JP2914672B2 - BSF (2) Antagonist - Google Patents
BSF (2) AntagonistInfo
- Publication number
- JP2914672B2 JP2914672B2 JP1007944A JP794489A JP2914672B2 JP 2914672 B2 JP2914672 B2 JP 2914672B2 JP 1007944 A JP1007944 A JP 1007944A JP 794489 A JP794489 A JP 794489A JP 2914672 B2 JP2914672 B2 JP 2914672B2
- Authority
- JP
- Japan
- Prior art keywords
- bsf
- polypeptide
- amino acid
- present
- polypeptides
- 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.)
- Expired - Lifetime
Links
Description
【発明の詳細な説明】 ＜産業上の利用分野＞ 本発明はヒトＢ細胞刺激因子２（以下「BSF2」と称
す）に拮抗作用を有するポリペプチドに関する。本発明
のポリペプチドは医薬として有用である。DETAILED DESCRIPTION OF THE INVENTION The present invention <relates> relates polypeptide having antagonistic activity to human B cell stimulating factor 2 (hereinafter referred to as "BSF 2"). The polypeptide of the present invention is useful as a medicine.
＜従来の技術・発明が解決しようとする課題＞ ヒトBSF2はＢ細胞の抗体産生細胞への分化を誘導する
因子として研究されている。近年になってBSF2をコード
するcDNAが単離され、DNA配列に関する情報および精製
されたBSF2の部分的なアミノ酸配列等より、BSF2は28ア
ミノ酸残基のシグナルペプチドを有する184アミノ酸残
基（下記アミノ酸配列（Ｉ）で示される）から構成され
ていることが明らかになった。<Problems to be Solved by Conventional Techniques / Inventions> Human BSF 2 has been studied as a factor that induces the differentiation of B cells into antibody-producing cells. In recent years, cDNA encoding BSF 2 has been isolated, and based on information about the DNA sequence and the partial amino acid sequence of purified BSF 2 , etc., BSF 2 has 184 amino acid residues having a signal peptide of 28 amino acid residues. (Shown by the following amino acid sequence (I)).
最近の知見を総合すると、BSF2はＢ細胞に抗体産生を
誘導し、ハイブリドーマ，プラズマサイトーマ，ミエロ
ーマ等を増殖させ、HLA（human leukocyte antigen）ク
ラスＩ抗原の発現を誘導し、血液幹細胞にコロニーを誘
導し、肝臓細胞に急性期蛋白質を誘導し、神経細胞に突
起を誘導すると考えられる。この様にBSF2は種々の重要
な生理活性を有し、広く細胞の増殖に関与していると考
えられている。 Summarizing recent findings, BSF 2 induces antibody production in B cells, proliferates hybridomas, plasmacytomas, myeloma, etc., induces expression of human leukocyte antigen (HLA) class I antigen, and colonies blood stem cells. , Which induces acute-phase proteins in liver cells, and induces processes in nerve cells. Thus, BSF 2 has various important physiological activities and is considered to be widely involved in cell growth.
一方、BSF2の異常産生が心房内粘液腫、子宮けい癌、
エンドトキシン、ショック、ミエローマ（骨髄腫）、慢
性関節リウマチ、キャスルマン症候群の疾患におえる免
疫異常の病因因子である可能性が報告されている（平野
ら,Proc.Natl.Acad.Sci.U.S.A.84,228頁,1987年）。従
ってBSF2の拮抗剤はこれらの疾患の治療薬または診断薬
として期待される。しかしながらBSF2拮抗物質に関する
報告はこれまで皆無である。On the other hand, abnormal production of BSF 2 is due to intra-atrial myxoma, cervical cancer,
It has been reported that endotoxin, shock, myeloma (myeloma), rheumatoid arthritis, and the pathogenesis of immune abnormalities in diseases of Castleman syndrome have been reported (Hirano et al., Proc. Natl. Acad. Sci. USA 84 , 228). 1987). Thus the BSF 2 antagonists are expected as therapeutic or diagnostic agents of these diseases. However, there have been no reports on BSF 2 antagonists.
本願発明者等はBSF2の分子構造、とりわけBSF2が細胞
膜上に存在するBSF2レセプターと結合する部分の構造を
研究する過程において、BSF2のＮ末端およびＣ末端より
複数個のアミノ酸が欠損したポリペプチドがBSF2に対し
拮抗作用を有することを見い出した。BSF2の一部を構成
するポリペプチドがBSF2に対し拮抗的に作用することは
従来全く知られていない新知見である。本発明はこの知
見に基づき更に検討を加えて完成したもので、BSF2に対
し拮抗作用を有するポリペプチドに関するものである。
このようなポリペプチドはBSF2が主因となっている疾
患、例えば慢性関節リウマチ、ミエローマ（骨髄腫）、
あるいはエンドトキシン・ショック治療薬として有望で
ある。The molecular structure of the present inventors have BSF 2, especially in the process of BSF 2 to study the structure of the portion that binds to the BSF 2 receptors present on cell membranes, a plurality of amino acid residues from the N-terminus and C-terminus of the BSF 2 deficient polypeptide was found to have an antagonistic effect on BSF 2. It is new finding has not been known conventionally at all the polypeptide constituting part of the BSF 2 acts antagonistically to BSF 2. The present invention has been completed by the addition of further studies based on this finding, the present invention relates to a polypeptide having an antagonistic action against BSF 2.
Such polypeptides are mainly caused by BSF 2 such as rheumatoid arthritis, myeloma (myeloma),
Alternatively, it is promising as a therapeutic drug for endotoxin shock.
＜課題を解決するための手段＞ 本発明は、下記のアミノ酸配列のいずれか一つを含
み、40個までのアミノ酸数からなるポリペプチドであっ
て、かつヒトＢ細胞刺激因子２に対し拮抗作用を有する
ポリペプチドを提供する。<Means for Solving the Problems> The present invention relates to a polypeptide comprising any one of the following amino acid sequences, comprising up to 40 amino acids, and antagonizing human B cell stimulating factor 2: A polypeptide having the formula:
また、本発明は、下記のアミノ酸配列のいずれか一つ
を含み、40個までのアミノ酸数からなるポリペプチドで
あって、該ポリペプチドの構造中の１〜２個のアミノ酸
を他のアミノ酸に置き換えた構造を有し、かつBSF2に対
し拮抗作用を有するポリペプチドを提供する。本発明の
ポリペプチドはBSF2のアミノ酸配列から見た場合、概ね
２つの群に大別される。一つの群は下記のアミノ酸配列
式（II）（この部分は前記アミノ酸配列式（Ｉ）で示さ
れるポリペプチドのＮ末端から数えて56〜66番迄のアミ
ノ酸配列に相当する） で示されるポリペプチドの全部、又は一部を連続して含
むものであり、具体的には、例えば以下の（III）〜（V
III）に示すアミノ酸配列、で示されるポリペプチドで
ある。Further, the present invention relates to a polypeptide comprising any one of the following amino acid sequences and comprising up to 40 amino acids, wherein 1 to 2 amino acids in the structure of the polypeptide are replaced with other amino acids. has a replacement structure, and to BSF 2 provides a polypeptide having an antagonism. Polypeptides of the present invention when viewed from the amino acid sequence of BSF 2, it is generally classified into two groups. One group includes the following amino acid sequence formula (II) (this portion corresponds to the amino acid sequence from No. 56 to No. 66 from the N-terminal of the polypeptide represented by the amino acid sequence formula (I)): And all or some of the polypeptides represented by the following formulas. Specifically, for example, the following (III) to (V)
And a polypeptide represented by the amino acid sequence shown in III).
また本発明は、これらの他に例えば以下に示す（IX）
および（Ｘ）といったポリペプチドをも包含する。これ
らは前記アミノ酸配列（II）の部分構造を有していない
ポリペプチドである。 In addition, the present invention provides, in addition to these, the following (IX)
And polypeptides such as (X). These are polypeptides not having the partial structure of the amino acid sequence (II).
なお、本発明は、これらのポリペプチドに限定される
ものではない。つまりある特定のポリペプチドの１〜２
個のアミノ酸が他のアミノ酸に置き換えられた場合、ま
たこれらのアミノ酸が欠損した場合においても、ほぼ同
等かそれ以上の活性を示すことはよく知られているとこ
ろである。本発明においても同様に、前述したアミノ酸
配列（III）〜（Ｘ）に示すポリペプチドまたはアミノ
酸配列（Ｉ）で示されるBSF2の一部を構成するポリペプ
チドの１〜２個のアミノ酸を他のアミノ酸に置き換えた
もの、または欠損したものであっても本質的にBSF2の部
分構造を含有し、かつBSF2に対し拮抗作用を有するポリ
ペプチドは本発明に係るポリペプチドである。 Note that the present invention is not limited to these polypeptides. That is, a specific polypeptide of 1-2
It is well known that when amino acids are replaced with other amino acids, or when these amino acids are deleted, they exhibit almost the same or higher activity. Similarly, in the present invention, other one to two amino acids of the polypeptide which constitutes a part of the BSF 2 represented by amino acid sequence described above (III) ~ polypeptide or amino acid sequence shown in (X) (I) those were replaced by amino acids, or be one lacking essentially free of the BSF 2 partial structures, and polypeptides having antagonistic action against BSF 2 is a polypeptide according to the present invention.
本発明のポリペプチドは、その構成アミノ酸数が20〜
40個程度であり、特に組換えDNA技術を用いることな
く、化学合成することができる。ペプチド合成は通常の
Merrifield固相法（J.Med.Chem.1979,22,586〜588）に
従ってBOC法により行った。カップリングの進行はKaise
r試験（Anal.Biochem.1970,34,595〜598）を用いてモニ
ターした。The polypeptide of the present invention has a constituent amino acid number of 20 to
The number is about 40, and can be chemically synthesized without using recombinant DNA technology. Peptide synthesis is normal
This was performed by the BOC method according to the Merrifield solid phase method (J. Med. Chem. 1979 , 22, 586-588). The progress of the coupling is Kaise
Monitoring was performed using the r test (Anal. Biochem. 1970 , 34, 595-598).
以下本発明において製造した前記（III）〜（Ｘ）の
アミノ酸配列を有するポリペプチドのアミノ酸分析の結
果およびHPLC（高速液体クロマトグラフィー）分析の結
果を表１に示す。なお、アミノ酸分析は本発明のポリペ
プチドを6NHClで120℃,15時間加水分解した後アミノ酸
分析機MLC−203システム３（ATTO社製）を用い常法に従
って実施したものであり、HPLC分析はYMC−Ｒ＆Ｄ（5mi
cron）（日本分光社製）カラムを用いて0.1％TFA存在
下、アセトニトリルを０％〜70％のリニアグラジエント
（linear gradient）を25分間で展開し（flow rate＝1m
l/nim）、260nmの紫外部吸収によりモニターした結果で
ある。Table 1 below shows the results of amino acid analysis and HPLC (high performance liquid chromatography) analysis of the polypeptides having the amino acid sequences of (III) to (X) produced in the present invention. The amino acid analysis was carried out by hydrolyzing the polypeptide of the present invention with 6N HCl at 120 ° C. for 15 hours and then using an amino acid analyzer MLC-203 system 3 (manufactured by ATTO) in accordance with a conventional method. -R & D (5mi
cron) (manufactured by JASCO Corporation) in the presence of 0.1% TFA, developing a linear gradient of acetonitrile from 0% to 70% in 25 minutes (flow rate = 1 m)
l / nim), the result of monitoring by ultraviolet absorption at 260 nm.
表中のポリペプチドのNo.は前述の各アミノ酸配列のN
o.に対応している。（）内は推定されるアミノ酸数であ
る。また＊印はカウントされないものである。 The polypeptide No. in the table is the N of each amino acid sequence described above.
o. The number in parentheses is the estimated number of amino acids. The asterisks are not counted.
次に本発明のポリペプチドのBSF2に対する拮抗作用を
示す。拮抗作用は;96穴のマイクロプレートの各ウェル
に１×104個のSKW6CL−４（CL−４）細胞あるいはCESS
細胞を加え、適当量のBSF2と共に５日間、CO2中インキ
ュベーター中で培養する。培養上清を集め、上清中に含
まれる抗体（CL−４はIgM抗体を、CESSはIgM抗体を産生
する）量をELISA法により定量する。本発明のポリペプ
チドのBSF2に対する拮抗作用を調べる目的には本発明の
ポリペプチドを最終濃度10-5〜10-13Ｍの濃度範囲にな
るように適宜希釈し、BSF2を添加する30分前に加えて細
胞と予め反応させる。本発明のポリペプチドの添加によ
る抗体産生阻害率は次式により算出した。Following the antagonism of BSF 2 polypeptides of the present invention. Antagonistic activity: 1 × 10 4 SKW6CL-4 (CL-4) cells or CESS in each well of a 96-well microplate
Cells addition, appropriate amounts of BSF 2 with 5 days, cultured in a CO 2 incubator. The culture supernatant is collected, and the amount of antibody (CL-4 produces IgM antibody and CESS produces IgM antibody) contained in the supernatant is quantified by ELISA. The polypeptides of the present invention in order to investigate the antagonistic effect against BSF 2 polypeptides of the present invention a final concentration of 10 -5 to 10 -13 appropriately diluted to a concentration range of M, 30 minutes prior to addition of BSF 2 Pre-react with cells before adding. The antibody production inhibition rate by adding the polypeptide of the present invention was calculated by the following equation.
その結果を次の表２に示す。なお表中の本発明のポリ
ペプチドのNo.は前記第１表におけるポリペプチドに対
応している。 The results are shown in Table 2 below. The numbers of the polypeptides of the present invention in the table correspond to the polypeptides in Table 1.
表２に示すように本発明ポリペプチドはBSF2より誘導
させるCL−４あるいはCESS細胞の抗体産生に対し阻害作
用を有している。 The polypeptides of the invention as shown in Table 2 has an inhibitory effect on antibody production of CL-4 or CESS cells is derived from BSF 2.
＜発明の効果＞ 本発明に係る種々のポリペプチドは、BSF2に対して拮
抗剤として作用する。従って、これらのポリペプチド
は、BSF2の異常発生によって引き起こされると考えられ
ている心房内粘液腫、子宮けい癌、エンドトキシン・シ
ョック、ミエローマ（骨髄腫）、慢性関節リウマチ、キ
ャスルマン症候群等の免疫異常疾患に対する治療薬ある
いは診断薬として利用することが期待されることから、
本発明はこの種の免疫異常疾患に対する新たな治療薬及
び診断薬への道を開くものとして医薬産業上きわめて有
用である。Various polypeptides according to the present invention <Effects of the Invention> acts as an antagonist against BSF 2. Accordingly, these polypeptides, atrial myxoma, which is thought to be caused by abnormality of BSF 2, cervical cancer, endotoxic shock, myeloma (myeloma), rheumatoid arthritis, immune disorders such as Kyasuruman syndrome Because it is expected to be used as a therapeutic or diagnostic agent for diseases,
The present invention is extremely useful in the pharmaceutical industry as paving the way for new therapeutic and diagnostic agents for this type of immune disorder.
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 昭63−42688（ＪＰ，Ａ) 特開 昭63−56291（ＪＰ，Ａ) 特開 昭63−157996（ＪＰ，Ａ) Ｎａｆｕｒｅ，Ｖｏｌ．324，Ｎｏ. 6092（1986）ｐ．73−ｐ．76 Ｂｉｏｃｈｅｍ，Ｂｉｏｐｈｙｓ．Ｒ ｅｓ．Ｃｏｍｍｕｎ．，Ｖｏｌ．147, Ｎｏ．１（1987）ｐ．204−ｐ．211 (58)調査した分野(Int.Cl.6，ＤＢ名) C07K 14/54 ＣＡ（ＳＴＮ) ＣＡＯＬＤ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-63-42688 (JP, A) JP-A-63-56291 (JP, A) JP-A-63-157996 (JP, A) Nafure, Vol. 324, No. 6092 (1986) p. 73-p. 76 Biochem, Biophys. Res. Commun. , Vol. 147, no. 1 (1987) p. 204-p. 211 (58) Field surveyed (Int.Cl. 6 , DB name) C07K 14/54 CA (STN) CAOLD (STN) REGISTRY (STN)
Claims (2)
を含み、最大40個までのアミノ酸数からなるポリペプチ
ドであって、かつヒトＢ細胞刺激因子２に対し拮抗作用
を有するポリペプチド。 1. A polypeptide comprising any one of the following nine amino acid sequences, consisting of up to 40 amino acids, and having an antagonistic effect on human B-cell stimulating factor 2:
を含み、最大40個までのアミノ酸数からなるポリペプチ
ドであって、該ポリペプチドの構造中の１〜２個のアミ
ノ酸を他のアミノ酸に置き換えた構造を有し、かつヒト
Ｂ細胞刺激因子２に対し拮抗作用を有するポリペプチ
ド。 2. A polypeptide comprising any one of the following nine amino acid sequences and comprising up to 40 amino acids, wherein one or two amino acids in the structure of the polypeptide are replaced by other amino acids. A polypeptide having a structure replaced with an amino acid and having an antagonistic effect on human B-cell stimulating factor 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1007944A JP2914672B2 (en) | 1989-01-17 | 1989-01-17 | BSF (2) Antagonist |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1007944A JP2914672B2 (en) | 1989-01-17 | 1989-01-17 | BSF (2) Antagonist |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02188600A JPH02188600A (en) | 1990-07-24 |
| JP2914672B2 true JP2914672B2 (en) | 1999-07-05 |
Family
ID=11679607
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1007944A Expired - Lifetime JP2914672B2 (en) | 1989-01-17 | 1989-01-17 | BSF (2) Antagonist |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2914672B2 (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6217858B1 (en) * | 1997-02-11 | 2001-04-17 | Hadasit & Medical Research Services & Development Company, Ltd. | Pharmaceutical composition for treating hepatitis B virus (HBV) infection |
| JP2000516574A (en) * | 1996-06-20 | 2000-12-12 | コステル，ヘンク ウィルヘルムス | IL-6 having IL-6 antagonist or agonist activity and IL-6 receptor-derived peptide |
| EP1074268B1 (en) | 1998-03-17 | 2008-01-16 | Chugai Seiyaku Kabushiki Kaisha | Preventives or remedies for inflammatory intestinal diseases containing il-6 receptor antagonist antibodies |
| JP4698652B2 (en) * | 1998-03-17 | 2011-06-08 | 中外製薬株式会社 | A prophylactic or therapeutic agent for inflammatory bowel disease comprising an IL-6 antagonist as an active ingredient |
| UA80091C2 (en) | 2001-04-02 | 2007-08-27 | Chugai Pharmaceutical Co Ltd | Remedies for infant chronic arthritis-relating diseases and still's disease which contain an interleukin-6 (il-6) antagonist |
| GB2401040A (en) | 2003-04-28 | 2004-11-03 | Chugai Pharmaceutical Co Ltd | Method for treating interleukin-6 related diseases |
| BRPI0415505A (en) | 2003-10-17 | 2006-12-12 | Chugai Pharmaceutical Co Ltd | mesothelioma therapeutic agent |
| CA2625773C (en) | 2005-10-14 | 2015-05-12 | Fukuoka University | Inhibition of interleukin-6 (il-6) receptor promotes pancreatic islet transplantation |
| JP5191235B2 (en) | 2005-10-21 | 2013-05-08 | 中外製薬株式会社 | Heart disease treatment |
| AR057582A1 (en) | 2005-11-15 | 2007-12-05 | Nat Hospital Organization | AGENTS TO DELETE INDUCTION OF CYTOTOXIC T LYMPHOCYTES |
| AR059213A1 (en) | 2006-01-27 | 2008-03-19 | Univ Keio | THERAPEUTIC AGENTS FOR DISEASES INVOLVING COROIDAL NEOVASCULARIZATION |
| CN101495146B (en) | 2006-04-07 | 2012-10-17 | 国立大学法人大阪大学 | Muscle regeneration promoter |
| EP2898896A1 (en) | 2014-01-22 | 2015-07-29 | Université Pierre et Marie Curie (Paris 6) | Agents for use in the treatment of retinal inflammation |
| EP3747469A4 (en) | 2018-01-31 | 2022-03-23 | Motokazu Kato | Therapeutic agent for asthma containing il-6 inhibitor |
| JPWO2020213665A1 (en) | 2019-04-17 | 2020-10-22 |
-
1989
- 1989-01-17 JP JP1007944A patent/JP2914672B2/en not_active Expired - Lifetime
Non-Patent Citations (2)
| Title |
|---|
| Ｂｉｏｃｈｅｍ，Ｂｉｏｐｈｙｓ．Ｒｅｓ．Ｃｏｍｍｕｎ．，Ｖｏｌ．１４７，Ｎｏ．１（１９８７）ｐ．２０４−ｐ．２１１ |
| Ｎａｆｕｒｅ，Ｖｏｌ．３２４，Ｎｏ．６０９２（１９８６）ｐ．７３−ｐ．７６ |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02188600A (en) | 1990-07-24 |
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