acne: 1; pimples: 2; pustules: 3; nodules, cysts: 4.
  • Total score First, multiply the score of the most severe skin lesion type in each zone with the score of the zone factor to obtain each score. The sum of the scores of the 6 zones is the total score of the patient.
  • TRAIL-Mu3 and TRAIL-MuR5S4TR gels have a good therapeutic effect on acne, and their effect is better than that of compound isotretinoin gel.

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Abstract

La présente invention concerne une application de protéines mutantes TRAIL dans la préparation de médicaments pour le traitement de l'acné et une préparation. Les protéines mutantes TRAIL comprennent les protéines suivantes : TRAIL-Mu3, TRAIL-MuR5, TRAIL-MuR6, TRAIL-MuR5S4TR, Et TRAIL-MuR6S4TR. Les recherches expérimentales prouvent que les cinq protéines mutantes TRAIL peuvent inhiber la prolifération des sébocytes en culture primaire in vitro par induction de l'apoptose, les protéines mutantes présentant une activité biologique considérablement plus élevée que celle d'un médicament de contrôle à base d'isotrétinoïne. Les protéines mutantes existent sous diverses formes telles que des crèmes, des pommades, des gels, des sprays ou des masques. Les expériences animales démontrent que les cinq préparations faisant intervenir les protéines mutantes TRAIL permettent manifestement d'inhiber et de soulager les lésions cutanées dues à l'acné chez un modèle animal, et sont tout aussi capables de traiter l'acné chez l'humain.
PCT/CN2018/104064 2018-08-23 2018-09-05 Application de protéines mutantes trail dans la préparation de médicaments pour le traitement de l'acné et préparation associée WO2020037714A1 (fr)

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CN201810968829.9A CN109125709B (zh) 2018-08-23 2018-08-23 Trail突变体在制备治疗痤疮药物中的应用及一种制剂
CN201810968829.9 2018-08-23

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CN115068590A (zh) * 2021-03-10 2022-09-20 四川大学华西医院 一种肿瘤坏死因子相关凋亡诱导配体突变体的新用途

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WO2016138625A1 (fr) * 2015-03-02 2016-09-09 成都华创生物技术有限公司 Mutant de trail de type peptide de pénétration membranaire mur6, procédé de préparation et application associée
WO2017066962A1 (fr) * 2015-10-22 2017-04-27 成都华创生物技术有限公司 Mutéine mur5s4tr de trail à double cible, son procédé de préparation et son utilisation
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