JP2022166140A5 - - Google Patents
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- JP2022166140A5 JP2022166140A5 JP2022127059A JP2022127059A JP2022166140A5 JP 2022166140 A5 JP2022166140 A5 JP 2022166140A5 JP 2022127059 A JP2022127059 A JP 2022127059A JP 2022127059 A JP2022127059 A JP 2022127059A JP 2022166140 A5 JP2022166140 A5 JP 2022166140A5
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Description
カルボキシ末端リジン－アスパラギン－グルタメート－ロイシン（ＫＤＥＬ）配列（配列番号：６０）は、真核生物細胞内の可溶性タンパク質のカノニカル小胞体残留及び回収シグナルモチーフであり、ＫＤＥＬ受容体によって認識される（Capitani M, Sallese M, FEBS Lett 583: 3863-71 (2009)を参照されたい）。シグナルモチーフのＫＤＥＬファミリーは、多くのＫＤＥＬ様モチーフ、例えば、ＨＤＥＬ（配列番号：６２）、ＲＤＥＬ（配列番号：６４）、ＷＤＥＬ（配列番号：６５）、ＹＤＥＬ（配列番号：６６）、ＨＥＥＬ（配列番号：６８）、ＫＥＥＬ（配列番号：６９）、ＲＥＥＬ（配列番号：７０）、ＫＦＥＬ（配列番号：７３）、ＫＩＥＬ（配列番号：８５）、ＤＫＥＬ（配列番号：８６）、ＫＫＥＬ（配列番号：８９）、ＨＮＥＬ（配列番号：９３）、ＨＴＥＬ（配列番号：９４）、ＫＴＥＬ（配列番号：９５）及びＨＶＥＬ（配列番号：９６）を含み、これらの全てが、系統発生学上の複数の界にわたって小胞体の内腔の常在物であることが公知であるタンパク質のカルボキシ末端において見出される（Munro S, Pelham H, Cell 48: 899-907 (1987)、RaykhelIet al., JCell Biol 179: 1193-204 (2007)）。ＫＤＥＬシグナルモチーフファミリーは、合成構築物を使用して証明された少なくとも４６のポリペプチドバリアントを含む（Raykhel, J Cell Biol 179: 1193-204(2007)）。さらなるＫＤＥＬシグナルモチーフは、ＡＬＥＤＥＬ（配列番号：１０６）、ＨＡＥＤＥＬ（配列番号：１０７）、ＨＬＥＤＥＬ（配列番号：１０８）、ＫＬＥＤＥＬ（配列番号：１０９）、ＩＲＳＤＥＬ（配列番号：１１０）、ＥＲＳＴＥＬ（配列番号：１１１）、及びＲＰＳＴＥＬ（配列番号：１１２）を含む（Alanen H et al., JMol Biol 409: 291-7 (2011)）。大部分のＫＤＥＬシグナルモチーフを表す一般化コンセンサスモチーフは、［ＫＲＨＱＳＡ］－［ＤＥＮＱ］－Ｅ－Ｌ（配列番号：１３７）と記載されている（Hulo N et al., NucleicAcids Res 34: D227-30(2006)）。
Claims (15)
- 細胞標的化分子であって、
ｉ）細胞の表面に物理的に結合している細胞外標的生体分子に特異的に結合することができる結合領域であって、前記細胞外標的生体分子がＨＥＲ２／ｎｅｕ／ＥｒｂＢ２、ＣＤ３８、ＣＤ２０、ＣＴＬＡ－４、ＢＣＭＡ又はＳＬＡＭＦ７である、前記結合領域と、
ii）配列番号１のアミノ酸１～２５１に対して少なくとも９０％の同一性を有するアミノ酸配列を含む志賀毒素エフェクターポリペプチドであって、前記アミノ酸配列が、配列番号１のＳ４５からＩへのアミノ酸置換、配列番号１のＲ５５からＬへのアミノ酸置換、配列番号１のＩ５７からＦへのアミノ酸置換、配列番号１のＰ５９からＦへのアミノ酸置換、配列番号１のＥ６０からＴへのアミノ酸置換、配列番号１のＥ６１からＬへのアミノ酸置換、配列番号１のＧ１１０からＡへのアミノ酸置換、配列番号１のＲ１８８からＡへのアミノ酸置換、配列番号１のＣ２４２からＳへのアミノ酸置換、配列番号１のＲ２４８からＡへのアミノ酸置換、及び配列番号１のＲ２５１からＡへのアミノ酸置換を含み、かつ、前記アミノ酸配列が、
配列番号１の７５位に対応するアミノ酸残基でアスパラギン、
配列番号１の７７位に対応するアミノ酸残基でチロシン、
配列番号１の１１４位に対応するアミノ酸残基でチロシン、
配列番号１の１６７位に対応するアミノ酸残基でグルタメート、
配列番号１の１７０位に対応するアミノ酸残基でアルギニン、
配列番号１の１７６位に対応するアミノ酸残基でアルギニン、及び
配列番号１の２０３位に対応するアミノ酸残基でトリプトファン
を含む、前記志賀毒素エフェクターポリペプチドと
を含む、前記細胞標的化分子。 - 志賀毒素エフェクターポリペプチドが、配列番号１のアミノ酸１～２５１に対して少なくとも９５％の配列同一性を有するアミノ酸配列を含む、請求項１に記載の細胞標的化分子。
- 結合領域が、志賀毒素エフェクターポリペプチドのカルボキシ末端に融合され、単一の連続的なポリペプチドを形成する、請求項１又は２に記載の細胞標的化分子。
- 結合領域が、免疫グロブリン型結合領域を含む、請求項１～３のいずれかに記載の細胞標的化分子。
- 免疫グロブリン型結合領域が、
シングルドメイン抗体断片、一本鎖可変断片、抗体可変断片、相補性決定領域３断片、拘束ＦＲ３－ＣＤＲ３－ＦＲ４ポリペプチド、Ｆｄ断片、抗原結合断片、フィブロネクチン由来第１０フィブロネクチンIII型ドメイン、テネイシンIII型ドメイン、アンキリン反復モチーフドメイン、低密度リポタンパク質受容体由来Ａドメイン、リポカリン、Kunitzドメイン、プロテインＡ由来Ｚドメイン、ガンマ－Ｂ結晶由来ドメイン、ユビキチン由来ドメイン、Ｓａｃ７ｄ由来ポリペプチド、Ｆｙｎ由来ＳＨ２ドメイン、ミニタンパク質、Ｃ型レクチン様ドメイン足場、ラクダ科動物ＶＨＨ断片に由来する重鎖抗体ドメイン、軟骨魚類に由来する重鎖抗体ドメイン、免疫グロブリン新規抗原受容体（ＩｇＮＡＲ）、ＶＮＡＲ断片、多量体化ｓｃＦｖ断片（ダイアボディ、トリアボディ、テトラボディ）、二価ナノボディ、二重特異性タンデムｓｃＦｖ、及び二重特異性ミニボディ
から選択されるポリペプチドを含む、請求項４に記載の細胞標的化分子。 - リンカーペプチド（ＧｘＳ）ｎ（配列番号１１５）（式中ｘが１～６であり、ｎが１～３０である）を含む、請求項１～５のいずれかに記載の細胞標的化分子。
- ｘが４であり、ｎが１である、請求項６に記載の細胞標的化分子。
- 請求項１～７のいずれかに記載の細胞標的化分子と、薬学的に許容される賦形剤又は担体とを含む医薬組成物。
- 請求項１～７のいずれかに記載の細胞標的化分子をコードするポリヌクレオチド、又はその相補体。
- 請求項９に記載のポリヌクレオチドを含む発現ベクター。
- 請求項９に記載のポリヌクレオチド又は請求項１０に記載の発現ベクターを含む、宿主細胞。
- 請求項１～７のいずれかに記載の細胞標的化分子又は請求項８に記載の医薬組成物を含む、患者の疾患、障害又は状態の治療剤。
- 疾患、障害又は状態が、がん、腫瘍、増殖異常、免疫障害及び微生物感染から選択される、請求項１２に記載の治療剤。
- がんが、骨がん、乳がん、中枢／末梢神経系がん、胃腸がん、胚細胞がん、腺がん、頭頸部がん、血液がん、腎・尿路癌、肝がん、肺／胸膜がん、前立腺がん、肉腫、皮膚がん及び子宮がんから選択される、請求項１３に記載の治療剤。
- 免疫障害が、アミロイドーシス、強直性脊椎炎、喘息、クローン病、糖尿病、移植片拒絶、移植片対宿主病、橋本甲状腺炎、溶血性尿毒症症候群、ＨＩＶ関連疾患、全身性エリテマトーデス、多発性硬化症、多発動脈炎、乾癬、乾癬性関節炎、リウマチ様関節炎、強皮症、敗血症性ショック、シェーグレン症候群、潰瘍性大腸炎、及び血管炎から選択される疾患に関連する、請求項１３に記載の治療剤。
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201461932000P | 2014-01-27 | 2014-01-27 | |
| US61/932,000 | 2014-01-27 | ||
| US201462049325P | 2014-09-11 | 2014-09-11 | |
| US62/049,325 | 2014-09-11 | ||
| JP2020002993A JP2020073569A (ja) | 2014-01-27 | 2020-01-10 | 哺乳動物への応用のための脱免疫化された志賀毒素ａサブユニットエフェクターポリペプチド |
| JP2021102325A JP7126729B2 (ja) | 2014-01-27 | 2021-06-21 | 哺乳動物への応用のための脱免疫化された志賀毒素ａサブユニットエフェクターポリペプチド |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2021102325A Division JP7126729B2 (ja) | 2014-01-27 | 2021-06-21 | 哺乳動物への応用のための脱免疫化された志賀毒素ａサブユニットエフェクターポリペプチド |
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| Publication Number | Publication Date |
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| JP2022166140A JP2022166140A (ja) | 2022-11-01 |
| JP2022166140A5 true JP2022166140A5 (ja) | 2022-11-09 |
| JP7402556B2 JP7402556B2 (ja) | 2023-12-21 |
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| Application Number | Title | Priority Date | Filing Date |
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| JP2016546493A Active JP6646584B2 (ja) | 2014-01-27 | 2015-01-26 | 哺乳動物への応用のための脱免疫化された志賀毒素ａサブユニットエフェクターポリペプチド |
| JP2016546476A Active JP6655017B2 (ja) | 2014-01-27 | 2015-01-26 | Ｍｈｃクラスｉエピトープ送達ポリペプチド |
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