JP2021505172A5

JP2021505172A5 -

Info

Publication number: JP2021505172A5
Application number: JP2020531468A
Authority: JP
Filing date: 2018-12-06
Publication date: 2022-01-11

Claims

A method of mobilizing a population of hematopoietic stem cells from the bone marrow of a mammalian donor into peripheral blood, (i) a CXCR2 agonist selected from the group consisting of Gro-β, Gro-β T, and variants thereof, and (ii) A method comprising administering a CXCR4 antagonist, to said donor.

The method of claim 1, wherein : (a) the CXCR2 agonist is : (i) Gro-β T ; (ii) administered to the donor at a dose of about 100 μg / kg to about 250 μg / kg. (Iii) administer to the donor at a dose of about 125 μg / kg to about 225 μg / kg ; (iv) administer to the donor at a dose of about 150 μg / kg ; and / or (v) the donor. And / or (b) the CXCR4 antagonist : (i) subcutaneously administered to the donor ; (ii) prelixaform or a pharmaceutically acceptable salt thereof , optionally here. , The prelyxaform or a pharmaceutically acceptable salt thereof, at a dose of about 50 μg / kg to about 500 μg / kg , for example, at a dose of about 200 μg / kg to about 300 μg / kg , for example, about 240. at a dose of [mu] g / kg, it is administered to the donor.

A method of mobilizing a population of hematopoietic stem cells from the bone marrow of a mammalian donor into peripheral blood, the method comprising:
a. Administering mobilized doses of CXCR2 agonist and CXCR4 antagonist to said donor;
b. Obtaining input values for each of the one or more parameters listed in Table 2, which characterizes the donor's peripheral blood sample;
c. When the input value for each of the one or more parameters meets the corresponding reference criteria for each of the one or more parameters, the sample is used to treat one or more stem cell disorders in a mammalian patient. the hematopoietic stem cells for use in be grown in ex vivo, subjecting it to.

3. The method of claim 3, wherein (a) the one or more reference parameters are a combination of the parameters listed in any one of Tables 3-6 ; and / or (b) the sample. and when subjected to be grown in ex vivo, the method further comprises growing said hematopoietic stem cells ex vivo; and / or, (c) a said sample, treating one or more stem cell disorders When used in an ex vivo manner , the method further comprises injecting the hematopoietic stem cells or their progeny into a mammal suffering from one or more of the stem cell disorders.

A pharmaceutical composition comprising a population of hematopoietic stem cells or their progeny isolated from a mammalian donor, wherein (a) the ratio of CD34 + cells to leukocytes in the population is from about 0.0008 to about 0.0021 , or about 0.0010. ~ About 0.0018 ; or (b) the ratio of CD34 + cells to neutrophils in the population is about 0.0018 to about 0.0058 , or about 0.0026 to about 0.0046 ; or (c) lymph in the population. The ratio of CD34 + cells to spheres is about 0.0021 to about 0.0094 , or about 0.0025 to about 0.0035 ; or (d) the ratio of CD34 + cells to monospheres in the population is about 0.0071 to about 0.0174 , or , About 0.0100 to about 0.0140 ; or (e) the frequency of CD34 + cells in the population is about 0.051% to about 0.140% , or about 0.080% to about 0.120% ; or (f) the population. The ratio of CD34 + CD90 + CD45RA-cells to leukocytes in the population is about 0.0003 to about 0.0016 , or about 0.0006 to about 0.0012 ; or (g) the ratio of CD34 + CD90 + CD45RA-cells to neutrophils in the population. It is about 0.0007 to about 0.0043 , or about 0.0014 to about 0.0034 ; or (h) the ratio of CD34 + CD90 + CD45RA-cells to lymphocytes in the population is about 0.0008 to about 0.0069 , or about 0.0011 to. Or (i) the ratio of CD34 + CD90 + CD45RA-cells to monospheres in the population is about 0.0028 to about 0.0130 , or about 0.0063 to about 0.0083 ; or (j) in the population. The ratio of CD34 + CD90 + CD45RA-cells to CD34 + cells is about 0.393 to about 0.745 , or about 0.625 to about 0.725 ; or (k) the frequency of CD34 + CD90 + CD45RA-cells in the population is about 0.020% to about. It is 0.110% , or about 0.046% to about 0.086%.

A method of treating a stem cell disorder in a mammalian patient, said method comprising: mobilizing a population of hematopoietic stem cells in a mammalian donor according to the method according to any one of claims 1-4. And, injecting a therapeutically effective amount of hematopoietic stem cells or their progeny into the patient , optionally here the stem cell disorder is any one of the following:
Hemoglobinopathy disorders (sickle cell anemia, thalassemia, Fanconi anemia, aplastic anemia, and Wiskott - is selected from the group consisting of Aldrich syndrome),
Myelodysplastic disorder ,
Congenital immunodeficiency ,
Acquired immunodeficiency ( selected from the group consisting of human immunodeficiency virus or acquired immunodeficiency syndrome),
Metabolic disorders ( selected from the group consisting of glycogen accumulation, mucopolysaccharidosis, Gaucher's disease, Harler's disease, sphingolipid doses, and metachromatic leukodystrophy ),
Cancer ( leukemia, lymphoma, multiple myeloma, neuroblastoma, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, diffuse large cell type B-cell Lymphoma, or selected from the group consisting of non-Hodgkin's lymphoma),
Adenosine deaminase deficiency and severe combined immunodeficiency, hyperimmunoglobulin M syndrome, Chediac-East disease, hereditary lymphohistiocytosis, marble bone disease, osteodysplasia, storage disease, salacemia major, systemic sclerosis Disorders selected from the group consisting of disease, systemic lupus erythematosus, multiple sclerosis, and juvenile lupus erythematosus , or
Autoimmunity disorders ( multiple sclerosis, human systemic erythematosus, rheumatoid arthritis, inflammatory bowel disease, treatment of psoriasis, type 1 diabetes, acute diffuse encephalomyelitis, Addison's disease, generalized alopecia, tonic spondylitis , Antiphospholipid antibody syndrome, poor regeneration anemia, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune ovarian inflammation, Barrow disease, Bechet's disease, blisters Chronic fatigue immunodeficiency syndrome, chronic inflammatory demyelinating polyneuropathy, Crohn's disease, scarring psoriasis, coeliac sprue-dermatitis herpetiformis, Cold agglutinosis, CREST syndrome, Degos's disease, discoid erythematosus, autonomic neuropathy, endometriosis, essential mixed cryoglobulinemia, fibromyalgia-fibromyitis, Good Pasture syndrome, Graves' disease, Gillan -Valley syndrome, Hashimoto thyroiditis, purulent sweat adenitis, idiopathic and / or acute thrombocytopenic purpura, idiopathic pulmonary fibrosis, IgA neuropathy, interstitial cystitis, juvenile arthritis, Kawasaki disease, squamous lichen , Lime's disease, Meniere's disease, mixed connective tissue disease, severe myasthenia, neuromiotonia, opsocronus-myoclonus syndrome, optic neuritis, Ord's thyroiditis, cystitis vulgaris, malignant anemia, polychondritis, Polymyopathy and dermatomyitis, primary biliary cirrhosis, nodular polyarteritis, polyendocrine gland syndrome, rheumatic polymyopathy, primary agammaglobulinemia, Raynaud's phenomenon, Reiter's syndrome, rheumatism From fever, sarcoidosis, scleroderma, Schegren's syndrome, Stiff-Person's syndrome, hyperan arteritis, temporal arteritis, ulcerative colitis, vasculitis, vasculitis, leukoplakia, genital pain, and Wegener's granulomatosis. (Selected from the group of ) .

6. The method of claim 6, wherein the hematopoietic stem cells are : (a) self to the patient ; (b) allogeneic to the patient , optionally to the patient. In contrast, it is HLA compatible ; and / or (c) genetically modified to disrupt the endogenous gene , optionally where the endogenous gene is a major histocompatibility gene complex protein. Code.

A method of performing allogeneic hematopoietic stem cell transplantation in a patient in need thereof, comprising injecting a therapeutically effective amount of allogeneic hematopoietic stem cells into the patient, wherein the hematopoietic stem cells are expressed. Bone marrow of human donors by a method comprising administering to said donor (i) a CXCR2 agonist selected from the group consisting of Gro-β, Gro-β T, and variants thereof, and (ii) a CXCR4 antagonist. A method of mobilizing from to the peripheral blood of a human donor.

A method of preventing post-transplant infection, reducing the risk of developing, or reducing the severity in a patient in need thereof, comprising injecting a therapeutically effective amount of hematopoietic stem cells into the patient. Here, the hematopoietic stem cells are administered to the donor with (i) a CXCR2 agonist selected from the group consisting of Gro-β, Gro-β T, and variants thereof, and (ii) a CXCR4 antagonist. A method of mobilizing from the bone marrow of a human donor into the peripheral blood of a human donor by method.

A method for preventing graft-versus-host disease (GVHD), reducing the risk of developing it, or reducing its severity in patients in need thereof, injecting a therapeutically effective amount of hematopoietic stem cells into the patient. Here, the hematopoietic stem cells are fed with (i) a CXCR2 agonist selected from the group consisting of Gro-β, Gro-β T, and variants thereof, and (ii) a CXCR4 antagonist. A method of mobilizing from the bone marrow of a human donor into the peripheral blood of a human donor by a method comprising administration.

The method according to any one of claims 1 to 4 and 6 to 10 , wherein (a) the ^{CD34 dim} cells are more than the hematopoietic stem cells mobilized using the CXCR4 antagonist alone. It is present in peripheral blood in at least 2-10 fold higher amounts ; and / or (b) the CD34 ^dim cells suppress the proliferation of allogeneic T-lymphocytes when administered to the recipient. Can be done.

The method according to any one of claims 1 to 4 and 6 to 11, wherein the CXCR4 antagonist is administered to a mammalian donor about 30 to about 180 minutes before, about 40 minutes. Administer about 160 minutes to about 160 minutes, about 50 to about 150 minutes, about 60 to about 140 minutes, about 70 to about 130 minutes, or about 120 minutes before.

A method for producing Gro-β T, wherein the method comprises chemically synthesizing Gro-β T, wherein less than 5%, less than 1%, or less than 0.1% of the Gro-β T. Contains deamidated Asn65 residues.

A method of mobilizing a population of hematopoietic stem cells from the bone marrow of a mammalian donor into peripheral blood, (i) a CXCR2 agonist selected from the group consisting of Gro-β, Gro-β T, and variants thereof, and (ii) Administer to the donor a CXCR4 antagonist, wherein the Gro-β T <10%, <5%, <1%, or <0.1% contains a deamidated Asn65 residue. How to include.

14. The method of claim 14, wherein the CXCR4 antagonist is: (i) administered subcutaneously to the donor ; (ii) prelixaform or a pharmaceutically acceptable salt thereof , optionally said herein. Prelixaform or a pharmaceutically acceptable salt thereof, at a dose of about 50 μg / kg to about 500 μg / kg , for example, at a dose of about 200 μg / kg to about 300 μg / kg , for example , about 240 μg / kg. at a dose of kg, it is administered to the donor, and optionally wherein the CXCR4 antagonist, the donor mammal, administering the CXCR2 agonist is administered from about 30 minutes to about 180 minutes before, to.