JP6263467B2 - Bcma(cd269/tnfrsf17)結合タンパク質 - Google Patents
Bcma(cd269/tnfrsf17)結合タンパク質 Download PDFInfo
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- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
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Description
CDRH1は配列番号1又は配列番号182として提供される;
CDRH2は配列番号2又は配列番号183として提供される;
CDRH3は配列番号3又は配列番号184として提供される。
CDRL1は配列番号4又は配列番号185として提供される;
CDRL2は配列番号5又は配列番号186として提供される;
CDRL3は配列番号6又は配列番号187として提供される。
抗体の重鎖をコードする第1のベクターを提供するステップと、
抗体の軽鎖をコードする第2のベクターを提供するステップと、
哺乳動物宿主細胞(例えばCHO)を前記第1及び第2のベクターで形質転換するステップと、
前記宿主細胞から前記培地中に抗体の分泌を誘導する条件下でステップ(c)の宿主細胞を培養するステップと、
ステップ(d)の分泌された抗体を回収するステップと
を含む、方法が提供される。
1033-1039、Johnson, R,「Mannitol-sucrose mixtures-versatile formulations for protein peroxidise 19g19n」, J. Pharm. Sci, 91(2002)914-922、並びにHa, E Wang W, Wang Y.j.「Peroxide formation in polysorbate 80 and protein stability」, J.Pharm Sci, 91, 2252-2264, (2002)(これらの全内容は参照により本明細書に組み込まれており、それらを明示的に読者の参照とする)を参照のこと。
本明細書で使用する場合、「癌」、「新生物」及び「腫瘍」という用語は交換可能に使用され、単数形又は複数形のいずれかで、細胞が宿主生物にとって病的なものとなる悪性形質転換を経た細胞を指す。原発性癌細胞は、十分に確立された技術、特に組織学的検査によって非癌性細胞と容易に区別することができる。本明細書で使用する場合、癌細胞の定義には、原発性癌細胞だけでなく、癌細胞祖先に由来する任意の細胞も含まれる。これには、転移性癌細胞、並びに癌細胞に由来するインビトロ培養物及び細胞株が含まれる。通常、固形腫瘍として現れる種類の癌に言及する場合、「臨床的に検出可能な」腫瘍とは、例えばコンピュータ断層撮影(CT)スキャン、磁気共鳴イメージング(MRI)、X線、超音波又は身体検査での触診などの処置により、腫瘍塊に基づいて検出可能及び/又は患者から得られる試料中の1種以上の癌特異的抗原の発現のために検出可能な腫瘍のことである。腫瘍は、造血(又は血液学的(hematologic)又は血液系(hematological)又は血液関連)癌、例えば「液性腫瘍」と称され得る、血液細胞又は免疫細胞由来の癌であってもよい。血液系腫瘍に基づいた臨床症状の具体的な例としては、慢性骨髄性白血病、急性骨髄性白血病、慢性リンパ球性白血病及び急性リンパ性白血病などの白血病、多発性骨髄腫、MGUS及びワルデンシュトレーム型マクログロブリンなどの形質細胞悪性腫瘍、非ホジキンリンパ腫、ホジキンリンパ腫などのリンパ腫が挙げられる。
(1)ポリヌクレオチドに対する同一性は、所与の配列中のヌクレオチドの総数に、同一性パーセントを規定する整数(100で除したもの)を乗じ、次いでその積を前記配列中のヌクレオチドの前記総数から減ずること、又は:
nn ≦ xn-(xn・y)
[式中、nnはヌクレオチド改変数であり、xnは所与の配列中のヌクレオチドの総数であり、yは95%に対して0.95、97%に対して0.97又は100%に対して1.00であり、・は乗算演算子の記号であり、xnとyのいずれの非整数積もxnから減ずる前に最も近い整数に切り下げて丸められる]
によって計算される。ポリペプチドをコードするポリヌクレオチド配列の改変は、このコード配列中でナンセンス、ミスセンス又はフレームシフト突然変異を生じる場合があり、それによりこのような改変後にポリヌクレオチドによってコードされたポリペプチドを改変する。
na ≦ xa-(xa・y)
[式中、naはアミノ酸改変数であり、xaは配列中のアミノ酸の総数であり、yは95%に対して0.95、97%に対して0.97又は100%に対して1.00であり、・は乗算演算子の記号であり、xaとyのいずれの非整数積もxaからそれを減ずる前に最も近い整数に切り下げて丸められる]
によって計算される。
a)本明細書に記載される単離された核酸を含む発現ベクターを含む組換え宿主細胞を培養するステップであって、アルファ-1,6-フコシルトランスフェラーゼをコードするFUT8遺伝子が組換え宿主細胞中で不活性化されるステップと、
b)抗原結合タンパク質を回収するステップと
を含む、方法を提供する。
a)本明細書に記載される単離された核酸を含む発現ベクターを含む組換え宿主細胞を培養するステップであって、発現ベクターは、IgG1及びIgG3Fcドメインアミノ酸残基を有するFcドメインをコードする核酸配列を含む、ステップと、
b)抗原結合タンパク質を回収するステップと
を含む、方法もまた、提供される。
a)本明細書に記載される単離された核酸を含有する発現ベクターを含有する組換え宿主細胞を培養するステップであって、前記発現ベクターは、両方のIgG1及びIgG3 Fcドメインアミノ酸残基を有するキメラFcドメインをコードするFC核酸配列を更に含み、アルファ-1,6-フコシルトランスフェラーゼをコードするFUT8遺伝子は組換え宿主細胞内で不活性化される、ステップと、
b)抗原結合タンパク質を回収するステップと
を含む、方法が提供される。
また、限定されないが、化学療法剤などの1種以上の細胞傷害剤、薬物、増殖抑制剤、毒素(例えばタンパク毒素、細菌、真菌、植物、若しくは動物起源の酵素的に活性な毒素又はその断片)、又は放射性同位体(すなわち放射性コンジュゲート)にコンジュゲートした抗体を含む、本明細書に記載される本発明に係る抗原結合タンパク質を含む免疫コンジュゲート(交換可能に「抗体-薬物コンジュゲート」又は「ADC」とも称される)も提供される。
ABP-((リンカー)n-Ctx)m
(式中、ABPは抗原結合タンパク質であり、
リンカーは存在しないか又は本明細書に記載される切断可能又は切断可能でないリンカーのいずれかであり、
Ctxは本明細書に記載される任意の細胞傷害剤であり、
nは0、1、2、又は3であり、
mは1、2、3、4、5、6、7、8、9又は10である)
を有する免疫コンジュゲートを含む。
結合点は、抗体がプロテインG親和性樹脂に固定化されている間に実施される抗体の鎖間ジスルフィドの軽度の還元により産生されるシステインである(これにより、中間体を精製せずに大過剰の試薬の使用を可能にする)。固定化の間、大過剰のTCEPは鎖間ジスルフィドを完全に還元するが、樹脂に対する抗体の結合に影響を与えない。
一部の実施態様において、免疫コンジュゲートは、ドラスタチン又はドラスタチンのペプチド類似体及び誘導体である、アウリスタチン(米国特許第5,635,483号、同第5,780,588号)にコンジュゲートした抗原結合タンパク質又は抗体を含む。ドラスタチン及びアウリスタチンは、微小管の動態、GTP加水分解、並びに核***及び細胞***を妨害することが示されており(Woyke et al. (2001) Antimicrob. Agents and Chemother. 45(12):3580-3584)、抗癌活性(米国特許第5,663,149号)及び抗真菌活性(Pettit et al. (1998) Antimicrob. Agents Chemother. 42:2961-2965)を有する。ドラスチン又はアウリスタチン(これはドラスタチンのペンタプチド誘導体である)の薬物成分は、ペプチド薬物成分のN(アミノ)末端又はC(カルボキシル)末端を介して抗体に付着され得る(WO02/088172)。
メイタンシノイドは、チューブリン重合を阻害することによって作用する有糸***(mitototic)阻害剤である。メイタンシンは最初に東アフリカの低木マイテヌスセーラタ(Maytenus serrata)から単離された(米国特許第3,896,111号)。続いて、特定の微生物もまた、メイタンシノール及びC-3メイタンシノールエステルなどのメイタンシノイドを産生することが発見された(米国特許第4,151,042号)。高い細胞毒性のメイタンシノイド薬物薬物は、アクチノシネマ(Actinosynnema)などの微生物の発酵により産生されるアンサマイトシン前駆体から調製され得る。アンサマイトシンを単離する方法は米国特許第6,573,074号に記載されている。合成メイタンシノール並びにその誘導体及び類似体は、例えば、米国特許第4,137,230号、同第4,248,870号、同第4,256,746号、同第4,260,608号、同第4,265,814号、同第4,294,757号、同第4,307,016号、同第4,308,268号、同第4,308,269号、同第4,309,428号、同第4,313,946号、同第4,315,929号、同第4,317,821号、同第4,322,348号、同第4,331,598号、同第4,361,650号、同第4,364,866号、同第4,424,219号、同第4,450,254号、同第4,362,663号、及び同第4,371,533号に開示されている。
抗生物質のカリケアマイシンファミリーはサブ-ピコモルの濃度で二本鎖DNA破壊を生じることができる。カリケアマイシンファミリーのコンジュゲートの調製については、米国特許第5,712,374号、同5,714,586号、同5,739,116号、同5,767,285号、同5,770,701号、同5,770,710号、同5,773,001号、同5,877,296号(全てAmerican Cyanamid Company)を参照のこと。使用され得るカリケアマイシンの構造類似体としては、限定されないが、.ガンマ.1I、.アルファ.2I、.アルファ.3I、N-アセチル-.ガンマ.1I、PSAG及び.シータ.I1(Hinman et al., Cancer Research 53:3336-3342 (1993), Lode et al., Cancer Research 58:2925-2928 (1998)及び上述のAmerican Cyanamidによる米国特許)が挙げられる。抗体がコンジュゲートされ得る別の抗腫瘍剤は、葉酸代謝拮抗薬であるQFAである。カリケアマイシン及びQFAは両方、細胞内に作用部位を有し、原形質膜を容易に通過しない。従って、抗体媒介性内在化によるこれらの薬剤の細胞への取込により、それらの細胞毒性効果が増強する。
抗体にコンジュゲートされ得る他の抗腫瘍剤としては、BCNU、ストレプトゾイシン、ビンクリスチン及び5-フルオロウラシル、米国特許第5,053,394号、同5,770,710号に記載されており、まとめてLL-E33288複合体として公知の薬剤のファミリー、並びにエスペラマイシン(esperamicine)(米国特許第5,877,296号)が挙げられる。
抗体薬物コンジュゲートにおいて、抗体は、細胞傷害剤に直接、又はリンカーを介してコンジュゲートできる。適切なリンカーとしては、例えば切断可能及び切断可能でないリンカーが挙げられる。切断可能なリンカーは典型的に細胞内条件下で切断可能の影響を受けやすい。適切な切断可能リンカーとしては、例えば、リソソームプロテアーゼ又はエンドソームプロテアーゼなどの細胞内プロテアーゼにより切断可能なペプチドリンカーが挙げられる。例示的な実施形態において、リンカーは、バリン-シトルリン(val-cit)又はフェニルアラニン-リジン(phe-lys)リンカーなどのジペプチドリンカーであってもよい。他の適切なリンカーとしては、ヒドラゾンリンカーなどの5.5未満のpHで加水分解可能なリンカーが挙げられる。更なる適切な切断可能なリンカーとしてはジスルフィドリンカーが挙げられる。
1.1 免疫化戦略
抗ヒトBCMA mAbマウス親CA8を、完全長BCMAで免疫化したマウス由来のハイブリドーマから同定した。BALB/cマウスを、CFAと組み合わせた25μgの組換え(rBCMA)タンパク質を用いてi.p.により免疫化した。25μgの完全長rBCMAタンパク質+10μgのモノホスホリルリピドA-安定なエマルション(MPL-SE)(Corixa Corporation、Seattle、WA)を用いてマウスを一カ月間隔で3回追加免疫し、融合の3日前にi.v.により30μgのrBCMAタンパク質の前融合物追加免疫を与えた。ClonaCell-HYハイブリドーマクローニングキット(StemCell Technologies、Vancouver、BC)を使用して又は従来の方法を使用してハイブリドーマを生成し、クローニングのいずれかをした。従来の方法において、免疫化した動物の脾臓由来のB細胞を、PEG(Sigma-Aldrich、St.Louis、MO)の存在下でSp2/0骨髄腫細胞と融合した。一晩回収した後、融合細胞を96ウェルプレート中に限界希釈で播種し、ヒポキサンチン-アミノプテリン-チミジン選択に供した。ハイブリドーマ培養上清を、ELISA及びフローサイトメトリーにより抗BCMA抗体の存在について試験した。
2.1 CA8ハイブリドーマ可変領域のクローニング
全RNAをCA8ハイブリドーマ細胞から抽出し、次いで重鎖及び軽鎖可変ドメインcDNA配列を逆転写及びポリメラーゼ連鎖反応(RT-PCR)により生成した。RT-PCRについてのフォワードプライマーはマウス免疫グロブリン遺伝子リーダー配列に特異的な縮重プライマーの混合物であり、リバースプライマーは抗体定常領域に特異的であった。アイソタイプは未知であったので、IgG1、IgG2a及びIgG2bについてのリバースプライマーをこの場合に使用した。プライマーを設計するために、マウスVH及びVk遺伝子のリーダー配列のDNA多配列アラインメントを生成した。
キメラ抗体をコードするDNA発現構築物を、哺乳動物発現ベクター内でのクローニングのための制限酵素認識部位を含む重複オリゴヌクレオチド及びヒトシグナル配列を構築することによって新たに調製した。HindIII及びSpeI制限酵素認識部位を導入して、ヒトγ1定常領域を含有する哺乳動物発現ベクター内でのクローニングのためのシグナル配列を含有するVHドメインを構成した。HindIII及びBsiWI制限酵素認識部位を導入して、ヒトカッパ定常領域を含有する哺乳動物発現ベクター内でのクローニングのためのシグナル配列を含有するVLドメインを構成した。
ヒト化抗体バリアントをコードするDNA発現構築物を、哺乳動物発現ベクター内でのクローニングのための制限酵素認識部位を含む重複オリゴヌクレオチド及びヒトシグナル配列を構築することによって新たに調製した。HindIII及びSpeI制限酵素認識部位を導入して、ヒトγ1定常領域を含有する哺乳動物発現ベクター内でのクローニングのためのシグナル配列を含有するVHドメインを構成した。HindIII及びBsiWI制限酵素認識部位を導入して、ヒトカッパ定常領域を含有する哺乳動物発現ベクター内でのクローニングのためのシグナル配列を含有するVLドメインを構成した。
重鎖及び軽鎖をそれぞれコードする発現プラスミドをHEK293 6E細胞内に一過的に共トランスフェクトし、抗体を産生するように小規模で発現させた。ELISAにより抗体を定量した。ELISAプレートを1mg/mlにて抗ヒトIgG(Sigma I3382)でコーティングし、遮断溶液(トリス緩衝食塩水中の4%BSA)で遮断した。組織培養上清の種々の希釈物を加え、プレートを室温にて1時間インキュベートした。既知の標準的な抗体の希釈物もまた、プレートに加えた。プレートをTBST中で洗浄し、遮断溶液中に1/1000の希釈にて過酸化物で標識した抗ヒトカッパ軽鎖抗体(Sigma A7164)の添加により結合を検出した。プレートを、TBST中で洗浄する前に室温にて1時間インキュベートした。プレートをOPD基質(Sigma P9187)の添加により発現させ、2MのH2SO4の添加により発色を停止させた。吸光度を490nmにて測定し、既知の標準希釈についてのデータを使用して標準曲線をプロットした。標準曲線を使用して、組織培養上清中の抗体の濃度を推定した。プロテインAを使用して大規模で抗体調製物を精製し、ナノドロップ(Nanodrop)(Thermo Scientific)を使用して濃度を測定した。
脱フコシル化抗体を生成するために、重鎖及び軽鎖それぞれをCHO DG44 MS705 BioWa細胞中に共トランスフェクトし、抗体を産生する規模で発現させた。簡潔に述べると、30μgのDNAをNot1を用いて一晩線形化し、DNAをエタノール沈殿させ、TE緩衝液中に再溶解した。培養物から、2.4×107個のBioWa DG44細胞を得て、14mlの温PBS-スクロース中で洗浄した。細胞を回転させ、ペレットを1.6mlのPBS-スクロース中に再懸濁した。PBS-スクロース中に懸濁した上述の細胞の半分(0.8ml)を、30μgの線形化DNA(50μlのTE緩衝液中)と共にBioRadキュベットに加えた。BioRad GenePulserを25μFのキャパシタンスを用いて380Vにプログラムし、キュベットを電気穿孔のために入れた。得られた850ulの電気穿孔した細胞及びDNAを(80ml)温SFM512培地(フェノールレッド、2XHT(ヌクレオシド)、グルタマックス(glutamax)及びGibcoサプリメント4を含む)に加えた。最後に、得られた80mlの細胞懸濁液を4×96-ウェルプレートの一つの各ウェルに移した(150μl/ウェル)。48時間後、約130μlの馴化を除去することによって培地を、ヌクレオシドを含まないように変化させ、150μlの新しい選択培地であるSFM512培地(フェノールレッド及びグルタマックスを含む)と置き換えた。3〜4日毎に、130〜150μlの馴化培地を除去し、新しい選択培地と置き換えた。色の変化についてウェルをモニターし、以前に記載したようにIgG濃度についてアッセイした。
S307118G03、S332121F02、S332126E04、S322110D07、S336105A07、S335115G01及びS335122F05ハイブリドーマ細胞から全RNAを抽出した。次いで重鎖及び軽鎖可変ドメインcDNA配列を逆転写及びポリメラーゼ連鎖反応(RT-PCR)により生成した。RT-PCRについてのフォワードプライマーはマウス免疫グロブリン遺伝子リーダー配列に特異的な縮重プライマーの混合物であり、リバースプライマーは、抗体定常領域、この場合、アイソタイプIgG2aに特異的であった。Jones及びBendig(Bio/Technology 9:88, 1991)に記載されている戦略に基づいてプライマーを設計した。正確なV領域配列の後の検証を可能にするために両方のV領域配列についてRT-PCRを実施した。RT-PCRにより生成したV領域産物についてのDNA配列データを得た。
哺乳動物発現ベクター内でのV遺伝子PCR産物のインフュージョンアドバンテージPCRクローニング(Clonetech)によってキメラ抗体をコードするDNA発現構築物を新たに調製した。このクローニング法により、マウス可変領域と、ヒトIgG1 H鎖及びカッパL鎖定常領域との融合が可能となった。
クローニングを段落2.3についてと同様に実施した。
関連重鎖及び軽鎖(以下の表8に記載した)をコードする発現プラスミドを、HEK293 6E細胞内で一過的に共トランスフェクトし、抗体を産生するように小規模で発現させた。抗体は上清から精製したプロテインAであり、ナノドロップ分光光度計を使用して定量化した。
4.1 ヒト又はcyno BCMAを発現する細胞に対するキメラCA8の結合を示すFMAT結合アッセイ
凍結保存したトランスフェクトしたヒト、cyno BCMA及び偽トランスフェクトしたHEK293細胞をLN2保存から収集した。広範囲の異なる濃度にてヒトキメラCA8抗体を用いてアッセイウェルを調製し、ヒトBCMA HEK293、cyno BCMA HEK293及び偽トランスフェクト細胞それぞれと混合した。抗ヒトIgG FMATブルー二次コンジュゲートをヒトキメラCA8を検出するために加えた。結果をABI8200(FMAT)プレートリーダーで読み取る前にアッセイプレートを最低90分間そのままにした。
Fc融合物として発現されたヒトBCMA及びcyno BCMAに対する結合についてキメラCA8抗体を試験した。ヒトBCMA-Fc及びcyno BCMA-FcをELISAプレートにコーティングし、非特異的結合を減少させるためにBSAを使用してプレートを遮断した。CA8キメラ抗体を、5ug/ml〜0.1ug/mlの濃度範囲で、ヒト及びcyno BCMAでコーティングしたELISAプレートに加えた。必要に応じて、抗ヒトIgG HRPがコンジュゲートした二次抗体を使用していくらかの結合したヒトキメラCA8抗体を検出した。HRP基質(TMB)を加えてELISAを発展させた。これにより、ELISAアッセイにおいてCA8抗体が組換えヒト及びcyno BCMAに結合したことが示された。
CA8キメラ抗体を注入し、プロテインA上で捕捉した。(プロテインA誘導性センサチップを使用した)。残余のプロテインA結合を高濃度のヒトIgG溶液の注入により遮断した。次いでBCMA-Fc、TACI-Fc又はBAFF-R-Fc溶液を抗体に対する結合について試験した。3個のタンパク質を順に注入し、結合事象を測定した。各タンパク質の注入の間に表面を再生した。
4.4.1 多発性骨髄腫細胞及びBCMA発現細胞に対するマウス抗BCMA抗体の結合
多発性骨髄腫細胞株H929及びARH77-hBCMA 10B5 BCMAを発現するトランスフェクト細胞を、5μg/mLにてマウスS332211D07、S3332121F02若しくはS332126E04又はマウスアイソタイプ対照で染色した。多発性骨髄腫細胞株H929をマウスS307118G03で染色した。細胞を室温(RT)にて20分間インキュベートし、次いでFACS緩衝液(PBS+0.5%BSA+0.1%アジ化ナトリウム)で洗浄して、未結合の抗体を除去した。細胞をRTにて15分間、二次PE標識化抗マウスIgG抗体とインキュベートし、次いでFACS緩衝液で洗浄して、未結合の抗体を除去した。細胞をFACSにより分析して、細胞に結合した抗体を検出した。
多発性骨髄腫細胞株のパネルを使用してキメラCA8の結合を決定した。細胞株H929、OPM-2、JJN-3及びU266を、RTにて20分間、様々な濃度でキメラCA8又は関係のない抗体(シナジス(Synagis))のいずれかで染色した。次いで細胞をFACS緩衝液(PBS+0.5%BSA+0.1%アジ化ナトリウム)で洗浄して、未結合の抗体を除去した。細胞を、RTにて15分間、二次PE標識化抗ヒトIgG抗体とインキュベートし、次いでFACS緩衝液で洗浄して、未結合の抗体を除去した。細胞をFACSにより分析して、平均蛍光強度(MFI)値を測定して結合を決定した。
ARH77-hBCMA 10B5 BCMA発現トランスフェクト細胞又はH929細胞を、RTにて20分間、種々の濃度でキメラCA8又はJ6M0、J6M1、J6M2、J9M0、J9M1、J9M2と指定したCA8のヒト化バリアントのいずれかで染色した。次いで細胞をFACS緩衝液(PBS+0.5%BSA+0.1%アジかナトリウム)で洗浄して、未結合の抗体を除去した。細胞を、RTにて15分間、二次PE標識化抗ヒトIgG抗体とインキュベートし、次いでFACS緩衝液で洗浄して、未結合の抗体を除去した。細胞をFACSにより分析し、平均蛍光強度(MFI)値を測定して結合を決定した。
このアッセイの目的は、BCMAリガンド、BAFF又はAPRILのいずれかの結合能力を中和するために、種々の濃度にて野生型及びアフコシル化(ポテリジェント)形態の両方において抗体CA8、及びヒト化型J6M0の能力を評価することであった。
一セットの実験において、H-929細胞を96ウェルプレートにおいて無血清培地中で75,000個の細胞/ウェルにて播種した。キメラCA8抗体を24時間後に加えて、200ug/mlまでの最終ウェル濃度を得た。10分後、BAFF又はAPRILリガンドを細胞に加えて、それぞれ0.6又は0.3ug/mlの最終ウェル濃度を得た。30分後、細胞を溶解し、MSD pNFカッパBアッセイを使用してリン酸化NfカッパBレベルを測定した。
IC50は、BAFF誘導性NfカッパB中和について10nMであり、APRIL誘導性NfカッパB中和について257nMであり(2回の独立した実験の平均)、それらを表7に示す。
ProteON XPR36(Biorad)においてCA8キメラ及びヒト化バリアントの開始スクリーニングを行った。この方法は以下の通りであった。第一級アミンカップリングによりプロテインAをGLCチップ(Biorad、カタログ番号:176-5011)上に固定し、次いでCA8バリアントをこの表面上で捕捉し、結合曲線を二重で参照するために使用した組換えヒトBCMA(社内又は市販のUS Biological、B0410)物質(2回のみの実施))を、0nM注入(すなわち緩衝液のみ)を用いて256、64、16、4、1nMにて通過させた。使用した緩衝液はHBS-EP緩衝液である。50mM NaOHを使用して捕捉表面を再生した。ProteOn XPR36に内在している分析ソフトウェアを使用してデータを1:1モデルに適合した。実施1はヒト化CA8バリアント(J0〜J5シリーズ)の第1のスクリーニングに対応し、実施2はヒト化CA8バリアント(J5〜J9シリーズ)の第2のスクリーニングに対応する。両方の実施は25℃で行った。
第一級アミンカップリングによりプロテインAをCM5チップ(GE Healthcare、カタログ番号:BR-1005-30)に固定し、次いでこの表面を使用して抗体分子を捕捉した。256nM、64nM、16nM、4nM及び1nMにて検体として組換えヒトBCMA(US Biological、B0410)を使用した。50mM NaOHを使用して捕捉表面の再生を行った。全ての結合曲線は緩衝液注入(すなわち0nM)により二重に参照し、T100評価ソフトウェアに内在している1:1モデルを使用してデータを適合した。ランニング緩衝液としてHBS-EPを使用して実施を37℃にて行った。
第一級アミンカップリングによりプロテインAをCM5チップ(GE Healthcare、カタログ番号:BR-1005-30)に固定し、次いでこの表面を使用して抗体分子を捕捉した。256nM、64nM、16nM、4nM及び1nMにて検体として組換えヒトBCMA(US Biological、B0410)を使用した。50mM NaOHを使用して捕捉表面の再生を行った。全ての結合曲線は緩衝液注入(すなわち0nM)により二重に参照し、T100評価ソフトウェアに内在している1:1モデルを使用してデータを適合した。ランニング緩衝液としてHBS-EPを使用して、実験1について25℃及び37℃並びに実験2について37℃のみで実施を行った。
ProteOn XPR36(Biorad)においてハイブリドーマの第2のバッチ由来の新規キメラバリアントの開始スクリーニングを行った。この方法は以下の通りであった。第一級アミンカップリングによりプロテインAをGLMチップ(Biorad、カタログ番号:176-5012)上に固定し、次いで抗BCMAバリアントをこの表面上で捕捉し、結合曲線を二重で参照するために使用した組換えヒトBCMA(社内の物質)を、0nM注入(すなわち緩衝液のみ)を用いて256、64、16、4、1nMにて通過させた。使用した緩衝液はHBS-EP緩衝液である。50mM NaOHを使用して捕捉表面の再生を行った。ProteOn XPR36に内在している分析ソフトウェアを使用してデータを1:1モデルに適合した。実施は25℃にて行った。
5.1 BCMAを発現するARH77細胞におけるキメラCA8及び脱フコシル化キメラCA8型のADCC効力
ヒトナチュラルキラー(NK)細胞を、2時間、5:1のE:T比にて種々の濃度の抗体の存在下で、ユーロピウム標識したARH77 BCMAトランスフェクト標的細胞(10B5)とインキュベートした。標的細胞からのユーロピウムの放出を測定し、特異的溶解を計算した。
ヒトPBMCを、2時間、5:1のE:T比にてCA8抗体の種々の濃度のヒト化型(5ug/ml〜0.005ug/ml)の存在下で、ユーロピウム標識したARH77 BCMAトランスフェクト標的細胞(10B5)とインキュベートした。標的細胞からのユーロピウムの放出を測定し、特異的溶解を計算した。
結果:CA8のヒト化型のJ5、J6、J7、J8及びJ9シリーズの全ては、用量依存的にARH77高BCMA発現細胞株10B5に対してADCC活性を示した。ADCCは、キメラCA8分子を使用した実験において見出されたものと同様のレベルであった。図9を参照のこと。
ヒトナチュラルキラー(NK)標的細胞を、2時間、5:1のE:T比にて種々の濃度の抗体の存在下で、ユーロピウム標識したARH77 BCMAトランスフェクト標的細胞(10B5)とインキュベートした。標的細胞からのユーロピウムの放出を測定し、特異的溶解を計算した。
ヒト多発性骨髄腫細胞株に対するキメラCA8抗体、キメラCA8-mcMMAF抗体薬物コンジュゲート及びキメラCA8-vcMMAE抗体薬物コンジュゲートのADCC活性を測定する。キメラCA8抗体-薬物コンジュゲートを用いて多発性骨髄腫細胞株を処理して、成長阻害及び死に必要なADC濃度を決定した。
4N DNA含量を有する細胞の蓄積が、キメラCA8により誘導される有糸***停止の特異的結果であるかどうかを決定するために、増加させた濃度のコンジュゲートしていないキメラCA8、キメラCA8-vcMMAE又はキメラCA8-mcMMAFによる48時間の処理後、抗ホスホ-ヒストンH3抗体を用いてADC NCI-H929細胞を染色した。
サブ-2N DNA含量を有する細胞の蓄積が、キメラCA8 ADCにより誘導されるアポトーシスの特異的結果であるかどうかを決定するために、増加させた濃度のコンジュゲートしていないキメラCA8、キメラCA8-vcMMAE又はキメラCA8-mcMMAFによる48時間の処理後、NCI-H929細胞を抗アネキシン-V抗体で染色した。キメラCA8 ADCによる処理の結果、アポトーシスの特異的マーカーである、アネキシン-Vについて陽性染色したNCI-H929細胞の用量依存性蓄積が生じた。キメラCA8-mcMMAF ADCにより、キメラCA8-vcMMAE ADCより低い濃度にてアネキシン-V陽性細胞の蓄積が引き起こされた。図14を参照のこと。
細胞を96ウェルプレート中に播種した(100μLのRPMI+10%FBS入りの1個のウェル当たり4,000個の細胞)。細胞播種の6時間後にネイキッド抗体又はADCを加え、プレートを144時間インキュベートした。抗体又はADCCの存在下で増殖阻害を、Cell Titre gloを使用して144時間に測定した。データ点は、三連のCellTiterGlo測定の平均を表す。エラーバーは標準誤差を表す。
細胞を96ウェルプレート中に播種した(100μLのRPMI+10%FBS入りの1個のウェル当たり4,000個の細胞)。細胞播種の6時間後に抗体又はADCを加え、プレートを144時間インキュベートした。ADCの存在下で成長阻害を、Cell Titre gloを使用して144時間に測定した。三連のCellTiterGlo測定の平均を表す。表15a及び15bは異なるシリーズの抗体で異なる時間に行った実験からである。多発性骨髄腫細胞株NCI-H929及びU266-B1を表15aにおいて抗体について使用した。
MMAE又はMMAFにコンジュゲートしたアフコシル化J6M0を、そのADCC活性がコンジュゲーションによって支障を来されないことを確実にするためにBCMA形質転換体を使用してADCCアッセイにおいて試験した。PBMC(PBMC:標的細胞の比50:1)を加える前に、ユーロピウム標識したARH77-10B5細胞を、10000ng/ml以下の濃度にて30分間、種々のJ6M0 WT及びポテリジェントBCMA抗体とインキュベートした。2時間後、細胞培地のアリコートをサンプリングし、強化溶液と混合した。プレート振盪器で30分後、ユーロピウムの放出をVictor 2 1420マルチラベルリーダーでモニターした。データ点は三連の値の平均を表す。このデータは2回の実験を表す。
ヒトPBMCを、種々の濃度のアフコシル化(ポテリジェント)J6M0の存在下で50:1のE:T比にて多発性骨髄腫標的細胞とインキュベートした。18時間後にエフェクター+標的細胞混合物中に残存している標的細胞の割合を、標的細胞を検出するために蛍光標識抗CD138抗体を使用してFACSにより測定し、溶解の割合を計算した。これはいくつかの実験の代表である。
6.1 インビトロで検出された抗体効力がインビボでも実証され得ることを確実にするためにヒトMM細胞株のマウス異種移植片を試験した。異種移植片研究について選択した細胞株は、インビトロで死滅するADC及びADCCに感受性があるNCI-H929であった。T及びB細胞を欠くが、ADCC活性を可能にするNK細胞を維持する免疫不全CB.17 SCIDマウスにおいて研究を行った。しかしながら、ヒトIgG1はマウスFc受容体と会合できるが、ポテリジェント増強は、ヒトFc受容体を用いて行う場合、親和性を改良しないことに留意すべきである。
J6M0のADCC及びADCの両方の活性を独立して分析するために、我々はMMAF又はMMAEコンジュゲーションの存在下及び非存在下でJ6M0抗体を試験した。コンジュゲートしていないJ6M0を試験することによって、いくらかの抗腫瘍効果は、ADCC及び機能的阻害活性の一部の組み合わせが原因となるようであった。
7.1 BCMAが細胞外に存在し、血液中で検出され得るかどうかは現在知られていない。この研究において、我々はMM患者由来のヒトBCMAの血清レベルを決定した。54個のMM及びプラズマ細胞悪液質の患者由来の血清試料並びに20個の正常対照試料をELISAにより分析した。ヒト被験体の承認はWestern Institutional Review Boardから得た。
診療所において患者及び正常対照由来の血液を血清回収管中に回収した。MM患者の試料は種々の段階(進行、寛解、再発、新たに診断された、及びその他)由来であった。血液試料を10分間10,000rpmにて回転させ、血清を無菌微小遠心管内に移した。
〜1-500 単一
正常対進行性:p=.0010*
進行性対寛解:p=.0146*
〜1-500 三連
正常対進行性:p=.0004*
進行性対寛解:p=.0091*
〜1-50 試行1
正常対進行性:p=.0171*
進行性対寛解:p=.0777
〜1-50 試行2
正常対進行性:p=.0184*
進行性対寛解:p=.0876
*は有意性を示す。
Claims (28)
- BCMAに特異的に結合し、且つBCMAに対するBAFF及び/又はAPRILの結合を阻害する抗原結合タンパク質であって、
i)配列番号3のアミノ酸配列においてN99D変異を有するCDRH3、
ii)配列番号1のアミノ酸配列を有するCDRH1、
iii)配列番号2のアミノ酸配列を有するCDRH2、
iv)配列番号4のアミノ酸配列を有するCDRL1、
v)配列番号5のアミノ酸配列を有するCDRL2、及び
vi)配列番号6のアミノ酸配列を有するCDRL3
を含む、前記抗原結合タンパク質。 - FcγRIIIAに結合できるか、又はFcγRIIIA媒介性エフェクター機能を有し得、且つ内在化できる、請求項1に記載の抗原結合タンパク質。
- FcγRIIIAに対する増強された結合を有するか、又は増強されたFcγRIIIA媒介性エフェクター機能を有する、請求項2に記載の抗原結合タンパク質。
- 抗原結合タンパク質が、増強されたADCCエフェクター機能を有する、請求項3に記載の抗原結合タンパク質。
- 脱フコシル化される、請求項1〜4のいずれか1項に記載の抗原結合タンパク質。
- 抗原結合タンパク質がTaciに結合しない、請求項1〜5のいずれか1項に記載の抗原結合タンパク質。
- 抗体である、請求項1〜6のいずれか1項に記載の抗原結合タンパク質。
- 配列番号23により示される重鎖可変領域及び配列番号31により示される軽鎖可変領域を含む、請求項1〜7のいずれか1項に記載の抗原結合タンパク質。
- ヒト化モノクローナル抗体である、請求項1〜8のいずれか1項に記載の抗原結合タンパク質。
- 前記抗体がIgG1アイソタイプである、請求項9に記載の抗原結合タンパク質。
- 請求項1に記載の抗原結合タンパク質の抗原結合性断片であって、Fab、Fab'、F(ab')2、Fv、ダイアボディ、トリアボディ、テトラボディ、ミニ抗体、又はミニボディである、上記断片。
- 非ヒト霊長類BCMAに更に結合する、請求項1〜11のいずれか1項に記載の抗原結合タンパク質又はその抗原結合性断片。
- 150pMより強い親和性でBCMAに結合する、請求項1〜12のいずれか1項に記載の抗原結合タンパク質又はその抗原結合性断片。
- 請求項1〜13のいずれか1項に記載の抗原結合タンパク質又はその抗原結合性断片及び細胞傷害剤を含む、免疫コンジュゲート。
- 抗原結合タンパク質又はその抗原結合性断片がリンカーを介して細胞傷害剤に結合される、請求項14に記載の免疫コンジュゲート。
- 細胞傷害剤がアウリスタチン又はドラスタチンである、請求項14又は15に記載の免疫コンジュゲート。
- 細胞傷害剤がMMAE及びMMAFから選択される、請求項14〜16のいずれか1項に記載の免疫コンジュゲート。
- 細胞傷害剤が抗原結合タンパク質又はその抗原結合性断片に共有結合される、請求項14〜17のいずれか1項に記載の免疫コンジュゲート。
- リンカーが切断可能なリンカーである、請求項15〜18のいずれか1項に記載の免疫コンジュゲート。
- リンカーが切断可能でないリンカーである、請求項15〜18のいずれか1項に記載の免疫コンジュゲート。
- リンカーが、6-マレイミドカプロイル(MC)、マレイミドプロパノイル(MP)、バリン-シトルリン(val-cit)、アラニン-フェニルアラニン(ala-phe)、p-アミノベンジルオキシカルボニル(PAB)、N-スクシンイミジル4-(2-ピリジルチオ)ペンタノエート(SPP)、N-スクシンイミジル4-(N-マレイミドメチル)シクロヘキサン-1カルボキシレート(SMCC)、及びN-スクシンイミジル(4-ヨード-アセチル)アミノベンゾエート(SIAB)から選択される、請求項15〜20のいずれか1項に記載の免疫コンジュゲート。
- 免疫コンジュゲートが、腫瘍細胞と接触した場合、腫瘍細胞により貪食される、請求項14〜21のいずれか1項に記載の免疫コンジュゲート。
- 請求項1〜22のいずれか1項に記載の抗原結合タンパク質若しくはその抗原結合性断片又は免疫コンジュゲート及び薬学的に許容可能な担体を含む、医薬組成物。
- 炎症性障害又は疾患を患っているヒト患者を治療するための、請求項23に記載の組成物。
- B細胞リンパ腫を患っているヒト患者を治療するための、請求項23に記載の組成物。
- B細胞リンパ腫が多発性骨髄腫(MM)又は慢性リンパ球性白血病(CLL)である、請求項25に記載の組成物。
- B細胞リンパ腫を患っているヒト患者を治療するのに使用するための請求項1〜22のいずれか1項に記載の抗原結合タンパク質若しくはその抗原結合性断片又は免疫コンジュゲート。
- B細胞リンパ腫が多発性骨髄腫(MM)又は慢性リンパ球性白血病(CLL)である、請求項27に記載の抗原結合タンパク質若しくはその抗原結合性断片又は免疫コンジュゲート。
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JP2019147816A (ja) * | 2011-05-27 | 2019-09-05 | グラクソ グループ リミテッドGlaxo Group Limited | Bcma(cd269/tnfrsf17)結合タンパク質 |
JP7018910B2 (ja) | 2011-05-27 | 2022-02-14 | グラクソ グループ リミテッド | Bcma(cd269/tnfrsf17)結合タンパク質 |
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