JPH08507916A - M−csfの結晶化 - Google Patents
M−csfの結晶化Info
- Publication number
- JPH08507916A JPH08507916A JP6501713A JP50171394A JPH08507916A JP H08507916 A JPH08507916 A JP H08507916A JP 6501713 A JP6501713 A JP 6501713A JP 50171394 A JP50171394 A JP 50171394A JP H08507916 A JPH08507916 A JP H08507916A
- Authority
- JP
- Japan
- Prior art keywords
- csf
- dimer
- csfα
- polypeptide
- crystallized
- 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.)
- Withdrawn
Links
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/53—Colony-stimulating factor [CSF]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
- C07K14/7153—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for colony-stimulating factors [CSF]
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.結晶化M-CSFを含有する組成物であって、該M-CSFは2つのM-CSFポリペプチ ドモノマーのダイマーであり、それぞれのモノマーは、成熟M-CSFαポリペプチ ド、成熟M-CSFβポリペプチド、および成熟M-CSFγポリペプチドからなる群から 選択されるポリペプチド配列と実質的に同一のアミノ酸配列を有する、組成物。 2.前記結晶化ダイマーが、P212121対称を有する、請求項1に記載の組成物。 3.前記M-CSFが再溶解したときに生物学的に活性である、請求項2に記載の組 成物。 4.前記2つのM-CSFポリペプチドモノマーが、相互にジスルフィド結合してい る、請求項1に記載の組成物。 5.前記2つのM-CSFポリペプチドモノマーのそれぞれがM-CSFαポリペプチドで ある、請求項1に記載の組成物。 6.それぞれのモノマーが、約145から約156アミノ酸長のアミノ酸配列を有し、 該配列が成熟M-CSFポリペプチドのアミノ末端から測定して約145から156残基の 間に位置するカルボン酸末端を有する、請求項1に記載の組成物。 7.前記ポリペプチドの少なくとも一つが、成熟M-CSFαポリペプチドの4位か ら158位の残基を有する、請求項6に記載の組成物。 8.前記M-CSFポリペプチドモノマーの少なくとも一つが、グ リコシル化されていない、請求項1に記載の組成物。 9.それそれが146から162アミノ酸を含有する、2つのポリペプチドモノマーを 有するM-CSFαダイマーを結晶化する方法であって、該方法が以下の工程: a)該M-CSFαダイマー溶液と沈澱剤とを混合し、それによって、M-CSFα混 合物を形成させる工程; b)結晶化M-CSFαダイマーを沈澱させる工程;および c)該結晶化M-CSFαダイマーを単離する工程 を包含する、方法。 10.前記沈澱剤が、ポリエチレングリコールを包含する、請求項9に記載の方 法。 11.前記M-CSFダイマーが、細菌の細胞から単離された組換えM-CSFである、請 求項9に記載の方法。 12.前記ポリペプチドモノマーの少なくとも一つが、グリコシル化されていな い、請求項9に記載の方法。 13.前記ポリペプチドモノマーの少なくとも一つが、成熟M-CSFαポリペプチ ドの4位から158位の残基を有する、請求項9に記載の方法。 14.前記結晶化M-CSFαダイマーが再溶解したときに生物学的に活性である、 請求項9に記載の方法。 15.前記M-CSFα結晶を沈澱させる工程が、前記M-CSFαダイマー混合物を沈澱 剤溶液で平衡化させる工程を包含する、請求項9に記載の方法。 16.前記沈澱剤溶液が、前記M-CSFα混合物の濃度よりも高 い濃度の沈澱剤を含有する、請求項15に記載の方法。 17.前記平衡化させる工程が、前記M-CSFα混合物を表面に添加し、該添加し たM-CSFα混合物を前記沈澱剤溶液槽で平衡化させる工程を包含する、請求項1 5に記載の方法。 18.前記結晶化M-CSFαダイマーを沈澱させる工程が、M-CSFα種結晶をM-CSF αダイマー混合物に添加する工程を包含する、請求項9に記載の方法。 19.前記結晶化M-CSFαダイマーを沈澱させる工程が、前記M-CSFα混合物の温 度を変化させる工程を包含する、請求項9に記載の方法。 20.結晶化M-CSFα(4-158)。 21.前記結晶化M-CSFが、少なくとも二次元で少なくとも約0.3mmの大きさのM- CSFの結晶を含有する、請求項20に記載の結晶化M-CSF。 22.前記結晶化M-CSFが、照射X線を回折してM-CSFの三次元構造を表す回折パ ターンを作り得る、請求項20に記載の結晶化M-CSF。 23.前記回折パターンが、少なくとも5オングストロームの精度で、M-CSFα (4-158)の一部分の三次元構造を表し、該一部分が残基4から残基153の間のア ミノ酸残基を含む、請求項22に記載の結晶化M-CSF。 24.2つのM-CSFポリペプチドモノマーを含有するM-CSFダイマーの三次元構造 を決定する方法であって、それぞれのモノマーは、成熟M-CSFの約残基1から約 残基5で始まる約146 から162アミノ酸の間のアミノ酸を有し、該方法が以下の工程: a)該M-CSFダイマーを結晶化させる工程; b)該結晶化M-CSFを照射して、該結晶化M-CSFに特徴的な回折パターンを得 る工程;および c)該回折パターンを該M-CSFダイマーの三次元構造に変換する工程 を包含する、方法。 25.M-CSF結晶に由来するM-CSFの三次元構造を使用する方法であって、該M-CS Fの三次元構造がM-CSFレセプター結合領域を含有し、該方法が、M-CSFの三次元 構造のレセプター結合領域と相互に作用し、M-CSFアゴニストあるいはアンタゴ ニストとして機能する構造を有する化合物を同定する工程を包含する、方法。 26.前記M-CSFの三次元構造が、添付書類1に示される構造情報と実質的に同 一のα-炭素座標を含有する、請求項25に記載の方法。 27.M-CSFアゴニストあるいはM-CSFアンタゴニストを同定するための方法であ って、該方法が以下の工程: a)M-CSFダイマーを結晶化して少なくとも一つのM-CSF結晶を形成させる工 程、ここで、該M-CSFダイマーはM-CSFレセプター結合領域を決定するアミノ酸残 基群を含有する; b)工程(a)の手順で生産されたM-CSF結晶を照射して、該M-CSF結晶の回折 パターンを得る工程; c)該回折パターンからM-CSFの三次元構造を決定する工程、ここで、該三次 元構造はM-CSFレセプター結合領域を含む;および d)三次元構造を有するM-CSFアゴニスト化合物あるいはM-CSFアンタゴニス ト化合物を同定する工程、ここで、該三次元構造は、該M-CSFレセプター結合領 域の三次元構造中に存在する、必須のM-CSFレセプター結合溶剤に接近可能な残 基を機能的に複製し、該M-CSFアゴニストあるいはM-CSFアンタゴニストは、M-CS Fに応答性の細胞に対する変化したシグナル伝達能力を有している、 を包含する、方法。 28.前記溶剤に接近可能が残基がM-CSFダイマーの界面の形成に関与しない、 請求項27に記載の方法。 29.M-CSFアンタゴニストを生産する方法であって、該方法が以下の工程; a)シグナル伝達に関与する溶剤に接近可能なアミノ酸残基を変更する工程 、ここで、該変更はM-CSFのM-CSFレセプターへの結合を損なわない;および b)該M-CSFアンタゴニストをM-CSFバイオアッセイにおける活性についてテ ストする工程 を包含する、方法。 30.前記溶剤に接近可能なアミノ酸が、化学修飾により変更されている、請求 項29に記載の方法。 31.M-CSFモノマーあたり少なくとも一つ、好ましくは5よ りも少ない、溶剤に接近可能なアミノ酸がアミノ酸置換により改変されている、 請求項29に記載の方法。 32.前記M-CSFがヘテロダイマーであり、1つのモノマーのみが置換された溶 剤に接近可能なアミノ酸を有し、該溶剤に接近可能なアミノ酸が、シグナル伝達 に関与している、請求項29に記載の方法。 33.前記M-CSFがヘテロダイマーであり、両方のモノマーが異なる置換された 溶剤に接近可能なアミノ酸を有し、該溶剤に接近可能なアミノ酸がシグナル伝達 に関与している、請求項29に記載の方法。 34.単離され、精製され、可溶性の機能的なM-CSFレセプター。 35.M-CSFアゴニストおよびM-CSFアンタゴニストをスクリーニングする方法で あって、該方法が以下の工程: a)該アゴニストあるいは該アンタゴニストを可溶性の機能的M-CSFレセプタ ーと接触させる工程;および b)該アゴニストあるいは該アンタゴニストと該レセプターとの相互作用を 測定する工程 を包含する、方法。
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PCT/US1993/005548 WO1993025687A1 (en) | 1992-06-09 | 1993-06-09 | Crystallization of m-csf |
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JP2004155357A Division JP2004285076A (ja) | 1992-06-09 | 2004-05-25 | M−csfの結晶化 |
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EP (2) | EP0668914B1 (ja) |
JP (2) | JPH08507916A (ja) |
AT (1) | ATE195553T1 (ja) |
CA (1) | CA2137793C (ja) |
DE (1) | DE69329247T2 (ja) |
WO (1) | WO1993025687A1 (ja) |
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- 1993-06-09 CA CA002137793A patent/CA2137793C/en not_active Expired - Lifetime
- 1993-06-09 AT AT93915279T patent/ATE195553T1/de not_active IP Right Cessation
- 1993-06-09 JP JP6501713A patent/JPH08507916A/ja not_active Withdrawn
- 1993-06-09 WO PCT/US1993/005548 patent/WO1993025687A1/en active IP Right Grant
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- 1993-06-09 DE DE69329247T patent/DE69329247T2/de not_active Expired - Lifetime
- 1993-06-09 EP EP99108304A patent/EP0955365A3/en not_active Withdrawn
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JP2013513367A (ja) * | 2009-12-10 | 2013-04-22 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | 優先的にヒトcsf1r細胞外ドメイン4に結合する抗体及びそれらの使用 |
JP2015120697A (ja) * | 2009-12-10 | 2015-07-02 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | 優先的にヒトcsf1r細胞外ドメイン4に結合する抗体及びそれらの使用 |
JP2017123850A (ja) * | 2009-12-10 | 2017-07-20 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | 優先的にヒトcsf1r細胞外ドメイン4に結合する抗体及びそれらの使用 |
Also Published As
Publication number | Publication date |
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DE69329247T2 (de) | 2001-05-31 |
EP0955365A2 (en) | 1999-11-10 |
ATE195553T1 (de) | 2000-09-15 |
DE69329247D1 (de) | 2000-09-21 |
EP0668914A1 (en) | 1995-08-30 |
EP0668914B1 (en) | 2000-08-16 |
US6184354B1 (en) | 2001-02-06 |
EP0955365A3 (en) | 2000-12-20 |
JP2004285076A (ja) | 2004-10-14 |
WO1993025687A1 (en) | 1993-12-23 |
CA2137793A1 (en) | 1993-12-23 |
CA2137793C (en) | 2003-04-22 |
US5866114A (en) | 1999-02-02 |
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