JP7507790B2 - EpCAM結合タンパク質および使用方法 - Google Patents
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- JP7507790B2 JP7507790B2 JP2021568209A JP2021568209A JP7507790B2 JP 7507790 B2 JP7507790 B2 JP 7507790B2 JP 2021568209 A JP2021568209 A JP 2021568209A JP 2021568209 A JP2021568209 A JP 2021568209A JP 7507790 B2 JP7507790 B2 JP 7507790B2
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Description
本出願は、2019年5月14日に出願された米国仮出願第62/847,778号、2019年5月14日に出願されたPCT出願第PCT/US2019/032307号、2019年5月14日に出願されたPCT出願第CT/US2019/032224号、2019年5月14日に出願されたPCT出願第PCT/US2019/US032302号、および、2019年5月14日に出願されたPCT出願第PCT/US2019/032306号の利益を主張し、上記文献は各々、全体として参照により本明細書に組み込まれる。
この明細書で言及されるすべての公報、特許、および特許出願は、個々の公報、特許、または特許出願が、それぞれ、明確かつ個々に引用によって組み込まれると示されるのと同じ程度まで、引用によって本明細書に組み込まれる。
-非CDRループは、EpCAM結合ドメインに特異的な結合部位を含み、
-EpCAM結合ドメインは、結合部分によってその標的との結合からマスキングされ、
-EpCAM結合ドメインは、切断可能なリンカーが切断されると、その標的に結合することができる。
-非CDRループは、第1の標的抗原結合ドメインまたは第2の標的抗原結合ドメインに特異的な結合部位を含み、
-第1の標的抗原結合ドメインまたは第2の標的抗原結合ドメインの少なくとも1つは、結合部分によってその標的の結合からマスキングされ、および、
-マスキングされる第1の標的抗原結合ドメインまたは第2の標的抗原結合ドメインは、切断可能なリンカーの切断時にその標的に結合することができる。
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、本発明を限定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」、および「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。さらに、「含むこと(including)」、「含む(includes)」「有すること(having)」、「有する(has)」、「とともに(with)」との用語またはその変形が、詳細な記載および/または請求項のいずれかで使用される程度まで、そのような用語は、用語「含む(comprising)」に類似した方法で含まれるように意図される。
EpCAMに結合するタンパク質、その医薬組成物、同様にそのようなタンパク質を作るための核酸、組換え発現ベクター、および宿主細胞が本明細書に記載されている。さらに、疾患、疾病、および障害の予防および/または処置において、開示されたEpCAM結合タンパク質を使用する方法も提供される。いくつかの実施形態では、EpCAM結合タンパク質は、本明細書に記載されているようなEpCAM結合ドメインを含む多特異性(例えば、三重特異性)タンパク質の一部である。
一態様では、本開示のEpCAM結合タンパク質を含む多特異性タンパク質または多価タンパク質が本明細書に記載される。いくつかの実施形態では、多特異性タンパク質は、CD3に特異的に結合するドメインをさらに含む。いくつかの実施形態では、多特異性タンパク質は、ヒトのCD3に特異的に結合するドメインをさらに含む。いくつかの実施形態では、多特異性タンパク質は、CD3ガンマに特異的に結合するドメインをさらに含む。いくつかの実施形態では、多特異性タンパク質は、CD3デルタに特異的に結合するドメインをさらに含む。いくつかの実施形態では、多特異性タンパク質は、CD3イプシロンに特異的に結合するドメインをさらに含む。
本開示の一実施形態は、本明細書で開示されるEpCAM結合ドメインを含む、条件付きで活性な多特異性タンパク質を提供する(例えば、いくつかの実施形態では、本開示は、本開示のEpCAM結合ドメインを含む、EpCAMを標的とする三重特異性促進/ProTriTACタンパク質を提供する)。
本開示のEpCAM結合タンパク質は、ある実施例では、キメラ抗原受容体(CAR)、またはProCAR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細胞またはNK細胞は、例えば、本明細書に記載される抗EpCAM単一ドメイン抗体を含有するEpCAM結合タンパク質を含むCARを発現するために使用され得る。一実施形態では、本明細書に記載されるEpCAM結合タンパク質を含むCARは、ヒンジ領域を介して膜貫通ドメインに、さらには共刺激ドメイン、例えば、OX40、CD27、CD28、CD5、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、あるいは4-1BBから得られる機能的シグナル伝達ドメインに結合される。いくつかの実施形態では、CARは、4-1BBおよび/または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さらに含む。EpCAM結合ドメインを含むProCARのための例示的な配列は、配列番号485-491、または、配列番号485-491から選択される配列と少なくとも約75%~100%同一、例えば、約75%、約80%、約85%、約90%、約91%、約92%、約93%、約94%、約95%、約96%、約97%、約98%、約99%、あるいは100%同一の配列において提供される。
本開示の条件付きで活性なキメラ抗原受容体、T細胞受容体融合タンパク質、およびT細胞受容体は、真核細胞膜に挿入するための膜貫通ドメインを含む。いくつかの実施形態では、膜貫通ドメインは、EpCAM結合ドメインと細胞内ドメインとの間に挿入される。いくつかの実施形態では、膜貫通ドメインは、EpCAM結合ドメインと共刺激ドメインとの間に挿入される。
場合によっては、本開示の条件付きで活性なキメラ抗原受容体、T細胞受容体融合タンパク質、およびT細胞受容体は、ヒンジ領域(本明細書では「スペーサー」とも呼ばれる)を含み、ここで、ヒンジ領域は、EpCAM結合ドメインと膜貫通ドメインとの間に挿入される。場合によっては、ヒンジ領域は、免疫グロブリン重鎖ヒンジ領域である。場合によっては、ヒンジ領域は、受容体に由来したヒンジ領域ポリペプチドである(例えば、CD8由来のヒンジ領域)。
一実施形態では、本開示は、条件付きで活性なキメラ抗原受容体(CAR)を提供する。CARは一般に、標的抗原結合ドメイン、膜貫通ドメイン、および細胞内シグナル伝達ドメインを含む、複数のドメインを含む。本開示の条件付きで活性なCARは、結合部分、EpCAMに結合する標的抗原結合ドメイン、膜貫通ドメイン、および細胞内シグナル伝達ドメインを含む、複数のドメインを含む。いくつかの実施形態では、細胞内シグナル伝達ドメインは、限定されないが、ZAP70、CD3ゼータ、および4-1BBを含む、タンパク質のシグナル伝達ドメインである。
一実施例では、本開示は条件付きで活性なT細胞受容体融合タンパク質を提供する。本明細書で使用される場合、「T細胞受容体(TCR)融合タンパク質」または「TFP」は、典型的に、T細胞の表面中またはその表面上で同時に配置される時、一般に、i)標的細胞上の表面抗原に結合すること、およびii)無傷のTCR複合体の他のポリペプチド成分と相互作用すること、ができるTCRを含む様々なポリペプチドに由来する組換えポリペプチドを含む。
一実施形態では、本開示は、条件付きで活性なT細胞受容体を提供する。T細胞受容体は一般に、アルファ、ベータ、デルタ、ガンマ、イプシロン、およびゼータのサブユニットを含む、複数のサブユニットを含む。本開示の条件付きで活性なT細胞受容体は結合部分を含む。いくつかの実施形態では、結合部分は、限定されないが、アルファサブユニット、ベータサブユニット、またはそれらの組み合わせを含む、T細胞受容体サブユニットに結合される。
一実施形態では、本開示は、本開示のキメラ抗原受容体または条件付きで活性なキメラ抗原受容体、条件付きで活性なT細胞受容体融合タンパク質、あるいは条件付きで活性なT細胞受容体を含む、細胞を提供する。細胞は哺乳動物細胞であってもよい。
本開示は、条件付きで活性なキメラ抗原受容体、T細胞受容体融合タンパク質、またはT細胞受容体を含む細胞を生成する方法を提供する。方法は一般に、本開示の条件付きで活性なキメラ抗原受容体、T細胞受容体融合タンパク質、あるいはT細胞受容体をコードするヌクレオチド配列を含む哺乳動物細胞を、発現ベクターまたはRNA(例えば、インビトロで転写されたRNA)を用いて、遺伝子的に改変する工程を含む。遺伝子変化は、インビトロで、エクスビボで、エクスビボで実行することができる。細胞は、例えば、免疫細胞(例えば、Tリンパ球またはNK細胞)、幹細胞、あるいは前駆細胞であってもよい。
いくつかの実施形態では、T細胞源は対象から得られる。「対象」という用語は、本開示全体にわたり使用されるとき、免疫応答が誘発される場合のある生体(例えば哺乳動物)を含むように意図される。対象の例として、ヒト、イヌ、ネコ、マウス、ラット、およびそれらのトランスジェニック種が挙げられる。T細胞は、同種異系T細胞(例えば同種異系ドナー由来のCAR T細胞)、ナチュラルキラー細胞(例えば、ドナー由来のナチュラルキラー細胞)、末梢血単核球、骨髄、リンパ節組織、臍帯血、胸腺組織、感染症の部位からの組織、腹水、胸水、脾臓組織、および腫瘍を含むがこれらに限定されない多数の源から得ることができる。本開示のある実施形態では、当該技術分野で利用可能な任意数のT細胞が使用されてもよい。本開示のある実施形態では、T細胞は、FICOLL(商標)分離など当業者に知られる任意数の技法を用いて対象から採取される一単位の血液から得ることができる。一実施形態では、個体の循環血液からの細胞は、アフェレーシスにより得られる。アフェレーシス産物は一般的に、T細胞、単球、顆粒球、B細胞、他の有核白血球、赤血球、および血小板を含むリンパ球を包含している。一実施形態では、アフェレーシスにより採取される細胞は、血漿分画を取り除き、その後の処理工程のために適切な緩衝液または培地に細胞を配するために洗浄される。本開示の一実施形態では、細胞はリン酸緩衝生理食塩水(PBS)により洗浄される。代替的な実施形態では、洗浄溶液はカルシウムを欠いており、かつ、マグネシウムを欠く場合があるか、またはすべてではないが多くの二価のカチオンを欠く場合がある。カルシウムがない場合、最初の活性化工程は、活性化の拡大を生じさせる場合がある。当業者が容易に理解するように、洗浄工程は、製造業者の指示に従い、半自動化「フロースルー」遠心分離機(例えば、Cobe 2991細胞プロセッサ、Baxter CytoMate、またはHaemonetics Cell Saver 5)を用いるなどにより、当業者に知られる方法により達成することができる。洗浄後、細胞は、様々な生体適合性の緩衝液、例えばCaを含まないPBS、Mgを含まないPBS、PlasmaLyte A、あるいは緩衝液を含むか含まない他の食塩水中で再懸濁されてもよい。代替的に、望ましくないアフェレーシス試料の構成要素は取り除かれてもよく、細胞は培養培地に直接再懸濁される。
T細胞は、一般的に例えば米国特許第6,352,694号、6,534,055号、6,905,680号、6,692,964号、5,858,358号、6,887,466号、6,905,681号、7,144,575号、7,067,318号、7,172,869号、7,232,566号、7,175,843号、5,883,223号、6,905,874号、6,797,514号、6,867,041号、および米国特許出願公報第20060121005号に記載されるような方法を用いて活性化および拡張することができる。
本明細書に記載されるEpCAM結合タンパク質は、EpCAM結合ドメイン(例えば本開示のEpCAM結合sdAb)およびEpCAMを標的とする多特異性タンパク質(例えば、本明細書に記載されるようなEpCAMを標的とする三重特異性または三重特異性促進タンパク質)を含むものであり、(i)アミノ酸が、遺伝子コードによりコードされたもので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他の化合物と融合し、あるいは(iii)追加のアミノ酸が、リーダー配列、分泌配列、またはタンパク質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またはアナログを包含している。
また、いくつかの実施形態では、本明細書に記載されるEpCAM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。いくつかの実施形態では、ポリヌクレオチド分子はDNA構築物として提供される。他の実施形態では、ポリヌクレオチド分子はメッセンジャーRNA転写物として提供される。
いくつかの実施形態では、本明細書に記載されるEpCAM結合タンパク質、EpCAM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、またはこのベクターおよび少なくとも1つの薬学的に許容可能な担体により形質転換される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」は、成分の生物学的活性の有効性に干渉せず、投与対象である患者に対して毒性ではない任意の担体を含むが、これに限定されるものではない。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、様々な種類の湿潤剤、無菌液などを含む。このような担体は、従来の方法により製剤化することができ、適切な用量で対象に投与可能である。好ましくは、組成物は無菌である。これら組成物は、防腐剤、乳化剤、および分散剤などのアジュバントをさらに包含していてもよい。微生物作用の予防は、様々な抗菌剤および抗真菌剤を包含することにより確実となり得る。さらなる実施形態は、凍結乾燥形態で包装される、または水性媒体に包装される上述のEpCAM結合タンパク質のうち1つ以上を提供する。
ある実施形態では、対象におけるEpCAMを発現する悪性細胞に関連する疾病を処置する方法も提供され、該方法は、本開示のEpCAM結合ドメインまたは該EpCAM結合ドメインを含む多特異性タンパク質(任意選択で活性な多特異性タンパク質を含む)、本明細書に記載されるようなEpCAM結合タンパク質を含むCARまたはProCAR、あるいはこれらを含む医薬組成物を有効量で、必要とする対象に投与する工程を含む。いくつかの実施形態では、前記疾病は癌である。
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本開示の他の実施形態に従い、in vitroまたはin vivoでEpCAMの発現を検出するためのキットが提供される。このキットは、前述のEpCAM結合タンパク質(例えば、標識された抗EpCAM単一ドメイン抗体またはその抗原結合フラグメントを含有するEpCAM結合タンパク質)、および標識を検出するための1つ以上の化合物を含む。いくつかの実施形態では、標識は、蛍光標識、酵素標識、放射性標識、核磁気共鳴活性標識、発光標識、および発色団標識からなる群から選択される。
実施例1から選択した抗EpCAM重鎖の単一ドメイン抗体のみを、組換えタンパク質の発現のためにDNA構築物へとクローニングした。これら発現構築物はすべて、シグナルペプチドをコードした。一組の抗EpCAM構築物(配列番号153~179)を、成熟分泌融合タンパク質のN末端上でヒト化抗CD3 scFvドメイン、続いてラマ抗EpCAMドメイン、配列GGGGSGGGSにより連結される2つのドメイン、およびC末端上でHHHHHHHを伴う融合タンパク質を発現するようにデザインした。もう一組の抗EpCAM構築物(配列番号180~1206)を、成熟分泌融合タンパク質のN末端上でラマ抗EpCAMドメイン、続いてヒト化抗CD3-scFvドメイン、配列GGGGSGGGSにより連結される2つのドメイン、およびC末端上でHHHHHHHを伴う融合タンパク質を発現するようにデザインした。
そのCDR配列をヒト生殖系列配列抗体の上にグラフトし、一方で一部のラマフレームワーク配列を保持して抗体が確実に活性を失わないようにすることにより、実施例1で特定したラマ抗EpCAM抗体配列のうち3つをヒト化した(配列番号207~209)。
本開示のEpCAMを標的とする融合タンパク質(例えば、抗EpCAM重鎖の単一ドメイン抗体のみ、抗CD3 scFv、および抗アルブミンドメインを含む三重特異性タンパク質である融合タンパク質)を、異種移植片モデルを対象に評価する。in vivoで例示的なEpCAMを標的とする融合タンパク質の有効性を求めるために、複数の異種移植片腫瘍モデルを使用する。異種移植片腫瘍試験に使用する一般的な腫瘍細胞株の例として、A549(非小細胞肺癌)細胞、DU-145(前立腺)細胞、MCF-7(乳房)細胞、Colo205(結腸)細胞、3T3/]GF-IR(マウス線維芽細胞)細胞、NCI H441細胞、HEP G2(幹細胞)細胞、MDA MB 231(乳房)細胞、HT-29(結腸)細胞、MDA-MB-435s(乳房)細胞、U266細胞、SH-SYSY細胞、Sk-Mel-2細胞、NCI-H929、RPM18226、およびA431細胞が挙げられる。免疫欠損NOD/SCIDマウスに対し亜致死的に照射し(2Gy)、1X106腫瘍細胞(例えばNCI H441細胞)を右背側脇腹に皮下接種する。腫瘍が100~200mm3に達したとき、マウスを3つの治療群に割り付ける。群2と3には、1.5x107の活性化ヒトT細胞を腹腔内注射する。三日後、群3の動物に、続いて例示的なEpCAMを標的とする三重特異性抗原結合タンパク質を投与する。群1と2には溶媒のみを投与する。体重と腫瘍体積を、例示的なEpCAMを標的とする三重特異性タンパク質の投与後少なくとも5日後から開始して30日間判定する。
本試験は、上皮性卵巣癌に対する処置として本開示の例示的なEpCAMを標的とする三重特異性抗原結合タンパク質を試験するための第I/II相臨床試験である。
1.1 最大耐用量(MTD)は本試験の第I相項目において求める。
1.2 選択基準を満たす患者を、先の実施例のEpCAMを標的とする三重特異性タンパク質に対する試験に登録する。
1.3 目標は、参加者に重度または管理不能な副作用を生じさせることなく安全に投与することができる先の実施例のEpCAMを標的とする三重特異性タンパク質の最高用量を特定することである。投与する用量は、以前に試験に登録した参加者の数、およびその用量が忍容される程度に左右される。すべての参加者が同じ用量の投与を受けるわけではない。
2.1 その後の第II相項目は、例示的なEpCAMを標的とする三重特異性タンパク質の治療薬を用いた治療が少なくとも20%の奏効率をもたらすかどうかを目標として、MTDで処置を行う。
第II相の主要アウトカム---EpCAMを標的とする三重特異性タンパク質の治療により、患者の少なくとも20%が臨床応答(芽細胞応答(blast response)、軽度応答、部分応答、または完全応答)を達成するかどうかを求める。
・組織学的または細胞学的に上皮性卵巣癌を確認した患者。過去にわずか1つの白金ベースのレジメン療法による第一線の白金ベースの化学療法が失敗した後、再発上皮性卵巣癌または疾患進行の可能性がある患者。
・骨髄機能、腎機能、肝機能、および心エコー検査の検査値が十分な患者。
構築物
図6:本明細書で提供するEpCAMバインダ配列を使用して、以下のProCAR構築物を作製した。抗ヒトEpCAM sdAb、FLAGエピトープ、CD8ヒンジ/膜貫通ドメイン、4-1BB細胞内ドメイン、およびCD3ゼータ細胞内ドメイン(配列番号485)を含む例示的な構築物。抗ヒト血清アルブミンsdAb、抗ヒトEpCAM sdAb、FLAGエピトープ、CD8ヒンジ/膜貫通ドメイン、4-1BB細胞内ドメイン、およびCD3ゼータ細胞内ドメイン(配列番号486)を含む例示的な構築物。抗ヒト血清アルブミンsdAb、抗ヒトEpCAM sdAb、FLAGエピトープ、CD8ヒンジ/膜貫通ドメイン、4-1BB細胞内ドメイン、およびCD3ゼータ細胞内ドメイン(配列番号487)を含む例示的な構築物。抗ヒト血清アルブミンsdAb、抗ヒトEpCAM sdAb、FLAGエピトープ、CD8ヒンジ/膜貫通ドメイン、4-1BB細胞内ドメイン、およびCD3ゼータ細胞内ドメイン(配列番号488)を含む例示的な構築物。抗ヒト血清アルブミンsdAb、プロテアーゼ切断部位3、抗ヒトEpCAM sdAb、FLAGエピトープ、CD8ヒンジ/膜貫通ドメイン、4-1BB細胞内ドメイン、およびCD3ゼータ細胞内ドメイン(配列番号489)を含む例示的な構築物。抗ヒト血清アルブミンsdAb、プロテアーゼ切断部位3、抗ヒトEpCAM sdAb、FLAGエピトープ、CD8ヒンジ/膜貫通ドメイン、4-1BB細胞内ドメイン、およびCD3ゼータ細胞内ドメイン(配列番号490)を含む例示的な構築物。抗GFP sdAb、FLAGエピトープ、CD8ヒンジ/膜貫通ドメイン、4-1BB細胞内ドメイン、およびCD3ゼータ細胞内ドメイン(配列番号491)を含む例示的な構築物。
健康なドナーから単離した300,000個の一次ヒトT細胞に、図6に示した構築物から作製したレンチウイルス上清1mLを感染させ、抗EpCAM CAR-T細胞を生成した。次いでこの細胞を、示した二次抗体とともに抗FLAG抗体およびEpCAM-Fcにより染色した。データをフローサイトメトリーにより解析した。図7は、抗FLAG染色に基づき低(図7A)、中程度(図7B)、または高(図7C)CAR発現にグループ分けされたCAR-T細胞のEpCAM-Fc/Alexa Fluor647染色のヒストグラムを提供する。
健康なドナーから単離した300,000個の一次ヒトT細胞に、図21に示した構築物から作製したレンチウイルス上清1mLを感染させ、抗EpCAM CAR-T細胞を生成した。次いでこの細胞を、示した二次抗体とともに抗FLAG抗体およびEpCAM-Fcにより染色した。データをフローサイトメトリーにより解析した。
健康なドナーから単離した300,000の一次ヒトT細胞に、図1の示された構築物から作製したレンチウイルス上清1mLを感染させ、抗EpCAM CAR-T細胞を生成した。続いてこの細胞を、ルシフェラーゼを安定して発現するEpCAM発現癌細胞との種々の比(CAR-T:標的細胞)で共培養した。72時間後に癌細胞生存率の代わりとしてルシフェラーゼ活性を読み取り、抗GFP対照CAR-T細胞であるC1081に対して正常化した。
健康なドナーから単離した300,000の一次ヒトT細胞に、図6の示された構築物から作製したレンチウイルス上清1mLを感染させ、抗EpCAM CAR-T細胞を生成した。続いてこの細胞を、ヒト血清アルブミン(HSA)の有無にかかわらずルシフェラーゼを安定して発現するEpCAM発現癌細胞との種々の比(CAR-T:標的細胞)で共培養した。72時間後に癌細胞生存率の代わりとしてルシフェラーゼ活性を読み取り、抗GFP対照CAR-T細胞であるC1081に対して正常化した。
健康なドナーから単離したCD4/CD8陽性T細胞を示された構築物を発現するレンチウイルスに感染させることにより、キメラ抗原受容体発現T細胞(CAR T細胞)を生成した。図6は、使用した構築物を伴う略図を示す。Fcでタグ付けしたEpCAM細胞外ドメイン(EC D)により細胞をインキュベートした。細胞を洗浄し、未結合のFcでタグ付けしたEpCAM ESDを取り除いた。ヒトFcを認識するDyLight650にコンジュゲートされる二次抗体により細胞をインキュベートした。細胞への二次抗体の結合をフローサイトメトリーにより測定した。
健康なドナーから単離した300,000個の一次ヒトT細胞を、図1の示された構築物から作製したレンチウイルス上清1mLを感染させ、 抗EpCAM CAR-T細胞を生成した。続いてこの細胞を、PBS中で洗浄し、次いでPBSまたは組換えUPAプロテアーゼ400nMを含有するPBSを用いて室温で1時間処理し、抗マウスBV421および抗ヒトFc Alexa Fluor 647二次抗体とともに抗FLAG抗体およびEpCAM-Fcで染色し、フローサイトメトリーにより解析した。
健康なドナーから単離した300,000個の一次ヒトT細胞を、図1の示された構築物から作製したレンチウイルス上清1mLを感染させ、 抗EpCAM CAR-T細胞を生成した。続いてこの細胞を、PBS中で洗浄し、次いでPBSまたは組換えUPAプロテアーゼ400nMを含有するPBSを用いて室温で1時間処理し、抗マウスBV421および抗ヒトFc Alexa Fluor 647二次抗体とともに抗FLAG抗体およびEpCAM-Fcで染色し、フローサイトメトリーにより解析した。
本試験では、例示的なEpCAMを標的とするProTriTAC分子の忍容性を評価した。腫瘍のない7週齢でメスのNSGマウスに、試験の開始時、すなわち0日目に2×107の拡大ヒトT細胞を腹腔内注射した。2日目、マウスを様々な群に分け、リンカー配列L040を含有する例示的なEpCAMを標的とするProTriTAC分子(配列番号494)、EpCAMを標的とするTriTAC分子(配列番号492)、切断不能リンカーを含有するEpCAMを標的とするProTriTAC分子(EpCAM ProTriTAC(NCLV)(配列番号495)、および対照としてGFP TriTAC分子(配列番号493)を様々な濃度で投与することにより、処置を開始した。これらの分子は10日間かけて1日1回、0.03mg/kg、0.1mg/kg、0.3mg/kg、および1mg/kgの用量で投与した。2日目からマウスの体重を毎日記録した。図14A~14Cに示すように、切断不能リンカーを含有するEpCAMを標的とするProTriTAC分子(ProTriTAC (NCLV))とGPF TriTAC(陰性対照として使用)は、1mg/kgの最高用量であってもマウスにおいて忍容性が十分に優れていた。L040のリンカー配列を含有するEpCAM標的ProTriTAC分子は、1mg/kgの用量で忍容性が十分に優れていたが、EpCAMを標的とするTriTACは0.1mg/kgで忍容性が優れていた。このため、L040リンカー配列を含有するEpCAMを標的とするProTriTACは、EpCAMを標的とするTriTACと比較して少なくとも約10倍の忍容性改善をマウスに与えたことを観察した。
ヒト、カニクイザル、またはマウスEpCAMに対する種々の例示的なEpCAMを標的とするProTriTACタンパク質の親和性を、結合アッセイにおいて測定し、試験されたProTriTACタンパク質とヒトEpCAMとの相互作用に関する結合動力学にも着目した。結合動力学は図15A、15B、および15Cに示す。
本明細書に記載されるような例示的なEpCAM結合ドメイン、H13(配列番号207)、H90(配列番号209)、またはH90.2(配列番号497)を包含する3つの例示的なヒト化EpCAMを標的とするProTriTACタンパク質を、EpCAMを発現する結腸癌細胞HC116を用いて、T細胞依存性細胞毒性(TDCC)アッセイ(Nazarian AA,Archibeque IL,Nguyen YH,Wang P,Sinclair AM,Powers DA.2015.J Biomol Screen.20:519-27を参照)にて試験した。H90.2およびH138.2のEpCAM結合ドメイン配列は、それぞれEpCAM結合ドメイン配列H90およびH138にかなり類似していたが、フレームワーク4の第1のアミノ酸が修飾されていた(配列番号 582を参照)。具体的に、EpCAM結合ドメイン配列H90およびH138は、Asn脱アミド化を取り除くようにWGへと改質したAsn脱アミド化(NG)部位を包含しており、タンパク質安定性の面での改善(薬物の製造可能性を改善するのに都合の良い可能性が高い)が企図された。
EpCAM結合ドメインH13を包含するEpCAM ProTriTACのin vivo有効性を、確立されたHT29大腸腫瘍モデルを対象に評価し、EpCAM結合ドメインH13を包含するEpCAM TriTACと比較した。
EpCAM結合ドメインH13またはH90.2(TriTACフォーマット、ProTriTAC NCLVフォーマット、および切断可能なリンカーL040を伴うProTriTACフォーマットにある)を包含する結合タンパク質をカニクイザルに投与し、その薬物動態特性を評価した。図25Aおよび図25Bは、カニクイザルにおける試験されたタンパク質の経時的な血漿中濃度を示す。加えて、表13は薬物動態パラメータを要約する。
本試験では、EpCAM結合ドメインH90を包含する、EpCAMを標的とするTriTACタンパク質またはEpCAMを標的とするProTriTACタンパク質、あるいは対照TriTACタンパク質の様々な用量を、LoVo腫瘍モデル(結腸癌モデル)を抱えるマウスに注射した。結果を図29A~29Kに示す。ProTriTACおよびTriTACの安全性と忍容性も試験し、その結果を図30A~30Eに示す。生存率を図30A~30Bに示し、臨床化学パラメータ(ALT、AST、および総ビリルビン)を図30C、30D、および30Eに示す。全体的な結果は、ProTriTACフォーマットの忍容性は、同じLoVo腫瘍を抱えるマウスにおいてTriTACフォーマットよりも約30倍優れていたことを実証している。この観察を病理組織学的試験によりさらに裏付け、その概要を31と表14に提供する。
Claims (10)
- (a)EpCAM結合ドメインと、(b)CD3ε結合ドメインと、(c)ヒト血清アルブミンタンパク質に結合するバルク血清タンパク質結合ドメインとを含む多特異性タンパク質であって、配列番号495、498-502、569-570、572、573、575、576、577、および578のいずれか1つのアミノ酸配列を含む多特異性タンパク質。
- 前記バルク血清タンパク質結合ドメインは、リンカーを含む結合部分と、マスキング部分とを含み、ここで、前記マスキング部分は、それぞれの標的に対する前記EpCAM結合ドメインまたは前記CD3ε結合ドメインの結合をマスキングすることができる、請求項1に記載の多特異性タンパク質。
- 前記EpCAM結合ドメインは、配列番号1-38、207-209、および496-497のいずれか1つのアミノ酸配列を含む、請求項1に記載の多特異性タンパク質。
- (i)請求項1から3のいずれか1つに記載の多特異性タンパク質と、(ii)薬学的に許容可能な担体とを含む医薬組成物。
- 癌の処置を必要とする対象の癌を処置するための薬剤の製造における、請求項1から3のいずれか1つに記載の多特異性タンパク質の使用。
- 前記対象はヒトである、請求項5に記載の使用。
- 前記癌は固形腫瘍を含む、請求項5に記載の使用。
- 前記固形腫瘍は転移性である、請求項7に記載の使用。
- 前記癌は、大腸癌、前立腺癌、神経内分泌癌、甲状腺癌、非小細胞肺癌、小細胞肺癌、胃癌、卵巣癌、子宮内膜癌、膵臓癌、胆道癌、胆嚢癌、食道癌、乳癌、または腺癌を含む、請求項5に記載の使用。
- 請求項1から3のいずれか1つに記載の多特異性タンパク質の生成のためのプロセスであって、前記多特異性タンパク質の発現を可能にする条件下で、前記多特異性タンパク質をコードする1つ以上の核酸配列を含むベクターを用いて形質転換されたかトランスフェクトされた宿主を培養する工程と、培養物から生成された多特異性タンパク質を回収および精製する工程とを含むプロセス。
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US11623958B2 (en) | 2016-05-20 | 2023-04-11 | Harpoon Therapeutics, Inc. | Single chain variable fragment CD3 binding proteins |
AU2017268460B2 (en) | 2016-05-20 | 2023-12-14 | Harpoon Therapeutics, Inc. | Single domain serum albumin binding protein |
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US20240228656A1 (en) * | 2020-11-06 | 2024-07-11 | Harpoon Therapeutics, Inc. | Epcam targeting trispecific protein for treatment of cancer |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017201488A1 (en) | 2016-05-20 | 2017-11-23 | Harpoon Therapeutics, Inc. | Single domain serum albumin binding protein |
WO2018098356A1 (en) | 2016-11-23 | 2018-05-31 | Harpoon Therapeutics, Inc. | Psma targeting trispecific proteins and methods of use |
JP2018517431A (ja) | 2015-05-21 | 2018-07-05 | ハープーン セラピューティクス,インク. | 三重特異性結合タンパク質と使用方法 |
Family Cites Families (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR901228A (fr) | 1943-01-16 | 1945-07-20 | Deutsche Edelstahlwerke Ag | Système d'aimant à entrefer annulaire |
US6905680B2 (en) | 1988-11-23 | 2005-06-14 | Genetics Institute, Inc. | Methods of treating HIV infected subjects |
US6534055B1 (en) | 1988-11-23 | 2003-03-18 | Genetics Institute, Inc. | Methods for selectively stimulating proliferation of T cells |
US5858358A (en) | 1992-04-07 | 1999-01-12 | The United States Of America As Represented By The Secretary Of The Navy | Methods for selectively stimulating proliferation of T cells |
US6352694B1 (en) | 1994-06-03 | 2002-03-05 | Genetics Institute, Inc. | Methods for inducing a population of T cells to proliferate using agents which recognize TCR/CD3 and ligands which stimulate an accessory molecule on the surface of the T cells |
US5061620A (en) | 1990-03-30 | 1991-10-29 | Systemix, Inc. | Human hematopoietic stem cell |
EP1621554B2 (en) | 1992-08-21 | 2012-08-29 | Vrije Universiteit Brussel | Immunoglobulins devoid of light chains |
US7175843B2 (en) | 1994-06-03 | 2007-02-13 | Genetics Institute, Llc | Methods for selectively stimulating proliferation of T cells |
US6692964B1 (en) | 1995-05-04 | 2004-02-17 | The United States Of America As Represented By The Secretary Of The Navy | Methods for transfecting T cells |
US7067318B2 (en) | 1995-06-07 | 2006-06-27 | The Regents Of The University Of Michigan | Methods for transfecting T cells |
EP1051493A2 (en) | 1998-01-26 | 2000-11-15 | Unilever Plc | Method for producing antibody fragments |
AU2291700A (en) | 1999-01-19 | 2000-08-07 | Unilever Plc | Method for producing antibody fragments |
US7572631B2 (en) | 2000-02-24 | 2009-08-11 | Invitrogen Corporation | Activation and expansion of T cells |
IL151287A0 (en) | 2000-02-24 | 2003-04-10 | Xcyte Therapies Inc | A method for stimulation and concentrating cells |
US6867041B2 (en) | 2000-02-24 | 2005-03-15 | Xcyte Therapies, Inc. | Simultaneous stimulation and concentration of cells |
US6797514B2 (en) | 2000-02-24 | 2004-09-28 | Xcyte Therapies, Inc. | Simultaneous stimulation and concentration of cells |
AU2001268855A1 (en) | 2000-05-26 | 2001-12-03 | National Research Council Of Canada | Single-domain antigen-binding antibody fragments derived from llama antibodies |
GB0110029D0 (en) | 2001-04-24 | 2001-06-13 | Grosveld Frank | Transgenic animal |
EP1433793A4 (en) | 2001-09-13 | 2006-01-25 | Inst Antibodies Co Ltd | METHOD FOR CREATING A CAMEL ANTIBODY LIBRARY |
JP2005289809A (ja) | 2001-10-24 | 2005-10-20 | Vlaams Interuniversitair Inst Voor Biotechnologie Vzw (Vib Vzw) | 突然変異重鎖抗体 |
US7745140B2 (en) | 2002-01-03 | 2010-06-29 | The Trustees Of The University Of Pennsylvania | Activation and expansion of T-cells using an engineered multivalent signaling platform as a research tool |
GB0228210D0 (en) | 2002-12-03 | 2003-01-08 | Babraham Inst | Single chain antibodies |
KR101229731B1 (ko) * | 2003-10-16 | 2013-03-07 | 암젠 리서치 (뮌헨) 게엠베하 | 다중특이적 탈면역화된 cd3-바인더 |
US7754482B2 (en) | 2004-05-27 | 2010-07-13 | The Trustees Of The University Of Pennsylvania | Artificial antigen presenting cells and uses therefor |
LT2176298T (lt) * | 2007-05-30 | 2018-04-10 | Xencor, Inc. | Būdai ir kompozicijos, skirti cd32b ekspresuojančių ląstelių slopinimui |
EP2170960B1 (en) * | 2007-07-13 | 2015-07-29 | Bac Ip B.V. | Single-domain antigen-binding proteins that bind mammalian igg |
WO2011079283A1 (en) * | 2009-12-23 | 2011-06-30 | Bioalliance C.V. | Anti-epcam antibodies that induce apoptosis of cancer cells and methods using same |
PL391627A1 (pl) * | 2010-06-25 | 2012-01-02 | Adamed Spółka Z Ograniczoną Odpowiedzialnością | Przeciwnowotworowe białko fuzyjne |
JP2013540701A (ja) * | 2010-08-12 | 2013-11-07 | セラクローン サイエンシーズ, インコーポレイテッド | 抗赤血球凝集素抗体組成物およびその使用方法 |
WO2012158818A2 (en) * | 2011-05-16 | 2012-11-22 | Fabion Pharmaceuticals, Inc. | Multi-specific fab fusion proteins and methods of use |
JP6145088B2 (ja) * | 2011-05-21 | 2017-06-07 | マクロジェニクス,インコーポレーテッド | 脱免疫化血清結合ドメイン及び血清半減期を延長するためのその使用 |
SG11201404285VA (en) | 2012-02-22 | 2014-10-30 | Univ Pennsylvania | Compositions and methods for generating a persisting population of t cells useful for the treatment of cancer |
WO2014159915A1 (en) * | 2013-03-14 | 2014-10-02 | The Board Of Regents Of The University Of Texas System | Her3 specific monoclonal antibodies for diagnostic and therapeutic use |
JP2018503399A (ja) * | 2015-01-14 | 2018-02-08 | コンパス セラピューティクス リミテッド ライアビリティ カンパニー | 多特異性免疫調節抗原結合構築物 |
EP3430058A4 (en) * | 2016-03-15 | 2019-10-23 | Generon (Shanghai) Corporation Ltd. | MULTISPECIFIC FAB FUSION PROTEINS AND USES THEREOF |
WO2018073185A1 (en) * | 2016-10-17 | 2018-04-26 | Vetoquinol Sa | Modified antibody constant region |
JP7090347B2 (ja) * | 2017-05-12 | 2022-06-24 | ハープーン セラピューティクス,インク. | メソテリン結合タンパク質 |
EP3794044A4 (en) * | 2018-05-14 | 2022-02-16 | Harpoon Therapeutics, Inc. | DOUBLE BOND FRACTION |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2018517431A (ja) | 2015-05-21 | 2018-07-05 | ハープーン セラピューティクス,インク. | 三重特異性結合タンパク質と使用方法 |
WO2017201488A1 (en) | 2016-05-20 | 2017-11-23 | Harpoon Therapeutics, Inc. | Single domain serum albumin binding protein |
WO2018098356A1 (en) | 2016-11-23 | 2018-05-31 | Harpoon Therapeutics, Inc. | Psma targeting trispecific proteins and methods of use |
Non-Patent Citations (3)
Title |
---|
[$HARP] Harpoon Therapeutics - IPO Preview (2019.02.08), Biocapitalist [オンライン],2019年02月08日,pp.1-4,インターネットURL:https://biocapitalist.tistory.com/71 [検索日:2024/04/04] |
Cancer Treatment Reviews,2010年,Vol.36,pp.458-467,doi:10.1016/j.ctrv.2010.03.001 |
PLoS ONE,Vol.10, No.9,e0137065 (pp.1-16),doi:10.1371/journal.pone.0137065 |
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