WO2018214860A1 - Méthode et composition pharmaceutique pour le traitement de l'anémie aplastique - Google Patents

Méthode et composition pharmaceutique pour le traitement de l'anémie aplastique Download PDF

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WO2018214860A1
WO2018214860A1 PCT/CN2018/087769 CN2018087769W WO2018214860A1 WO 2018214860 A1 WO2018214860 A1 WO 2018214860A1 CN 2018087769 W CN2018087769 W CN 2018087769W WO 2018214860 A1 WO2018214860 A1 WO 2018214860A1
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s1pr1
group
mice
aplastic anemia
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从玉文
善亚军
李忠堂
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北京蔚蓝之源医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

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  • the present invention relates to the field of biomedicine, and in particular to a method and a pharmaceutical composition for treating aplastic anemia.
  • the invention relates to the treatment of aplastic anemia by administering a 1-phospho-sphingosine receptor 1 signaling inhibitor to a subject in need thereof.
  • Aplastic anemia is a hematopoietic failure syndrome with multiple blood cells caused by multiple causes. China and Southeast Asia are high-risk areas with aplastic anemia, and the annual incidence rate is 2-3 times that of Europe and America. According to the number of neutrophils (0.5 ⁇ 10 9 /L), the number of platelets (20 ⁇ 10 9 /L) and the rapid onset of the disease, it is divided into severe aplastic anemia (SAA) and non-severe aplastic anemia. In patients with severe aplastic anemia, neutrophils less than 0.2 ⁇ 10 9 /L are extremely severe aplastic anemia (VSAA). SAA, especially VSAA, has a poor prognosis. If effective treatment is not taken in time, the patient may be life-threatening due to infection or bleeding.
  • the main treatments for aplastic anemia include allogeneic hematopoietic stem cell transplantation, combined immunosuppressive therapy, and supportive care.
  • HLA full-phase contracted intercellular allogeneic hematopoietic stem cell transplantation is the preferred treatment for SAA.
  • Anti-thymocyte/lymphocyte globulin (ATG/ALG) combined with cyclosporine (CsA) immunosuppressive therapy (IST) is the treatment of choice for SAA patients who are not suitable for allogeneic hematopoietic stem cell transplantation (allo-HSCT). %-80% of patients recover their blood completely or partially.
  • IST has become more and more clinically used as a first-line treatment for SAA in recent years due to the lack of compatriot donors.
  • ATG is a heterologous serum that can cause a variety of adverse reactions, including immediate and delayed allergic reactions. Therefore, there remains a need in the art for new therapeutic agents for the treatment of aplastic anemia.
  • S1P 1-phospho-sphingosine receptor 1
  • S1PR1 1-phospho-sphingosine receptor 1
  • the present invention also provides a method of treating aplastic anemia in a subject comprising administering to the subject a therapeutically effective amount of an S1PR1 signaling inhibitor.
  • the S1PR1 signaling inhibitor is a small molecule S1PR1 signaling inhibitor, an anti-S1PR1 antibody, an anti-sense RNA, siRNA, and a genome editing system
  • the S1PR1 signaling inhibitor is a S1PR1 functional antagonist.
  • the S1PR1 signaling inhibitor is an S1PR1 competitive antagonist.
  • the S1PR1 functional antagonist is selected from the group consisting of the compounds of Tables 1 and 2, or a pharmaceutically acceptable salt thereof, preferably selected from the group consisting of FTY720, RPC1063, MT-1303, BAF-312, ACT-128800, KRP -203, or a pharmaceutically acceptable salt thereof.
  • the S1PR1 competitive antagonist is the S1PR1 competitive antagonist selected from the group consisting of NIBR-0213, Ex26, TASP0251078, or a pharmaceutically acceptable salt thereof.
  • the aplastic anemia is acquired aplastic anemia.
  • the S1PR1 signaling inhibitor is administered by intravenous, intramuscular, intraperitoneal, intracranial, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical or inhalation routes.
  • the invention provides the use of an S1PR1 signaling inhibitor for the manufacture of a medicament for the treatment of aplastic anemia.
  • the S1PR1 signaling inhibitor is a small molecule S1PR1 signaling inhibitor, an anti-S1PR1 antibody, an anti-sense RNA, an RNAi, a small RNA, a miRNA, and a genome editing system
  • the S1PR1 signaling inhibitor is a S1PR1 functional antagonist.
  • the S1PR1 signaling inhibitor is an S1PR1 competitive antagonist.
  • the S1PR1 functional antagonist is selected from the group consisting of the compounds of Tables 1 and 2, or a pharmaceutically acceptable salt thereof, preferably selected from the group consisting of FTY720, RPC1063, MT-1303, BAF-312, ACT-128800, KRP -203, or a pharmaceutically acceptable salt thereof.
  • the S1PR1 competitive antagonist is selected from the group consisting of NIBR-0213, Ex26, TASP0251078, or a pharmaceutically acceptable salt thereof.
  • the aplastic anemia is acquired aplastic anemia.
  • the S1PR1 signaling inhibitor is administered by intravenous, intramuscular, intraperitoneal, intracranial, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical or inhalation routes.
  • Figure 1 Effect of different dosing regimens of S1PR1 functional antagonist FTY720 on survival of aplastic anemia mice. P ⁇ 0.001 compared with the model control group.
  • FIG. 1 Effect of FTY720 and cyclosporine A on survival of aplastic anemia mice.
  • FTY720 and cyclosporine A were administered one day after lymphocyte infusion for 6 consecutive days.
  • the FTY720 group and the cyclosporine A group were compared with the model control group (P ⁇ 0.05 and P ⁇ 0.001); the FTY720 and the cyclosporine A group were compared P ⁇ 0.05.
  • FIG. 3 Effect of FTY720 and S1PR1 functional antagonist RPC1063 on survival of aplastic anemia mice.
  • the FTY720 group and RPC1063 were administered one day after lymphocyte infusion for 6 consecutive days.
  • the FTY720 group and the RPC1063 group were compared with the model control group (P ⁇ 0.01).
  • FIG. 4 Effect of S1PR1 competitive antagonist NIBR-0213 on survival of aplastic anemia mice.
  • NIBR-0213 was administered 3 hours after lymphocyte infusion for 4 consecutive days.
  • the NIBR-0213 group was compared with the model control group (P ⁇ 0.05).
  • FIG. 5 Effect of FTY720 and NIBR-0213 on survival of aplastic anemia mice.
  • FTY720 and NIBR-0213 were administered on day 5 after lymphocyte infusion for 5 consecutive days.
  • the FTY720 group and the NIBR-0213 group were compared with the model control group (P ⁇ 0.05 and P ⁇ 0.01).
  • FIG. Effect of S1PR1 functional antagonists Siponimod, Ponesimod and KRP-203 on survival of aplastic anemia mice.
  • Siponimod, Ponesimod, and KRP-203 were administered on day 1 after lymphocyte infusion for 5 consecutive days.
  • the Siponimod group, the Ponesimod group, and the KRP-203 group were compared with the model control group (P ⁇ 0.001).
  • FIG. 7 Effect of S1PR1 functional antagonist MT-1303 and competitive antagonist EX26 on survival of aplastic anemia mice.
  • MT-1303 and EX26 were administered on the first day after lymphocyte infusion for 6 consecutive days.
  • Aplastic anemia is an autoimmune disease of T lymphocyte-mediated immune disorders, but the pathogenesis and target antigens that trigger autoimmune responses are not well understood. It is currently believed that AA is a bone marrow hematopoietic failure caused by immune abnormality inhibition of hematopoiesis, which is mainly related to the function of CD4+ T cell subsets.
  • CD4+CD25+ regulatory T cells are important subsets of CD4+ T cells with immunosuppressive and immune tolerance, and their number and/or function changes with tumors, infections, autoimmune diseases, transplantation Rejection is closely related to allergic diseases.
  • Thl7 cells are a novel CD4+ T cell that induces an excessive autoimmune response, which is exactly the opposite of the role of Treg cells in preventing autoimmune diseases.
  • studies at home and abroad have shown that there is an imbalance of Th17/Treg cells in AA patients, and it is even believed that Th17 cells are directly involved in the pathogenesis of AA.
  • T lymphocyte immune mediated is the theoretical basis of immunosuppressive therapy (IST) using antithymocyte globulin (ATG) combined with cyclosporine (CsA) in patients with aplastic anemia.
  • ATG mainly reduces the number of peripheral blood T lymphocytes by cell lysis, while CsA can selectively reduce T lymphocytes and their mediated immune response, and the two can achieve the best therapeutic effect.
  • Th17 cells in children with AA after IST treatment and in the complete remission period decreased, and the Th17/Treg imbalance was corrected, but the proportion of Treg cells did not change significantly.
  • S1P 1-phospho-sphingosine receptor S1PR1
  • S1PR1 signaling inhibitors can promote the differentiation of thymic Treg precursor cells, enhance the function of Treg mature cells and mediate immune tolerance, and inhibit the polarization of Th17 cells by inhibiting the S1PR1 signaling pathway on lymphocyte membranes. Significantly increase the proportion of Treg/Thl7 to achieve treatment for aplastic anemia.
  • the invention provides a method of treating aplastic anemia in a subject comprising administering to the subject a therapeutically effective amount of an S1PR1 signaling inhibitor.
  • Aplastic anemia includes congenital aplastic anemia and acquired aplastic anemia.
  • Congenital aplastic anemia is mainly caused by mutations in the FA gene. It is currently believed that hematopoietic stem cell reduction or deficiency, hematopoietic microenvironment damage and T lymphocyte hyperfunction are the main pathogenesis of acquired aplastic anemia.
  • the aplastic anemia is acquired aplastic anemia.
  • subject refers to a mammal, preferably a primate, more preferably a human.
  • the S1PR1 "signal inhibitor” is an "antagonist” of S1PR1, including “functional antagonists” and “competitive antagonists.”
  • a functional antagonist of S1PR1 means a modulator that activates the receptor S1PR1 but causes ubiquitination of the cell membrane S1PR1, ultimately leading to functional antagonism of the receptor.
  • the S1PR1 competitive antagonist is able to compete for the binding of the natural ligand to S1PR1, thereby antagonizing the function of S1PR1.
  • S1PR1 natural ligands, functional antagonists, and competitive antagonist signaling mechanisms are described in detail in Obinata H, Hla T. Fine-tuning S1 P therapeutics. Chem Biol. 2012 Sep 21; 19(9): 1080-2.
  • S1PR1 signaling inhibitor may include small molecule compounds, and may also encompass antibodies against S1PR1, antisense RNA, RNAi, small RNA, miRNA, genome editing systems, and the like.
  • the "S1PR1 signal inhibitor” is an S1PR1 small molecule compound antagonist.
  • S1PR1 small molecule functional antagonists have been extensively described in the art, and many have entered clinical trials, such as clinical trials for the treatment of diseases such as multiple sclerosis. These functional antagonists can be used in the present invention.
  • S1PR1 small molecule functional antagonists suitable for use in the present invention include, but are not limited to, those disclosed in Expert Opin. Ther. Patents (2008) 18(10), 1141-1159; Expert Opin. Ther. Patents (2016) 26 ( 4), 455-470; Expert Opin. Ther. Patents (2013) 23(7), 817-841; Nature Reviews Drug Discovery (2013) 12, 688-702; Bioorg. Med. Chem. Lett. 23 (2013) 6377- 6389 and those in Current Topics in Medicinal Chemistry (2011) 11, 726-757.
  • S1PR1 functional antagonist useful in the present invention may be selected from the compounds of Table 1 below or a pharmaceutically acceptable salt thereof:
  • the S1PR1 functional antagonist useful in the present invention may also be selected from the compounds of Table 2 below or a pharmaceutically acceptable salt thereof:
  • the small molecule functionally antagonizing S1PR1 may, for example, be selected from the group consisting of FTY720, RPC1063, MT-1303, BAF-312, ACT-128800, KRP-203, or a pharmaceutically acceptable salt thereof.
  • the S1PR1 functional antagonist is FTY720 or a pharmaceutically acceptable salt thereof.
  • FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol) is an agonist (functional antagonist) of the S1P receptor (except S1P2).
  • FTY720 is phosphorylated in vivo and its phosphorylated form is a strong agonist of the S1P receptor (other than S1P2). Therefore, the FTY720 of the present invention also encompasses its phosphorylated form, namely FTY720 phosphate (FTY720-p).
  • the structure of FTY720-p is as follows:
  • the S1PR1 functional antagonist is KRP-203 or a pharmaceutically acceptable salt thereof.
  • the KRP-203 of the present invention also covers its phosphorylated form, and its structure is as follows:
  • the S1PR1 functional antagonist is MT-1303 or a pharmaceutically acceptable salt thereof.
  • the MT-1303 of the present invention also covers its phosphorylated form, and its structure is as follows:
  • Small molecule S1PR1 competitive antagonists have also been described in the art.
  • Various small molecule S1PR1 competitive antagonists can be used in the present invention as long as they are capable of antagonizing the receptor function of S1PR1.
  • an S1PR1 competitive antagonist useful in the present invention may be selected from the group consisting of NIBR-0213, Ex 26, VPC23019, TASP0251078, or a pharmaceutically acceptable salt thereof.
  • NIBR-0213 The structure of NIBR-0213 is as follows:
  • VPC23019 The structure of VPC23019 is as follows:
  • TASP0251078 The structure of TASP0251078 is as follows:
  • the "S1PR1 signal inhibitor” described in the present invention also includes an antibody against S1PR1, an antisense RNA, an RNAi, an siRNA, a miRNA, and a genome editing system. That is to say, treatment of aplastic anemia can be achieved by regulating the receptor function of S1PR1 by using an antibody against S1PR1, an antisense RNA, an RNAi, a small RNA, a miRNA, and a genome editing system.
  • Antibodies against S1PR1 can be readily prepared by those skilled in the art. For example, an animal against S1PR1 can be recovered and its function can be identified by immunizing the animal with the S1PR1 full-length protein or a fragment thereof, and then from the immunized animal. It is also within the ability of those skilled in the art to prepare monoclonal antibodies directed against S1PR1 using hybridoma fusion techniques or antibody library screening techniques.
  • Antisense RNA refers to an RNA transcript that is complementary to all or a portion of a target (eg, S1PR1) primary transcript or mRNA and blocks the expression of an isolated target nucleic acid fragment (U.S. Pat. No. 5,107,065).
  • Antisense RNA can be complementary to any portion of a particular gene transcript (e. g., a S1PR1 gene transcript), i.e., a 5' non-coding sequence, a 3' non-coding sequence, an intron, or a coding sequence.
  • RNA interference refers to the process of sequence-specific post-transcriptional gene silencing in animals mediated by short interfering RNA (siRNA) (Fire et al. (1998) Nature 391: 806).
  • siRNA short interfering RNA
  • One of skill in the art can readily design RNAi constructs that interfere with S1PR1 gene expression.
  • Small RNAs appear to function by base pairing with complementary RNA or DNA target sequences. When bound to RNA, small RNAs or RNA that triggers the target sequence cleave or initiate translational inhibition. When bound to a DNA target sequence, it is believed that the small RNA can mediate DNA methylation of the target sequence. Regardless of the specific mechanism, the consequence of these events is that gene expression is inhibited. It is also within the scope of the invention to modulate S1PR1 gene expression by small RNA.
  • MicroRNAs are non-coding RNAs that have been identified in animals and plants from about 19 to about 24 nucleotides in length (Lagos-Quintana et al., (2001) Science 294: 853-858; Lagos-Quintana Et al., (2002) Curr. Biol. 12:735-739; Lau et al., (2001) Science 294:858-862; Lee and Ambros, Science 294: (2001) 862-864; Llave et al., (2002) Plant Cell 14: 1605-1619; Mourelatos et al, (2002) Genes. Dev. 16: 720-728; Park et al, (2002) Curr. Biol.
  • MicroRNAs modulate target genes, such as the S1PR1 gene, by binding to complementary sequences located in transcripts produced by these genes.
  • Genomic editing systems suitable for the present invention include, but are not limited to, zinc finger nuclease systems, TALEN systems, and CRISPR systems.
  • a suitable genome editing system is the CRIPSR/Cas9 system, which comprises a Cas9 nuclease and a guide RNA that is capable of targeting the S1PR1 gene to regulate its function.
  • the invention also provides the use of an S1PR1 signaling inhibitor for the manufacture of a medicament for the treatment of aplastic anemia, wherein the S1PR1 signaling inhibitor is as defined above.
  • the present invention provides a pharmaceutical composition for treating aplastic anemia comprising an S1PR1 signal inhibitor as an active ingredient, and a pharmaceutically acceptable carrier, wherein the S1PR1 signal inhibitor is as above Defined.
  • compositions of the present invention comprise an effective amount of one or more S1PR1 signaling inhibitors dissolved or dispersed in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable refers to molecular entities and compositions that do not produce an undesirable, allergic or other untoward reaction when administered to an animal, such as a human, as desired.
  • the preparation of a pharmaceutical composition comprising at least one S1PR1 signal inhibitor is known to those skilled in the art in light of the present disclosure and is exemplified in "Remington: The Science and Practice of Pharmacy," 21st Edition, 2005, which The reference is incorporated herein.
  • human administration it should be understood that the preparation should also meet the criteria for sterility, pyrogenicity, overall safety, and purity required by the drug approval authority.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, antioxidants, salts, coatings, surfactants, preservatives (eg, methyl or propyl paraben, sorbic acid, antibacterial).
  • Agent antifungal agent
  • isotonic agent such as paraffin
  • adsorbent for example, kaolin, bentonite
  • drug stabilizer for example, sodium lauryl sulfate
  • gel adhesive
  • adhesive eg, syrup, gum arabic, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, carboxymethylcellulose, alginate
  • excipients eg, lactose, polyethylene glycol
  • disintegrants eg Agar, starch, lactose, calcium phosphate, calcium carbonate, alginic acid, sorbitol, glycine
  • wetting agents eg, cetyl alcohol, glyceryl monostearate
  • lubricants eg, quarters) Ammonium salt
  • edible oil eg, almond oil, coconut oil, oily ester or propylene glycol
  • sweeteners eg, flavoring agents, coloring agents, fillers (eg, starch, lac
  • the composition can comprise a plurality of antioxidants to retard oxidation of one or more components.
  • antioxidants include ascorbic acid, cysteine hydrochloride, sodium sulfite, sodium hydrogensulfite, sodium metabisulfite, ascorbyl palmitate, butylated hydroxytoluene, butylated hydroxyanisole, lecithin, propyl gallate, and tocopherol.
  • microorganisms can be achieved by the use of preservatives such as various antibacterial and antifungal agents including, but not limited to, parabens (for example, methylparaben, p-hydroxyl Propyl benzoate), chlorobutanol, phenol, sorbic acid, thimerosal or a combination thereof.
  • preservatives such as various antibacterial and antifungal agents including, but not limited to, parabens (for example, methylparaben, p-hydroxyl Propyl benzoate), chlorobutanol, phenol, sorbic acid, thimerosal or a combination thereof.
  • Pharmaceutically acceptable salts include acid addition salts such as those formed with the free amino groups of the protein component or with mineral acids (for example, hydrochloric acid, hydrobromic acid or phosphoric acid) or organic acids (for example, acetic acid, oxalic acid, tartaric acid, benzene). a salt formed from formic acid, lactic acid, phosphonic acid, citric acid, maleic acid, fumaric acid, succinic acid, naphthalenesulfonic acid, clavulanic acid, stearic acid or mandelic acid.
  • mineral acids for example, hydrochloric acid, hydrobromic acid or phosphoric acid
  • organic acids for example, acetic acid, oxalic acid, tartaric acid, benzene.
  • the salt formed with the free carboxyl group may also be derived from an inorganic base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide or iron hydroxide or an organic base (eg, isopropylamine, trimethylamine, Histidine or procaine).
  • an inorganic base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide or iron hydroxide or an organic base (eg, isopropylamine, trimethylamine, Histidine or procaine).
  • the carrier can be a solvent or dispersion medium including, but not limited to, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.), liquid ( For example, triglycerides, vegetable oils, liposomes, and combinations thereof.
  • a coating such as lecithin
  • a surfactant For example, hydroxypropyl cellulose
  • compositions can be administered by any suitable method known to those of ordinary skill in the art (see, for example, Remington: The Science and Practice of Pharmacy, 21st ed., 2005).
  • Pharmaceutical compositions can be administered intravenously, intramuscularly, intraperitoneally Administration within the inner, cerebrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical or inhalation routes.
  • the S1PR1 signaling inhibitor When administered orally, the S1PR1 signaling inhibitor may take the form of a tablet, capsule, sachet, vial, powder, granule, lozenge, reconstitutable powder or liquid preparation.
  • a sterile injectable solution is prepared, if necessary, by incorporating the required amount of the active compound into a suitable solvent containing a plurality of the other ingredients described above, followed by filtration sterilization.
  • dispersions are prepared by incorporating a plurality of sterile active ingredients into a sterile vehicle containing a base dispersion medium and/or such other ingredients.
  • the preferred method of preparation is a vacuum drying or freeze drying technique which produces the active ingredient from a previously sterilized liquid medium Add any other powder of the desired ingredients. If necessary, the liquid medium should be suitably buffered and the liquid diluent first rendered isotonic with sufficient saline or glucose prior to injection. It is also contemplated to prepare highly concentrated compositions for direct injection, where it is contemplated that the use of DMSO as a solvent results in extremely rapid penetration, delivering high concentrations of active agent to small areas.
  • terapéuticaally effective amount refers to an amount of a substance, compound, material, or composition comprising a compound that is at least sufficient to produce a therapeutic effect after administration to a subject. Thus, it is an amount necessary to prevent, cure, ameliorate, block or partially arrest the symptoms of a disease or condition.
  • the actual dosage of a composition of the invention administered to a patient can be determined according to the following physical and physiological factors: body weight, sex, severity of symptoms, type of disease being treated, prior or current therapeutic intervention, unknown idiopathy of the patient, Administration time, excretion rate of specific compounds, and route of administration. In any event, the concentration of the active ingredient in the composition and the appropriate dosage for the subject will be determined by the medical personnel responsible for administration.
  • the S1PR1 signaling inhibitor is administered at a dose of 0.001-20 mg/kg body weight, such as 0.005-10 mg/kg body weight or 0.005-5 mg/kg body weight.
  • the S1PR1 signaling inhibitor or the pharmaceutical composition is administered once daily, twice daily, three times a day, or every two days, every three days, every four days, every five days, every Apply once every six days or every seven days.
  • prolonged absorption of the injectable compositions can be brought about by the use of agents that delay absorption (e.g., aluminum monostearate, gelatin, or a combination thereof) in the compositions.
  • agents that delay absorption e.g., aluminum monostearate, gelatin, or a combination thereof
  • Aplastic anemia includes congenital AA and acquired AA.
  • Congenital AA animal models include mice such as Fanc–A-, Fanc-C-, and Fanc–G- and other gene-deficient mouse models.
  • Acquired AA models include animal models of hematopoietic stem cell reduction, hematopoietic microenvironmental damage, immune-mediated and hematopoietic stem cell reduction combined with immune mediated.
  • hematopoietic stem cell reduction combined with immune-mediated mouse AA model namely adult C57BL/6J male ⁇ BALB / C female sub-generation mouse sub-lethal dose (5Gy) irradiation, infusion of parental lymphocytes
  • This model is the closest to the pathogenesis and clinical manifestations of patients with aplastic anemia, and the experimental repeatability is good.
  • mice were exposed to a total of 60 Co ⁇ -rays at a dose of 5.0 Gy at a dose rate of 48.58 cGy/min.
  • Donor Take the inguinal and mesenteric lymph node cells of C57 mice. Intravenous infusion of 5 ⁇ 10 6 / 6 hours after irradiation
  • FTY720 was administered at a dose of 3 mg/kg.d, divided into intraperitoneal injection group (8 mice, once a day for 6 times), and intragastric administration group (administered once a day for 6 times and a total of 6 times). Ten times, 4 mice per group) and model control group (6 mice, given an equal amount of adjuvant), each group started to be administered one day after lymphocyte infusion.
  • the number of peripheral blood platelets, red blood cells, and neutrophils in the model control group was continuously reduced after lymphocyte infusion, accompanied by decreased hemoglobin value and weight loss, and lymphocyte transfusion. All patients died within 20 days after the injection, and the average survival time was 16.17 ⁇ 1.17 days.
  • the number of peripheral blood platelets, erythrocytes and neutrophils and hemoglobin values in the FTY720 mice were significantly higher than those in the model control group at 7, 10 and 14 days after lymphocyte infusion, and the differences between the groups were not significant. The effect of the FTY720 intraperitoneal administration group was slightly better.
  • mice in FTY720 increased significantly compared with the control group at 10 and 14 days after lymphocyte infusion, and the time to death was delayed.
  • the FTY720 intraperitoneal administration group, the intragastric administration group for 6 days, and the 10-day group were treated with lymphocytes after infusion.
  • the average survival time was 18.00, 2/4 and 1/4 in 60 days, and the average survival time was 58.00 ⁇ 5.66, 51.00 ⁇ 14.28 and 52.75 ⁇ 14.50 days, respectively. There was significant difference compared with the model control group (P ⁇ 0.001). )(figure 1).
  • mice were exposed to a total of 60 Co ⁇ -rays at a dose of 5.0 Gy at a dose rate of 48.58 cGy/min.
  • Donor Take the inguinal and mesenteric lymph node cells of C57 mice. 5 ⁇ 10 6 / each was infused through the tail vein 6 hours after the irradiation.
  • mice in FTY720 group were intraperitoneally injected with 3 mg/kg.d; 8 mice in cyclosporine group A were intraperitoneally injected with 50 mg/kg.d; 7 mice in model control group were given corresponding adjuvants, and each group was in lymphoid Dosing was started one day after cell infusion for 6 consecutive days.
  • the number of peripheral blood platelets and red blood cells was continuously reduced after lymphocyte infusion in the model control group, accompanied by a decrease in hemoglobin value and weight loss, and 6/7 mice in lymphocytes.
  • the infusion was fatal within 20 days and the average survival time was 17.17 ⁇ 1.47 days.
  • the number of peripheral blood platelets and red blood cells and the hemoglobin value of FTY720 and cyclosporine A mice increased to different degrees on the 7th, 10th and 14th day after lymphocyte infusion, compared with the model control mice, at multiple time points and models.
  • mice There was a statistically significant difference between the control group and the mice; FTY720 was superior to the positive drug cyclosporine A, and the 10 and 14 day hemoglobin values of the FTY720 group were statistically different from those of the cyclosporine A group.
  • the weight of the cyclosporine group A mice was significantly lower than that of the control group after 7 days of lymphocyte infusion, showing a certain toxicity.
  • the mice in the FTY720 group were compared with the control group and cyclosporine 10 and 14 days after lymphocyte infusion. There was a significant increase in the A group and there were statistical differences.
  • the mice in FTY720 and cyclosporine A group lag behind the control group, and died 2/8 and 5/8 in the 60 days after lymphocyte infusion.
  • the average survival time was 37.50 ⁇ 19.63 and 54.63 ⁇ 10.04 days, respectively. There was a statistically significant difference between the model control group (P ⁇ 0.05 and P ⁇ 0.001), and FTY720 was superior to the cyclosporine A group (P ⁇ 0.05) (Fig. 2).
  • FTY720 can be used to treat aplastic anemia.
  • the receptor for FTY720 in vivo is the G protein-coupled receptor, the sphingosine-1-phosphate receptor.
  • S1PR1 is a target for the treatment of immune diseases by FTY720.
  • S1PR1 is a target for the treatment of immune diseases by FTY720.
  • S1PR1 is a target for the treatment of immune diseases by FTY720.
  • the inventors examined the therapeutic effect of another S1PR1 functional antagonist RPC1063 on aplastic anemia mice.
  • mice were exposed to a total of 60 Co ⁇ -rays at a dose of 5.0 Gy at a dose rate of 48.58 cGy/min.
  • Donor Take the inguinal and mesenteric lymph node cells of C57 mice. Intravenous infusion of 5 ⁇ 10 6 / 6 hours after irradiation
  • mice in FTY720 group were intraperitoneally injected with 3 mg/kg.d; 6 mice in RPC1063 group were intraperitoneally injected with 5 mg/kg.d; 5 mice in model control group were given corresponding adjuvants, and each group was infused with lymphocytes. Dosing was started the day after, for 6 consecutive days.
  • the number of peripheral blood platelets and red blood cells was continuously reduced after lymphocyte infusion in the model control group, accompanied by a decrease in hemoglobin value.
  • the number of peripheral blood platelets and red blood cells and hemoglobin values in the FTY720 and RPC1063 treatment groups were increased at 7, 10, and 14 days after lymphocyte infusion, compared with the model control mice.
  • the FTY720 group and the model control group mice There was no significant difference between the FTY720 and RPC1063 mice compared with the statistical difference.
  • the model control mice all died within 40 days after lymphocyte infusion, and the average survival time was 21.8 ⁇ 6.10 days. The death time of mice in FTY720 and RPC1063 group was significantly delayed.
  • mice in FTY720 group were all within 50 days after lymphocyte infusion.
  • the mean survival time was 42.50 ⁇ 5.82 days, which was statistically different from the model control group (P ⁇ 0.001).
  • the RPC1063 group survived half of the 60 days after lymphocyte infusion, and the average survival time was 40.50 ⁇ 19.96. Day ( Figure 3).
  • the results showed that S1PR1 functional antagonist RPC1063 can also be used to treat aplastic anemia, further demonstrating that S1PR1 is a therapeutic target for aplastic anemia.
  • S1PR1 is a therapeutic target for aplastic anemia
  • the inventors also examined the therapeutic effect of the S1PR1 competitive antagonist NIBR-0213 on aplastic anemia mice.
  • mice were exposed to a total of 60 Co ⁇ -rays at a dose of 5.0 Gy at a dose rate of 48.58 cGy/min.
  • Donor Take the inguinal and mesenteric lymph node cells of C57 mice. Intravenous infusion of 5 ⁇ 10 6 / 6 hours after irradiation
  • mice in the NIBR-0213 administration group were intraperitoneally injected with 5 mg/kg.d; 5 mice in the model control group were intraperitoneally injected with the same amount of adjuvant. Each group started dosing 3 hours after lymphocyte infusion for 4 consecutive days.
  • the number of peripheral blood platelets and red blood cells was continuously reduced after lymphocyte infusion in the model control group, accompanied by a decrease in hemoglobin value.
  • the number of peripheral blood platelets and red blood cells and the hemoglobin value of NIBR-0213 mice were increased to different degrees on the 7th, 10th and 14th day after lymphocyte infusion, and compared with the model at various time points. There was a statistically significant difference between the groups of mice.
  • the model control mice died 4/5 in 60 days after lymphocyte infusion, and the average survival time was 30.20 ⁇ 18.05 days.
  • the NIBR-0213 treatment group began to lag behind and died within 60 days after lymphocyte infusion.
  • the mean survival time was 53.00 ⁇ 11.31 days, which was statistically different (P ⁇ 0.05) compared with the model control group (Fig. 4).
  • the results indicate that the S1PR1 competitive antagonist NIBR-0213 can also be used to treat aplastic anemia, further demonstrating that S1PR1 is a therapeutic target for aplastic anemia.
  • This example compares the therapeutic effects of the S1PR1 functional antagonist FTY720 and the competitive antagonist NIBR-0213 on aplastic anemia mice.
  • mice were exposed to a total of 60 Co ⁇ -rays at a dose of 5.0 Gy at a dose rate of 48.58 cGy/min.
  • Donor Take the inguinal and mesenteric lymph node cells of C57 mice. Intravenous infusion of 5 ⁇ 10 6 / 6 hours after irradiation
  • mice in the FTY720 administration group were intraperitoneally injected with 3 mg/kg.d; 5 mice in the NIBR-0213 administration group were intraperitoneally injected with 5 mg/kg.d; 5 mice in the model control group were intraperitoneally injected with the same amount of adjuvant. Each group started dosing five days after lymphocyte infusion for 5 consecutive days.
  • Figure 5 and Tables 5.1-2.3 observe the effects of S1PR1 functional antagonist FTY720 and competitive antagonist NIBR-0213 on the survival and peripheral blood of aplastic anemia mice.
  • the results showed that all the mice in the model control group died within 40 days after lymphocyte infusion, and the average survival time was 22.40 ⁇ 7.09 days.
  • the mice in the FTY720 and NIBR-0213 treatment groups had 2/60 days after lymphocyte infusion. 5 and 3/5 mice survived, and the average survival time was 47.60 ⁇ 21.65 and 47.60 ⁇ 12.18 days, respectively, compared with the model control group (P ⁇ 0.05 and P ⁇ 0.01) (Fig. 5).
  • the number of white blood cells in the FTY720 and NIBR-0213 treatment groups was significantly higher than that in the control group on the 7th day after lymphocyte infusion. There was a significant difference between the two groups. The difference between the two groups was not significant in the FTY720 and NIBR-0213 treatment groups. The number of red blood cells and platelets on day 7, 10 and 14 after infusion was higher than that in the model control group. There was no significant difference due to individual differences. The results showed that both the S1PR1 functional antagonist FTY720 and the competitive antagonist NIBR-0213 can be used to treat aplastic anemia.
  • Example 6 Therapeutic effect of S1PR1 functional antagonists BAF-312, ACT-128800 and KRP-203 on aplastic anemia mice
  • S1PR1 is a therapeutic target for aplastic anemia
  • the inventors also examined the therapeutic effects of the S1PR1 functional antagonists BAF-312, ACT-128800, and KRP-203 on aplastic anemia mice.
  • mice were exposed to a total of 60Co ⁇ -rays at a dose of 5.0 Gy at a dose rate of 48.58 cGy/min.
  • Donor Take the inguinal and mesenteric lymph node cells of C57 mice. Intravenous infusion of 5 ⁇ 106/only 6 hours after irradiation
  • BAF-312 and ACT-12880 were given intraperitoneal injection of 10 mg/kg.d, KRP-203 administration group was intraperitoneally injected with 5 mg/kg.d; model control group of 6 mice were given equal doses of adjuvant, each group in lymphoid Dosing was started one day after cell infusion for 5 consecutive days.
  • BAF-312 (Siponimod), ACT-128800 (Ponesimod) and KRP-203 are functional antagonists of S1PR1, respectively.
  • Yinqiao disease and other diseases they are currently at different stages of clinical research.
  • hematopoietic stem cells were used to reduce the mouse aplastic anemia model induced by combined immune mediated, and the therapeutic effects of BAF-312, ACT-128800 and KRP-203 on aplastic anemia mice were compared.
  • the leukocytes of the model control group were progressively decreased after lymphocyte infusion, and the number of neutrophils and lymphocytes decreased.
  • the number of white blood cells in the BAF-312, ACT-128800 and KRP-20340 treatment groups was 14 days after lymphocyte infusion. Significantly higher than the control group; on the 10th day after lymphocyte infusion, although there was no significant difference in leukocytes between the treatment groups and the control group, the number of neutrophils in peripheral blood of each treatment group was significantly higher than that of the control group, while lymph The number of cells was significantly lower than that of the control group, indicating that the S1PR1 functional antagonist can specifically promote neutrophil recovery (Tables 6.2-6.4).
  • the hemoglobin and red blood cell counts of the model control mice were progressively decreased after lymphocyte infusion.
  • the BAF-312, ACT-128800 and KRP-20340 treatment groups were significantly higher at 7-14 days after infusion. In the control group, the treatment with BAF-312 and KRP-20340 was better (Tables 6.6 and 6.7).
  • the results showed that S1PR1 functional antagonists BAF-312, ACT-128800, and KRP-203 were also used to treat aplastic anemia, further demonstrating that S1PR1 is a therapeutic target for aplastic anemia.
  • Example 7 Therapeutic effect of S1PR1 functional antagonist MT-1303 and competitive antagonist EX26 on aplastic anemia mice
  • S1PR1 is a therapeutic target for aplastic anemia
  • the inventors also examined the therapeutic effects of the S1PR1 functional antagonist MT-1303 and the competitive antagonist EX26 on aplastic anemia mice.
  • mice were exposed to a total of 60 Co ⁇ -rays at a dose of 5.0 Gy at a dose rate of 60.6 cGy/min.
  • Donor Take the inguinal and mesenteric lymph node cells of C57 mice. Intravenous infusion of 5 ⁇ 10 6 / 6 hours after irradiation
  • the MT1303 and EX26 administration groups were intraperitoneally injected with 5 mg/kg.d; the model control group of 6 mice was intraperitoneally injected with the same amount of adjuvant. Each group started dosing one day after lymphocyte infusion for 6 consecutive days.
  • MT1303 is a functional antagonist of S1PR1 and is currently in the clinical research stage of III as a new drug for the treatment of diseases such as multiple sclerosis.
  • EX26 is a competitive antagonist of S1PR1.
  • hematopoietic stem cells were used to reduce the aplastic anemia model induced by combined immune mediated, and the therapeutic effects of MT1303 and EX26 on aplastic anemia mice were compared.
  • mice in the model control group died 4/6 within 20 days after lymphocyte infusion, while mice in the MT1303 and EX26 treatment groups had 7/7 and 5/7 mice within 20 days after lymphocyte infusion.
  • Survival Figure 7
  • the body weight decreased progressively 7 days after lymphocyte infusion.
  • the body weight of the MT1303 and EX26 treatment groups was higher than that of the control group, and the MT1303 group was after the infusion.
  • There was a statistical difference between the 14 days and the control group (Table 7.1).
  • the leukocytes decreased progressively, and the number of neutrophils and lymphocytes decreased.
  • peripheral blood neutrophils were found in each treatment group. The number of the cells was higher than that of the control group; the number of lymphocytes in the MT1303 treatment group was significantly lower than that in the control group, but the difference between the EX26 treatment group and the model control group was not significant (Table 7.2-7.4).
  • the hemoglobin and red blood cell counts of the model control group were progressively decreased after lymphocyte infusion.
  • the MT1303 treatment group was higher than or significantly higher than the control group at 3 time points after 7-14 days of infusion.
  • EX26 treatment group Hemoglobin and red blood cell counts were higher than the control group 14 days after infusion, but there was no statistical difference (Tables 7.6 and 7.7).
  • S1PR1 functional antagonist MT1303 and competitive antagonist EX26 can also be used to treat aplastic anemia, further demonstrating that S1PR1 is a therapeutic target for aplastic anemia.

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Abstract

La présente invention concerne une méthode et une composition pharmaceutique pour le traitement de l'anémie aplastique, et spécifiquement l'application d'un inhibiteur de signal S1PR1 à un sujet en ayant besoin un traitement de l'anémie aplasique.
PCT/CN2018/087769 2017-05-22 2018-05-22 Méthode et composition pharmaceutique pour le traitement de l'anémie aplastique WO2018214860A1 (fr)

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