JPS62252729A - Promote for recovering hematopoietic function - Google Patents
Promote for recovering hematopoietic functionInfo
- Publication number
- JPS62252729A JPS62252729A JP62010037A JP1003787A JPS62252729A JP S62252729 A JPS62252729 A JP S62252729A JP 62010037 A JP62010037 A JP 62010037A JP 1003787 A JP1003787 A JP 1003787A JP S62252729 A JPS62252729 A JP S62252729A
- Authority
- JP
- Japan
- Prior art keywords
- hematopoietic function
- leu
- amino acid
- acid sequence
- hematopoietic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Landscapes
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Abstract
Description
【発明の詳細な説明】
(産業上の利用分野)
本発明はヒト顆粒球コロニー刺激因子(以下G−C3F
と略す)を有効成分と覆る骨髄移植後の造血機能回復促
進剤に関する。DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to human granulocyte colony stimulating factor (hereinafter referred to as G-C3F).
The present invention relates to an agent for promoting recovery of hematopoietic function after bone marrow transplantation, which contains as an active ingredient
(従来の技術〕
骨髄移植(以下BMTとei>とは先天的または後人的
な造血障害を示ブ患者に対し、健康な他人または自己の
骨髄を移植することをいう。(Prior Art) Bone marrow transplantation (hereinafter referred to as BMT) refers to the transplantation of healthy bone marrow from another person or from one's own body to a patient exhibiting a congenital or acquired hematopoietic disorder.
近年このBMTは白血病、悪性リンパ腫などの血液疾患
や、ある種のガンに対する治療法として精ツノ的に行わ
れるようになってぎている。そして、その効果もあがり
つつおる。〔臨床と研究、61巻、1480−1487
. (1984) ;二[クスペリメンタル へマトロ
ジ−(Exp、tlematol、)、 12205−
215(1984)参照〕しかし、この治療法も臨床上
いくつかの問題点がある。In recent years, BMT has been increasingly used as a treatment for blood diseases such as leukemia and malignant lymphoma, as well as certain types of cancer. And the effects are increasing. [Clinical and Research, Vol. 61, 1480-1487
.. (1984); 2 [Experimental Hematology (Exp, Tlematol), 12205-
215 (1984)] However, this treatment method also has some clinical problems.
BMT直後の感染、間質性肺炎(IP)、移植片対宿主
病(GVHD)等がその主なものである。The main causes include infection immediately after BMT, interstitial pneumonia (IP), and graft-versus-host disease (GVHD).
このうち感染はBMT直後の無造血期におこるもので、
これに対する対策としては現在、無菌室療法がとられて
いる。ところが、患者の造血機能が回復してくるまでに
3週間程度の期間が必要であり、遅い場合には1ケ月以
上かかることがある。Of these, infection occurs during the non-hematopoietic period immediately after BMT.
As a countermeasure against this, sterile room therapy is currently being used. However, it takes about three weeks for the patient's hematopoietic function to recover, and in some cases it may take more than a month.
この間患者を無菌室内において治療するわけであるが、
この治療は高価であり、患者にとって経済的な負担が過
大になるのみならず、医師にとっても多大の労力を余儀
無くされるという問題点を有している。During this time, the patient will be treated in a sterile room.
This treatment is expensive and has the problem that it not only imposes an excessive financial burden on the patient, but also requires a great deal of effort on the part of the doctor.
IPは移植成立後発症する場合が多い。IPに対する対
策としてはスルファメトキリゾール−トリメトプリム(
Sulfamethoxazole−rrimettt
oprim)の、いわゆるST合剤の予防的投与が実施
されているが、ST合剤には骨髄抑制作用があるため、
造血機能が充分回復した患者でないと使用できない〔臨
床免疫第15巻、第9号、700−707(1983)
、臨床免疫第15巻、第9号、687−699(19
83) ;Exp、 flema【ol、第12巻、2
05〜215(1984)参照)。又、GVHDは移植
片生着後おこる急性G V HDが警戒すべきものであ
るが、この予防に投与されるメ1〜トレキビ−1−(M
TX)にも骨髄抑制があり、又、最近使用されるように
なったシクロスポリンA(C3A)にも強い腎毒性があ
るという問題をかかえている(臨床とω(究、第61巻
、第5号、1480−1487(1984)参照)。い
ずれにしてもこの様な状況下にあってBMT後の造血機
能の早期回復が強く望まれるところである。IP often develops after transplantation. As a countermeasure against IP, sulfamethoxylizole-trimethoprim (
Sulfamethoxazole-rrimett
Prophylactic administration of a so-called ST combination drug (oprim) has been carried out, but since the ST combination drug has a myelosuppressive effect,
Can only be used in patients whose hematopoietic function has fully recovered [Clinical Immunology Vol. 15, No. 9, 700-707 (1983)
, Clinical Immunology Vol. 15, No. 9, 687-699 (19
83) ;Exp, flema [ol, Vol. 12, 2
05-215 (1984)). In addition, acute GVHD that occurs after graft survival is something to be wary of;
TX) also causes bone marrow suppression, and cyclosporine A (C3A), which has recently been used, has the problem of strong nephrotoxicity (Clinical and ω (Research, Vol. 61, No. 5). No. 1480-1487 (1984)).In any case, under these circumstances, early recovery of hematopoietic function after BMT is strongly desired.
しかしながら、現在のところ、こtしに答うべき適切な
薬剤がないため、患者の造血機能が自然に回復してくる
のを待っているという状態である。However, at present, there is no appropriate drug to address this issue, so patients are left waiting for the patient's hematopoietic function to recover naturally.
このような状況を打開するべく検討を重ねた結果、本出
願人が先に出願し製造に成功した純粋なヒトG−C8F
を利用することに着想し、これを実現サペくω1究を更
に進めた。As a result of repeated studies to overcome this situation, we have developed pure human G-C8F, which the applicant had previously applied for and successfully manufactured.
I came up with the idea of using this, and further advanced my ω1 research to realize this idea.
なお、C3Fとはヒ1〜又は動物の骨髄細胞の顆粒球系
幹細胞に作用して単球・マクロファージ及び好中球への
分裂増殖と分化とを誘導する因子であって、(Hetc
alt等;エクスペリメンタル へマトロジ−(Exp
、 Hematol、 )1 、185. (1973
)参照)、ヒ]〜−〇SFに関しても、これまでに多数
の報告が既になされている。(Stanley等、フエ
デラルプロシーデング(Fed、Proc、) 35.
2272(1975); Burgass等、ブラッド
(Bfood) 49.573(1977)、その他多
数あり〕
しかし、前述のC3Fは完全に純化されたものではなく
、又純粋で均質の大量生産可能な取得法も確立していな
かった。In addition, C3F is a factor that acts on granulocytic stem cells of human or animal bone marrow cells to induce proliferation and differentiation into monocytes, macrophages, and neutrophils.
alt etc; Experimental hematology (Exp
, Hematol, )1, 185. (1973
), h]~-○ SF have already been reported in large numbers. (Stanley et al., Federal Proceedings (Fed, Proc.) 35.
2272 (1975); Burgas et al., Bfood 49.573 (1977), and many others] However, the above-mentioned C3F is not completely purified, and there is no method for obtaining pure and homogeneous C3F that can be mass-produced. It had not been established.
BMT後の造血能回復を促進プる薬剤の開発のためには
、大量均一なG−C3Fの取得が前(?であり、本出願
人の先の成功(特願昭59.−153273@。In order to develop a drug that promotes the recovery of hematopoietic ability after BMT, it is necessary to obtain a large amount of uniform G-C3F, and the present applicant's previous success was achieved (Japanese Patent Application No. 59-153273@).
特願昭60−220450号、特願昭60−26945
5号、特願昭60−269456@、特願昭60−27
0838号、特願昭60−270839号参照)はこれ
を−挙に可能にしたのである。Patent Application No. 1983-220450, Patent Application No. 1983-26945
No. 5, patent application No. 60-269456@, patent application No. 60-27
No. 0838, Japanese Patent Application No. 60-270839) has made this possible.
そこで、本発明者は該ヒl”G C3Fをマウスに連
[1投与したところj6血機能の昂進があることを認め
た。(実験例1参照)
ついで、G−C3Fを[3MT後の造血機能回復促進^
IIとして用いうるが否かについて検問を行ったところ
G−C3F投−り群にCF U −Sの増加が認められ
た。これによってG−C3FにB M T 1!2の造
血機能促進効果のあることが確認されたのである。(実
験例2参照)
又、造血機能の回復が遅い実験系においては、コントロ
ール群で生存率が33%であるのに対し、G−C3F投
与群は75%の高率を示す事が確認された。これはG−
C3Fの造血機能促進効果の表れである。(実験例3参
照)
本発明者は以上の知見に基づき本発明を完成した。Therefore, the present inventor found that when the human G-C3F was continuously administered to mice, blood function was enhanced (see Experimental Example 1). Promote functional recovery^
When examining whether or not it could be used as II, an increase in CFU-S was observed in the G-C3F throwing group. This confirmed that G-C3F has an effect of promoting hematopoietic function of BMT 1!2. (See Experimental Example 2) In addition, in an experimental system where recovery of hematopoietic function is slow, it was confirmed that the survival rate was 33% in the control group, while the survival rate was as high as 75% in the G-C3F administration group. Ta. This is G-
This is an expression of the hematopoietic function promoting effect of C3F. (See Experimental Example 3) The present inventor completed the present invention based on the above knowledge.
本発明はヒhG−C5Fを有効成分とする[3MT後の
造血機能回復促進剤を提供する・bのである。The present invention provides an agent for promoting recovery of hematopoietic function after 3MT, which contains human hG-C5F as an active ingredient.
本発明の有効成分であるヒ1−G−C3FはII!度が
高く単離されたヒトG−csr:であればぞの由来は問
わないが、本出願人が先に出願した方法によって取得さ
れた下記のヒトG−C3Fが特に好ましく用いられる。Hi-1-G-C3F, which is the active ingredient of the present invention, is II! Highly isolated human G-csr: Although its origin does not matter, the following human G-C3F obtained by the method previously filed by the present applicant is particularly preferably used.
(1)次の理化学的性質を有するヒトG−C3F。(1) Human G-C3F having the following physical and chemical properties.
■分子間ニドデシル硫酸Jトリウム−ポリアクリルアミ
ドゲル電気泳動法による測定で
19000±1ooo。■19000±1ooo as measured by intermolecular nidodecyl sulfate J thorium-polyacrylamide gel electrophoresis.
■等電点: PI =5.5±0.1 、 p I=5
.8±0.1゜p)=8.1±o、iの三つの等電点の
うら少なくとも1つを有する。■Isoelectric point: PI=5.5±0.1, pI=5
.. 8±0.1°p)=8.1±o, i has at least one of the three isoelectric points.
■紫外部吸収: 280nmに極大吸収を有し、250
nmに極少値を持つ。■Ultraviolet absorption: Maximum absorption at 280 nm, 250 nm
It has a minimum value in nm.
(4)N末端から21番目迄のアミノ酸配列が次の如く
である。(4) The amino acid sequence from the N-terminus to the 21st is as follows.
112N−rhr−Pro−Leu−Gly−Pro−
^1a−3er−3er−LeLl−PrO−G l
n−3er−Phe−Leu−Leu−Lys−Cys
−Leu−G I u−G I n−Va I −(2
)次のアミノ酸配列またはその一部で表わされるポリペ
プチドを有するヒトG−C3F。112N-rhr-Pro-Leu-Gly-Pro-
^1a-3er-3er-LeLl-PrO-G l
n-3er-Phe-Leu-Leu-Lys-Cys
-Leu-G I u-G I n-Va I -(2
) Human G-C3F having a polypeptide represented by the following amino acid sequence or a part thereof.
(Net)n Thr Pro Leu Gly P
ro Ala Ser Ser LeuPro Gl
n Ser Phe Leu Leu Lys C
ys Leu Clu Ginvat^rg Lys
Ile Gln Qly Asp Gly Ala A
la LeuGln Glu Lys X Cy
s Ala Thr Tyr Lys Leu
Cys旧s Pro Glu C1u Leu
Vat Leu Leu Gly 1li
s 5erLeu Gly Ile Pro Trp
^Ia Pro Leu Scr Scr CysPr
o Ser Gln 八la Leu Gln
Leu Ala GIyCVS LeuSer G
ln Leu His Ser Gly Leu Ph
e Leu Tyr GlnGly Leu Leu
Gln Ala Lcu Glu Gly Ile
Ser Pr。(Net)n Thr Pro Leu Gly P
ro Ala Ser Ser Ser LeuPro Gl
n Ser Phe Leu Leu Lys C
ys Leu Clu Ginvat^rg Lys
Ile Gln Qly Asp Gly Ala A
la LeuGln Glu Lys X Cy
s Ala Thr Tyr Lys Leu
Cys old s Pro Glu C1u Leu
Vat Leu Leu Gly 1li
s 5erLeu Gly Ile Pro Trp
^Ia Pro Leu Scr CysPr
o Ser Gln 八la Leu Gln
Leu Ala GIyCVS LeuSer G
ln Leu His Ser Gly Leu Ph
e Leu Tyr GlnGly Leu Leu
Gln Ala Lcu Glu Gly Ile
Ser Pr.
Glu Leu Gly Pro ’rhr Leu
Asp Tt+r Leu Gln Leu八3へ
vat Ala Asp Phe Ala
rhr Thr Ile rrp GlnGl
n Het Qlu Glu Leu Gly Met
Ala Pro Aha LeuGln Pro
丁hr Gln Gly Ala Met
Pro Ala Phe ^1aSer Al
a Phe Gln^rg^rg^Ia Gly Gl
y Vat LeuVat^Ia Ser tlis
Leu Gln Ser PhOLOu c+u Va
tSer ryr Arg Val Leu Arg
1lis Leu^Ia Gln Pr。Glu Leu Gly Pro 'rhr Leu
Asp Tt+r Leu Gln Leu 83
vat Ala Asp Phe Ala
rhr Thr Ile rrp GlnGl
n Het Qlu Glu Leu Gly Met
Ala Pro Aha LeuGln Pro
Dinghr Gln Gly Ala Met
Pro Ala Phe ^1aSer Al
a Phe Gln^rg^rg^Ia Gly Gl
y Vat LeuVat^Ia Ser tlis
Leu Gln Ser PhOLou c+u Va
tSer ryr Arg Val Leu Arg
1lis Leu^Ia Gln Pr.
(式中Xはteu又は1.eu−Vat−3er−Gl
uを示し、「1はO又は1を示す)
なお、上記のヒl〜G−C3Fで糖鎖部分を持つ糖蛋白
質の形をとるものが最も好ましいものである。(In the formula, X is teu or 1.eu-Vat-3er-Gl
(1 represents O or 1) In addition, the above-mentioned H1~G-C3F in the form of a glycoprotein having a sugar chain moiety is most preferable.
上記(1)のG−C3Fは特願昭59−153273号
明細よ又は特願昭60−220450月明細書に記載さ
れた製造法によって1qることかできる。The above (1) G-C3F can be produced by the production method described in Japanese Patent Application No. 59-153273 or Japanese Patent Application No. 1987-220450.
前者には、本出願人によって仏画パスツールω1に寄託
されているヒドロ腔底癌山来の細胞株C[−1U−1(
(C,N、C,H,)寄託?ftft−315)の培養
上清から単一【取17する方法が詳述されており、また
後者には同じくヒト[1腔底癌山来の細胞株CI−IU
−2((C,N、C,M、)寄託番号■−483)の培
養上清から製造する方法が記載されている。The former includes the cell line C[-1U-1(
(C, N, C, H,) Deposit? ftft-315) from the culture supernatant;
-2 ((C,N,C,M,) Deposit No. ■-483) is produced from the culture supernatant.
詳しくは夫々の明細書を参照されたい。Please refer to the respective specifications for details.
又(2)のG−C3Fは特願昭60−2694559.
特願昭60−269456号、特願昭60−27083
8号及び特願昭60−270839号の各明細書に記載
された製造方法によって得ることができる。これ等の各
明細書に記載されている方法はいわゆる道仏子組換え技
術による方法である。Moreover, G-C3F in (2) is patent application No. 60-2694559.
Patent Application No. 1983-269456, Patent Application No. 1983-27083
8 and Japanese Patent Application No. 60-270839. The methods described in each of these specifications are methods based on the so-called Daobutsu recombinant technology.
最初の2件には、E、coli’9の原核生物を宿主細
胞とする方法が、又後の2ftには、動物細胞を宿主と
する方法が開示されているので詳しくは夫々の明細書を
参照していただきたい。The first two articles disclose a method using E. coli'9 prokaryotes as host cells, and the second 2ft discloses a method using animal cells as hosts, so please refer to the respective specifications for details. Please refer to it.
なお、前述した糖鎖部分を有りる糖蛋白質の形をとるG
−C3Fは動物細胞を宿主とプる方法によって製造する
ことができる。In addition, G in the form of a glycoprotein that has the aforementioned sugar chain moiety
-C3F can be produced by using animal cells as a host.
1qられたヒトG−C3Fは凍結保存とするか又は凍結
乾燥、真空乾燥等の手段により水分を除去して保存する
ことができる。1q human G-C3F can be stored frozen or by removing moisture by freeze drying, vacuum drying, or the like.
又、所望によりヒj−G−C3Fを適当な緩衝液に溶解
した後にミリポアフィルタ−等で無菌濾過して注01剤
とすること−しできる。Furthermore, if desired, Hj-G-C3F can be dissolved in a suitable buffer solution and then sterile filtered using a Millipore filter or the like to prepare an injection agent.
更に本発明の造血機能回復促進剤は医薬製剤としての形
態をとるために必要な製剤担体や賦形剤を、更には安定
化剤、吸看防止剤を含むことができる。Furthermore, the hematopoietic function recovery promoting agent of the present invention can contain a pharmaceutical carrier and excipients necessary for taking the form of a pharmaceutical preparation, as well as a stabilizer and an adsorption prevention agent.
本発明の造血機能回復促進剤に含まれるヒトG−C3F
の投与量及び投、り回数は対象の疾患患者の病状を配慮
して決めることができるが、通常成人−人当りo、i〜
500μ9、好ましくは5〜io。Human G-C3F contained in the hematopoietic function recovery promoter of the present invention
The dosage and frequency of administration can be determined by taking into consideration the condition of the patient with the target disease, but it is usually administered at a dosage of o, i~ per adult.
500 μ9, preferably 5 to io.
μりのヒ]〜G−C3Fを含有する製剤を1週問に1〜
7回投与することができる。しかし本発明はヒトG−C
3Fの含有量によって限定されるものではない。μri-no-hi] ~ G-C3F-containing preparations once per week
Can be administered 7 times. However, the present invention
It is not limited by the content of 3F.
以下本発明を参考例(G−C8Fの製造例)、実験例(
薬理効果)、実施例(製剤例)を必げて説明するが、本
発明はこれ等に限定されるものではない。The present invention will be described below as a reference example (manufacturing example of G-C8F) and an experimental example (
Pharmacological effects) and Examples (formulation examples) will be described, but the present invention is not limited thereto.
参考例〔動物細胞(マウスC127細胞)を用いたヒト
G−C8Fの製造例〕
特願昭60−269456号明細書の実施例1〜12に
記載された方法でPTN−V2プラスミドを得、これを
Barrll−11で処理しておく。即ら、pT N
−v2プラスミド20μ(Jを1nm8 T r i
s−ト1c、l1(II 8.0> 、 7
l1lN M(JCl 、 100 mM
NaC,l!、2mH2−メルカプトエタノールB
SA100 uflに溶解uしめBamtiI(宝酒造
社製)20単位で処理し、フェノール処理、エーテル処
理、エタノール沈澱を行っておく。Reference Example [Example of production of human G-C8F using animal cells (mouse C127 cells)] A PTN-V2 plasmid was obtained by the method described in Examples 1 to 12 of Japanese Patent Application No. 60-269456, and this is treated with Barrll-11. That is, pT N
-v2 plasmid 20 μ (J 1 nm 8 Tri
s-t 1c, l1 (II 8.0>, 7
l1lN M (JCl, 100 mM
NaC,l! , 2mH2-mercaptoethanol B
Dissolved in SA100 ufl and treated with 20 units of BamtiI (manufactured by Takara Shuzo Co., Ltd.), followed by phenol treatment, ether treatment, and ethanol precipitation.
一方、マウスC127細胞は10%牛脂児血清(GIB
CO)を含むDLIIbQCCO’S minimal
essential培地中で増殖させる。径5cmの
プレートに増殖したC127細胞に、プレート当たり上
記調製DNAを10μ9の割り合いでリン酸−カルシウ
ム法(Haynes,J&Weissmann,C(1
983)Nucleic AcidRes, 11 、
887 − 706参照)にて形質転換を行い、グリ
レロール処理の後、12時間37°Cでインキュベート
した。On the other hand, mouse C127 cells were prepared using 10% beef tallow serum (GIB).
DLIIbQCCO'S minimal including CO)
Grow in essential medium. C127 cells grown on 5 cm diameter plates were treated with the above prepared DNA at a ratio of 10 μ9 per plate using the phosphate-calcium method (Haynes, J & Weissmann, C (1
983) Nucleic Acid Res, 11,
887-706), treated with grillerol, and incubated at 37°C for 12 hours.
次に、この細胞を3枚の新しい径5cmのプレートに移
し、1週間2回の割り合いで培地交換をした。Next, the cells were transferred to three new plates with a diameter of 5 cm, and the medium was exchanged twice a week.
16日目にFoci(集塊)を形成した部分をそれぞれ
新しいプレートに移し、上述の培地で継代培養し、G−
CSF−生産能の高いクローンを選別した。その結果〜
1mg/ρのレベルのG−C’SF生産があった。The parts that formed Foci (agglomerates) on the 16th day were transferred to new plates, subcultured in the above-mentioned medium, and G-
Clones with high CSF-producing ability were selected. the result~
There was a level of GC'SF production of 1 mg/ρ.
なお、回収、精製、検定方法については上記の特願昭6
0− 269456号明細ぷの該当実施例に開示しであ
る通りのものを用いた。Regarding recovery, purification, and testing methods, please refer to the above patent application filed in 1983.
0-269456 specification was used as disclosed in the relevant examples.
実験例1
G−CSF連日連日投込商機能の関係(マウス)G
CSFリンプル0.1 d(CI−IU−2由来のG−
CSF2.5μU、「1−プロパツール1%、同系マウ
ス血清10%を含む生理食塩液)をマウス(C57[3
L− 8W、オス)に1日1回連E1投与し下記の大
々の[1に殺して牌臓中のCFtJ−C数、CFtJ−
S数及び末梢好中球数を測定しコントロール“リンプル
0.17(n−プロパツール1%、同系マウス血清10
%を含む生理食塩液)を投与したマウスのそれらと比較
した。結果を表−1、表−2及び表−3に示す。c r
: u − sとは赤血球、好中球、巨核球、好酸球、
単球に分化し1qる能力を持つ幹細胞のことであり、C
FU−Cとは好中球、単球(マクロファージ)そして場
合によっては好酸球に分化し得る能力を持つ幹細胞をい
う。Experimental example 1 Relationship between G-CSF daily investment function (mouse) G
CSF Rimple 0.1 d (G- from CI-IU-2
A mouse (C57 [3
L-8W, male) were administered E1 once a day, and the number of CFtJ-C in the spleen, CFtJ-
The number of S and peripheral neutrophils were measured, and control "Ripple 0.17 (n-propatool 1%, syngeneic mouse serum 10
compared with those of mice administered with saline (containing % saline). The results are shown in Table-1, Table-2 and Table-3. cr
: u-s refers to red blood cells, neutrophils, megakaryocytes, eosinophils,
It is a stem cell that has the ability to differentiate into monocytes and produce 1q.
FU-C refers to stem cells that have the ability to differentiate into neutrophils, monocytes (macrophages), and in some cases, eosinophils.
表−1、表−2、表−3から明らかな通りG−CSFを
マウスに連日投与覆ると造血機能の昂進が認められる。As is clear from Tables 1, 2, and 3, when G-CSF is administered to mice on a daily basis, hematopoietic function is enhanced.
表−1
p( 危険率)***<0.001<**<0.01表
−2
p(危険率)***<0.001<*本<0.01表−
3
末梢血1m3当りの末梢好中球数(測定回数n=4)p
(危険率)***<Q、QQl<*傘<0.Ql<*<
Q、05実験例2
G C3FのBMT後のm血 能回1促進効果マウス
(C57[3L 8W、オス)に95ORのX線を全
身照射し、直ちに同系マウスの骨髄細胞2X10 個
を尾静脈より移416シた。このマウスについて、移植
後5日[IJ、り実験例1で用いたコントロール又はG
−C3F−リンプル0.1〃fを連日投与し、投与開始
後6日目及び12日[1の稗及び骨髄のCFU−3数を
数えた。Table-1 p(Risk rate) ***<0.001<**<0.01Table-2 p(Risk rate)***<0.001<*Book<0.01Table-
3 Number of peripheral neutrophils per m3 of peripheral blood (number of measurements n = 4) p
(Risk rate) ***<Q, QQl<*Umbrella<0. Ql<*<
Q, 05 Experimental Example 2 G C3F m-blood function 1 promotion effect after BMT A mouse (C57 [3L 8W, male) was irradiated with 95OR X-rays whole body, and 2 x 10 bone marrow cells of a syngeneic mouse were immediately injected from the tail vein. Moved 416 times. For this mouse, 5 days after transplantation [IJ, control used in Experiment 1 or G
-C3F-rimple 0.1 f was administered every day, and the number of CFU-3 in the glen and bone marrow was counted on the 6th and 12th day after the start of administration.
結果は表−4、表−5に示す。The results are shown in Tables 4 and 5.
実験例3
造血能回復の′−い実験系での生存率
マウス(C57[31−8W1オス)に95ORのXt
lAを全身照射し、直ちに同系マウスの骨髄細胞7.5
X10 個を尾静脈より移植した。このマウスについ
て、移植後5日目より実験例1で用いたコン1〜ロール
又はG−C3Fリンプル0.IIIIIlを連日11E
1間投与し、その後の生存率(照射後400日目をみた
。結果は以下に示す通りであった。Experimental Example 3 Survival rate in experimental system for recovery of hematopoietic ability Mice (C57 [31-8W1 male)
Immediately after whole body irradiation with 1A, syngeneic mouse bone marrow cells 7.5
X10 cells were transplanted from the tail vein. From day 5 after transplantation, these mice were treated with Control 1 to Roll used in Experimental Example 1 or G-C3F Rimple 0. IIIIIIl every day 11E
The survival rate (400 days after irradiation was observed) was as shown below.
生存率
C0ntr”01群 33.3%(n=12)G−C3
F処首群 75.0%(n=12)生存率の顕著な向
上はG−C8Fの造血機回復促進剤果によるものと推定
される。Survival rate C0ntr”01 group 33.3% (n=12) G-C3
The remarkable improvement in the survival rate (75.0% (n=12) in the F-decapitation group is presumed to be due to the effect of G-C8F on promoting recovery of the hematopoietic system.
実施例1(製剤例)
参考例によって得られたヒI−G−C3Fを無菌処理し
た後−20℃で凍結された凍結物を用いて注射剤とした
。Example 1 (Formulation Example) Human I-G-C3F obtained in Reference Example was sterilized and then frozen at -20°C to prepare an injection.
実施例2(製剤例)
参と例によって得られたヒ1〜G−C8Fを無菌操作で
10mバイアル瓶に5rd充填し、−20℃で凍結乾燥
後ゴム栓にて施栓した凍結乾燥物を用いて注射剤とした
。。Example 2 (Formulation example) Hi1~G-C8F obtained in Example 1 and Example were filled into 10 m vials for 5rd time using aseptic operation, freeze-dried at -20°C, and then capped with a rubber stopper. It was made into an injection. .
本発明の造血機能回復促進剤は、造血障害をおこしてい
る患者への治療法である骨髄移植を行なった後の造血機
能回復を促進させる効果があり、これによって白血病等
の多くの難病患者の治癒に対する期待が高まった。The hematopoietic function recovery promoter of the present invention has the effect of promoting hematopoietic function recovery after bone marrow transplantation, which is a treatment for patients with hematopoietic disorders, and thereby is effective in promoting hematopoietic function recovery in patients with many intractable diseases such as leukemia. Hopes for a cure rose.
Claims (1)
移植後の造血機能回復促進剤。 2 ヒト顆粒球コロニー刺激因子が以下の理化学的性質
を有するものであることを特徴とする特許請求の範囲第
1項記載の造血機能回復促進剤。 (1)分子量:ドデシル硫酸ナトリウム−ポリアクリル
アミドグル電気泳動法による測定で19000±100
0。 (2)等電点:PI=5.5±0.1、PI=5.8±
0.1、PI=6.1±0.1の三つの等電点のうち少
なくとも1つを有する。 (3)紫外部吸収:28nmに極大吸収を有し、250
nmに極少値を持つ。 (4)N末端から21残基目迄のアミノ酸配列が次の如
くである。 【アミノ酸配列があります】 3 ヒト顆粒球コロニー刺激因子が、以下のアミノ酸配
列又はその一部で表わされるポリペプチドを有するもの
であることを特徴とする特許請求の範囲第1項記載の造
血機能回復促進剤。 【アミノ酸配列があります】 (式中XはLeu又はLeu−Val−Ser−Glu
を示し、nは0又は1を示す。)[Scope of Claims] 1. A hematopoietic function recovery promoter after bone marrow transplantation, which contains human granulocyte colony stimulating factor as an active ingredient. 2. The hematopoietic function recovery promoter according to claim 1, wherein the human granulocyte colony stimulating factor has the following physicochemical properties. (1) Molecular weight: 19,000 ± 100 as measured by sodium dodecyl sulfate-polyacrylamide glucose electrophoresis
0. (2) Isoelectric point: PI=5.5±0.1, PI=5.8±
0.1, PI=6.1±0.1. (3) Ultraviolet absorption: maximum absorption at 28 nm, 250
It has a minimum value in nm. (4) The amino acid sequence from the N-terminus to the 21st residue is as follows. [There is an amino acid sequence] 3. Hematopoietic function recovery according to claim 1, characterized in that the human granulocyte colony stimulating factor has a polypeptide represented by the following amino acid sequence or a part thereof. Accelerator. [There is an amino acid sequence] (In the formula, X is Leu or Leu-Val-Ser-Glu
, and n represents 0 or 1. )
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62010037A JPH0618779B2 (en) | 1986-01-22 | 1987-01-21 | Hematopoietic function recovery promoter |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP61-10280 | 1986-01-22 | ||
JP1028086 | 1986-01-22 | ||
JP62010037A JPH0618779B2 (en) | 1986-01-22 | 1987-01-21 | Hematopoietic function recovery promoter |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP7286407A Division JP2838867B2 (en) | 1986-01-22 | 1995-10-09 | Stem cell proliferation promoter |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS62252729A true JPS62252729A (en) | 1987-11-04 |
JPH0618779B2 JPH0618779B2 (en) | 1994-03-16 |
Family
ID=26345198
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP62010037A Expired - Lifetime JPH0618779B2 (en) | 1986-01-22 | 1987-01-21 | Hematopoietic function recovery promoter |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0618779B2 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0276820A (en) * | 1988-06-15 | 1990-03-16 | Ajinomoto Co Inc | Agent for supporting transplantation treatment of bone marrow |
JPH03504854A (en) * | 1988-03-29 | 1991-10-24 | イミュノメヂックス・インコーポレーテッド | cytotoxin therapy |
WO1994028919A1 (en) * | 1993-06-08 | 1994-12-22 | Ajinomoto Co., Inc. | Hematopoietic cell proliferation accelerator |
JPH08208509A (en) * | 1986-01-22 | 1996-08-13 | Chugai Pharmaceut Co Ltd | Agent for promoting multiplication of stem cell |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS53121916A (en) * | 1977-03-29 | 1978-10-24 | Morinaga Milk Industry Co Ltd | Production of treating agent for leucocyte reducing disease |
JPS54140707A (en) * | 1978-03-20 | 1979-11-01 | Morinaga Milk Ind Co Ltd | Hgi glycoprotein which stimulates proliferation of human granulocyte, preparation of hgi glycoprotein, and remedy for hypoleukocytosis containing hgi glycoprotein |
JPS57114525A (en) * | 1980-12-31 | 1982-07-16 | Hayashibara Biochem Lab Inc | Preparation of human colonial stimulating factor |
JPS59137417A (en) * | 1983-01-28 | 1984-08-07 | Morinaga Milk Ind Co Ltd | Preparation of colonization stimulation factor and kallikrein originated from human urine |
JPS6232326A (en) * | 1985-08-02 | 1987-02-12 | Yamato Scale Co Ltd | Fixing quantity charging device |
JPS62132899A (en) * | 1985-12-03 | 1987-06-16 | Chugai Pharmaceut Co Ltd | Novel polypeptide |
JPS62174026A (en) * | 1985-10-04 | 1987-07-30 | Chugai Pharmaceut Co Ltd | Remedy for leukpenia |
JPS62236488A (en) * | 1985-09-17 | 1987-10-16 | Chugai Pharmaceut Co Ltd | Csf gene |
JPS63500636A (en) * | 1985-08-23 | 1988-03-10 | 麒麟麦酒株式会社 | DNA encoding multipotent granulocyte colony stimulating factor |
JPS6444200A (en) * | 1987-08-12 | 1989-02-16 | Kenji Hoshino | Stereophonic sound field recording and reproducing system |
JPH0615477A (en) * | 1992-07-02 | 1994-01-25 | Tanaka Kikinzoku Kogyo Kk | Ag brazer |
JPH0618778A (en) * | 1992-06-30 | 1994-01-28 | Kyocera Corp | Automatic focus detecting device |
-
1987
- 1987-01-21 JP JP62010037A patent/JPH0618779B2/en not_active Expired - Lifetime
Patent Citations (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS53121916A (en) * | 1977-03-29 | 1978-10-24 | Morinaga Milk Industry Co Ltd | Production of treating agent for leucocyte reducing disease |
JPS54140707A (en) * | 1978-03-20 | 1979-11-01 | Morinaga Milk Ind Co Ltd | Hgi glycoprotein which stimulates proliferation of human granulocyte, preparation of hgi glycoprotein, and remedy for hypoleukocytosis containing hgi glycoprotein |
JPS57114525A (en) * | 1980-12-31 | 1982-07-16 | Hayashibara Biochem Lab Inc | Preparation of human colonial stimulating factor |
JPS59137417A (en) * | 1983-01-28 | 1984-08-07 | Morinaga Milk Ind Co Ltd | Preparation of colonization stimulation factor and kallikrein originated from human urine |
JPS6232326A (en) * | 1985-08-02 | 1987-02-12 | Yamato Scale Co Ltd | Fixing quantity charging device |
JPS63500636A (en) * | 1985-08-23 | 1988-03-10 | 麒麟麦酒株式会社 | DNA encoding multipotent granulocyte colony stimulating factor |
JPS62236488A (en) * | 1985-09-17 | 1987-10-16 | Chugai Pharmaceut Co Ltd | Csf gene |
JPS62236497A (en) * | 1985-09-17 | 1987-10-16 | Chugai Pharmaceut Co Ltd | Novel glycoprotein and production thereof |
JPS62174026A (en) * | 1985-10-04 | 1987-07-30 | Chugai Pharmaceut Co Ltd | Remedy for leukpenia |
JPS62132899A (en) * | 1985-12-03 | 1987-06-16 | Chugai Pharmaceut Co Ltd | Novel polypeptide |
JPS6444200A (en) * | 1987-08-12 | 1989-02-16 | Kenji Hoshino | Stereophonic sound field recording and reproducing system |
JPH0618778A (en) * | 1992-06-30 | 1994-01-28 | Kyocera Corp | Automatic focus detecting device |
JPH0615477A (en) * | 1992-07-02 | 1994-01-25 | Tanaka Kikinzoku Kogyo Kk | Ag brazer |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH08208509A (en) * | 1986-01-22 | 1996-08-13 | Chugai Pharmaceut Co Ltd | Agent for promoting multiplication of stem cell |
JPH03504854A (en) * | 1988-03-29 | 1991-10-24 | イミュノメヂックス・インコーポレーテッド | cytotoxin therapy |
JPH0276820A (en) * | 1988-06-15 | 1990-03-16 | Ajinomoto Co Inc | Agent for supporting transplantation treatment of bone marrow |
WO1994028919A1 (en) * | 1993-06-08 | 1994-12-22 | Ajinomoto Co., Inc. | Hematopoietic cell proliferation accelerator |
Also Published As
Publication number | Publication date |
---|---|
JPH0618779B2 (en) | 1994-03-16 |
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