JP2022130410A - メソテリン結合タンパク質 - Google Patents
メソテリン結合タンパク質 Download PDFInfo
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- JP2022130410A JP2022130410A JP2022091781A JP2022091781A JP2022130410A JP 2022130410 A JP2022130410 A JP 2022130410A JP 2022091781 A JP2022091781 A JP 2022091781A JP 2022091781 A JP2022091781 A JP 2022091781A JP 2022130410 A JP2022130410 A JP 2022130410A
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- binding protein
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- mesothelin
- domain mesothelin
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Abstract
Description
本出願は、各々が全体において参照により本明細書に組み込まれている、2017年5月12日出願の米国仮特許出願62/505,719号及び2018年4月13日出願の米国仮特許出願62/657,417号の利益を主張するものである。
本出願は、ASCIIフォーマットで電子的に提出され、参照によって本明細書に組み込まれる配列表を含んでいる。2018年5月11日に作成された上記のASCIIのコピーは、47517-719_601_SL.txtのファイル名であり、145,039バイトのサイズである。
本明細書で言及される刊行物、特許、及び特許出願は全て、あたかも個々の刊行物、特許、又は特許出願がそれぞれ参照により組み込まれるべく具体的且つ個々に指示されるかのように、及び、その全体にわたって、同程度まで参照により本明細書に組み込まれる。
f1-r1-f2-r2-f3-r3-f4
式中、r1は、SEQ ID NO:51と同一である、又はこれに対して1つ以上のアミノ酸残基置換を含んでおり;r2は、SEQ ID NO:52と同一である、又はこれに対して1つ以上のアミノ酸残基置換を含んでおり;及びr3は、SEQ ID NO:53と同一である、又はこれに対して1つ以上のアミノ酸残基置換を含んでおり;及びここで、f1、f2、f3、及びf4はフレームワーク残基である。幾つかの実施形態において、前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:1-29、30-40、58、及び60-62から成る群から選択された配列に少なくとも80%同一の配列を含む。幾つかの実施形態において、前記単一ドメインメソテリン結合タンパク質は、該結合タンパク質のヒト化を結果としてもたらす1つ以上の修飾を含む。幾つかの実施形態において、修飾は、アミノ酸残基の置換、付加、又は欠失を含む。幾つかの実施形態において、前記単一ドメインメソテリン結合タンパク質は、111~124のアミノ酸を含む。幾つかの実施形態において、前記単一ドメインメソテリン結合タンパク質は、非ヒトソース由来のVHHドメインを含む。幾つかの実施形態において、前記単一ドメインメソテリン結合タンパク質はラマVHHドメインを含む。幾つかの実施形態において、前記エピトープは、SEQ ID NO:57のアミノ酸残基296-390を含む領域I、SEQ ID NO:57のアミノ酸残基391-486を含む領域II、又はSEQ ID NO:57のアミノ酸残基487-598を含む領域IIIに位置する。
f1-r1-f2-r2-f3-r3-f4
式中、r1は、SEQ ID NO:54と同一である、又はこれに対して1つ以上のアミノ酸残基置換を含んでおり;r2は、SEQ ID NO:55と同一である、又はこれに対して1つ以上のアミノ酸残基置換を含んでおり;及びr3は、SEQ ID NO:56と同一である、又はこれに対して1つ以上のアミノ酸残基置換を含んでおり;及びここで、f1、f2、f3、及びf4はフレームワーク残基である。幾つかの実施形態において、前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:30-40、58、及び60-62から成る群から選択された配列に少なくとも80%同一の配列を含む。幾つかの実施形態において、前記単一ドメインメソテリン結合タンパク質は、111~119のアミノ酸を含む。幾つかの実施形態において、前記単一ドメインメソテリン結合タンパク質は、非ヒトソース由来のVHHドメインを含む。幾つかの実施形態において、前記単一ドメインメソテリン結合タンパク質はラマVHHドメインを含む。幾つかの実施形態において、前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:57として明記される配列を含むヒトメソテリンタンパク質に結合する。幾つかの実施形態において、前記単一ドメインメソテリン結合タンパク質はメソテリンのエピトープに結合し、前記エピトープは、SEQ ID NO:57のアミノ酸残基296-390を含む領域I、SEQ ID NO:57のアミノ酸残基391-486を含む領域II、又はSEQ ID NO:57のアミノ酸残基487-598を含む領域IIIに位置する。幾つかの実施形態において、前記単一ドメインメソテリン結合タンパク質は、キメラ抗体又はヒト化抗体である。幾つかの実施形態において、前記単一ドメインメソテリン結合タンパク質は単一ドメイン抗体である。幾つかの実施形態において、前記単一ドメインメソテリン結合タンパク質はヒト化単一ドメイン抗体である。
本明細書で使用される用語は、特定の事例のみを記載することを目的としており、本発明を制限することを意図していない。本明細書で使用されるように、単数形「a」、「an」、及び「the」は、文脈が他に明白に示していない限り、同様に複数形を含むように意図される。更に、用語「含んでいる(including)」、「含む(includes)」、「有している(having)」、「有する(has)」、「含んだ(with)」、又はそれらの変異形が発明を実施するための形態及び/又は請求項の何れかで使用される程度には、上記のような用語は「含んでいる(comprising)」という用語と同様の洋式で包括的であることが意図されている。
MSLN結合タンパク質
本開示のMSLN結合タンパク質、例えば抗MSLN単一ドメイン抗体は、特定の例において、キメラ抗原受容体(CAR)へと組み込むことができる。操作された免疫エフェクター細胞、例えばT細胞又はNK細胞は、本明細書に記載されるような抗MSLN単一ドメイン抗体を含むCARを発現するために使用され得る。一実施形態において、本明細書に記載されるような抗MSLN単一ドメイン抗体を含むCARは、ヒンジ領域を介して膜貫通ドメインに、及び更には共刺激ドメイン、例えばOX40、CD27、CD28、CD5、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、又は4-1BBから得られる機能的シグナル伝達ドメインに接続される。幾つかの実施形態において、CARは、4-1BB及び/又はCD3ゼータなどの細胞内シグナル伝達ドメインをコードする配列を更に含む。
特定の実施形態において、本開示のMSLN結合タンパク質は、メソテリンを発現する腫瘍細胞を有する被験体に投与すると、インビボで腫瘍細胞の成長を減少する。腫瘍細胞の成長の減少の測定は、当該技術分野で周知の複数の異なる方法によって判定され得る。非限定的な実施例は、腫瘍寸法の直接測定、切除した腫瘤の測定及び対照被験体との比較、解析の向上のために同位体又は発光分子(例えばルシフェラーゼ)を使用する又は使用しない画像処理技術(例えばCT又はMRI)を介した測定などを含む。特異的な実施形態において、本開示の抗原結合剤の投与は結果として、対照の抗原結合剤と比較して、腫瘍成長の少なくとも約10%、20%、30%、40%、50%、60%、70%、80%、90%、又は100%の腫瘍細胞のインビボ成長の減少をもたらし、腫瘍の完全寛解及び消失を示す。更なる実施形態において、本開示の抗原結合剤の投与は結果として、対照の抗原結合剤と比較して、約50-100%、約75-100%、又は約90%-100%の腫瘍細胞のインビボ成長の減少をもたらす。更なる実施形態において、本開示の抗原結合剤の投与は結果として、対照の抗原結合剤と比較して、約50-60%、約70-80%、約80-90%、又は約90%-100%の腫瘍細胞のインビボ成長の減少をもたらす。
本明細書に記載されるMSLN結合タンパク質は、(i)アミノ酸が遺伝子コードによってコードされるものではないアミノ酸残基で置換され、(ii)成熟ポリペプチドがポリエチレングリコールなどの別の化合物と融合され、又は、(iii)追加のアミノ酸が、リーダー配列、分泌配列、或いは免疫原ドメインを遮断するための及び/又はタンパク質の精製のための配列などのタンパク質に融合される、誘導体又はアナログを包含する。
幾つかの実施形態において、本明細書に記載されるMSLN結合タンパク質をコードするポリヌクレオチド分子も提供される。幾つかの実施形態において、ポリヌクレオチド分子はDNA構築物として提供される。他の実施形態において、ポリヌクレオチド分子はメッセンジャーRNA転写産物として提供される。
幾つかの実施形態において、本明細書に記載されるMSLN結合タンパク質、MSLN結合タンパク質のポリペプチドをコードするポリヌクレオチドを含むベクター、或いはこのベクター及び少なくとも1つの薬学的に許容可能な担体によって形質転換された宿主細胞を含む、医薬組成物も提供される。用語「薬学的に許容可能な担体」としては、限定されないが、成分の生物学的活性の有効性に干渉せず、且つ、投与される患者にとって毒性ではない任意の担体が挙げられる。適切な医薬担体の例は当該技術分野で周知であり、リン酸緩衝生理食塩水、水、油/水エマルジョンなどのエマルジョン、様々なタイプの湿潤剤、無菌液などを含む。こうした担体は、従来の方法によって製剤することができ、適切な投与量で被験体に投与可能である。好ましくは、組成物は無菌である。これらの組成物は、防腐剤、乳化剤、及び分散剤などのアジュバントを更に含み得る。微生物の作用の予防は、様々な抗菌剤及び抗真菌剤の包含によって確保され得る。更なる実施形態は、凍結乾燥形態で包装される、或いは水性媒体に包装される、抗MSLN単一ドメイン抗体又はその抗原結合性フラグメントなどの、上記結合タンパク質の1つ以上を提供する。
本明細書にはまた、幾つかの実施形態において、本明細書に記載されるようなMSLN結合タンパク質の投与を含む、個体の免疫系を刺激するための方法と使用が提供される。幾つかの例において、本明細書に記載されるMSLN結合タンパク質の投与は、標的抗原を発現する細胞への細胞毒性を引き起こす、及び/又は持続させる。幾つかの例において、細胞は、癌細胞、ウイルス感染細胞、細菌感染細胞、自己反応性のT又はB細胞、損傷を受けた赤血球、動脈プラーク、或いは繊維症の組織である。
ロニック酸;パナキシトリオール;パノミフェン;パラバクチン;パゼリプチン;ペガスパルガーゼ;ペルデシン;ペントサンポリサルフェートナトリウム;ペントスタチン;ペントロゾール;ペルフルブロン;ペルフォスファミド;ペリルアルコール;フェナジノマイシン;酢酸フェニル;ホスファターゼ阻害剤;ピシバニール;塩酸ピロカルピン;ピラルビシン;ピリトレキシム;プラセチンA;プラセチンB;プラスミノゲンアクチベータインヒビター;白金複合体;白金化合物;白金トリアミン複合体;ポルフィマーナトリウム;ポルフィロマイシン;プレドニゾン;プロピルビス-アクリドン;プロスタグランジンJ2;プロテアソーム阻害剤;タンパク質Aベースの免疫モジュレータ;プロテインキナーゼC阻害剤;プロテインキナーゼC阻害剤、微細藻類;チロシンホスファターゼタンパク質阻害剤;プリンヌクレオシドホスホリラーゼ阻害剤;プルプリン;ピラゾロアクリジン;ピリドキシル化したヘモグロビン・ポリオキシエチレン抱合体;rafアンタゴニスト;ラルチトレキセド;ラモセトロン;rasファルネシルタンパク質トランスフェラーゼ阻害剤;ras阻害剤;ras-GAP阻害剤;脱メチル化レティプチン;レニウムRe 186エチドロネート;リゾキシン;リボザイム;RIIレチンアミド;ログレチミド;ロヒツキン;ロムルチド;ロキニメックス;ラビジノンB1;ラボキシル;サフィンゴル;セイントピン;SarCNU;サルコフィトールA;サルグラモスチム;Sdi 1模倣物;セムスチン;セネスセンス由来の阻害剤1;センスオリゴヌクレオチド;シグナル伝達阻害剤;シグナル伝達モジュレータ;一本鎖抗原結合タンパク質;シゾフィラン;ソブゾキサン;ナトリウムボロカプテート;フェニル酢酸ナトリウム;サルバロル;ソマトメジン結合タンパク質;ソナーミン;スパルフォシック酸;スピカマイシンD;スピロマスチン;スプレノペンチン;スポンジスタチン1;スクワラミン;幹細胞阻害剤;幹細胞分割阻害剤;スティピアミド;ストロメリシン阻害剤;サルフィノジン;超活性血管作用性小腸ペプチドアンタゴニスト;サラディスタ;スラミン;スウェインソニン;合成グリコサミノグリカン;タリムスチン;タモキシフェンメチオジド;タウロマスチン;タザロテン;テコガランナトリウム;テガフール;テルラピリウム;テロメラーゼ阻害剤;テモポルフィン;テモゾロミド;テニポシド;テトラクロロデカオキシド;テトラゾミン;サリブラスチン;チオコラリン;トロンボポイエチン;トロンボポイエチン模倣物;チマルファジン;チモポイエチン受容体アゴニスト;チモトリナン;甲状腺刺激ホルモン;スズエチルエチオプロプリン;チラパザミン;チタノセン二塩化物;トプセンチン;トレミフェン;全能性幹細胞因子;翻訳阻害剤;トレチノイン;トリアセチルウリジン;トリシビリン;トリメトレキサート;トリプトレリン;トロピセトロン;テュロステリド;チロシンキナーゼ阻害剤;チルホスチン;UBC阻害剤;ウベニメクス;尿生殖洞由来の成長阻害因子;ウロキナーゼ受容体アンタゴニスト;バプレオチド;バリオリンB;ベクターシステム、赤血球遺伝子治療薬;ベラレゾール;ベラミン;アメリカツリスガラ;ベルテポルフィン;ビノレルビン;ビンザルチン;Vitaxin(登録商標);ボロゾール;ザノテロン;ゼニプラチン;ジラスコルブ;及びジノスタチンスチマラマー。追加の抗癌剤は5-フルオロウラシル及びロイコボリンである。サリドマイド及びトポイソメラーゼ阻害剤を利用する方法での使用時、これらの2つの薬剤は特に有用である。幾つかの実施形態において、本開示の抗MSLNの単一ドメイン結合タンパク質は、ゲムシタビンと組み合わせて使用される。
本開示の他の実施形態に従い、インビトロ又はインビボでメソテリンの発現を検出するためのキットが提供される。キットは、前述のMSLN結合タンパク質(例えば、標識された抗MSLN単一ドメイン抗体又はその抗原結合フラグメント)、及びラベルを検出するための1つ以上の化合物を含む。幾つかの実施形態において、ラベルは、蛍光ラベル、酵素ラベル、放射性ラベル、核磁気共鳴活性ラベル、発光ラベル、及び発色団ラベルから成る群から選択される。
典型的な抗MSLN単一ドメイン抗体配列を、Expi293細胞(Invitrogen)へとトランスフェクトする。トランスフェクトされたExpi293細胞からの調整培地中の典型的な抗MSLN抗体の量を、プロテインAチップを備えたOctet器機を使用し、且つ標準曲線として対照抗MSLN抗体を使用して、定量する。
本開示に係るMSLN結合タンパク質を含むMSLN標的三重特異性分子の配列を、リーダー配列が先行し6xヒスチジンタグが後続する、哺乳動物発現ベクターpCDNA 3.4(Invitrogen)へとクローン化した。Expi293F細胞(Life Technologies A14527)を、Expi 293培地中の0.2~8×1e6細胞/mL間でOptimum Growth Flasks(Thomson)の懸濁液において維持した。精製されたプラスミドDNAを、Expi293 Expression System Kit(Life Technologies A14635)プロトコルに従ってExpi293細胞へとトランスフェクトし、トランスフェクション後4-6日間維持した。トランスフェクトされたExpi293細胞からの、調製培地中の試験されている典型的な三重特異性タンパク質の量を、プロテインAチップを備えたOctet器機を使用し、且つ標準曲線に対して対照の三重特異性タンパク質を使用して、定量した。
この研究は、本開示の典型的な抗体として配列修飾又は置換を持たない比較対象のラマ抗MSLN抗体と比較して、ADCCを媒介する本開示の典型的な抗MSLN単一ドメイン抗体の能力を判定することを対象とする。両方の抗体は、追加の免疫グロブリンドメインを含む多重ドメインタンパク質として発現される。
ドナーを白血球泳動し(leukophoresed)、NK細胞を、Milteni AutoMacs Proの負選択システムを使用して細胞精製群によりleukopackから単離する。NK細胞をロッカー(rocker)上で4℃で一晩保持し、その後洗浄し、計数して、ADCCアッセイでの使用のために完全RPMIにおいて4×106細胞/mLで再懸濁する。
癌細胞に対する、本開示に係る典型的な抗MSLN単一ドメイン抗体の抗腫瘍活性を評価するために、補体のソースとしてヒト血清の存在下でのA431/H9及びNCI-H226細胞モデルの細胞毒性活性を試験する。典型的な抗MSLN単一ドメイン抗体を、追加の免疫グロブリンドメインを含む多重ドメインタンパク質として発現する。本開示の典型的な抗MSLN単一ドメイン抗体を含む多重ドメインタンパク質が、A431/H9の約40%、及びNCI-H226中皮腫細胞株の30%よりも多くを死滅させることにより強力なCDC活性を及ぼし、メソテリン陰性A431細胞株に対して活性を示さないことを、確認する。本開示の典型的な抗体として配列修飾又は置換を有していない、比較対象のラマ抗MSLN抗体は、同じ濃度で活性を示さない。
ヒトT細胞依存性細胞毒性(TDCC)アッセイを使用して、T細胞が腫瘍細胞を死滅させるよう導く、三重特異性分子を含むT細胞エンゲージャー(engagers)の能力を測定した(Nazarian et al. 2015. J Biomol Screen. 20:519-27)。このアッセイに使用されるCaov3細胞を操作し、ルシフェラーゼを発現させた。5つの異なる健康なドナー(ドナー02、ドナー86、ドナー41、ドナー81、及びドナー34)からのT細胞及び標的癌細胞Caov3を共に混合し、MSLN結合ドメイン(MH6T)を含む様々な量のMSLN標的三重特異性抗原結合タンパク質(SEQ ID NO:58)を加え、混合物を37℃で48時間インキュベートした。Caov3細胞及びT細胞も、GFPを標的とする対照三重特異性分子、GFP TriTAC(SEQ ID NO:59)により37℃で48時間インキュベートした。48時間後、残る生存可能な腫瘍細胞を、発光アッセイによって定量した。
このアッセイにおいて、健康なドナーのT細胞を、MSLNを発現する標的癌細胞(Caov3細胞、Caov4細胞、OVCAR3細胞、及びOVCAR8細胞)、又はMSLNを発現しない標的癌細胞(NCI-H510A細胞、MDAPCa2b細胞)でインキュベートした。この研究に使用される標的細胞の各々を操作し、ルシフェラーゼを発現させた。MH6T(SEQ ID NO:58)ドメインを含む様々な量のMSLN標的三重特異性抗原結合性のタンパク質を、上述のT細胞と標的癌細胞の混合物に加えた。混合物を37℃で48時間インキュベートした。48時間後、残る生存可能な標的癌細胞を、発光アッセイによって定量した。
このアッセイにおいて、カニクイザルドナーからの末梢血単核球(PBMC;T細胞はPBMCの構成要素である)を、MSLNを発現する細胞(CaOV3細胞及びOVCAR3細胞)と混合し、様々な量のMSLN標的三重特異性抗原結合タンパク質(MH6Tドメイン、SEQ ID NO:58を含む)を混合物に加え、37℃で48時間インキュベートした。並行して、カニクイザルPBMC及びMSLN発現細胞の混合物を、上述のように、37℃で48時間、GFPを標的とする様々な量の対照TriTAC分子GFP TriTAC(SEQ ID NO:59)でインキュベートした。このアッセイに使用される標的癌細胞を操作し、ルシフェラーゼを発現させた。48時間後、残る生存可能な標的細胞を、発光アッセイによって定量した。
この試験の目標は、(MH6Tドメイン;SEQ ID NO:58を含む)MSLN標的三重特異性抗原結合タンパク質が、T細胞にMSLN発現細胞を死滅させるよう導くタンパク質の能力に影響を与えたかどうかを評価することであった。この研究に使用されるNCI-H2052中皮腫細胞を操作し、ルシフェラーゼを発現させた。健康なドナーのT細胞及びMSLN発現細胞(NCI-H2052)を組み合わせ、(MH6Tドメインを含む)様々な量のMSLN標的三重特異性抗原結合タンパク質を混合物に加えた。混合物をHSAの存在下又は不在下で、37℃で48時間インキュベートした。NCI-H2052細胞及びT細胞の混合物も、HSAの存在下で、GFPを標的とする対照三重特異性分子、GFP TriTAC(SEQ ID NO:59)により37℃で48時間インキュベートした。48時間後、残る生存可能な標的細胞を、発光アッセイによって定量した。
このアッセイに使用される標的癌細胞CaOv4を操作し、ルシフェラーゼを発現させた。このアッセイにおいて、4つの異なる健康なドナー(ドナー02、ドナー86、ドナー35、及びドナー81)からのT細胞及びCaov4細胞を共に混合し、(MH6Tドメイン;SEQ ID NO:58を含む)様々な量のMSLN標的三重特異性抗原結合タンパク質を加え、混合物を37℃で48時間インキュベートした。Caov4細胞及びT細胞も、GFPを標的とする対照三重特異性分子、GFP TriTAC(SEQ ID NO:59)により37℃で48時間インキュベートした。発光アッセイを使用して標的癌細胞の生存率を測定する前に、TDCCアッセイからの調整培地を48時間で集めた。調整培地中のTNF-αの濃度を、AlphaLISAアッセイキット(Perkin Elmer)を使用して測定した。
このアッセイに使用されるOVCAR8細胞を操作し、ルシフェラーゼを発現させた。このアッセイにおいて、4つの異なる健康なドナー(ドナー02、ドナー86、ドナー35、及びドナー81)からのT細胞及びOVCAR8細胞を共に混合し、(MH6Tドメイン;SEQ ID NO:58を含む)様々な量のMSLN標的三重特異性抗原結合タンパク質を加え、混合物を37℃で48時間インキュベートした。OVCAR8細胞及びT細胞も、GFPを標的とする対照三重特異性分子、GFP TriTAC(SEQ ID NO:59)により37℃で48時間インキュベートした。48時間後、T細胞を集め、T細胞上でのCD69発現をフローサイトメトリーによって測定した。
この研究のために、MSLNを発現する特定の標的癌細胞(Caov3細胞、CaOV4細胞、OVCAR3細胞、及びOVCAR8細胞)及びMSLNを発現しない特定の癌細胞(MDAPCa2b細胞及びNCI-H510A細胞)を、MSLN標的三重特異性抗原結合タンパク質(MH6Tドメイン;SEQ ID NO:58を含む)又は対照GFP TriTAC分子(SEQ ID NO:59)でインキュベートした。インキュベーションの後、細胞を洗浄し、未結合のMH6T又はGFP TriTAC分子を取り除き、Alexa Fluor 647に抱合されるTriTAC分子中の抗アルブミンドメインを認識できる二次抗体で更にインキュベートした。(MH6Tドメインを含む)MSLN標的三重特異性抗原結合タンパク質の結合、又はMSLN発現又は非MSLN発現細胞へのGFP TriTACの結合を、フローサイトメトリーによって測定した。
この研究のために、4つの健康なドナーからのT細胞を、陰性対照として、(MH6Tドメイン;SEQ ID NO:58を含む)MSLN標的三重特異性抗原結合タンパク質又は緩衝液でインキュベートした。インキュベーションの後、細胞を洗浄し、未結合の(MH6Tドメインを含む)MSLN標的三重特異性抗原結合タンパク質を取り除き、(MH6Tドメインを含む)MSLN標的三重特異性抗原結合タンパク質中の抗アルブミンドメインを認識できる、Alexa Fluor 647を抱合した二次抗体で更にインキュベートした。結合をフローサイトメトリーによって測定した。
この研究のために、107のNCI-H292細胞及び107のヒトPBMCを、NCGマウスの2つの群(群ごとに8匹のマウス)において共に皮下移植した。5日後、1つの群のマウスに、(MH6Tドメイン;SEQ ID NO:58を含む)MSLN標的三重特異性抗原結合タンパク質を、10日間毎日(5-14日目)、0.25mg/kgの投与量で注入し;他の群のマウスにはビヒクル対照を注入した。腫瘍堆積を数日毎に測定し、36日目に試験を終了した。図11に示されるように、ビヒクル対照を注入されたマウスと比較して腫瘍成長の有意な阻害を、(MH6Tドメインを含む)MSLN標的三重特異性抗原結合タンパク質を注入されたマウスにおいて観察した。
この研究のために、2匹のカニクイザルに、10mg/kgの投与量の(MH6Tドメイン;SEQ ID NO:58を含む)MSLN標的三重特異性抗原結合タンパク質を静脈内注入し、血清サンプルを注入後の様々な時点で集めた。血清中の(MH6Tドメインを含む)MSLN標的三重特異性抗原結合タンパク質の量を、電気化学発光(electrochemiluminescient)アッセイにおいて、(MH6Tドメインを含む)MSLN標的三重特異性抗原結合タンパク質を認識する抗イディオタイプ抗体を使用して測定した。図12は、様々な時点での血清の(MH6Tドメインを含む)MSLN標的三重特異性抗原結合タンパク質レベルのプロットを示す。その後、データを使用して、表VIIに提供されるように(MH6Tドメインを含む)MSLN標的三重特異性抗原結合タンパク質の薬物動態特性を算出した。
Claims (68)
- 単一ドメインメソテリン結合タンパク質であって、SEQ ID NO:41、42、43、又は44と同一の配列、或いはSEQ ID NO:41、42、43、又は44に対して1つ以上のアミノ酸残基置換を含む、1つ以上の保存領域を備えている、単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:41と同一の配列、或いはSEQ ID NO:41に対して1つ以上のアミノ酸残基置換を含む、保存領域を備えている、ことを特徴とする請求項1に記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:42と同一の配列、或いはSEQ ID NO:42に対して1つ以上のアミノ酸残基置換を含む、保存領域を備えている、ことを特徴とする請求項1又は2に記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:43と同一の配列、或いはSEQ ID NO:43に対して1つ以上のアミノ酸残基置換を含む、保存領域を備えている、ことを特徴とする請求項1、2、又は3の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:44と同一の配列、或いはSEQ ID NO:44に対して1つ以上のアミノ酸残基置換を含む、保存領域を備えている、ことを特徴とする請求項1、2、又は3の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、(i)SEQ ID NO:41に相当するアミノ酸の伸張部;(ii)SEQ ID NO:42に相当するアミノ酸の伸張部;(iii)SEQ ID NO:43に相当するアミノ酸の伸張部;及び(iv)SEQ ID NO:44に相当するアミノ酸の伸張部を含む、ことを特徴とする請求項1に記載の単一ドメインメソテリン結合タンパク質。
- 以下の式を含む、単一ドメインメソテリン結合タンパク質であって:
f1-r1-f2-r2-f3-r3-f4
式中、r1は、SEQ ID NO:51と同一である、又はこれに対して1つ以上のアミノ酸残基置換を含んでおり;r2は、SEQ ID NO:52と同一である、又はこれに対して1つ以上のアミノ酸残基置換を含んでおり;及びr3は、SEQ ID NO:53と同一である、又はこれに対して1つ以上のアミノ酸残基置換を含んでおり;及びここで、f1、f2、f3、及びf4はフレームワーク残基である
ことを特徴とする単一ドメインメソテリン結合タンパク質。 - 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:1-40、58、及び60-62から成る群から選択される配列に対し少なくとも80%同一の配列を含む、ことを特徴とする請求項1乃至7の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、該結合タンパク質のヒト化を結果としてもたらす1つ以上の修飾を含む、ことを特徴とする請求項1乃至8の何れ1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記修飾は、アミノ酸残基の置換、付加、又は欠失を含む、ことを特徴とする請求項9に記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、111~124のアミノ酸を含む、ことを特徴とする請求項1乃至10の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、非ヒトソース由来のVHHドメインを含む、ことを特徴とする請求項1乃至11の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、ラマVHHドメインを含む、ことを特徴とする請求項1乃至12の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質はメソテリンのエピトープに結合し、前記エピトープは、SEQ ID NO:57のアミノ酸残基296-390を含む領域I、SEQ ID NO:57のアミノ酸残基391-486を含む領域II、又はSEQ ID NO:57のアミノ酸残基487-598を含む領域IIIに位置する、ことを特徴とする請求項1乃至13の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 単一ドメインメソテリン結合タンパク質であって、SEQ ID NO:45、46、47、48、49、又は50と同一の配列、或いはSEQ ID NO:45、46、47、48、49、又は50に対して1つ以上のアミノ酸残基置換を含む、1つ以上の保存領域を備えている、単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:45と同一の配列、或いはSEQ ID NO:45に対して1つ以上のアミノ酸残基置換を含む、保存領域を備えている、ことを特徴とする請求項15に記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:46と同一の配列、或いはSEQ ID NO:46に対して1つ以上のアミノ酸残基置換を含む、保存領域を備えている、ことを特徴とする請求項15又は16に記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:47と同一の配列、或いはSEQ ID NO:47に対して1つ以上のアミノ酸残基置換を含む、保存領域を備えている、ことを特徴とする請求項15、16、又は17の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:48と同一の配列、或いはSEQ ID NO:48に対して1つ以上のアミノ酸残基置換を含む、保存領域を備えている、ことを特徴とする請求項15乃至18の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:49と同一の配列、或いはSEQ ID NO:49に対して1つ以上のアミノ酸残基置換を含む、保存領域を備えている、ことを特徴とする請求項15乃至19の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:50と同一の配列、或いはSEQ ID NO:50に対して1つ以上のアミノ酸残基置換を含む、保存領域を備えている、ことを特徴とする請求項15乃至20の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、(i)SEQ ID NO:45に相当するアミノ酸の伸張部;(ii)SEQ ID NO:46に相当するアミノ酸の伸張部;(iii)SEQ ID NO:47に相当するアミノ酸の伸張部;(iv)SEQ ID NO:48に相当するアミノ酸の伸張部;(v)SEQ ID NO:49に相当するアミノ酸の伸張部;及び(vi)SEQ ID NO:50に相当するアミノ酸の伸張部を含む、ことを特徴とする請求項1に記載の単一ドメインメソテリン結合タンパク質。
- 以下の式を含む、単一ドメインメソテリン結合タンパク質であって:
f1-r1-f2-r2-f3-r3-f4
式中、r1は、SEQ ID NO:54と同一である、又はこれに対して1つ以上のアミノ酸残基置換を含んでおり;r2は、SEQ ID NO:55と同一である、又はこれに対して1つ以上のアミノ酸残基置換を含んでおり;及びr3は、SEQ ID NO:56と同一である、又はこれに対して1つ以上のアミノ酸残基置換を含んでおり;及びここで、f1、f2、f3、及びf4はフレームワーク残基である
ことを特徴とする単一ドメインメソテリン結合タンパク質。 - 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:30-40、58、及び60-62から成る群から選択される配列に対し少なくとも80%同一の配列を含む、ことを特徴とする請求項15乃至23の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、111~119のアミノ酸を含む、ことを特徴とする請求項15乃至24の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、非ヒトソース由来のVHHドメインを含む、ことを特徴とする請求項15乃至25の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、ラマVHHドメインを含む、ことを特徴とする請求項15乃至26の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:57として明記される配列を含むヒトメソテリンタンパク質に結合する、ことを特徴とする請求項15乃至27の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質はメソテリンのエピトープに結合し、前記エピトープは、SEQ ID NO:57のアミノ酸残基296-390を含む領域I、SEQ ID NO:57のアミノ酸残基391-486を含む領域II、又はSEQ ID NO:57のアミノ酸残基487-598を含む領域IIIに位置する、ことを特徴とする請求項15乃至28の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質はキメラ抗体又はヒト化抗体である、ことを特徴とする請求項1乃至29の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は単一ドメイン抗体である、ことを特徴とする請求項1乃至30の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、ヒト化単一ドメイン抗体である、ことを特徴とする請求項15乃至31の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:58に明記されるような配列を含む、ことを特徴とする請求項1乃至32の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 請求項1乃至33の何れか1つに記載の単一ドメインメソテリン結合タンパク質をコードする、ポリヌクレオチド。
- 請求項34に記載のポリヌクレオチドを含む、ベクター。
- 請求項35に記載のベクターにより形質転換される、宿主細胞。
- (i)請求項1乃至33の何れか1つに記載の単一ドメインメソテリン結合タンパク質、請求項33に記載のポリヌクレオチド、請求項35に記載のベクター、又は請求項36に記載の宿主細胞、及び(ii)薬学的に許容可能な担体を含む、医薬組成物。
- 請求項1乃至33の何れか1つに記載の単一ドメインメソテリン結合タンパク質の産生のためのプロセスであって、メソテリン結合タンパク質の発現を可能とする条件下で請求項1乃至33の何れか1つに記載の単一ドメインメソテリン結合タンパク質をコードする核酸配列を含むベクターにより形質転換又はトランスフェクトされる宿主を培養する工程、及び、培養物から産生されたタンパク質を回収及び精製する工程を含む、プロセス。
- 増殖性疾患又は腫瘍疾患の処置又は改善のための方法であって、必要とする被験体への請求項1乃至33の何れか1つに記載のメソテリン結合タンパク質の投与を含む、方法。
- 被験体はヒトである、ことを特徴とする請求項39に記載の方法。
- 前記方法は、請求項1乃至33の何れか1つに記載の単一ドメインメソテリン結合タンパク質と組み合わせた薬剤の投与を更に含む、ことを特徴とする請求項40に記載の方法。
- 前記単一ドメインメソテリン結合タンパク質は、メソテリンを発現する腫瘍細胞に選択的に結合する、ことを特徴とする請求項39乃至41の何れか1つに記載の方法。
- 前記単一ドメインメソテリン結合タンパク質は、メソテリンを発現する腫瘍細胞のT細胞死滅を媒介する、ことを特徴とする請求項42に記載の方法。
- 前記腫瘍疾患は固形腫瘍疾患である、ことを特徴とする請求項39乃至43の何れか1つに記載の方法。
- 前記固形腫瘍疾患は、中皮腫、肺癌、胃癌、卵巣癌、又は三種陰性乳癌を含む、ことを特徴とする請求項44に記載の方法。
- 前記固形腫瘍疾患は転移性である、ことを特徴とする請求項45に記載の方法。
- 単一ドメインメソテリン結合タンパク質であって、前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:51-56及び63-179から選択された1つ以上のCDRを含む、単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:51、54、及び63-101の何れか1つに明記される配列を含むCDR1を備える、ことを特徴とする請求項47に記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:52、55、及び102-140の何れか1つに明記される配列を含むCDR2を備える、ことを特徴とする請求項47又は48に記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:53、56、及び141-179の何れか1つに明記される配列を含むCDR3を備える、ことを特徴とする請求項47乃至49の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:180-218の何れか1つに明記されるような配列を含むフレームワーク領域1(f1)を含む、ことを特徴とする請求項47乃至50の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:219-257の何れか1つに明記されるような配列を含むフレームワーク領域2(f2)を含む、ことを特徴とする請求項47乃至51の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:258-296の何れか1つに明記されるような配列を含むフレームワーク領域3(f3)を含む、ことを特徴とする請求項47乃至52の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:297-335の何れか1つに明記されるような配列を含むフレームワーク領域4(f4)を含む、ことを特徴とする請求項47乃至53の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 前記単一ドメインメソテリン結合タンパク質は、SEQ ID NO:1-40及び58の何れか1つに明記されるようなアミノ酸配列を含む、ことを特徴とする請求項47乃至54の何れか1つに記載の単一ドメインメソテリン結合タンパク質。
- 請求項47乃至55の何れか1つに記載の単一ドメインメソテリン結合タンパク質をコードする、ポリヌクレオチド。
- 請求項56に記載のポリヌクレオチドを含む、ベクター。
- 請求項57に記載のベクターにより形質転換される、宿主細胞。
- (i)請求項47乃至55の何れか1つに記載の単一ドメインメソテリン結合タンパク質、請求項56に記載のポリヌクレオチド、請求項57に記載のベクター、又は請求項58に記載の宿主細胞、及び(ii)薬学的に許容可能な担体を含む、医薬組成物。
- 請求項47乃至55の何れか1つに記載の単一ドメインメソテリン結合タンパク質の産生のためのプロセスであって、メソテリン結合タンパク質の発現を可能とする条件下で請求項47乃至55の何れか1つに記載の単一ドメインメソテリン結合タンパク質をコードする核酸配列を含むベクターにより形質転換又はトランスフェクトされる宿主を培養する工程、及び、培養物から産生されたタンパク質を回収及び精製する工程を含む、プロセス。
- 増殖性疾患又は腫瘍疾患の処置又は改善のための方法であって、必要とする被験体への請求項47乃至55の何れか1つに記載のメソテリン結合タンパク質の投与を含む、方法。
- 被験体はヒトである、ことを特徴とする請求項61に記載の方法。
- 前記方法は、請求項1乃至33の何れか1つに記載の単一ドメインメソテリン結合タンパク質と組み合わせた薬剤の投与を更に含む、ことを特徴とする請求項62に記載の方法。
- 前記単一ドメインメソテリン結合タンパク質は、メソテリンを発現する腫瘍細胞に選択的に結合する、ことを特徴とする請求項61乃至63の何れか1つに記載の方法。
- 前記単一ドメインメソテリン結合タンパク質は、メソテリンを発現する腫瘍細胞のT細胞死滅を媒介する、ことを特徴とする請求項64に記載の方法。
- 前記腫瘍疾患は固形腫瘍疾患である、ことを特徴とする請求項61乃至65の何れか1つに記載の方法。
- 前記固形腫瘍疾患は、中皮腫、肺癌、胃癌、卵巣癌、又は三種陰性乳癌を含む、ことを特徴とする請求項66に記載の方法。
- 前記固形腫瘍疾患は転移性である、ことを特徴とする請求項67に記載の方法。
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