JP2021513844A - グリピカン3抗体およびそのコンジュゲート - Google Patents
グリピカン3抗体およびそのコンジュゲート Download PDFInfo
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- JP2021513844A JP2021513844A JP2020543351A JP2020543351A JP2021513844A JP 2021513844 A JP2021513844 A JP 2021513844A JP 2020543351 A JP2020543351 A JP 2020543351A JP 2020543351 A JP2020543351 A JP 2020543351A JP 2021513844 A JP2021513844 A JP 2021513844A
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- 150000003573 thiols Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
本願は、2018年2月15日に出願された米国出願第62/631,353号の優先権の恩典を主張し、その内容全体が、参照により組み込まれる。
本明細書において使用される「モノクローナル抗体」という用語は、実質的に均一な抗体の集団から得られる抗体を表す、すなわち、微量に存在し得る天然に存在する可能性がある変異を除き、集団を構成する各抗体は同一である。「モノクローナル」という修飾語は、実質的に均一な抗体の集団から得られているという抗体の特徴を示し、いずれかの特定の方法によって抗体を産生することを要求するものと解釈すべきではない。例えば、本発明にしたがって使用されるべきモノクローナル抗体は、Kohlerら(1975)Nature256:495によって最初に記載されたハイブリドーマ法によって作製され得、または組換えDNA法によって作製され得る(例えば、米国特許第4,816,567号参照)。「モノクローナル抗体」は、例えば、Clacksonら(1991)Nature,352:624−628およびMarksら(1991)J.Mol.Biol.,222:581−597に記載されている技術を用いて、ファージ抗体ライブラリーからも単離され得、またはその他の方法によって作製され得る。本明細書に記載されている抗体は、モノクローナル抗体である。
詳細な説明
I.総論
II.本発明の抗体
A.定常領域の選択
B.組換え抗体の発現
III.核酸
IV.抗体−薬物コンジュゲート
R7Bは、−Hまたは−OHである。
薬物負荷量−「p」
V.治療上の適用
方法
抗体選択
競合結合アッセイ
飽和結合アッセイ
表面プラズモン共鳴によって測定された親和性
ヒト化抗体の設計
表1:hGPC3−1可変重(vH)鎖バリアント中のヒト化されている変異
表4:hGPC3−1軽鎖バリアント中の特異的フレームワーク変異
表5:hGPC3−1軽鎖バリアント中の特異的CDR−L1脱アミド変異
インビトロ細胞傷害アッセイ
インビボ活性研究
皮下HCCおよび肺癌モデル
S239Cまたは天然のシステインにコンジュゲート実験動物管理評価・認定協会したときの、SGD−5937またはSGD−6859のマレイミドおよびチュブリシンMアセテート安定性のインビボでの評価
結果
[実施例1]ヒト化mAbの設計および試験
表6:hGPC3−1抗体バリアントのhGPC3結合
[実施例3]HCC腫瘍に対するヒト化GPC3−1ecSGD−6859またはGPC3−1(S239C、Q295C)SGD−5937またはGPC3−1SGD−6183のインビボ抗腫瘍活性
[実施例4]S239Cまたは天然のシステインに結合したときの、SGD−5937またはSGD−6859のマレイミドおよびチュブリシンMアセテート安定性のインビボでの評価
Claims (59)
- ヒトグリピカン−3(GPC3)タンパク質に特異的に結合する抗体であって、前記抗体が配列番号1の3つの重鎖相補性決定領域(CDR)および配列番号2の3つの軽鎖CDRを含み、前記CDRがKabatによって定義されるとおりである、抗体。
- ヒト化抗体、キメラ抗体またはベニヤ化抗体である、請求項1に記載の抗体。
- 配列番号1と少なくとも80%の配列同一性を有する成熟重鎖領域と配列番号2と少なくとも80%の配列同一性を有する成熟軽鎖可変領域とを含む、前記請求項のいずれか一項に記載の抗体。
- 配列番号1と少なくとも90%の配列同一性を有する成熟重鎖可変領域と配列番号2と少なくとも90%の配列同一性を有する成熟軽鎖可変領域とを含むヒト化抗体である、前記請求項のいずれか一項に記載の抗体。
- 前記成熟重鎖可変領域が配列番号1と少なくとも95%の配列同一性を有し、前記成熟軽鎖可変領域が配列番号2と少なくとも95%の配列同一性を有する、前記請求項のいずれか一項に記載の抗体。
- H24がVまたはAによって占められ、H38がQ、RまたはKによって占められ、H48がMまたはIによって占められ、H66がRまたはKによって占められ、H67がVまたはAによって占められ、H69がLによって占められ、H71がAによって占められ、H73がKまたはTによって占められ、H93がGまたはAによって占められ、H94がRによって占められ、および前記軽鎖の以下のアミノ酸残基が存在する:L45がRまたはKによって占められ、L46がLまたはRによって占められ、L105がEまたはVによって占められ、L106がIまたはMによって占められ、付番がKabat付番システムによる、前記請求項のいずれか一項に記載の抗体。
- 以下の可変領域フレームワーク位置が指定されているとおりに占められている:H24がVによって占められ、H38がQによって占められ、H48がMによって占められ、H66がRによって占められ、H67がVによって占められ、H69がLによって占められ、H71がAによって占められ、H73がKによって占められ、H93がGによって占められ、H94がRによって占められ、付番がKabat付番システムによる、前記請求項のいずれか一項に記載の抗体。
- 以下の可変領域フレームワーク位置が指定されているとおりに占められている:L45がRによって占められ、L46がLによって占められ、L105がEによって占められ、L106がIによって占められ;付番がKabat付番システムによる、前記請求項のいずれか一項に記載の抗体。
- HALA、HALB、HALC、HBLA、HBLB、HBLC、HBLD、HBLE、HBLB−Q、HBLB−V、HCLA、HCLB、HCLC、HDLA、HDLBおよびHDLCである、請求項1に記載の抗体。
- 前記成熟重鎖可変領域が重鎖定常領域に融合されており、前記成熟軽鎖可変領域が軽鎖定常領域に融合されている、前記請求項のいずれか一項に記載の抗体。
- 前記重鎖定常領域が、天然のヒト定常領域に比してFcγ受容体に対する低下した結合を有する前記天然のヒト定常領域の変異体形態である、請求項10に記載の抗体。
- 前記重鎖定常領域がIgG1イソタイプの重鎖定常領域である、請求項10に記載の抗体。
- 前記重鎖定常領域が、配列番号5または配列番号6を含むアミノ酸配列を有し、および前記軽鎖定常領域が配列番号7を含むアミノ酸配列を有する、請求項10に記載の抗体。
- 前記抗体が細胞傷害剤または細胞増殖抑制剤にコンジュゲートしている、前記請求項のいずれか一項に記載の抗体。
- 前記コンジュゲートした細胞傷害剤がチュブリシンである、請求項14に記載の抗体。
- 前記コンジュゲートした細胞傷害剤が、
前記コンジュゲートしたチュブリシンが塩形態、特に、薬学的に許容され得る塩形態またはその溶媒和物であり、式中、波線は前記チュブリシンが前記抗体にコンジュゲートしている部位を示し;
R2Aは、−C(=O)R2Bであり、R2Bは、メチル、エチル、プロピル、イソ−プロピル、2−メチル−プロパ−1−イル、2,2−ジメチル−プロパ−1−イルもしくはビニルであり、またはR2Aは、メチル、エチル、プロピル、イソ−プロピル、プロパ−2−エン−1−イルもしくは2−メチル−プロパ−2−エン−1−イルであり;および
R7Bは、−Hまたは−OHである、請求項14に記載の抗体。 - 塩形態、特に、薬学的に塩形態の、もしくはその溶媒和物の式
Aは、ストレッチャー単位であり;
R2Aは、−C(=O)R2Bであり、R2Bは、メチル、エチル、プロピル、イソ−プロピル、2−メチル−プロパ−1−イル、2,2−ジメチル−プロパ−1−イルもしくはビニルであり、またはR2Aは、メチル、エチル、プロピル、イソ−プロピル、プロパ−2−エン−1−イルもしくは2−メチル−プロパ−2−エン−1−イルであり;
R7Bは、−Hまたは−OHであり;
Abは、請求項1〜16のいずれか一項に記載された抗体であり;
Sは、前記抗体からの硫黄原子であり;および
下付き文字pは、1〜4の整数である、
抗GPC3抗体−薬物コンジュゲート化合物。 - Abへの結合がAbの操作されたシステイン残基の硫黄原子を介している、請求項19〜22のいずれか一項に記載の抗体−薬物コンジュゲート化合物。
- Abへの結合が、付番のEUインデックスシステムにしたがって、前記重鎖定常領域の239位における硫黄原子または操作されたシステイン残基を介している、請求項19〜22のいずれか一項に記載の抗体−薬物コンジュゲート化合物。
- pが2である、請求項19〜22のいずれか一項に記載の抗体−薬物コンジュゲート化合物。
- 抗体−薬物コンジュゲート組成物であって、塩形態の、特に、薬学的に塩形態のもしくはその溶媒和物の式:
Aは、ストレッチャー単位であり;
R2Aは、−C(=O)R2Bであり、R2Bは、メチル、エチル、プロピル、イソ−プロピル、2−メチル−プロパ−1−イル、2,2−ジメチル−プロパ−1−イルもしくはビニルであり、またはR2Aは、メチル、エチル、プロピル、イソ−プロピル、プロパ−2−エン−1−イルもしくは2−メチル−プロパ−2−エン−1−イルであり;
R7Bは、−Hまたは−OHであり;
Abは、請求項1に記載された抗体であり;
Sは、前記抗体からの硫黄原子であり;および
下付き文字pは、各抗体薬物コンジュゲート化合物に対して1〜4の整数であり;および
前記組成物の平均薬物負荷量が約2であり、
下付き文字pは、1〜4の整数であり;
前記組成物の平均薬物負荷量が約2である、抗体−薬物コンジュゲート組成物。 - Abへの結合がAbの操作されたシステイン残基の硫黄原子を介している、請求項26〜29のいずれか一項に記載の抗体−薬物コンジュゲート組成物。
- Abへの結合が、付番のEUインデックスシステムにしたがって、前記重鎖定常領域の239位における硫黄原子または操作されたシステイン残基を介している、請求項26〜29のいずれか一項に記載の抗体−薬物コンジュゲート組成物。
- GPC3を発現するがんを有する患者を処置する方法であって、前記請求項のいずれか一項に記載の組成物の有効レジメンを前記患者に投与することを含む、方法。
- 前記がんが、肝細胞癌(HCC)、肺癌、ウィルムス腫瘍(腎芽腫)、卵巣明細胞癌、結腸直腸癌または肉腫である、請求項32に記載の方法。
- 前記がんがHCCである、請求項32に記載の方法。
- 自己免疫疾患を有する患者を処置する方法であって、請求項1〜32のいずれか一項に記載の組成物の有効レジメンを前記患者に投与することを含む、方法。
- 請求項1〜35のいずれかに記載の抗体と薬学的に許容され得る担体とを含む医薬組成物。
- 前記3つの重鎖CDRが配列番号10、11および12に記載されているとおりであり、ならびに前記3つの軽鎖CDRが配列番号13、14および15に記載されているとおりである、請求項1に記載の抗体。
- 前記抗体が配列番号10、11および12に記載されているとおりの前記3つの重鎖CDRと、配列番号13、14および15に記載されているとおりの前記3つの軽鎖CDRとを含む、ヒトGPC3タンパク質に特異的に結合する抗体。
- 配列番号10、11および12に記載されているとおりの前記3つの重鎖CDRと、配列番号13、14および15に記載されているとおりの前記3つの軽鎖CDRとを含む重鎖可変領域をコードする配列を含む単離されたポリヌクレオチド。
- 配列番号1に記載されているアミノ酸配列を有する重鎖可変領域と配列番号2に記載されているアミノ酸配列を有する軽鎖可変領域とを有する成熟重鎖領域を含む、請求項39に記載のポリヌクレオチド。
- 請求項39または40に記載のポリヌクレオチドを含む単離されたベクター。
- 請求項41に記載のベクターを含む単離された宿主細胞。
- 前記宿主細胞がCHO細胞である、請求項42に記載の宿主細胞。
- 抗GPC3抗体またはその抗原結合断片を作製する方法であって、
a)前記抗体またはその抗原結合断片をコードするポリヌクレオチドの発現に適した条件下で請求項42に記載の宿主細胞を培養すること、および
b)前記抗体またはその抗原結合断片を単離すること、
を含む、方法。 - 前記宿主細胞がCHO細胞である、請求項44に記載の方法。
- 抗GPC3抗体薬物コンジュゲートを作製する方法であって、
a)前記抗体またはその抗原結合断片をコードするポリヌクレオチドの発現に適した条件下で請求項42に記載の宿主細胞を培養すること、
b)前記抗体またはその抗原結合断片を単離すること、および
c)前記抗体またはその抗原結合断片に細胞傷害剤をコンジュゲートすること、
を含む、方法。 - 前記宿主細胞がCHO細胞である、請求項46に記載の方法。
- 前記細胞傷害剤がチュブリシンである、請求項46に記載の方法。
- GPC3を発現するがんを有する患者を処置する方法であって、塩形態の、特に、薬学的に塩形態の、もしくはその溶媒和物の式:
Aは、ストレッチャー単位であり;
R2Aは、−C(=O)R2Bであり、R2Bは、メチル、エチル、プロピル、イソ−プロピル、2−メチル−プロパ−1−イル、2,2−ジメチル−プロパ−1−イルもしくはビニルであり、またはR2Aは、メチル、エチル、プロピル、イソ−プロピル、プロパ−2−エン−1−イルもしくは2−メチル−プロパ−2−エン−1−イルであり;
R7Bは、−Hまたは−OHであり;
Abは、請求項1に記載された抗体であり;
Sは、前記抗体からの硫黄原子であり;および
下付き文字pは、各抗体薬物コンジュゲート化合物に対して1〜4の整数であり;および
前記組成物の平均薬物負荷量が約2である、方法。 - 前記がんが、HCC、肺癌、ウィルムス腫瘍(腎芽腫)、卵巣明細胞癌、結腸直腸癌または肉腫である、請求項49〜52のいずれか一項に記載の方法。
- 前記がんがHCCである、請求項53に記載の方法。
- 医薬組成物であって、塩形態の、特に、薬学的に塩形態の、もしくはその溶媒和物の式:
Aは、ストレッチャー単位であり;
R2Aは、−C(=O)R2Bであり、R2Bは、メチル、エチル、プロピル、イソ−プロピル、2−メチル−プロパ−1−イル、2,2−ジメチル−プロパ−1−イルもしくはビニルであり、またはR2Aは、メチル、エチル、プロピル、イソ−プロピル、プロパ−2−エン−1−イルもしくは2−メチル−プロパ−2−エン−1−イルであり;
R7Bは、−Hまたは−OHであり;
Abは、配列番号1の前記3つの重鎖相補性決定領域(CDR)と配列番号2の前記3つの軽鎖CDRとを含む抗体であり、
前記CDRは、Kabatによって定義されているとおりであり、
Sは、前記抗体からの硫黄原子であり;および
下付き文字pは、2である、
医薬組成物。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009232848A (ja) * | 2004-07-09 | 2009-10-15 | Chugai Pharmaceut Co Ltd | 抗グリピカン3抗体 |
JP2017522861A (ja) * | 2014-05-22 | 2017-08-17 | ジェネンテック, インコーポレイテッド | 抗gpc3抗体及びイムノコンジュゲート |
JP2017530100A (ja) * | 2014-09-11 | 2017-10-12 | シアトル ジェネティックス, インコーポレイテッド | 第3級アミン含有薬物物質の標的送達 |
WO2017181109A1 (en) * | 2016-04-15 | 2017-10-19 | Michael Molloy | Anti-human vista antibodies and use thereof |
JP2017532048A (ja) * | 2014-07-02 | 2017-11-02 | カリプソ バイオテク エス アーCalypso Biotech Sa | Il−15に対する抗体 |
US20170326249A1 (en) * | 2016-05-10 | 2017-11-16 | Bristol-Myers Squibb Company | Antibody-drug conjugate of an anti-glypican-3 antibody and a tubulysin analog, preparation and uses |
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US7361336B1 (en) | 1997-09-18 | 2008-04-22 | Ivan Bergstein | Methods of cancer therapy targeted against a cancer stem line |
JP4281869B2 (ja) | 2001-06-22 | 2009-06-17 | 中外製薬株式会社 | 抗グリピカン3抗体を含む細胞増殖抑制剤 |
WO2004022597A1 (ja) | 2002-09-04 | 2004-03-18 | Chugai Seiyaku Kabushiki Kaisha | Gpc3の血中可溶化n端ペプチドに対する抗体 |
JP6005519B2 (ja) * | 2009-11-30 | 2016-10-12 | バイオテスト・アクチエンゲゼルシヤフト | 全身性エリテマトーデス(sle)を治療するためのヒト化抗il−10抗体 |
AR100353A1 (es) * | 2014-05-08 | 2016-09-28 | Chugai Pharmaceutical Co Ltd | Droga de direccionamiento a glipicano 3 (gpc3) que se administra a un paciente que responde a la terapia con drogas de direccionamiento a gpc3 |
AR114112A1 (es) | 2018-02-15 | 2020-07-22 | Seattle Genetics Inc | Anticuerpos de glipicano 3 y conjugados de los mismos |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009232848A (ja) * | 2004-07-09 | 2009-10-15 | Chugai Pharmaceut Co Ltd | 抗グリピカン3抗体 |
JP2017522861A (ja) * | 2014-05-22 | 2017-08-17 | ジェネンテック, インコーポレイテッド | 抗gpc3抗体及びイムノコンジュゲート |
JP2017532048A (ja) * | 2014-07-02 | 2017-11-02 | カリプソ バイオテク エス アーCalypso Biotech Sa | Il−15に対する抗体 |
JP2017530100A (ja) * | 2014-09-11 | 2017-10-12 | シアトル ジェネティックス, インコーポレイテッド | 第3級アミン含有薬物物質の標的送達 |
WO2017181109A1 (en) * | 2016-04-15 | 2017-10-19 | Michael Molloy | Anti-human vista antibodies and use thereof |
US20170326249A1 (en) * | 2016-05-10 | 2017-11-16 | Bristol-Myers Squibb Company | Antibody-drug conjugate of an anti-glypican-3 antibody and a tubulysin analog, preparation and uses |
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