JP6263386B2 - インビボで標的指向抗体を用いるがん療法 - Google Patents
インビボで標的指向抗体を用いるがん療法 Download PDFInfo
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- C07K16/3069—Reproductive system, e.g. ovaria, uterus, testes, prostate
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Description
a)CLDN6に対する特異性;
b)約100nMまたはそれ以下、好ましくは約5〜10nMまたはそれ以下、より好ましくは約1〜3nMまたはそれ以下の、CLDN6への結合親和性;
c)CLDN6を発現する腫瘍細胞を枯渇させる能力;
d)CLDN6を発現する腫瘍細胞の増殖を停止または遅延させる能力;
e)CLDN6を発現する腫瘍細胞を有する対象の生存期間を延長する能力。
1.2010年4月13日に寄託された、GT512muMAB 36A、アクセッション番号DSM ACC3059;
2.2010年4月13日に寄託された、GT512muMAB 27A、アクセッション番号DSM ACC3058;または
3.2010年4月13日に寄託された、GT512muMAB 5F2D2、アクセッション番号DSM ACC3057。
1.2010年4月13日に寄託された、GT512muMAB 36A、アクセッション番号DSM ACC3059;
2.2010年4月13日に寄託された、GT512muMAB 27A、アクセッション番号DSM ACC3058;または
3.2010年4月13日に寄託された、GT512muMAB 5F2D2、アクセッション番号DSM ACC3057。
以下、参考形態の例を付記する。
<1>
インビボで腫瘍の成長を阻害する抗体であって、腫瘍の細胞がクローディン6(CLDN6)を発現し、抗体がCLDN6に結合する能力を有する抗体。
<2>
前記抗体がCLDN6への結合によって前記腫瘍の成長を阻害する、<1>に記載の抗体。
<3>
前記抗体はCLDN6に特異的である、<1>または<2>に記載の抗体。
<4>
前記抗体は、モノクローナル抗体、キメラ抗体、ヒト抗体またはヒト化抗体であるか、抗体のフラグメントまたは合成抗体である、<1>〜<3>のいずれか一に記載の抗体。
<5>
前記腫瘍が、卵巣がん、特に卵巣腺癌および卵巣奇形癌、小細胞肺がん(SCLC)および非小細胞肺がん(NSCLC)を含む肺がん、特に扁平上皮肺癌および腺癌、胃がん、乳がん、肝がん、膵がん、皮膚がん、特に基底細胞癌および扁平上皮癌、悪性黒色腫、頭頚部がん、特に悪性多形性腺腫、肉腫、特に滑膜肉腫および癌肉腫、胆管がん、膀胱のがん、特に移行上皮癌および乳頭癌、腎がん、特に明細胞腎細胞癌および乳頭状腎細胞癌を含む腎細胞癌、結腸がん、回腸のがんを含む小腸がん、特に小腸腺癌および回腸の腺癌、精巣胎芽性癌、胎盤性絨毛癌、子宮頸がん、精巣がん、特に精巣精上皮腫、精巣奇形腫および胎児性精巣がん、子宮がん、胚細胞性腫瘍、特に奇形癌または胎児性癌、好ましくは精巣の胚細胞性腫瘍、ならびにそれらの転移形態から成る群より選択される、<1>〜<4>のいずれか一に記載の抗体。
<6>
(i)アクセッション番号DSM ACC3059(GT512muMAB 36A)、DSM ACC3058(GT512muMAB 27A)、またはDSM ACC3057(GT512muMAB 5F2D2)の下で寄託されたクローンによって産生されるまたは前記クローンから得ることができる抗体、
(ii)(i)の下の抗体のキメラ化またはヒト化形態である抗体、
(iii)(i)の下の抗体の特異性を有する抗体、および
(iv)(i)の下の抗体の抗原結合部分または抗原結合部位を含み、(i)の下の抗体の抗原結合部分または抗原結合部位が、好ましくは(i)の下の抗体の可変領域を含む抗体、
から成る群より選択される抗体。
<7>
少なくとも1つの治療エフェクター成分に取り付けられた<1>〜<6>のいずれか一に記載の抗体であって、前記治療エフェクター成分が、好ましくは、放射性標識、細胞毒または細胞傷害性酵素である抗体。
<8>
<1>〜<7>のいずれか一に記載の抗体を産生する能力を有するハイブリドーマ。
<9>
アクセッション番号DSM ACC3059(GT512muMAB 36A)、DSM ACC3058(GT512muMAB 27A)、またはDSM ACC3057(GT512muMAB 5F2D2)の下で寄託されたハイブリドーマ。
<10>
好ましくは治療用または予防用腫瘍ワクチンの形態にある、<1>〜<7>のいずれか一に記載の前記抗体を含む医薬組成物。
<11>
腫瘍疾患の処置または防止に使用するための、<10>に記載の医薬組成物。
<12>
腫瘍疾患を有する患者または腫瘍疾患を発症する危険性がある患者を処置する方法であって、前記腫瘍の細胞がクローディン6(CLDN6)を発現し、前記方法がCLDN6に結合する能力を有する抗体の投与を含む方法。
<13>
前記抗体が、患者に投与されたときに、CLDN6への結合によって、患者における腫瘍の成長を阻害する、<12>に記載の方法。
<14>
前記抗体が少なくとも1つの治療エフェクター成分に取り付けられており、前記治療エフェクター成分が、好ましくは、放射性標識、細胞毒または細胞傷害性酵素である、<12>または<13>に記載の方法。
<15>
前記抗体がCLDN6に特異的である、<12>〜<14>のいずれか一に記載の方法。
<16>
前記抗体がモノクローナル抗体、キメラ抗体、ヒト抗体またはヒト化抗体であるか、抗体のフラグメントまたは合成抗体である、<12>〜<15>のいずれか一に記載の方法。
<17>
前記方法が、<10>または<11>に記載の医薬組成物の投与を含む、<12>〜<16>のいずれか一に記載の方法。
<18>
前記腫瘍疾患が、卵巣がん、特に卵巣腺癌および卵巣奇形癌、小細胞肺がん(SCLC)および非小細胞肺がん(NSCLC)を含む肺がん、特に扁平上皮肺癌および腺癌、胃がん、乳がん、肝がん、膵がん、皮膚がん、特に基底細胞癌および扁平上皮癌、悪性黒色腫、頭頚部がん、特に悪性多形性腺腫、肉腫、特に滑膜肉腫および癌肉腫、胆管がん、膀胱のがん、特に移行上皮癌および乳頭癌、腎がん、特に明細胞腎細胞癌および乳頭状腎細胞癌を含む腎細胞癌、結腸がん、回腸のがんを含む小腸がん、特に小腸腺癌および回腸の腺癌、精巣胎芽性癌、胎盤性絨毛癌、子宮頸がん、精巣がん、特に精巣精上皮腫、精巣奇形腫および胎児性精巣がん、子宮がん、胚細胞性腫瘍疾患、特に奇形癌または胎児性癌、好ましくは精巣の胚細胞性腫瘍疾患、ならびにそれらの転移形態から成る群より選択される、<11>に記載の医薬組成物または<12>〜<17>のいずれか一に記載の方法。
<19>
CLDN6が、配列表の配列番号:1に従う核酸配列または前記核酸配列の変異体を含む核酸によってコードされるアミノ酸配列を含む、<1>〜<7>のいずれか一に記載の抗体、<10>、<11>および<18>のいずれか一に記載の医薬組成物、または<12>〜<18>のいずれか一に記載の方法。
<20>
CLDN6が、配列表の配列番号:2に従うアミノ酸配列または前記アミノ酸配列の変異体を含む、<1>〜<7>および<19>のいずれか一に記載の抗体、<10>、<11>、<18>および<19>のいずれか一に記載の医薬組成物、または<12>〜<19>のいずれか一に記載の方法。
A.CLDN6に対するマウス抗体の生成
a.完全長CLDN6およびCLDN6フラグメントをコードする発現ベクターの生成
完全長CLDN6(配列番号:2)をコードする非天然コドン最適化DNA配列(配列番号:10)を、化学合成によって調製し(GENEART AG,ドイツ)、pcDNA3.1/myc−Hisベクター(インビトロジェン(Invitrogen),米国)にクローニングすることにより、ベクターp3953を得た。停止コドンの挿入により、ベクターがコードするmyc−Hisタグに融合することなく、CLDN6タンパク質を発現させることが可能になった。市販の抗CLDN6抗体(ARP,01−8865;R&D Systems,MAB3656)を用いるウエスタンブロット分析、フローサイトメトリ分析および免疫蛍光分析によって、CLDN6の発現を調べた。
ベクターp3953を使用し、標準的技術によって、CLDN6を安定に発現するHEK293およびP3X63Ag8U.1細胞株を生成させた。
muMAB 5F2D2:0日目、16日目および36日目に、Balb/cマウスを、25μgのp3974プラスミドDNAで、4μlのPEI−マンノース(PEI−Man;PolyPlus Transfectionのin vivo−jetPEI(商標)−Man)(5%グルコースを含むH2O中の150mM PEI−Man)と共に、腹腔内注射によって免疫した。48日目および62日目に、CLDN6を安定に発現するようにp3953ベクターでトランスフェクトされた2×107個のP3X63Ag8U.1骨髄腫細胞で、腹腔内注射により、マウスを免疫した。62日目に投与された細胞は、注射前に、3000radを照射したものであった。
免疫マウスから単離された6×107個の脾細胞を、マウス骨髄腫細胞株P3X63Ag8.653(ATCC,CRL1580)の細胞3×107個と、PEG1500(Roche,CRL10783641001)を使って融合した。細胞を平底マイクロタイタープレートに1ウェルあたり約5×104細胞の密度で播種し、10%熱不活化ウシ胎児血清、1%ハイブリドーマ融合およびクローニング用添加剤(HFCS,Roche,CRL11363735)、10mM HEPES、1mMピルビン酸ナトリウム、4.5%グルコース、0.1mM2−メルカプトエタノール、1×ペニシリン/ストレプトマイシンおよび1×HATサプリメント(インビトロジェン(Invitrogen),CRL21060)を含有するRPMI選択培地中で約2週間培養した。10〜14日後に、抗CLDN6モノクローナル抗体について、個々のウェルをフローサイトメトリによってスクリーニングした。抗体分泌ハイブリドーマを限界希釈法によってサブクローニングし、抗CLDN6モノクローナル抗体について再び試験した。安定なサブクローンを培養することで、特性付けのために、組織培養培地中に少量の抗体を生成させた。親細胞の反応性を保持しているクローン(フローサイトメトリによって試験した)を各ハイブリドーマから少なくとも1つは選択した。各クローンにつき9バイアル細胞バンクを作成し、液体窒素中で保存した。
CLDN6および他のクローディンへのモノクローナル抗体の結合を調べるために、HEK293T細胞を、対応するクローディンコードプラスミドで一過性にトランスフェクトし、発現をフローサイトメトリで分析した。トランスフェクト細胞と非トランスフェクト細胞を識別するために、HEK293T細胞をレポーターとしての蛍光マーカーで同時トランスフェクトした。トランスフェクションの24時間後に、細胞を0.05%トリプシン/EDTAで収穫し、FACS緩衝液(2%FCSおよび0.1%アジ化ナトリウムを含有するPBS)で洗浄し、FACS緩衝液中に、2×106細胞/mlの濃度で再懸濁した。100μlの細胞懸濁液を、表示した濃度の適当な抗体と共に、4℃で30分間インキュベートした。市販のマウス抗クローディン抗体である抗CLDN6(R&D,CRL MAB3656)、抗CLDN3(R&D,MAB4620)および抗CLDN4(R&D,MAB4219)を陽性対照とし、一方、マウスIgG2b(Sigma,CRL M8894)をアイソタイプ対照とした。細胞をFACS緩衝液で3回洗浄し、アロフィコシアニン(APC)コンジュゲート抗マウスIgG1+2a+2b+3a特異的二次抗体(Dianova,CRL115−135−164)と共に、4℃で30分間インキュベートした。細胞を2回洗浄し、FACS緩衝液に再懸濁した。BD FACSArrayを使ったフローサイトメトリで結合を分析した。垂直軸上の抗体結合に対して、蛍光マーカーの発現を水平軸上にプロットした。
NEC8細胞を、CLDN6、3、4および9発現について、免疫ブロット分析によって分析した。陽性対照としてHEK293T細胞をCLDN6、3、4、9で一過性にトランスフェクトするか、陰性対照としてモックプラスミドでトランスフェクトした。細胞をレムリ緩衝液中に収穫し、溶解し、SDS−PAGEに付した。ゲルをブロットし、抗CLDN3(インビトロジェン(Invitrogen),34−1700)、抗CLDN4(インビトロジェン(Invitrogen),32−9400)、抗CDLN6(ARP,01−8865)または抗CLDN9(サンタクルーズ バイオテクノロジー(Santa Cruz),sc−17672)抗体で、それぞれ染色した。ペルオキシダーゼ標識二次抗体と共にインキュベートした後、ブロットをECL試薬で発色させ、LAS−3000イメージャー(富士フイルム)を使って可視化した。
抗CLDN6抗体と共にインキュベートした標的細胞へのヒト補体の添加後に、非溶解細胞における細胞内ATPの含有量を測定することによって、補体依存性細胞傷害(CDC)を決定した。超高感度な分析方法として、ルシフェラーゼの生物発光反応をATPの測定に使用した。
キメラ化モノクローナル抗CLDN6抗体を、内因性にCLDN6を発現するNEC8細胞およびCLDN6ノックダウンを有するNEC8細胞(NEC8 LVTS2 54)に対する抗体依存性細胞性細胞傷害(ADCC)を誘導するその能力について、ルシフェラーゼに基づくアッセイ系で分析した。
早期抗体処置のために、PBS200μl中のHEK293−CLDN6細胞(CLDN6を安定に発現するHEK293細胞)5×106個を、無胸腺ヌードFoxn1nuマウスの側腹部に皮下接種した。HEK293モック細胞を陰性対照として使用した。各実験群は8匹の6〜8週齢雌マウスから成った。(それぞれHEK293−CLDN6細胞またはHEK293モック細胞が移植されたマウスの場合、食塩水対照群は、10匹のマウスからなった)。接種の3日後に、週に2回、静脈内注射と腹腔内注射を交互に行うことにより、200μgの精製マウスモノクローナル抗体muMAB 5F2D2、27Aおよび36Aを、46日間適用した。PBSで処置した実験群を陰性対照とした。腫瘍体積(TV=(長さ×幅2)/2)を隔週ごとに監視した。TVはmm3の単位で表され、経時的な腫瘍成長曲線の構築を可能にする。腫瘍が1500mm3を上回る体積に到達したら、マウスを屠殺した。
ヒトCLDN6、3、4および9へのマウスモノクローナル抗体muMAB 5F2D2、27Aおよび36Aの結合を、対応するヒトクローディンを一過性に発現するHEK293T細胞を使って、フローサイトメトリによって分析した。非トランスフェクト(Q3集団)細胞とトランスフェクト(Q4集団)細胞とを識別するために、HEK293Tを蛍光マーカーで同時トランスフェクトした。使用した抗体濃度は、CLDN6への結合を飽和させる濃度(25μg/ml)であった。ヒトCLDN6、3、4および9の発現を、ヒトクローディン6(R&D Systems,MAB3656)、ヒトクローディン3(R&D Systems,MAB4620)およびヒトクローディン4(R&D Systems,MAB 4219)に対する市販のモノクローナル抗体で確認した。
ルシフェラーゼ依存的アッセイを使って非溶解細胞内の内因性ATPを検出することにより、抗CLDN6抗体のCDC活性を分析した。この目的のために、ヒトCLDN6を安定に発現するCHO−K1細胞を、様々な濃度のmuMAB 5F2D2、27Aもしくは36Aまたは内部対照としての抗CLDN6(R&D Systems,MAB3656)で処理した。
muMAB 5F2D2の治療効果を、安定にトランスフェクトされたHEK293−CLDN6異種移植片およびHEK293モック異種移植片を無胸腺ヌードFoxn1nuマウスに移植する早期処置異種移植モデルにおいて調べた。
NEC8細胞におけるCLDN3、4、6および9発現を免疫ブロット分析によって調べた。精巣胚細胞性腫瘍細胞株NEC8は、CLDN6の発現だけを示し(A)、CLDN3、4または9の発現は、それぞれ示さなかった(B);図15参照。使用した抗CLDN3、4および9抗体の特異性は、対応するヒトクローディンをコードする発現ベクターで一過性にトランスフェクトされたHEK293T細胞を使って、ウエスタンブロットによって調べた。
Claims (12)
- (i)アクセッション番号DSM ACC3059(GT512muMAB 36A)、DSM ACC3058(GT512muMAB 27A)、またはDSM ACC3057(GT512muMAB 5F2D2)の下で寄託されたクローンによって産生されるまたは前記クローンから得ることができる抗体、
(ii)(i)の抗体のキメラ化形態である抗体、および
(iii)(i)の抗体のヒト化形態である抗体、
から成る群より選択されるものであり、CLDN6と結合するとともに、インビボでCLDN6を発現する腫瘍細胞の成長を阻害する、抗体。 - 少なくとも1つの治療エフェクター成分に取り付けられた抗体であって、
前記治療エフェクター成分が、放射性標識、細胞毒または細胞傷害性酵素である、請求項1に記載の抗体。 - 請求項1または2に記載の抗体を産生する能力を有するハイブリドーマ。
- アクセッション番号DSM ACC3059(GT512muMAB 36A)、DSM ACC3058(GT512muMAB 27A)、またはDSM ACC3057(GT512muMAB 5F2D2)の下で寄託されたハイブリドーマ。
- 請求項1または2に記載の抗体を含む医薬組成物。
- 治療用または予防用腫瘍ワクチンの形態にある、請求項5に記載の医薬組成物。
- 腫瘍疾患の処置または防止に使用するための、請求項5または6に記載の医薬組成物。
- 腫瘍疾患を有する患者または腫瘍疾患を発症する危険性がある患者を処置するための医薬品の製造のための、請求項1または2に記載の抗体の使用であって、
前記腫瘍の細胞がクローディン6(CLDN6)を発現し、前記CLDN6が、配列表の配列番号:2のアミノ酸配列または前記配列番号:2のアミノ酸配列との間の同一性の程度が少なくとも90%である前記アミノ酸配列の変異体からなる、医薬品の製造のための抗体の使用。 - 前記抗体が、患者に投与されたときに、前記CLDN6への結合によって、患者における腫瘍の成長を阻害する、請求項8に記載の使用。
- 前記抗体が少なくとも1つの治療エフェクター成分に取り付けられており、
前記治療エフェクター成分が、放射性標識、細胞毒または細胞傷害性酵素である、請求項8または9に記載の使用。 - 前記腫瘍疾患が、卵巣がん、小細胞肺がん(SCLC)および非小細胞肺がん(NSCLC)を含む肺がん、胃がん、乳がん、肝がん、膵がん、皮膚がん、悪性黒色腫、頭頚部がん、肉腫、胆管がん、膀胱のがん、腎がん、結腸がん、回腸のがんを含む小腸がん、精巣胎芽性癌、胎盤性絨毛癌、子宮頸がん、精巣がん、子宮がん、胚細胞性腫瘍疾患、ならびにそれらの転移形態から成る群より選択される、請求項8〜請求項10のいずれか一項に記載の使用。
- 前記CLDN6が、配列表の配列番号:1の核酸配列または前記配列番号:1の核酸配列との間の同一性の程度が少なくとも90%である前記核酸配列の変異体を含む核酸によってコードされるアミノ酸配列を含む、請求項8〜請求項11のいずれか一項に記載の使用。
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CN103140501A (zh) | 2013-06-05 |
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EP2404936A1 (en) | 2012-01-11 |
JP2013533247A (ja) | 2013-08-22 |
US20180142033A1 (en) | 2018-05-24 |
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US20210079113A1 (en) | 2021-03-18 |
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US20130183305A1 (en) | 2013-07-18 |
MX365074B (es) | 2019-05-22 |
KR101960004B1 (ko) | 2019-03-20 |
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