JP2017525750A - ジスルフィド含有タンパク質からコンジュゲートを作製するための方法 - Google Patents
ジスルフィド含有タンパク質からコンジュゲートを作製するための方法 Download PDFInfo
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- JP2017525750A JP2017525750A JP2017513617A JP2017513617A JP2017525750A JP 2017525750 A JP2017525750 A JP 2017525750A JP 2017513617 A JP2017513617 A JP 2017513617A JP 2017513617 A JP2017513617 A JP 2017513617A JP 2017525750 A JP2017525750 A JP 2017525750A
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Abstract
Description
広範な種類の化学的部分(「ペイロード」)が、酵素、抗体、および他のポリペプチドまたはタンパク質に共有結合し、コンジュゲートを形成してきた。ペイロードは、それらが結合しているタンパク質を位置付けるため(例えば、標識)、タンパク質の物理化学的性質もしくは安定性を改変するため(例えば、PEG化)、タンパク質を別の分子もしくはタンパク質に結合することを可能にするため(コンジュゲートを別の化合物または別のコンジュゲートに連結するための官能基またはカップリング基)、またはペイロードもしくはタンパク質の機能もしくは活性を改変するために(例えば、ワクチンコンジュゲート)使用され得る。タンパク質は、また、抗体−薬物コンジュゲート(ADC)など、結合したペイロードを特定の組織または細胞種に送達する担体としても作用し得る。タンパク質に有用に連結され得る部類のペイロードとしては、検出可能な部分(標識)、タンパク質を表面または別の化合物に結合するアンカー部分、タンパク質にコンジュゲートされた場合に免疫応答を誘発する抗原、化学相補性のカップリングパートナー(coupling partner)と容易に反応する(したがって、タンパク質を別の構成体(entity)に連結する)カップリング基、ならびに細胞毒(cytotoxins)および他の生物活性剤などの治療的な部分が挙げられる。
DCM ジクロロメタン
DIC ジイソプロピルカルボジイミド
DIPEA ジイソプロピルエチルアミン
EDT エタンジチオール
HBTU N,N,N’,N’−テトラメチル−O−(1H−ベンゾトリアゾール−1−イル)ウロニウムヘキサフルオロリン酸
MeCN アセトニトリル
NMP N−メチルピロリジノン
PBS リン酸緩衝化生理食塩水
TCEP トリス(カルボキシエチル)ホスフィン
TFA トリフルオロ酢酸
TIPS トリイソプロピルシラン
(a)結合、−O−、−S−、−S−S−、−NH−、−N((C1〜C6)アルキル)−、−NH−C(O)−NH−、−C(O)−NH−、−NH−C(O)−、
(b)(C1〜C20)アルキレン、(C2〜C20)アルケニレン、(C2〜C20)アルキニレン、−Z−(C1〜C20)アルキレン−、−Z−(C2〜C20)アルケニレン、−Z−(C2〜C20)アルキニレン、(C1〜C20)アルキレン−Z−(C1〜C20)アルキレン、(C2〜C20)アルケニレン−Z−(C2〜C20)アルケニレン、(C2〜C20)アルキニレン−Z−(C2〜C20)アルキニレン、[式中、Zは−C(O)−、−NH−、−N(C1〜C6)アルキル)−、−NH−C(O)−NH−、−C(O)−NH−、−NH−C(O)−、(C3〜C7)シクロアルキレン、フェニレン、ヘテロアリーレン、またはヘテロシクレンであり、前記(C1〜C20)アルキレン、前記(C2〜C20)アルケニレン、および前記(C2〜C20)アルキニレン部分はそれぞれ独立に、酸素原子が少なくとも1個および好ましくは2個の炭素原子により分けられるように、前記部分内に内部分散された1個または複数の酸素原子を任意選択で含有する]、
(c)(C3〜C7)シクロアルキレン、(C3〜C7)シクロアルキレン−Y−(C3〜C7)シクロアルキレン、−Y−(C3〜C7)シクロアルキレン、フェニレン、−Y−フェニレン、フェニレン−Y−フェニレン、ヘテロアリーレン、Y−ヘテロアリーレン、ヘテロアリーレン−Y−ヘテロアリーレン、ヘテロシクレン、−Y−ヘテロシクレン、またはヘテロシクレン−Y−ヘテロシクレン、[式中、Yは、(C1〜C20)アルキレン、(C2〜C20)アルケニレン、(C2〜C20)アルキニレン、−O−、−C(O)−、−S−、−NH−、−N((C1〜C6)アルキル)−、−NH−C(O)−NH−、−C(O)−NH−、または−NH−C(O)−であり、前記(C3〜C7)シクロアルキレン、前記フェニレン、前記ヘテロアリーレン、および前記ヘテロシクレン部分は、それぞれ独立に、ハロ、(C1〜C4)アルキル、またはハロ置換(C1〜C4)アルキルから選択される1〜3個の置換基で任意選択で置換される]、
(d)−[OCH2CH2]v−(式中、vは1〜20、好ましくは1〜10である)、および
(e)1〜100個のアミノ酸、好ましくは1〜30個または1〜6個のアミノ酸を含むペプチド
から選択される1つまたは複数の構成成分も含み得る。
各Sは、ポリペプチドまたはポリペプチド複合体のシステイン残基の硫黄原子であり、
T1およびT2は、それぞれ1〜5個の炭素原子を介して2個の硫黄原子を連結するテザーを表し、T1はL1にも結合し、T2はL2にも結合しており、
L1およびL2はそれぞれ、T1またはT2をそれぞれAに連結する連結基を表し、
L3は、AをRに連結する連結基であり、
Aは、L1、L2、およびL3を連結する基を表し、
Rは、ペイロードまたはペイロードを結合するための反応性官能基を表す)
を含むポリペプチド−ペイロードコンジュゲート。
のものである、実施形態1〜11のいずれかのポリペプチド−ペイロードコンジュゲート。
L1、L2、およびL3は、連結基であり、
Aは、N、CH、フェニル、C3〜6シクロアルキル、または環員としてN、O、およびSから選択される最大2個のヘテロ原子を有する5〜6員のヘテロ環基もしくはヘテロアリール基である)
の化合物またはその塩。
のものである、実施形態13〜16のいずれか1つの化合物。
の活性化されたポリペプチドまたはポリペプチド複合体を実施形態13〜18のいずれか1つの化合物と接触させるステップを含む、ポリペプチド−ペイロードコンジュゲートを調製する方法。
還元されたポリペプチドまたはポリペプチド複合体をジクロロアセトンと接触させて、活性化されたポリペプチドまたはポリペプチド複合体を提供するステップと
を含む方法により、活性化されたポリペプチドまたはポリペプチド複合体を調製するステップをさらに含む、実施形態19または20の方法。
方法A;
溶離液A:水+0.1%ギ酸、溶離液B:アセトニトリル+0.08%ギ酸
グラジエント:2分間でBを3から80%へ−流速1.0ml/分、カラム:Proswift Monolith 4.6×50mm、40℃
方法B;
溶離液A:水+0.1%ギ酸、溶離液B:アセトニトリル+0.04%ギ酸
グラジエント:2分間でBを3から80%へ−流速1.0ml/分、カラム:Proswift Monolith 4.6×50mm、40℃
方法C;
溶離液A:水+3.75mM酢酸アンモニウム+2%アセトニトリル、溶離液B:アセトニトリル
グラジエント:1.7分間でBを2から98%へ−流速1.0ml/分、カラム:Acquity CSH 2.1×50mm、50℃
方法D(HRMS);
溶離液A:水+0.05%ギ酸+3.75mM酢酸アンモニウム、溶離液B:アセトニトリル+0.04%ギ酸
グラジエント:4.4分間でBを2から98%へ−流速1.0ml/分、カラム:Acquity CSH 2.1×50mm、50℃
IgGからのFcの調製
0.61mLのTris 0.1M pH8.0およびLys−C(100μLの0.1mg/mL水中溶液)をIgG(0.639mLの78.26mg/mL PBS中溶液 pH7.4、0.336μmol)に順に添加した。得られた混合物を37℃で45分間インキュベートした。セファロースビーズに固定化したプロテインAを混合物に添加し、続いてPBS緩衝液で3回洗浄し、Lys−CおよびFab断片を除去した。次いで、Fcを、グリシン0.1M pH2.5を2回添加し、Tris 1M pH8.0へ溶出することにより解離した。溶出したFcは、Amicon 10K MWCO遠心濾過機を使用してPBS pH7.4に緩衝液交換し、Fc(700μL、19.6mg/mL、13.7mg、77%)を得た。LCMS ESI(PNGase Fによる脱グリコシル化後):50410。
Fc−アジドコンジュゲート(14)の調製
ジアジド官能基を有する抗Her2 IgGの調製(15)
フェニルジスルフィドを有する抗Her2 IgG(16)の調製
抗Her2 IgG−ジMMAF 17の調製
Claims (23)
-
各Sは、前記ポリペプチドまたはポリペプチド複合体のシステイン残基の硫黄原子であり、
T1およびT2はそれぞれ、1〜5個の炭素原子を介して2個の硫黄原子を連結するテザーを表し、T1はL1にも結合し、T2はL2にも結合しており、
L1およびL2はそれぞれ、T1またはT2をそれぞれAに連結する連結基を表し、
L3はAをRに連結する連結基であり、
Aは、L1、L2、およびL3を連結する基を表し、および
Rは、ペイロードまたはペイロードを結合するための反応性官能基を表す)
を含むポリペプチド−ペイロードコンジュゲート。 - 前記ポリペプチドが抗体または抗体Fcである、請求項1に記載のポリペプチド−ペイロードコンジュゲート。
- T1およびT2のそれぞれが、前記結合した硫黄原子同士を連結する3炭素原子の鎖を含む、請求項2に記載のポリペプチド−ペイロードコンジュゲート。
- T1が、式−CH2−C(=N−O−[L1])−CH2−(式中[L1]は、T1のL1への結合点を示す)の基を表す、請求項1に記載のポリペプチド−ペイロードコンジュゲート。
- T2が、式−CH2−C(=N−O−[L2])−CH2−(式中[L2]は、T2のL2への結合点を示す)の基を表す、請求項4に記載のポリペプチド−ペイロードコンジュゲート。
- L1およびL2が同一である、請求項5に記載のポリペプチド−ペイロードコンジュゲート。
- 前記ポリペプチドが抗体または抗体Fcであり、T1に結合する前記2個の硫黄原子が、コンジュゲートしていない抗体または抗体Fcにおいてジスルフィド結合を形成する、請求項6に記載のポリペプチド−ペイロードコンジュゲート。
- 前記ポリペプチドが抗体または抗体Fcであり、T2に結合する前記2個の硫黄原子が、コンジュゲートしていないポリペプチドにおいてジスルフィド結合を形成する、請求項7に記載のポリペプチド−ペイロードコンジュゲート。
- Rが、治療剤、検出可能な標識、抗原、または結合基を表す、請求項8に記載のポリペプチド−ペイロードコンジュゲート。
- Rが細胞毒を表す、請求項9に記載のポリペプチド−ペイロードコンジュゲート。
- Aが、N、CH、フェニル、C3〜6シクロアルキル、または環員としてN、O、およびSから選択される最大2個のヘテロ原子を有する5〜6員のヘテロ環基もしくはヘテロアリール基である、請求項10に記載のポリペプチド−ペイロードコンジュゲート。
- 式
のものである、請求項11に記載のポリペプチド−ペイロードコンジュゲート。 - 式(IIa)
L1、L2、およびL3は、連結基であり、
Aは、N、CH、フェニル、C3〜6シクロアルキル、または環員としてN、O、およびSから選択される最大2個のヘテロ原子を有する5〜6員のヘテロ環基もしくはヘテロアリール基である)
の化合物またはその塩。 - L1およびL2が同一である、請求項13に記載の化合物。
- Rが細胞毒である、請求項14に記載の化合物。
- L3が、−(CH2)1〜6−、−(CH2CH2O)1〜6−、および−(OCH2CH2)1〜6−から選択される少なくとも1つの基を含む、請求項14に記載の化合物。
- L3が、−C(O)−、−NHC(O)−、−C(O)NH−、および−S−から選択される少なくとも1つの基を含む、請求項14に記載の化合物。
- 式
- R−L3−が、式R−Z−C(=O)−(式中、Zは、−(CH2)1〜6−、−(CH2CH2O)1〜6−、および−(OCH2CH2)1〜6−から選択される少なくとも1つの基を含む)のものである、請求項18に記載の化合物。
- 式(IIIa)または(IIIb):
の活性化されたポリペプチドまたはポリペプチド複合体を請求項19に記載の化合物と接触させるステップを含む、ポリペプチド−ペイロードコンジュゲートを調製する方法。 - 前記ポリペプチドまたはポリペプチド複合体が、抗体または抗体のFc部分である、請求項20に記載の方法。
- 抗体または抗体Fcの少なくとも2つのジスルフィド結合を還元して、還元されたポリペプチドまたはポリペプチド複合体を作製するステップと、
前記還元されたポリペプチドまたはポリペプチド複合体をジクロロアセトンと接触させて、前記活性化されたポリペプチドまたはポリペプチド複合体を提供するステップと
を含む方法により、前記活性化されたポリペプチドまたはポリペプチド複合体を調製するステップをさらに含む、請求項21に記載の方法。 - 請求項1に記載のポリペプチド−ペイロードコンジュゲートおよび少なくとも1つの薬学的に許容される担体、希釈剤、または緩衝液を含む医薬組成物。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013190292A2 (en) * | 2012-06-19 | 2013-12-27 | Polytherics Limited | Novel process for preparation of antibody conjugates and novel antibody conjugates |
WO2014064423A1 (en) * | 2012-10-24 | 2014-05-01 | Polytherics Limited | Drug-protein conjugates |
WO2014064424A1 (en) * | 2012-10-24 | 2014-05-01 | Polytherics Limited | Drug-protein conjugates |
WO2014083505A1 (en) * | 2012-11-30 | 2014-06-05 | Novartis Ag | Methods for making conjugates from disulfide-containing proteins |
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GB0316294D0 (en) | 2003-07-11 | 2003-08-13 | Polytherics Ltd | Conjugated biological molecules and their preparation |
US8673848B2 (en) * | 2012-01-27 | 2014-03-18 | Novartis Ag | Synthetic apelin mimetics for the treatment of heart failure |
US20090131306A1 (en) | 2007-06-15 | 2009-05-21 | Adherex Technologies, Inc. | Chemically modified cyclic peptides containing cell adhesion recognition (car) sequences and uses therefor |
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EP2822597A1 (en) * | 2012-03-09 | 2015-01-14 | UCL Business Plc. | Chemical modification of antibodies |
-
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013190292A2 (en) * | 2012-06-19 | 2013-12-27 | Polytherics Limited | Novel process for preparation of antibody conjugates and novel antibody conjugates |
WO2014064423A1 (en) * | 2012-10-24 | 2014-05-01 | Polytherics Limited | Drug-protein conjugates |
WO2014064424A1 (en) * | 2012-10-24 | 2014-05-01 | Polytherics Limited | Drug-protein conjugates |
WO2014083505A1 (en) * | 2012-11-30 | 2014-06-05 | Novartis Ag | Methods for making conjugates from disulfide-containing proteins |
Non-Patent Citations (4)
Title |
---|
BIOCONJUGATE CHEMISTRY, vol. 23, JPN6019023681, 2012, pages 2262 - 2277, ISSN: 0004061335 * |
ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 12, no. 16, JPN5017003816, 18 February 2014 (2014-02-18), pages 2606 - 2614, ISSN: 0004186617 * |
TETRAHEDRON LETTERS, vol. 55, JPN6019023676, 1 March 2014 (2014-03-01), pages 2270 - 2273, ISSN: 0004186616 * |
TETRAHEDRON, vol. 52, no. 43, JPN6019023679, 1996, pages 13751 - 13766, ISSN: 0004186618 * |
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