JP2010505909A - 癌を治療するための、o−アセチル化型のgd2ガングリオシドに特異的なモノクローナル抗体の使用 - Google Patents
癌を治療するための、o−アセチル化型のgd2ガングリオシドに特異的なモノクローナル抗体の使用 Download PDFInfo
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Abstract
Description
治療または診断のためのインビボでのモノクローナル抗体の使用のためには、後者が特定の特異性、親和性、および非毒性という要件を満たす必要がある。しかし、モノクローナルおよびキメラ抗GD2抗体について行われた臨床研究から、キメラ化またはヒト化で解決されない大きな悪性副作用である抗GD2抗体による神経毒性が立証された。実際、抗GD2抗体を投与された神経外胚葉起源の癌患者は、抗体を投与されている間痛みに苦しみ、これらの患者の一部は末梢神経系の神経障害を発症した。この作用は、末梢系の神経線維細胞の表面にGD2ガングリオシドが存在することで説明される。
)に記載されている。
GD2ガングリオシドを認識せず、O−アセチル化GD2ガングリオシドに特異的なモノクローナル抗体は、末梢神経線維を認識せず、そのため神経毒性を生じないという利点を有し得る。したがって、このような抗体は抗GD2モノクローナル抗体と比較して、GD2ガングリオシドをO−アセチル化型で発現する神経外胚葉起源のヒトの癌等の特定の種類の癌の免疫ターゲッティングに大きな利点を有し得る。
マの全RNA抽出物から、hu−Cγ1cDNAを増幅させた。反応混合液は以下の通りである:0.5μgのオリゴd(T)18(NEW ENGLAND BIOLABS社、ビバリー、マサチューセッツ州、米国)、1μgのRNA、および0.5mMのdNTP(PROMEGA社、マディソン、ウィスコンシン州、米国)、これらを滅菌水で12μLにする(qsp12μL)。この混合液を65℃(乾燥制御された浴)で5分間、その後4℃(氷水)で2分間インキュベートしてRNAを変性させる。次いでこの反応混合液に、4μLの5×First−strand Buffer溶液(Invitrogen Life Biotechnologies社)、10mMのDTT(Invitrogen Life Biotechnologies社)、160UのRnasine(PROMEGA社)、および800Uの逆転写酵素(Invitrogen Life Biotechnologies社)を加える。得られた混合液を37℃で1時間、その後反応を停止させるために70℃で15分間インキュベートする。以下の合成オリゴヌクレオチドを用いたPCR遺伝子増幅によって、hu−Cγ1cDNAのコピーを得る;5’−Nhel hu−Cγ1:5’−CA GCT AGC ACC AAG GGC CCA TCG GTC TTC C−3’(センスプローブ、配列番号19)および3’−XbaI hu−Cγ1:5’−AGC CTC TCC CTG TCT CCG GGT AAA TAA TCT AGA CG−3’(アンチセンスプローブ、配列番号20)。
を用いてSSC/FL1−Hウィンドウ内で、10000個の細胞を分析する。二次抗体のみで非特異的に標識されたコントロールを用いてベースを調節した後に1Logを超える蛍光を有する細胞を陽性と呼ぶ。
%ADCC活性=(上清中の51Cr−自発的に遊離した51Cr)/(全51Cr−自発的に遊離した51Cr)
Claims (27)
- GD2ガングリオシドを認識せず、O−アセチル化GD2ガングリオシドを認識する抗体の、癌の治療のための使用であって、GD2ガングリオシドを認識する抗体を治療的投与に使用するときに認められる毒性がなく、前記抗体が、腫瘍細胞が発現するO−アセチル化GD2分子を認識し、末梢神経およびその他の正常神経組織の表面で発現するGD2分子は認識しないものである、使用。
- O−アセチル化型のGD2ガングリオシドのみを認識する前記抗体が、O−アセチル化GD2に対して107リットル/molを超える親和性を有し、GD2自体に対してその10分の1より低い親和性を有するκ−IgGである、請求項1に記載の使用。
- O−アセチル化型のGD2ガングリオシドのみを認識する前記抗体が、モノクローナル抗体または前記抗体の断片である、請求項1または2に記載の使用。
- O−アセチル化型のGD2ガングリオシドのみを認識する前記抗体が、元の抗体の特性を修飾するため、特にその免疫原性を低減するため、またはその毒性活性を増大させるため、または注入後のそのクリアランスを早めるまたは遅らせるため、当業者に公知の遺伝学的技術を用いて数個のアミノ酸を他のアミノ酸に置換した前記元の抗体に相当する、請求項3に記載の使用。
- O−アセチル化型のGD2ガングリオシドのみを認識する前記抗体が、配列番号3、配列番号4および配列番号5で表されるアミノ酸配列を含んでなるH鎖可変領域の相補性決定領域を有し、配列番号6、配列番号7および配列番号8で表されるアミノ酸配列を含んでなるL鎖可変領域の相補性決定領域を有する8B6抗体である、請求項3に記載の使用。
- O−アセチル化型のGD2ガングリオシドのみを認識する前記抗体が、キメラ抗体またはその断片である、請求項3に記載の使用。
- O−アセチル化型のGD2ガングリオシドのみを認識する前記抗体が、ヒト抗体またはその断片である、請求項3に記載の使用。
- O−アセチル化型のGD2ガングリオシドのみを認識する前記抗体が、配列番号3、配列番号4および配列番号5で表されるアミノ酸配列を含んでなるH鎖可変領域の相補性決定領域を有し、配列番号6、配列番号7および配列番号8で表されるアミノ酸配列を含んでなるL鎖可変領域の相補性決定領域を有するキメラまたはヒト化抗体である、請求項6、7または8のいずれか一項に記載の使用。
- 前記癌が、神経芽細胞腫、黒色腫、膠芽腫、または小細胞肺癌である、請求項1〜8に記載の使用。
- 前記抗体またはその断片が、分子Xに結合しており、該分子Xが、毒性分子、薬剤、プロドラッグ、または特異性に関連しない二次抗体であることを特徴とする、請求項1〜9に記載の使用。
- 前記毒性分子が、毒性の化学分子、生物学的分子、または放射性分子であり、前記分子が、O−アセチル化GD2ガングリオシドを発現する腫瘍細胞を死滅させることを意図したものである、請求項10に記載の使用。
- 前記抗体が、糖の付加でFc領域が変異しており、これによって免疫細胞および補体系分子の活性化を調節する、請求項1〜9のいずれかに記載の使用。
- O−アセチル化型のGD2ガングリオシドのみを認識するモノクローナル抗体であって、元の抗体の特性を修飾するため、特にその免疫原性を低減するため、またはその毒性活性を増大させるため、または注入後のそのクリアランスを早めるまたは遅らせるため、当業者に公知の遺伝学的技術を用い、数個のアミノ酸を他のアミノ酸に置換した前記元の抗体に相当する、モノクローナル抗体。
- キメラまたはヒト化された、GD2ガングリオシドを認識せずO−アセチル化型のGD2ガングリオシドを認識するモノクローナル抗体またはその断片であって、H鎖可変領域の相補性決定領域が、配列番号3、配列番号4、および配列番号5で表されるアミノ酸配列を有し、L鎖可変領域の相補性決定領域が、配列番号6、配列番号7および配列番号8で表されるアミノ酸配列を有する、請求項13に記載のモノクローナル抗体またはその断片。
- キメラまたはヒト化された、配列番号1で表される推定アミノ酸配列を有する重鎖可変領域を有し、配列番号2で表される推定アミノ酸配列を有する軽鎖可変領域を有する、請求項14に記載のモノクローナル抗体またはその断片。
- CHO細胞株を用いて得られる、請求項13、14、または15のいずれか一項に記載のモノクローナル抗体またはその断片。
- 前記抗体またはその断片が、分子Xに結合しており、前記分子Xが、毒性分子、薬剤、プロドラッグ、または特異性に関係しない二次抗体である、請求項13〜16のいずれか一項に記載の抗体に由来する医薬分子。
- 前記毒性分子が、毒性の化学分子、生物学的分子、または放射性分子であり、前記分子が、O−アセチル化GD2ガングリオシドを発現する腫瘍細胞を死滅させることを意図したものである、請求項17に記載の医薬分子。
- 前記治療分子が、糖の付加でFc領域が変異しており、これによって免疫細胞および補体系分子の活性化を調節する、請求項17〜18に記載の医薬分子。
- 腫瘍細胞の表面にO−アセチル化GD2ガングリオシドを発現する癌を診断するための分子であって、前記分子が請求項13〜16のいずれか一項に記載の抗体またはその断片に由来し、前記抗体または前記断片が、蛍光または放射活性により前記抗体を検出するための薬剤に結合している、分子。
- 請求項13〜16のいずれか一項に記載の抗体をコードするDNA配列。
- プロモーターに機能的に連結された、請求項21のDNA配列を含んでなる発現ベクター。
- 請求項22の発現ベクターを含んでなる細胞。
- 前記細胞が動物細胞である、請求項23に記載の細胞。
- 請求項13〜16のいずれか一項に記載の抗体を産生する、非ヒト形質転換体。
- O−アセチル化GD2ガングリオシドに対する抗体の製造方法であって、
好適な条件下で、請求項23〜25のいずれか一項に記載の細胞または非ヒト形質転換体中で請求項21に記載のDNA配列を発現させ、前記抗体を回収することを含んでなる、方法。 - 請求項23〜25のいずれかに記載の細胞または非ヒト形質転換体が、抗体の蓄積する条件下で培養される、請求項26に記載の方法。
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Cited By (5)
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005070967A2 (en) * | 2004-01-22 | 2005-08-04 | Merck Patent Gmbh | Anti-cancer antibodies with reduced complement fixation |
JP2006521085A (ja) * | 2002-12-17 | 2006-09-21 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Gd2に結合するマウス14.18抗体のヒト化抗体(h14.18)およびそのil−2融合タンパク質 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9904581D0 (sv) * | 1999-12-15 | 1999-12-15 | A & Science Invest Ab | A novel helicobacter pylori-binding substance and use thereof |
FR2906808B1 (fr) * | 2006-10-10 | 2012-10-05 | Univ Nantes | Utilisation d'anticorps monoclonaux specifiques de la forme o-acetylee du ganglioside gd2 dans le traitement de certains cancers |
-
2006
- 2006-10-10 FR FR0608881A patent/FR2906808B1/fr active Active
-
2007
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2006521085A (ja) * | 2002-12-17 | 2006-09-21 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Gd2に結合するマウス14.18抗体のヒト化抗体(h14.18)およびそのil−2融合タンパク質 |
WO2005070967A2 (en) * | 2004-01-22 | 2005-08-04 | Merck Patent Gmbh | Anti-cancer antibodies with reduced complement fixation |
Non-Patent Citations (4)
Title |
---|
JPN5009017582; CERATO E: HYBRIDOMA V16 N4, 199708, P307-316 * |
JPN5009017583; MEZAZIGH A: GLYCOCONJUGATE JOURNAL V10 N4, 19930820, P300-301 * |
JPN5009017585; YE J N: INTERNATIONAL JOURNAL OF CANCER V50 N2, 19920121, P197-201 * |
JPN6012045673; 日本免疫学会総会・学術集会記録, 1990, Vol.20, p.325 * |
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JP2014524737A (ja) * | 2011-06-24 | 2014-09-25 | サイチューン | IL−15およびIL−15RαSUSHIドメインに基づいた免疫サイトカイン |
JP2016520569A (ja) * | 2013-04-29 | 2016-07-14 | オージーディー2 ファーマ | がん幹細胞がんのための新規な治療及び診断ストラテジーとしてのo−アセチル化gd2ガングリオシドのターゲティング |
JP2019151647A (ja) * | 2013-04-29 | 2019-09-12 | オージーディー2 ファーマ | がん幹細胞がんのための新規な治療及び診断ストラテジーとしてのo−アセチル化gd2ガングリオシドのターゲティング |
JP2021100418A (ja) * | 2013-04-29 | 2021-07-08 | オージーディー2 ファーマ | がん幹細胞がんのための新規な治療及び診断ストラテジーとしてのo−アセチル化gd2ガングリオシドのターゲティング |
KR20160081977A (ko) * | 2013-11-11 | 2016-07-08 | 오제데2 파르마 | 세포사멸-촉진 활성을 가지는 gd2-o-아세틸화된 강글리오사이드에 대한 항체 |
JP2017501212A (ja) * | 2013-11-11 | 2017-01-12 | オージーディー2 ファーマ | プロアポトーシス活性を有するgd2−o−アセチル化ガングリオシドに対する抗体 |
KR102340725B1 (ko) | 2013-11-11 | 2021-12-20 | 오제데2 파르마 | 세포사멸-촉진 활성을 가지는 gd2-o-아세틸화된 강글리오사이드에 대한 항체 |
JP2018507910A (ja) * | 2015-02-12 | 2018-03-22 | ジ・アリゾナ・ボード・オブ・リージェンツ・オン・ビハーフ・オブ・ジ・ユニバーシティ・オブ・アリゾナ | 神経芽細胞腫を治療する方法 |
JP2020504092A (ja) * | 2016-12-05 | 2020-02-06 | オージーディー2 ファーマ | 薬物の治療可能性を改善するためのoアセチル化gd2ガングリオシドに対する抗体の使用 |
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JP5844790B2 (ja) | 2016-01-20 |
JP5519283B2 (ja) | 2014-06-11 |
AU2007306384A1 (en) | 2008-04-17 |
CN101616935A (zh) | 2009-12-30 |
AU2007306384B2 (en) | 2012-04-12 |
CA2703466C (fr) | 2015-09-08 |
RU2009117299A (ru) | 2010-11-20 |
CN101616935B (zh) | 2013-08-21 |
FR2906808B1 (fr) | 2012-10-05 |
WO2008043777A1 (fr) | 2008-04-17 |
FR2906808A1 (fr) | 2008-04-11 |
EP2076542B1 (fr) | 2012-08-15 |
US20100150910A1 (en) | 2010-06-17 |
AU2007306384C1 (en) | 2012-10-25 |
ES2392631T3 (es) | 2012-12-12 |
CA2703466A1 (fr) | 2008-04-17 |
WO2008043777B1 (fr) | 2008-06-19 |
EP2076542A1 (fr) | 2009-07-08 |
US8951524B2 (en) | 2015-02-10 |
RU2462476C2 (ru) | 2012-09-27 |
JP2014062107A (ja) | 2014-04-10 |
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