WO2003049754A1 - Utilisation du peptide de croissance osteogenique dans la'melioriation de l'hemopoiese - Google Patents

Utilisation du peptide de croissance osteogenique dans la'melioriation de l'hemopoiese Download PDF

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Publication number
WO2003049754A1
WO2003049754A1 PCT/CN2002/000772 CN0200772W WO03049754A1 WO 2003049754 A1 WO2003049754 A1 WO 2003049754A1 CN 0200772 W CN0200772 W CN 0200772W WO 03049754 A1 WO03049754 A1 WO 03049754A1
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Prior art keywords
hematopoietic
cells
proliferation
sogp
pharmaceutical composition
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PCT/CN2002/000772
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English (en)
Chinese (zh)
Inventor
Wenying Cheng
Honghong Chen
Tongyi Chen
Deyuan Shi
Yi Lu
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Shanghai Yizhong Biotechnology Co., Ltd.
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Priority to AU2002349719A priority Critical patent/AU2002349719A1/en
Publication of WO2003049754A1 publication Critical patent/WO2003049754A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • osteogenic growth peptide in promoting hematopoiesis
  • the invention relates to the application of Osteogenic Growth Peptide (OGP) in promoting hematopoietic. Background technique
  • Osteogenic Growth Peptide is a 14-amino acid polypeptide found in Bab and others in 1988 that can promote bone cell growth.
  • Osteogenic Growth Peptide is a 14-amino acid polypeptide found in Bab and others in 1988 that can promote bone cell growth.
  • the body is fractured or the bone marrow is injured, in addition to the local osteogenic response in the fractured or damaged bone marrow, there is also a systemic osteogenic response [Bab I, et al. (1985) Calcif Tissue Int. 37: 551-555 Foldes J, et al. (1989) J Bone Miner Res. 4: 643-646].
  • Osteogenic Peptide Osteogenic Growth Peptide, OGP
  • OGP amino acid sequence of OGP is ALKRQRGTLYGFGG, which is the same as the amino acid sequence of the C-terminal segment of H4 histone, and contains 5 residue sequences of the T-cell receptor ⁇ chain V region and Bacillus subtil is) outB region [ Kayne PS, et al., (1988) Cell 55: 27-39; Bab I, et al. (1992) EMBO J 11: 1867-1873], its evolutionary degree is conservative, human and mouse homologous, and the same characteristics .
  • 0GP exists in the serum of humans and mammals, mainly in the form of binding, that is, the OGP-0GP binding protein (0GPBP) complex, which accounts for about 80% -97% of the total 0GP [Greenberg Z, et al. (1995) JCE & M. 80 (8): 2330-2335].
  • the molecular structure of 0GPBP is not completely clear at present. It is reported from related literature that it may be ⁇ 2 -macroglobulin, which is similar to other peptide regulators.
  • the role of 0GPBP may be to protect 0GP in serum from being degraded, so it can regulate 0GP. Level of active fraction in serum.
  • Recombinant human granulocyte colony stimulating factor (rhG-CSF, Wheel's blood) and / or recombinant human granulocyte colony stimulating factor (rhGM-CSF, whitening energy) are mainly used clinically to promote the recovery of hematopoietic function. They directly stimulate the proliferation of granulocytic hematopoietic progenitor cells, shorten the recovery time of leukocytes and neutrophils, and have high efficacy, but they are expensive and overburdened by the working class.
  • Tumors and leukemia cells have normal receptors for CSF. After treatment, it may increase the tumor recurrence rate by increasing the proliferation of host residual tumor cells; (2) ) CSF directly stimulates the proliferation of hematopoietic progenitor cells without self-renewal ability, leading to the depletion of hematopoietic progenitor cells; (3) selectively promotes the proliferation of granulocyte progenitor cells, but has no promotion effect on red blood cells and megakaryocytes; (4) clinical The use of white blood cells needs to be closely monitored to prevent juvenile cell proliferation.
  • the object of the present invention is to provide a new hematopoietic factor that promotes the proliferation of hematopoietic cells, mainly granulocytes, without stimulating the proliferation of some tumor cells.
  • Another object of the present invention is to provide a pharmaceutical composition for promoting the proliferation of hematopoietic cells mainly composed of granulocytes.
  • a pharmaceutical composition for promoting the proliferation of hematopoietic cells mainly composed of granulocytes.
  • OGP osteogenic growth peptide
  • the pharmaceutical composition treats the following diseases or conditions:
  • the pharmaceutical composition contains an osteogenic growth peptide and a hematopoietic factor selected from the group consisting of G-CSF, GM_CSF, TP0, or a mixture thereof.
  • OGP is used to prepare a pharmaceutical composition that promotes granulocyte proliferation.
  • the pharmaceutical composition is used before, during, or after radiotherapy or chemotherapy.
  • a method for promoting the growth of granulocyte progenitor cells in vitro comprising the steps of: culturing granulocyte progenitor cells in a medium suitable for the growth of granulocyte progenitor cells, wherein the medium contains 10- 14 -10- 5 mol / L osteogenic growth peptide.
  • said medium containing l (T 13 -l (T 5 m 0 l / L of osteogenic growth peptide more preferably the medium containing l (T 12 -l ( T 5 m 0 l / L osteogenic growth peptide.
  • Figure 1 shows the effect of sOGP on the number of white blood cells (WBC) in mice at different times after 4Gy irradiation.
  • Figure 2 shows the effect of different doses of sOGP on the number of white blood cells (WBC) on the 8th day after 4Gy irradiation in mice.
  • Figure 3 shows the effect of different doses of sOGP on the number of bone marrow nucleated cells on the 8th day after 4Gy irradiation in mice.
  • Figure 4 shows the effect of different doses of sOGP on the CFU-S and spleen coefficient of mice after 7.5Gy irradiation.
  • Figure 5 shows the effect of different doses of sOGP on the number of white blood cells (WBC) in normal mice
  • Figure 6 shows the effect of different doses of sOGP on the number of bone marrow nucleated cells in normal mice.
  • Figure 7 shows the effects of different doses of sOGP on colony formation of isolated human bone marrow granulocyte progenitor cells in vitro.
  • Figure 8 shows the effect of different doses of sOGP on the proliferation of erythroleukemia TF-1 cells. detailed description
  • sOGP can promote the proliferation of normal human bone marrow granulocyte progenitor cells, and that the colony formation rate of granulocyte progenitor cells in vitro cultures increases with increasing sOGP concentration within a certain concentration range , Showing a clear dose-response relationship.
  • sOGP can promote the recovery of hypopoietic function caused by radiation damage and chemotherapy drugs.
  • Subcutaneous injection of sOGP after 4Gy irradiation in mice can accelerate the recovery of peripheral blood leukocytes and bone marrow nucleated cells. It is significantly higher than the irradiation control group, showing a dose-response relationship within a certain dose range.
  • SOGP can also make the CFU-S and corresponding spleen coefficient of 7.5Gy irradiation mice significantly higher than the irradiation control group, and promote extramedullary hematopoietic.
  • sOGP can promote the recovery of bone marrow nucleated cells and peripheral blood leukocytes in mice injected with the chemotherapy drug cyclophosphamide, which is significantly different from the cyclophosphamide control group.
  • the animal experimental study of the present invention also found that sOGP can promote the increase of the number of nucleated cells in bone marrow of normal mice by 15-20%, increase the number of peripheral blood WBC by 30-40%, and increase platelets and red blood cells by about 10%, indicating that sOGP can promote Granulocytes are mainly hematopoiesis, and red and platelet lines are also increasing.
  • These studies of the present invention show that OGP can be regarded as an effective hematopoietic factor, and can have clinical application prospects.
  • one of the prerequisites for the restoration of normal hematopoietic and bone marrow transplantation is the existence of functional stromal cells and tissues that make up the hematopoietic microenvironment, which determines the proliferation of residual hematopoietic stem cells and the injection of hematopoietic stem cells from peripheral blood circulation into bone marrow tissue. And support hematopoiesis.
  • bone marrow containing stromal tissue can maintain the survival of hematopoietic stem cells.
  • Adding an appropriate amount of sOGP that promotes hematopoietic effects in this culture system will help the expansion of hematopoietic stem cells in vitro and provide more hematopoietic stem cells for transplantation. Combining in vivo and in vitro methods will provide a more effective solution for bone marrow transplantation.
  • sOGP stimulates the proliferation of bone marrow mesenchymal stem cells in the body, improves the hematopoietic microenvironment (mainly including fibrous tissue, bone and osteocytes), promotes the recovery of hematopoietic function that occurs naturally or induced bone marrow suppression or injury, and can stimulate the bone marrow Hematopoietic reconstruction after transplantation.
  • OGP organic radical polymer derived from OGP.
  • OGP organic radical polymer derived from OGP.
  • synthetic peptides include synthetic peptides, all homologues, isomers or genetic variants, and all other variants of OGP.
  • OGP is a single polypeptide with a defined sequence (Ala-Leu- Lys-Arg- Gln- Gly- Arg- Thr- Leu- Tyr- Gly- Phe- Gly_Gly).
  • genetic variant refers to a conserved sequence that contains at least about 40% of the native OGP amino acid sequence, a polypeptide that contains at least about 60% of the conserved sequence is preferentially protected, and a polypeptide that contains at least about 75% of the conserved sequence is more preferred.
  • the osteogenic growth peptide used in the present invention has the following amino acid sequence: Ala-Leu- Lys- Arg- Gln-Gly-Arg- Thr-Leu-Tyr_Gly_Phe- Gly-Gly.
  • OGP OGP-derived neuropeptide
  • the present invention also includes various OGPs and fragments thereof, as long as the purified polypeptide exhibits osteogenic and hematopoietic effects in vitro and in vivo.
  • OGP fragments may be small peptides containing 6 or more amino acids.
  • Polypeptides larger than 0GP and having osteogenic and hematopoietic effects are also included in the scope of the present invention.
  • OGP can be prepared by isolation, recombination, and artificial methods.
  • the sOGP artificially synthesized by the biochemical method is consistent with the structure of the naturally occurring OGP in the serum, and has the effect of promoting bone formation and hematopoiesis.
  • a pharmaceutical composition comprising the above-mentioned OGP polypeptide, said pharmaceutical composition comprising the OGP polypeptide as a basic active ingredient and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition of the OGP polypeptide is preferably non-toxic and dosage-stable.
  • the pharmaceutical composition of the present invention has the ability to improve the proliferative activity of human and mammalian hematopoietic stem / progenitor cells, and promotes hematopoietic reconstruction, and can be used to treat hypoxia caused by bone marrow injury caused by radiotherapy, chemotherapy or spontaneous, and promote bone marrow transplantation in China and abroad. Implantation of derived hematopoietic cells shortens recovery time and has no stimulating proliferation effect on some tumor cells.
  • the 0GP pharmaceutical composition of the present invention can promote the proliferation of bone marrow mesenchymal stem cells, improve the hematopoietic microenvironment, and benefit hematopoietic stem / progenitors.
  • Cell proliferation, speeding up the recovery of peripheral blood cells has the advantages of mitigating effects, two-way regulation, easy control, etc., and has no effect on promoting proliferation of leukemia cells such as human TF-1.
  • the main component that exerts a medicinal effect in the pharmaceutical composition of OGP of the present invention has the same structure as the naturally occurring human OGP, thereby significantly avoiding immunogenicity that may be caused after long-term use.
  • OGP peptides prepared by biochemical synthesis or by recombinant DNA technology can also be prepared into pharmaceutically acceptable salts, especially base addition salts, by various known methods.
  • these peptides can be treated with a suitable base in accordance with methods well known to those skilled in the art to prepare base addition salts of acidic amino acids.
  • OGP polypeptides can be made to suit specific clinical administration methods according to conventional methods known in the pharmaceutical field Formula of a drug compound.
  • an appropriate carrier or diluent such as water, physiological saline, isotonic glucose solution can be added to the OGP to prepare solutions, injections, emulsions, nasal drops, eye drops that can be administered by routes other than the gastrointestinal tract.
  • Excipients or carriers such as starch, lactose, talc, sucrose, glucose or glycerin, liquid paraffin, liposomes, or gelatin can also be added to make OGP into suppositories, tablets, and powders that can be administered via the gastrointestinal tract. , Granules, capsules or liposome encapsulants.
  • these preparations can also be supplemented with other auxiliary ingredients as needed, such as one or more diluents, fillers, emulsifiers, preservatives, surfactants, absorption Accelerators, buffers, fragrances and colorants.
  • auxiliary ingredients such as one or more diluents, fillers, emulsifiers, preservatives, surfactants, absorption Accelerators, buffers, fragrances and colorants.
  • the OGP pharmaceutical composition of the present invention can be administered by various conventional administration routes, for example, it can be administered via the gastrointestinal tract, subcutaneously, intradermally, intranasally, intravenously, intramuscularly, intrarectally, intraocularly, etc., but Among them, the preferred route of administration is intramuscular injection, subcutaneous injection, nasal spray or oral administration.
  • the OGP pharmaceutical composition of the present invention can also be administered at any time, for example, before, during, or after radiotherapy or chemotherapy.
  • the OGP peptides or their salts or pharmaceutical compositions containing these peptides or their salts of the present invention can be used to treat hematopoietic diseases caused by radiation, chemotherapy, or naturally occurring bone marrow injury Low function, speed up the implantation of bone marrow transplantation, and promote hematopoietic reconstruction.
  • 0GP can be applied in the following areas:
  • 0GP can treat osteoporosis, promote fracture healing and cartilage repair, at the same time can promote hematopoiesis, improve immunity, and improve the quality of life of patients.
  • the present invention is further described below with reference to specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention.
  • the experimental methods without specific conditions in the following examples are generally based on conventional conditions, for example, Sambrook et al., Molecular Cloning: The conditions described in the laboratory manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturing conditions Conditions recommended by the manufacturer.
  • Example 1
  • the purpose of this embodiment is to observe the therapeutic effect of sOGP on leukocytopenia, and to find a safe and effective drug for the treatment of tumor patients with low blood production caused by bone marrow injury after radiotherapy and chemotherapy.
  • Group A normal control group, without irradiation
  • Group B irradiation control group
  • Group C Huer blood positive drug control group, 10 g / kg / day;
  • Group D 0GP medication group, divided into 9 dose points
  • BMNC 1Bone marrow nucleated cells
  • WBC White blood cell
  • CFU-S 1 endogenous spleen nodules
  • mice were subcutaneously injected with SOGP 14 days after 4Gy irradiation, and the number of bone marrow nucleated cells increased significantly from 0. 025 to 12.80 nmol / mouse dose group compared with the irradiation control (P ⁇ 0. 01 ⁇ 0. 001) , Similar to the role of Wheeler blood.
  • the spleen nodules on the 8th day after irradiating the mice with a sublethal dose of 7.5 Gy showed that the number of CFU-S in the control group was significantly increased compared with the control group, and the spleen coefficient was significantly reduced.
  • different doses of sOGP were given.
  • the CFU-S in the dose group of 0. 02-2. 5nmol / rat / day was significantly higher than that in the irradiation control group (P ⁇ 0. 05 ⁇ 0. 01), and the spleen coefficient also increased significantly. (P ⁇ 0. 05), similar to the effect of Wheel's blood.
  • the purpose of this example is to observe whether sOGP can promote the hematopoietic function of normal mice, and provide a basis for the future clinical treatment of osteoporosis and fractures while improving the hematopoietic function, which is conducive to enhancing the immunity and improving the therapeutic effect.
  • Group A blank control group
  • Group B sOGP medication group, divided into 3 dose points
  • mice Normal mice were sc sOGP continuously for 14 days, and the following indicators were detected: 1 Peripheral blood: WBC, Pit, RBC 2 BMNC number, 3 Bone marrow cell classification count. Results:
  • mice sc s0GP 3 different doses 0.02, 0.10, and 0.50 nmol / mouse 14 days later, the three dose groups significantly increased peripheral blood WBC numbers by 30 to 40% compared to the blank control group ( Figure 5). Platelets And red blood cells increased by about 5-10%, indicating that sOGP mainly promotes granulocytic hematopoiesis, and the red and platelet lines also have an increasing trend.
  • the B-C number of the three dose groups of sOGP increased significantly by 15-20% compared with the blank control group.
  • Bone myeloid cell counts showed that the proportion of bone marrow cells in the sOGP group was the same as that of the blank control mice, but the sOGP group division index was 2 / 6 ⁇ 2, indicating that the bone marrow cell proliferation of the 0GP group was more active than that of the blank control group.
  • the particle red ratio of the drug group was 5/6> 1, and the latter was 3/6> 1.
  • the granulocyte proliferation was more significant.
  • 0GP makes the changes of bone marrow consistent with the peripheral blood, and promotes hematopoietic hematopoiesis.
  • Bone marrow cell semi-solid colony culture method was used. Bone marrow cell suspension was first prepared, and the cell concentration was adjusted to 1 X 10 6 cells / ml with RPMI-1640. Different concentrations of sOGP and Hueyer blood were added to the culture system, and cultured at 37 ° C and 5% C0 2 11 On the day, the number of CFU-G colonies was counted under a microscope (1 colony above 50 cells). The experiment was divided into three groups, that is, the negative control group (excluding sOGP and G-CSF), the Huey blood (G-CSF) positive control group, and the sOGP experimental group with different concentrations, and each experimental point was repeated 3-4 dishes. result: It can be seen from FIG.
  • Huer Blood directly stimulates the proliferation of granulocyte progenitor cells, and OGP may exert its hematopoietic activity by stimulating bone marrow mesenchymal stem cells, improving the hematopoietic microenvironment, and other mechanisms.
  • Example 4 Huer Blood directly stimulates the proliferation of granulocyte progenitor cells, and OGP may exert its hematopoietic activity by stimulating bone marrow mesenchymal stem cells, improving the hematopoietic microenvironment, and other mechanisms.
  • MTT solution add 5mg / ml MTT solution 10 ⁇ 1 to each well, and continue to culture for 4-6 hours;
  • the 0D value of the whitening-positive control group increased significantly with increasing concentration, and in the low concentration of whitening-energy range, the 0D value was very close to the negative control group, indicating that the whitening energy was within a certain range. Within the concentration range, it can significantly promote the proliferation of human erythroleukemia TF-1 cells and has a significant dose-effect relationship.
  • the OD value of each concentration gradient group of sOGP was similar to that of the negative control group, indicating that within this concentration range, sOGP did not promote the proliferation of CSF-dependent TF-1 red leukemia cells.

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  • Health & Medical Sciences (AREA)
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Abstract

Le peptide de croissance ostéogénique (OGP) est un type de polypeptide possédant 14 résidus d'acide aminé et est présent dans le corps de l'animal et de l'humain. Selon l'invention, l'OGP favorise non seulement l'ossification mais également la prolifération des cellules hématopoïétiques. L'invention porte sur l'utilisation du peptide de croissance ostéogénique dans la préparation d'une composition pharmaceutique pour améliorer la prolifération des cellules hématopoïétiques, telles que les granulocytes. Elle porte également sur un procédé d'utilisation de l'OGP dans le développement de cellule souche de granulocyte in vitro. L'OGP est différent du facteur de stimulation des granulocytes et granulocytes monocytes, en ce qu'il ne stimule pas les cellules leucémiques, telles que le TF-1 humain.
PCT/CN2002/000772 2001-11-23 2002-10-31 Utilisation du peptide de croissance osteogenique dans la'melioriation de l'hemopoiese WO2003049754A1 (fr)

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AU2002349719A AU2002349719A1 (en) 2001-11-23 2002-10-31 The use of osteogenic growth peptide in the enhancement of haemopoiesis

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CN01132276.4 2001-11-23
CNB011322764A CN1189209C (zh) 2001-11-23 2001-11-23 成骨生长肽在促进造血方面的应用

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024122716A1 (fr) * 2022-12-09 2024-06-13 (주)케어젠 Peptide pour régénérer le cartilage et ses utilisations

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114748604B (zh) * 2022-05-10 2023-04-07 四川大学 一种用于骨髓损伤和/或抑制的复合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992009697A1 (fr) * 1990-11-30 1992-06-11 Celtrix Laboratories, Inc. UTILISATION EN OSTEOPATHIE D'UNE PROTEINE MORPHOGENETIQUE D'ORIGINE OSSEUSE ASSOCIEE DE MANIERE SYNERGIQUE AVEC DU BETA DE FACTEUR DE CROISSANCE DE TRANSFORMATION (β-FCT).
WO1994020529A1 (fr) * 1993-03-04 1994-09-15 Yissum Research Development Company Oligopeptides de croissance osteogene et compositions pharmaceutiques les contenant
WO1995000166A1 (fr) * 1993-06-18 1995-01-05 Yissum Research Development Company Compositions pharmaceutiques utilisees pour stimuler la reconstruction du micro-environnement hematopoietique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992009697A1 (fr) * 1990-11-30 1992-06-11 Celtrix Laboratories, Inc. UTILISATION EN OSTEOPATHIE D'UNE PROTEINE MORPHOGENETIQUE D'ORIGINE OSSEUSE ASSOCIEE DE MANIERE SYNERGIQUE AVEC DU BETA DE FACTEUR DE CROISSANCE DE TRANSFORMATION (β-FCT).
WO1994020529A1 (fr) * 1993-03-04 1994-09-15 Yissum Research Development Company Oligopeptides de croissance osteogene et compositions pharmaceutiques les contenant
WO1995000166A1 (fr) * 1993-06-18 1995-01-05 Yissum Research Development Company Compositions pharmaceutiques utilisees pour stimuler la reconstruction du micro-environnement hematopoietique

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024122716A1 (fr) * 2022-12-09 2024-06-13 (주)케어젠 Peptide pour régénérer le cartilage et ses utilisations

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AU2002349719A1 (en) 2003-06-23
CN1189209C (zh) 2005-02-16

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