JP2021523703A - 調節t細胞表面抗原のエピトープおよびこれに特異的に結合する抗体 - Google Patents
調節t細胞表面抗原のエピトープおよびこれに特異的に結合する抗体 Download PDFInfo
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Abstract
Description
Lx1Lx2x3N
前記式1中、
x1〜x3は、それぞれ独立して、中性アミノ酸、酸性アミノ酸、塩基性アミノ酸または芳香族アミノ酸であってもよい。ここで、前記中性アミノ酸は、グリシン(glycine;G)、アラニン(alanine;A)、バリン(valine、V)、ロイシン(leucine、L)、イソロイシン(isoleucine、I)、セリン(serine、S)またはトレオニン(threonine、T)であってもよく、前記酸性アミノ酸は、アスパラギン酸(aspartic acid;D)、グルタミン酸(glutamic acid;E)、アスパラギン(asparagine;N)またはグルタミン(glutamine;Q)であってもよいし、前記塩基性アミノ酸は、リシン(lysine、K)、アルギニン(arginine;R)またはヒスチジン(histidine;H)であってもよく、前記芳香族アミノ酸は、フェニルアラニン(phenylalanine;F)またはチロシン(tyrosine;Y)であってもよい。
Lx1Lx2x3N
前記式1中、
x1〜x3は、それぞれ独立して、中性アミノ酸、酸性アミノ酸、塩基性アミノ酸または芳香族アミノ酸であってもよい。ここで、前記中性アミノ酸は、グリシン(glycine;G)、アラニン(alanine;A)、バリン(valine、V)、ロイシン(leucine、L)、イソロイシン(isoleucine、I)、セリン(serine、S)またはトレオニン(threonine、T)であってもよく、前記酸性アミノ酸は、アスパラギン酸(aspartic acid;D)、グルタミン酸(glutamic acid;E)、アスパラギン(asparagine;N)またはグルタミン(glutamine;Q)であってもよいし、前記塩基性アミノ酸は、リシン(lysine、K)、アルギニン(arginine;R)またはヒスチジン(histidine;H)であってもよく、前記芳香族アミノ酸は、フェニルアラニン(phenylalanine;F)またはチロシン(tyrosine;Y)であってもよい。
Lrig−1タンパク質のペプチド切断を防止するために、前記Lrig−1タンパク質のC−およびN−ターミナルにGSGSGSGリンカーを伸長させた。伸長した抗原配列は、14個のアミノ酸のペプチド−ペプチド重複によって15個のアミノ酸に翻訳された。最終LRIG1ペプチドのマイクロアレイの結果、1,091個の異なるペプチドがデュプリケート(duplicate)で確認され、追加的なHA(YPYDVPDYAG、102spots)コントロールペプチドによってフレーム(framed)された。
試料:製造例8のH6単クローン抗体
洗浄バッファ:PBS、0.05%Tween20(各培養後10秒経過した時、3回)によるpH7.4
ブロッキングバッファ(Blocking Buffer):RocklandブロッキングバッファMB−070(初のアッセイ30分前)
培養バッファ:10%ブロッキングバッファを追加した洗浄バッファ
アッセイの条件:培養バッファ内の抗体の濃度を1μg/ml、10μg/mlおよび100μg/mlに調節;4℃で16時間培養し、140rpmで撹拌
二次抗体:ヤギ抗−ヒトIgG(H+L)DyLight680(0.2μg/ml);常温で培養バッファ内で45分間染色
対照群抗体:マウス単クローン性抗−HA(12CA5)DyLight800(0.5μg/ml);常温で培養バッファ内で45分間染色
スキャナ:LI−COR Odyssey Imaging System;スキャニングオフセット(scanning offset)0.65mm、解像度21μm、7/7(red=700nm/green=800nm)のスキャニング強度
メインアッセイで干渉を起こしうる抗原−由来ペプチドと相互作用を起こしうるかを確認するために、培養バッファ内で二次抗体および対照群抗体を用いてLRIG1ペプチドのマイクロアレイ複製の前−染色(pre−staining)を行った。以後、培養バッファ内で製造例8のH6単クローン抗体(1μg/ml、10μg/mlおよび100μg/ml)とともに他のLRIG1ペプチドのマイクロアレイ複製の追加的培養を行った後、二次抗体および対照群抗体を用いて染色した。LI−COR Odyssey Imaging Systemを用いて7/7(red/green)のスキャニング強度で読み出し(read−out)を行った。スポット強度の定量化およびペプチド解読(peptide annotation)は16−ビットのグレースケールTIFFファイルで示した。PepSlide(R) Analyzerを用いてマイクロアレイイメージを分析した。その結果は図13〜15に示し、分析されたエピトープ配列は下記表8に示した。
図13〜15に示すように、調節T細胞上に存在するLrig−1タンパク質に特異的に結合して癌を効果的に治療する単クローン抗体(H6)は、Lrig−1タンパク質のうち、配列番号18〜29のアミノ酸配列で表されるエピトープに特異的に結合して上記の機能を発揮することを確認することができた。さらに、配列番号18および20で表されるエピトープは、ロイシン−リッチタンパク質(leucine rich repeat)を共通にしており、具体的には、N−ターミナルから5番目のアミノ酸位置に本発明の式1のアミノ酸配列で表される共通した配列(consensus sequence)を含んでいることが分かった。
Claims (20)
- 下記式1で表されるアミノ酸配列からなるポリペプチドを含むエピトープに特異的に結合する抗体または抗原結合断片:
[式1]
Lx1Lx2x3N
前記式1中、
x1〜x3は、それぞれ独立して、中性アミノ酸、酸性アミノ酸、塩基性アミノ酸または芳香族アミノ酸である。 - 前記x1〜x3は、それぞれ独立して、アスパラギン(asparagine;N)、アスパラギン酸(aspartic acid;D)、セリン(serine;S)、チロシン(tyrosine;Y)、アルギニン(arginine;R)、フェニルアラニン(phenylalanine;F)、リシン(lysine、K)、ヒスチジン(histidine;H)、ロイシン(leucine、L)、バリン(valine、V)、トレオニン(threonine、T)、アラニン(alanine;A)、グルタミン(glutamine;Q)、グルタミン酸(glutamic acid;E)およびグリシン(glycine;G)からなる群より選択されるアミノ酸である、請求項1に記載の抗体または抗原結合断片。
- 前記x1は、アスパラギン(asparagine;N)、フェニルアラニン(phenylalanine;F)、アスパラギン酸(aspartic acid;D)、リシン(lysine、K)、ヒスチジン(histidine;H)、バリン(valine、V)、アルギニン(arginine;R)およびトレオニン(threonine、T)からなる群より選択されるアミノ酸であり、
前記x2は、セリン(serine;S)、グルタミン(glutamine;Q)、アラニン(alanine;A)、アスパラギン(asparagine;N)、グルタミン酸(glutamic acid;E)、アスパラギン酸(aspartic acid;D)、フェニルアラニン(phenylalanine;F)およびグリシン(glycine;G)からなる群より選択されるアミノ酸であり、
前記x3は、チロシン(tyrosine;Y)、ヒスチジン(histidine;H)、グリシン(glycine;G)、アルギニン(arginine;R)、アスパラギン(asparagine;N)、ロイシン(leucine、L)、リシン(lysine、K)およびフェニルアラニン(phenylalanine;F)からなる群より選択されるアミノ酸である、請求項1に記載の抗体または抗原結合断片。 - 前記エピトープは、10〜20merからなる、請求項1に記載の抗体または抗原結合断片。
- 前記式1で表されるアミノ酸配列からなるポリペプチドは、前記エピトープのN−ターミナルから3〜6番目に位置する、請求項1に記載の抗体または抗原結合断片。
- 前記ポリペプチドは、配列番号4〜17のいずれか1つのアミノ酸配列で表される、請求項1に記載の抗体または抗原結合断片。
- 配列番号18〜29のいずれか1つのアミノ酸配列で表されるLrig−1タンパク質のエピトープに特異的に結合する抗体または抗原結合断片。
- Lrig−1(leucine−rich and immunoglobulin−like domains1)タンパク質のエピトープであって、
下記式1で表されるアミノ酸配列からなるポリペプチドを含むエピトープ:
[式1]
Lx1Lx2x3N
前記式1中、
x1〜x3は、それぞれ独立して、中性アミノ酸、酸性アミノ酸、塩基性アミノ酸または芳香族アミノ酸である。 - Lrig−1(leucine−rich and immunoglobulin−like domains1)タンパク質のエピトープであって、
配列番号18〜29のいずれか1つのアミノ酸配列で表されるポリペプチドを含む、エピトープ。 - 請求項9に記載のエピトープをコーディングする核酸分子。
- 請求項10に記載の核酸分子が挿入された発現ベクター。
- 請求項11に記載の発現ベクターが形質感染した宿主細胞株。
- 請求項1〜6のいずれか1項に記載の抗体または抗原結合断片を有効成分として含む癌の予防または治療用薬学組成物。
- 前記癌は、胃癌、肝臓癌、膠細胞腫、卵巣癌、大膓癌、頭頸部癌、膀胱癌、腎細胞癌、乳癌、転移癌、前立腺癌、膵臓癌、黒色腫または肺癌である、請求項13に記載の薬学組成物。
- 請求項7に記載の抗体または抗原結合断片を有効成分として含む癌の予防または治療用薬学組成物。
- 前記癌は、胃癌、肝臓癌、膠細胞腫、卵巣癌、大膓癌、頭頸部癌、膀胱癌、腎細胞癌、乳癌、転移癌、前立腺癌、膵臓癌、黒色腫または肺癌である、請求項15に記載の薬学組成物。
- 請求項1〜6のいずれか1項に記載の抗体または抗原結合断片;および薬物を含む抗体−薬物結合体。
- 請求項7に記載の抗体または抗原結合断片;および薬物を含む抗体−薬物結合体。
- 請求項1〜6のいずれか1項に記載の抗体または抗原結合断片を個体に投与するステップを含む癌の予防または治療方法。
- 請求項7に記載の抗体または抗原結合断片を個体に投与するステップを含む癌の予防または治療方法。
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US20210363244A1 (en) | 2021-11-25 |
EP3798227A1 (en) | 2021-03-31 |
KR20210087915A (ko) | 2021-07-13 |
CA3098815A1 (en) | 2019-11-14 |
CN112105629A (zh) | 2020-12-18 |
AU2019267050A1 (en) | 2020-11-26 |
EP3798227A4 (en) | 2022-03-02 |
KR20190129018A (ko) | 2019-11-19 |
JP7470987B2 (ja) | 2024-04-19 |
KR102652664B1 (ko) | 2024-04-02 |
KR102275514B1 (ko) | 2021-07-09 |
BR112020022655A2 (pt) | 2021-02-17 |
KR20220142975A (ko) | 2022-10-24 |
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