JP7453219B2 - Pd-1単一ドメイン抗体およびその治療用組成物 - Google Patents
Pd-1単一ドメイン抗体およびその治療用組成物 Download PDFInfo
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Description
本出願は、2018年10月11日に出願された米国仮特許出願第62/744,615号、および2019年1月11日に出願された米国仮特許出願第62/791,152号の利益を主張するものであり、その内容は、参照によりその全体が本明細書に組み込まれる。
特定の実施形態では、例えば以下の項目が提供される。
(項目1)
PD-1に特異的に結合する少なくとも1つの重鎖のみの可変ドメイン(PD-1 VHHドメイン)を含む、PD-1結合ポリペプチド構築物。
(項目2)
PD-1に特異的に結合する少なくとも1つの重鎖のみの可変ドメイン(PD-1 VHHドメイン)と、PD-1以外の標的に結合する1つ以上の追加の結合ドメインと、を含む、PD-1結合ポリペプチド構築物。
(項目3)
前記少なくとも1つのVHHドメインが、配列番号268、272、273、および313からなる群から選択されるアミノ酸配列を含む相補性決定領域1(CDR1)と、配列番号278または314に記載されるアミノ酸配列を含む相補性決定領域2(CDR2)と、配列番号283または315に記載されるアミノ酸配列を含む相補性決定領域3(CDR3)と、を含む、項目1に記載のPD-1結合ポリペプチド構築物。
(項目4)
配列番号268、272、273、および313からなる群から選択されるアミノ酸配列を含む相補性決定領域1(CDR1)と、配列番号278または314に記載されるアミノ酸配列を含む相補性決定領域2(CDR2)と、配列番号283または315に記載される選択されたアミノ酸配列を含む相補性決定領域3(CDR3)と、を含む、少なくとも1つの重鎖のみの可変ドメイン(PD-1 VHHドメイン)を含む、PD-1結合構築物。
(項目5)
PD-1に特異的に結合する前記PD-1 VHHドメインが、PD-1とPD-L1との相互作用を遮断する、項目1、2、3、または4のいずれかに記載のPD-1結合ポリペプチド構築物。
(項目6)
前記1つ以上の追加の結合ドメインが、共刺激分子に結合する、項目2に記載のPD-1結合ポリペプチド構築物。
(項目7)
前記1つ以上の追加の結合ドメインが、T細胞表面マーカーに結合する、項目2に記載のPD-1結合ポリペプチド構築物。
(項目8)
前記T細胞表面マーカーが、CD8である、項目7に記載のPD-1結合ポリペプチド構築物。
(項目9)
前記T細胞表面マーカーが、CD4である、項目7に記載のPD-1結合ポリペプチド構築物。
(項目10)
前記1つ以上の追加の結合ドメインが、PD1以外の免疫チェックポイントに結合する、項目2に記載のPD-1結合ポリペプチド構築物。
(項目11)
前記1つ以上の追加の結合ドメインが、免疫細胞上の活性化受容体に結合する、項目2に記載のPD-1結合ポリペプチド構築物。
(項目12)
前記1つ以上の追加のドメインが、腫瘍関連抗原(TAA)に結合する、項目2に記載のPD-1結合ポリペプチド構築物。
(項目13)
前記1つ以上の追加の結合ドメインが、サイトカイン受容体に結合する、項目2に記載のPD-1結合ポリペプチド構築物。
(項目14)
前記ポリペプチドが、免疫グロブリンFc領域を含む、項目1、2、3、または4のいずれかに記載のPD-1結合ポリペプチド構築物。
(項目15)
前記少なくとも1つのPD-1 VHHドメインが、配列番号251~267、284、もしくは312のいずれかに記載される配列、または配列番号251~267、284、もしくは312のいずれかと少なくとも85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、もしくは99%の配列同一性を示すアミノ酸の配列を含み、PD-1に結合する、項目1、2、3、または4のいずれかに記載のPD-1結合ポリペプチド構築物。
(項目16)
前記少なくとも1つのPD-1 VHHドメインが、それぞれ配列番号268、278、および283、それぞれ配列番号272、278、および283、またはそれぞれ配列番号273、278、および283に記載されるCDR1、CDR2、およびCDR3を含む、項目1または2に記載のPD-1結合ポリペプチド構築物。
(項目17)
配列番号268、272、273、および313からなる群から選択されるアミノ酸配列を含む相補性決定領域1(CDR1)と、配列番号278または314に記載されるアミノ酸配列を含む相補性決定領域2(CDR2)と、配列番号283または315に記載されるアミノ酸配列を含む相補性決定領域3(CDR3)と、を含む、PD-1に結合する単離された単一ドメイン抗体。
(項目18)
配列番号251~267もしくは284のいずれかに記載されるアミノ酸配列、または配列番号251~267、284、もしくは312のいずれかと少なくとも85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、もしくは99%の配列同一性を示すアミノ酸の配列を含み、PD-1に結合する、項目17に記載の単離された単一ドメイン抗体。
(項目19)
前記sdAbが、配列番号251、252、253、254、255、256、257、258、259、260、261、262、263、264、265、266、267、284、または312に記載されるアミノ酸の配列を含む、項目18に記載の単離された単一ドメイン抗体。
(項目20)
項目1~4のいずれかに記載のPD-1結合ポリペプチドをコードする、ポリヌクレオチド(複数可)。
(項目21)
項目17~19のいずれかに記載の単一ドメイン抗体をコードする、ポリヌクレオチド(複数可)。
(項目22)
項目20または21に記載のポリヌクレオチドを含む、ベクター。
(項目23)
項目20もしくは21に記載のポリヌクレオチド(複数可)、または項目22に記載のベクターを含む、細胞。
(項目24)
ポリペプチドを産生する方法であって、細胞に、項目20もしくは21に記載のポリヌクレオチド(複数可)、または項目22に記載のベクターを導入することと、前記ポリペプチド構築物を産生するための条件下で前記細胞を培養することと、を含む、方法。
(項目25)
項目1~4のいずれかに記載の結合分子または項目17~19のいずれかに記載の単一ドメイン抗体を含む結合分子を含む、操作された免疫細胞であって、任意選択的に、前記結合分子が、前記細胞から分泌可能である、操作された免疫細胞。
(項目26)
項目1~4のいずれかに記載のPD-1結合ポリペプチド、項目17~19のいずれかに記載の単一ドメイン抗体、または項目25に記載の操作された免疫細胞を含む、医薬組成物。
(項目27)
対象における免疫応答を刺激または誘発する方法であって、それを必要とする対象に、項目1~4のいずれかに記載のPD-1結合ポリペプチド、項目17~19のいずれかに記載の単一ドメイン抗体、または項目25に記載の操作された免疫細胞、または項目26に記載の医薬組成物を投与することを含む、方法。
(項目28)
対象における疾患または状態を治療する方法であって、それを必要とする対象に、治療有効量の項目1~4のいずれかに記載のPD-1結合ポリペプチド、項目17~19のいずれかに記載の単一ドメイン抗体、または項目25に記載の操作された免疫細胞、または項目26に記載の医薬組成物を投与することを含む、方法。
別段の定義がない限り、本開示に関連して使用される科学用語および技術用語は、当業者によって一般的に理解される意味を有するものとする。さらに、文脈による別段の要求または別段の明示的な指示がない限り、単数形の用語は複数形を含むものとし、複数形の用語は単数形を含むものとする。様々な出典または参考文献間の定義におけるいかなる矛盾についても、本明細書に提供される定義が制御する。
(1)疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile、
(2)中性親水性:Cys、Ser、Thr、Asn、Gln、
(3)酸性:Asp、Glu、
(4)塩基性:His、Lys、Arg、
(5)鎖配向に影響を及ぼす残基:Gly、Pro、
(6)芳香族:Trp、Tyr、Phe。
PD-1に特異的に結合する少なくとも1つのVHHドメインを含有するVHH含有ポリペプチドである、PD-1結合ポリペプチドが本明細書に提供される。いくつかの実施形態では、VHHドメインは、ヒトPD-1に結合する。いくつかの実施形態では、VHHドメインは、カニクイザルPD-1に結合する。いくつかの実施形態では、VHHドメインは、マウスPD-1に結合する。いくつかの実施形態では、VHH含有ポリペプチドは、本明細書に提供されるVHHドメインの複数のコピーを組み込む。そのような実施形態では、VHH含有ポリペプチドは、同じVHHドメインの複数のコピーを組み込んでもよい。いくつかの実施形態では、VHH含有ポリペプチドは、異なっているが、同じPD-1上の同じエピトープを認識するVHHドメインの複数のコピーを組み込んでもよい。VHH含有ポリペプチドは、以下のセクションIIIに記載される任意のものを含む、様々なフォーマットでフォーマットされ得る。
本明細書において、1つ以上の追加のドメインまたは部分に直接または間接的に連結されたPD-1に特異的に結合する少なくとも1つのVHHドメインを含有するPD-1結合ポリペプチドを含有する、融合タンパク質およびコンジュゲートが提供される。いくつかの実施形態では、本開示の融合タンパク質またはコンジュゲートは、単一ポリペプチドから構成される。いくつかの実施形態では、本開示の融合タンパク質またはコンジュゲートは、2つ以上のポリペプチドから構成される。いくつかの実施形態では、本開示のPD-1結合ポリペプチドは、PD-1に特異的に結合する少なくとも1つのVHHドメインを組み込む。いくつかの態様では、PD-1結合ポリペプチドは、多価である。いくつかの実施形態では、PD-1結合ポリペプチドは、PD-1に特異的に結合するVHHドメインの2つ以上のコピー、例えば、PD-1に特異的に結合するVHHドメインの3つ以上、4つ以上、5つ以上、または6つ以上のコピーを含む。特定の態様では、PD-1結合ポリペプチドは、多重特異性である。例えば、場合によっては、1つ以上の追加のドメインは、1つ以上のさらなる抗原またはタンパク質に結合する1つ以上の追加の結合ドメインであってもよい。
本明細書に提供されるPD-1に結合する少なくとも1つのVHHドメインと、Fcドメインとを含有する融合タンパク質である、PD-1結合ポリペプチドが本明細書に提供される。いくつかの実施形態では、本明細書に提供されるPD-1結合ポリペプチドは、PD-1に結合する1、2、3、または4個のVHHドメインと、Fcドメインと、を含む。
PAPELLGGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY TLPPSRDELT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK (配列番号8)
PAPGGPSVFL FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VKFNWYVDGV EVHNAKTKPR EEQYNSTYRV VSVLTVLHQD WLNGKEYKCK VSNKALPAPI EKTISKAKGQ PREPQVYTLP PSRDELTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG SFFLYSKLTV DKSRWQQGNV FSCSVMHEAL HNHYTQKSLS LSPGK (配列番号9)
PAPPVAGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVQFNWYVD GVEVHNAKTK PREEQFNSTF RVVSVLTVVH QDWLNGKEYK CKVSNKGLPA PIEKTISKTK GQPREPQVYT LPPSREEMTK NQVSLTCLVK GFYPSDISVE WESNGQPENN YKTTPPMLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGK(配列番号10)
PAPELLGGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVQFKWYV DGVEVHNAKT KPREEQYNST FRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKT KGQPREPQVY TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESSGQPEN NYNTTPPMLD SDGSFFLYSK LTVDKSRWQQ GNIFSCSVMH EALHNRFTQK SLSLSPGK (配列番号11)
PAPEFLGGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST YRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY TLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSR LTVDKSRWQE GNVFSCSVMH EALHNHYTQK SLSLSLGK(配列番号12)
PAPELLGGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSQE DPEVQFNWYV DGVEVHNAKT KPREEQFNST YRVVSVLTVL HQDWLNGKEY KCKVSNKGLP SSIEKTISKA KGQPREPQVY TLPPSQEEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGSFFLYSR LTVDKSRWQE GNVFSCSVMH EALHNHYTQK SLSLSLGK (配列番号13)
本明細書に提供されるPD-1に特異的に結合する少なくとも1つのVHHドメインと、1つ以上のさらなる部分とを含有するコンジュゲートが、本明細書に提供される。さらなる部分は、細胞傷害性薬剤などの治療薬であってもよいか、または検出剤であってもよい。いくつかの実施形態では、部分は、標的化部分、小分子薬剤(500ダルトン未満のモル質量の非ポリペプチド薬剤)、毒素、細胞増殖抑制剤、細胞傷害性薬剤、免疫抑制剤、診断目的に好適な放射性薬剤、治療目的のための放射性金属イオン、プロドラッグ活性化酵素、生物学的半減期を延長させる薬剤、または診断用もしくは検出可能な薬剤であり得る。
PD-1に結合する少なくとも1つのVHHドメインと、1つ以上の追加の結合ドメインとを含有する多重特異性である、PD-1結合ポリペプチドが本明細書に提供される。典型的には、1つ以上の追加のドメインは、PD-1以外の第2の抗原またはタンパク質に結合する。いくつかの態様では、さらなる抗原またはタンパク質は、腫瘍上に発現される抗原、またはT細胞、例えばCD3などの免疫細胞上に発現される分子もしくは受容体、または追加の阻害受容体(例えば、CTLA-4、LAG3、TIM3、VISTA、TIGIT、SIRPα、NKG2A、B7H3、B7H4)、または活性化受容体(例えば、OX40、GITR、41BB、CD40、CD27、CD28、もしくはICOS)であり得るか、または標的細胞(例えば、CD8またはCD4)に追加の特異性を付与するためのものであり得る。いくつかの実施形態では、1つ以上の追加のドメインは、第2の抗原またはタンパク質に特異的な抗体または抗原結合断片である。いくつかの実施形態では、追加のドメインは、VHHドメインである。
いくつかの実施形態では、PD-1結合ポリペプチドは、本明細書に提供される少なくとも1つのPD-1 VHHドメイン、およびT細胞上に発現される表面分子に結合することが可能な少なくとも1つの追加の結合分子であるか、またはこれらを含む、二重特異性構築物である。いくつかの実施形態では、表面分子は、T細胞受容体複合体の構成成分などのT細胞の活性化構成成分である。特定の態様では、表面分子は、T細胞上に発現され、抗原結合分子との相互作用時にT細胞活性化を誘発することが可能である、活性化T細胞抗原である。例えば、いくつかの態様では、抗原結合分子と活性化T細胞抗原との相互作用は、T細胞受容体複合体のシグナル伝達カスケードを引き起こすことによってT細胞活性化を誘発し得る。T細胞活性化を測定するための好適なアッセイは既知であり、増殖、分化、サイトカイン分泌、細胞傷害活性、および/または1つ以上の活性化マーカーの発現を測定または評価するための任意のアッセイを含む。いくつかの実施形態では、そのようなPD-1結合ポリペプチドの、その標的である標的細胞上に発現されるPD-1、およびT細胞上に発現されるT細胞分子、例えば、活性化T細胞抗原の両方への同時またはほぼ同時の結合は、標的細胞とT細胞との間の一時的な相互作用をもたらし、それによって、T細胞の活性化、例えば、細胞傷害活性、およびその後の標的細胞の溶解をもたらし得る。
いくつかの実施形態では、PD-1結合ポリペプチドは、拘束されたT細胞係合融合タンパク質である多重特異性ポリペプチド構築物である。特定の態様では、本明細書に提供される拘束された多重特異性構築物は、CD3およびPD-1などの活性化T細胞抗原に結合する。典型的には、提供される拘束された多重特異性ポリペプチド構築物は、腫瘍関連抗原(TAA)に結合する少なくとも1つの抗原結合ドメインも含有する。本明細書に提供される拘束された多重特異性ポリペプチド構築物は、免疫グロブリンFc領域を含む少なくとも第1の構成成分と、CD3に結合する少なくとも結合ドメイン(本明細書において互換的に使用される用語である、抗CD3結合ドメインまたはCD3結合ドメインと本明細書において称される)の1つ以上のコピーを含む第2の構成成分と、第1の構成成分および第2の構成成分を結合するポリペプチドリンカーなどのリンカーと、を含む。提供される多重特異性ポリペプチド構築物において、第1および第2の構成成分のうちの一方または両方は、PD-1に結合する少なくとも1つの提供されるVHHドメインを含有し、第1および第2の構成成分のうちの一方または両方は、少なくとも1つのTAA抗原結合ドメインを含有し、これは抗原に結合すると、拘束されたCD3結合領域を実質的にCD3に結合することが可能な状態にする。
本開示の多重特異性ポリペプチド構築物は、少なくとも第1の抗原結合ドメインおよび第2の抗原結合ドメインなどの、少なくとも1つの抗原結合ドメインを含む。いくつかの態様では、抗原結合ドメイン、または抗原結合ドメインの各々は独立して、抗体もしくは抗原結合断片、天然(natural)(または天然(native))同族結合パートナー、アンチカリン(操作されたリポカリン)、Darpin、Fynomer、Centyrin(操作されたフィブロネチシンIIIドメイン)、シスチン-ノットドメイン、Affilin、Affibody、または操作されたCH3ドメインから選択される。いくつかの実施形態では、天然同族結合パートナーは、TAAの天然同族結合パートナーの細胞外ドメインもしくはその結合断片、またはTAAへの結合活性を示すそのバリアントを含む。
拘束された多重特異性ポリペプチド構築物は、免疫グロブリンFc領域を含む。概して、拘束された多重特異性ポリペプチド構築物は、各々がFcを含有するポリペプチドによって形成される二量体である。Fcポリペプチドは、上記に記載されるいずれかであり得る。特定の実施形態では、Fc領域は、異なるポリペプチドが二量体化されてヘテロ二量体をもたらすことができるヘテロ二量体化を促進するように変異または修飾されるFcドメインによって形成される。したがって、いくつかの実施形態では、二量体は、多重特異性ポリペプチド構築物の2つのポリペプチド鎖が異なるヘテロ二量体である。
拘束された多重特異性ポリペプチド構築物は、CD3結合ドメインを含む。本開示の抗CD3結合ドメインは、T細胞上のCD3またはCD3複合体のメンバーの関与を介して、T細胞を活性化する。好ましい実施形態では、本開示の抗CD3結合ドメインは、CD3εとしても既知のCD3のイプシロン鎖に特異的に結合する。本開示の抗CD3ε結合ドメインは、T細胞上のCD3εの関与を介して、T細胞を活性化する。本開示の抗CD3結合ドメインは、CD3媒介性T細胞活性化をアゴナイズ、刺激し、活性化、および/または別の方法で増強する。CD3の生物学的活性としては、例えば、T細胞活性化、およびCD3とT細胞受容体(TCR)の抗原結合サブユニットとの間の相互作用を介した他のシグナル伝達が挙げられる。例えば、本開示の抗CD3結合ドメインは、CD3媒介性T細胞活性化を部分的または完全に調節、例えば、アゴナイズ、刺激、活性化、または別の方法で増強することによって、T細胞上のCD3εの関与を介して、T細胞を完全または部分的に活性化する。
拘束された多重特異性ポリペプチド構築物は、免疫グロブリンFc領域を含有する第1の構成成分、およびCD3結合領域を含有する第2の構成成分を結合または連結するリンカーを含有する。いくつかの実施形態では、リンカーは、Fc領域がCD3結合領域のN末端にあるように、Fc領域のC末端領域の末端に位置付けられる。提供される拘束された多重特異性ポリペプチド構築物は、第1および第2の構成成分を一緒に形成する第1および第2のポリペプチドを含有する二量体などの多量体であるため、提供される構築物は、第1のポリペプチドのFc部分およびCD3結合領域を結合するリンカーと、第2のポリペプチドのFc部分およびCD3結合領域を結合するリンカーとを含むことが理解される。いくつかの実施形態では、第1のポリペプチドは、ヘテロ二量体Fc領域の第1のFcポリペプチド、リンカー、およびCD3結合領域の第1のドメイン(例えば、VH)を含み、第2のポリペプチドは、ヘテロ二量体Fc領域の第2のFcポリペプチド、リンカー、およびCD3結合領域の第2のドメイン(例えば、VL)を含む。典型的には、拘束された多重特異性ポリペプチド構築物の第1および第2のポリペプチド中に存在するリンカーは、同一である。したがって、いくつかの実施形態では、CD3結合ドメインの各ドメインは、例えば、同じリンカーなどのリンカーを介して、ヘテロ二量体FcなどのFcの反対側のポリペプチドに連結される。
本開示の拘束された多重特異性ポリペプチド構築物は、本明細書に提供されるいずれかの中からの少なくとも1つのPD-1 VHHドメインを含む。いくつかの実施形態では、PD-1 VHHドメインは、配列番号245~287、294~299、および312~315のいずれかに記載されるアミノ酸の配列を含む。
本開示の多重特異性ポリペプチド構築物は、共刺激受容体に結合する1つ以上の共刺激受容体結合領域(CRBR)を含む。いくつかの実施形態では、提供される多重特異性ポリペプチド構築物の1つ以上のCRBRは、T細胞上に発現される共刺激受容体に結合する。いくつかの実施形態では、共刺激受容体は、活性化T細胞の表面上で上方制御、誘発、または発現される。いくつかの態様では、CRBRは、共刺激受容体に結合し、共刺激受容体を刺激する。いくつかの実施形態では、多重特異性ポリペプチドのCRBRへの共刺激受容体の作動性結合は、T細胞における下流シグナル伝達を誘発して、CD3の関与後にT細胞活性化または機能性を増強または強化する。いくつかの実施形態では、いくつかの実施形態では、CRBR、またはCRBRの各々は独立して、抗体もしくは抗原結合断片、共刺激受容体の天然同族結合パートナー、アンチカリン(操作されたリポカリン)、DARPin、フィノマー、センチリン(操作されたフィブロネチシンIIIドメイン)、シスチン-ノットドメイン、アフィリン、アフィボディ、または操作されたCH3ドメインである。
いくつかの実施形態では、PD-1結合ポリペプチドは、本明細書に提供される少なくとも1つのPD-1 VHHドメイン、およびナチュラルキラー(NK)細胞上に発現されるか、またはNK細胞を動員する表面分子に結合することが可能な少なくとも1つの追加の結合分子であるか、またはこれらを含む、二重特異性構築物である。特定の態様では、多重特異性構築物は、PD-1およびNK細胞表面分子に対して二重特異性である。いくつかの実施形態では、表面分子は、CD16(FcγRIII)である。具体的には、提供される二重特異性PD-1結合ポリペプチドは、ヒトCD16aなどのヒトNK細胞上に発現されるNK活性化受容体に特異的に結合することが可能である。
いくつかの実施形態では、PD-1結合ポリペプチドは、サイトカイン-抗体融合タンパク質(PD-1 VHH-サイトカイン融合体とも呼ばれる)である、多重特異性ポリペプチド構築物である。いくつかの態様では、本明細書に提供される少なくとも1つのPD-1 VHHドメインは、インターフェロンなどの少なくとも1つのサイトカインに直接または間接的に連結される。特定の実施形態では、サイトカインは、抗増殖活性、アポトーシス活性、および/または抗ウイルス活性を示すことが可能なインターフェロンである。いくつかの実施形態では、本明細書に提供されるPD-1 VHH-サイトカイン融合体の界面は、IFNAR1および/または2から構成される受容体に結合することが可能である。様々なアッセイのいずれかを使用して、IFNAR1および/または2への結合、癌細胞の成長速度および/もしくは増殖速度の低減もしくは減少、腫瘍サイズの縮小、腫瘍の排除、または癌細胞の死の誘発(例えば、アポトーシスを介した)に対するそのような融合タンパク質の効果を評価することができる。そのようなアッセイには、PD-1を発現することが既知の様々な癌細胞株を用いたインビトロアッセイ、または動物腫瘍モデルを採用したインビボアッセイが含まれる。
本明細書に記載される提供されるPD-1結合分子のいずれかを発現する操作された細胞が、本明細書に提供される。特定の実施形態では、提供されるPD-1結合分子は、細胞から分泌される。いくつかの実施形態では、例えば、本明細書に提供される抗PD-1 VHHドメインを含有するPD-1結合分子は、シグナルペプチド、例えば、抗体シグナルペプチド、または細胞外にドメインを得るための他の効率的なシグナル配列を含む。PD-1結合分子がシグナルペプチドを含み、操作された細胞によって発現される場合、シグナルペプチドは、免疫調節タンパク質を操作された細胞によって分泌させる。概して、シグナルペプチド、またはシグナルペプチドの一部分は、分泌を伴う結合分子から切断される。PD-1結合分子は、核酸(発現ベクターの一部であり得る)によってコードされ得る。いくつかの実施形態では、PD-1結合分子は、細胞(免疫細胞、例えば、初代免疫細胞など)によって発現および分泌される。
提供されるsdAbおよびPD-1結合ポリペプチドのいずれかをコードするポリヌクレオチドを含む核酸分子が提供される。いくつかの実施形態では、提供される核酸配列、特にDNA配列は、本明細書に提供される融合タンパク質をコードする。上記の実施形態のいずれかにおいて、核酸分子はまた、PD-1結合ポリペプチドの分泌を誘導するリーダー配列をコードしてもよく、そのリーダー配列は典型的には、分泌ポリペプチド中に存在しないように切断される。リーダー配列は、天然重鎖(またはVHH)リーダー配列であってもよいか、または別の異種リーダー配列であってもよい。
本明細書に提供されるPD-1結合ポリペプチド、またはそれを発現する操作された細胞のいずれかを含有する医薬組成物が本明細書に提供される。いくつかの実施形態では、本開示の融合タンパク質などのPD-1結合ポリペプチド(本明細書において「活性化合物」とも称される)、およびその誘導体、断片、類似体、および相同体は、投与に好適な医薬組成物に組み込まれ得る。いくつかの実施形態では、本明細書に提供されるPD-1結合ポリペプチドを含有する、キメラ抗原受容体などのキメラ受容体を発現する操作された細胞は、投与に好適な医薬組成物に組み込まれ得る。
本明細書に記載されるPD-1結合ポリペプチドまたはそれを発現する操作された細胞は、様々な治療的、診断的、および予防的適応症において有用である。例えば、PD-1結合ポリペプチドまたは操作された細胞は、対象における様々な疾患および障害の治療で有用である。そのような方法および使用には、例えば、腫瘍または癌などの疾患、状態、または障害を有する対象に、分子もしくは操作された細胞、またはそれを含有する組成物を投与することを伴う、治療方法および使用が含まれる。いくつかの実施形態では、分子または操作された細胞は、疾患または障害の治療をもたらすのに有効な量で投与される。使用には、そのような方法および治療における、ならびにそのような治療方法を実施するための薬剤の調製における、PD-1結合ポリペプチドまたは操作された細胞を含有する分子の使用が含まれる。いくつかの実施形態では、方法は、PD-1結合ポリペプチドもしくは操作された細胞、またはそれを含む組成物を、疾患または状態を有するか、または有する疑いがある対象に投与することによって実施される。いくつかの実施形態では、方法は、それによって対象における疾患または状態または障害を治療する。
本開示のPD-1結合ポリペプチドまたは操作された細胞は、単独で、または他の抗癌剤などの他の治療様式と組み合わせて投与され得る。これらは、他の治療様式の前、それと実質的に同時、または後に提供され得る(すなわち、同時または連続的に)。いくつかの実施形態では、本明細書に記載される治療方法は、以下を施すことをさらに含むことができる:放射線療法、化学療法、ワクチン接種、標的腫瘍療法、CAR-T療法、腫瘍溶解性ウイルス療法、癌免疫療法、サイトカイン療法、外科的切除、クロマチン修飾、アブレーション、凍結療法、腫瘍標的に対するアンチセンス剤、腫瘍標的に対するsiRNA剤、腫瘍標的に対するマイクロRNA剤もしくは抗癌剤/抗腫瘍剤、または抗体、サイトカイン、もしくは受容体細胞外ドメイン-Fc融合体などの生物製剤。
特に以下の実施形態が提供される。
II型インターフェロンが、IFN-ガンマであるか、またはその切断断片もしくはバリアントである、実施形態19に記載のPD-1結合ポリペプチド構築物。
抗CD3抗体または抗原結合断片を含むVHおよびVLが、ヘテロ二量体Fcの反対側のポリペプチドに連結され、
第1および第2の構成成分が、リンカーによって連結され、ヘテロ二量体Fc領域が、抗CD3抗体のN末端に位置付けられ、
第1および第2の構成成分のうちの一方または両方が、腫瘍関連抗原(TAA)に結合する少なくとも1つの抗原結合ドメインを含み、
第1および第2の構成成分のうちの一方または両方が、少なくとも1つの重鎖のみの可変ドメイン(PD-1 VHHドメイン)を含む、多重特異性ポリペプチド構築物。
第1および第2のポリペプチドのうちの一方または両方が独立して、TAAに結合する少なくとも1つの抗原結合ドメイン、および少なくとも1つのPD-1 VHHドメインを含む、実施形態60に記載の多重特異性ポリペプチド構築物。
配列番号35~65のいずれかのアミノ酸配列、または配列番号35~65のいずれかと少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、もしくは99%の配列同一性を示す配列を有するVHと、
配列番号66~85および293のいずれかのアミノ酸配列、または配列番号66~85および293のいずれかと少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、もしくは99%の配列同一性を示す配列を有するVLと、を有する、実施形態60~89のいずれかに記載の多重特異性ポリペプチド構築物。
第2のポリペプチドが、少なくとも1つのPD-1 VHHドメインを含み、N末端からC末端への順序で、ヘテロ二量体Fc領域の第2のFcポリペプチド、リンカー、任意選択的に、第1のポリペプチド中に存在するのと同じリンカー、および抗CD3抗体または抗原結合断片のVHまたはVLドメインのうちの他方を含み、少なくとも1つのPD-1 VHHドメインが、Fc領域に対してアミノ末端に、かつ/またはCD3結合領域に対してカルボキシ末端に位置付けられる、実施形態60~93のいずれかに記載の多重特異性ポリペプチド構築物。
第2のポリペプチドが、N末端からC末端への順序で、ヘテロ二量体Fc領域の第2のFcポリペプチド、リンカー、任意選択的に、第1のポリペプチド中に存在するのと同じリンカー、抗CD3抗体または抗原結合断片のVHまたはVLドメインのうちの他方、およびPD-1 VHHドメインを含む、実施形態60~96のいずれかに記載の多重特異性ポリペプチド構築物。
第2のポリペプチドが、N末端からC末端への順序で、PD-1 VHHドメイン、ヘテロ二量体Fc領域の第2のFcポリペプチド、リンカー、任意選択的に、第1のポリペプチド中に存在するのと同じリンカー、および抗CD3抗体または抗原結合断片のVHまたはVLドメインのうちの他方を含む、実施形態60~95および98のいずれかに記載の多重特異性ポリペプチド構築物。
102.少なくとも1つのPD-1 VHHドメインが、配列番号284に記載される配列を含む、実施形態60~101のいずれかに記載の多重特異性ポリペプチド構築物。
第2のポリペプチドが、N末端からC末端への順序で、PD-1 VHHドメインまたはCRBRのうちの1つ、ヘテロ二量体Fc領域の第2のFcポリペプチド、リンカー、任意選択的に、第1のポリペプチド中に存在するのと同じリンカー、抗CD3抗体または抗原結合断片のVHまたはVLドメインのうちの他方、およびPD-1 VHHドメインまたはCRBRのうちの他方を含む、実施形態139~149のいずれかに記載の多重特異性ポリペプチド構築物。
II型インターフェロンが、IFN-ガンマであるか、またはその切断断片もしくはバリアントである、実施形態243に記載のPD-1結合ポリペプチド構築物。
第2のポリペプチドが、N末端からC末端への順序で、PD-1 VHHドメインまたはCRBRのうちの1つ、ヘテロ二量体Fc領域の第2のFcポリペプチド、リンカー、任意選択的に、第1のポリペプチド中に存在するのと同じリンカー、抗CD3抗体または抗原結合断片のVHまたはVLドメインのうちの他方、およびPD-1 VHHドメインまたはCRBRのうちの他方を含む、実施形態310~317のいずれかに記載の多重特異性ポリペプチド構築物。
以下の実施例は、例示の目的にのみ含まれ、本発明の範囲を限定することを意図するものではない。
ヒトPD-1を標的とする単一ドメイン抗体を、ラマおよびアルパカの免疫化を介して生成した。ラマおよびアルパカを、以下のように記載されるヒトPD-1細胞外ドメインの組み換えバージョン(ECD、配列番号286に記載されるヒトPD-1のアミノ酸25~167、例えば、UniProt番号Q15116)で免疫化した。
LDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRSAGQFQ
例示的なラクダ科由来PD-1 sdAb、18H10を、ヒトVH3-23生殖系列を足場として使用してヒト化した。溶解性、特異性、安定性、および/または親和性に寄与するラクダ科残基は、未修飾のままであった。加えて、すべてのヒト化バリアントは、Leu11Glu(L11E)の修飾、ならびにSer112Lys(S112K)およびSer113Pro(S113P)のカルボキシ末端修飾を含有し、それは、これらが、sdAbに向けられた既存のADAの認識を阻害または低減することが知られているためである(US2016/0207981に記載されるように)。
PD-1発現細胞上の精製したsdAb-Fcについて、特異性および相対親和性を評価した。293個の細胞の一過性トランスフェクションについては、FreeStyle293細胞を、新鮮なFreeStyle293発現培地中で1×106細胞/mLにおいて再懸濁した。細胞を、トランスフェクション当たり50mLに播種し、37℃において振盪器上でインキュベートしながら、トランスフェクション試薬を調製した。50μgの各トランスフェクションプラスミドを、500μLのOptiMEMに希釈した。各トランスフェクション用の別個の管において、150μgのポリエチレンイミン(PEI、75μLの2mg/mL溶液)を、500μLのOptiMEMに添加し、次いでDNA:OptiMEM溶液と1:1で混合した。DNAおよびPEIを室温で15分間複合体化した。次いで、DNA:PEI複合体を、FreeStyle293細胞の調製したフラスコに滴下し、旋回によって混合した。トランスフェクトした細胞を37℃の振盪器で一晩インキュベートし、タンパク質発現のための時間を取った。使用したトランスフェクションプラスミドは、ヒト、カニクイザル、およびマウス起源のシトリンタグ付き完全長PD1タンパク質をコードした。
フローサイトメトリーによって、活性化ヒトT細胞へのPD-1-sdAb-Fc融合タンパク質の結合を評価した。
TCR関与がルシフェラーゼレポーター遺伝子の転写をもたらすPD-1発現Jurkatエフェクターレポーター細胞株を使用して、PD-1を標的とする例示的なsdAbがPD-1とPD-L1との相互作用を遮断する能力を評価した。アッセイでは、PD-L1発現aAPC/CHOK1細胞をJurkatレポーター細胞と共培養して、TCR特異的活性化シグナルを提供すると同時に、エフェクター細胞上のPD-1の関与を通してこのシグナルを抑制した。PD-1 sdAbが抑制されたシグナルを遮断し、TCR関与を強化する能力をモニタリングした。
拘束されたCD3結合を示すジスルフィド安定化抗CD3 Fv結合領域、ヘテロ二量体Fcドメイン、Fc領域に対してアミノ末端に、かつ/またはCD3結合領域に対してカルボキシ末端に位置付けられた1つ以上のTAA抗原結合ドメイン、およびFc領域に対してアミノ末端に、かつ/またはCD3結合領域に対してカルボキシ末端に位置付けられた、PD-1に対する単一ドメイン抗体(sdAb)を含有する阻害受容体結合領域(IRBR)を含有する、多重特異性ポリペプチド構築物を生成した。場合によっては、Fc領域に対してアミノ末端に、かつ/またはCD3結合領域に対してカルボキシ末端に位置付けられた、例えば41BBに対する少なくとも1つの共刺激受容体結合領域(CRBR)を含有するように、多重特異性ポリペプチド構築物を生成した。
Claims (27)
- PD-1に特異的に結合する少なくとも1つの重鎖のみの可変ドメイン(PD-1 VHHドメイン)を含む、PD-1結合ポリペプチド構築物であって、前記PD-1 VHHドメインが、
a)配列番号268に記載されるアミノ酸配列を含む相補性決定領域1(CDR1);
配列番号278に記載されるアミノ酸配列を含む相補性決定領域2(CDR2);および
配列番号283に記載されるアミノ酸配列を含む相補性決定領域3(CDR3);
b)配列番号272に記載されるアミノ酸配列を含むCDR1;
配列番号278に記載されるアミノ酸配列を含むCDR2;および
配列番号283に記載されるアミノ酸配列を含むCDR3;
c)配列番号273に記載されるアミノ酸配列を含むCDR1;
配列番号278に記載されるアミノ酸配列を含むCDR2;および
配列番号283に記載されるアミノ酸配列を含むCDR3;または
d)配列番号313に記載されるアミノ酸配列を含むCDR1;
配列番号314に記載されるアミノ酸配列を含むCDR2;および
配列番号315に記載されるアミノ酸配列を含むCDR3
を含む、PD-1結合ポリペプチド構築物。 - PD-1以外の標的に結合する1つ以上の追加の結合ドメインを含む、請求項1に記載のPD-1結合ポリペプチド構築物。
- PD-1に特異的に結合する前記PD-1 VHHドメインが、PD-1とPD-L1との相互作用を遮断する、請求項1または2のいずれかに記載のPD-1結合ポリペプチド構築物。
- 前記ポリペプチドが、免疫グロブリンFc領域を含む、請求項3に記載のPD-1結合ポリペプチド構築物。
- 前記1つ以上の追加の結合ドメインが、共刺激分子、T細胞表面マーカー、PD1以外の免疫チェックポイント、免疫細胞上の活性化受容体、腫瘍関連抗原(TAA)、またはサイトカイン受容体に結合する、請求項2に記載のPD-1結合ポリペプチド構築物。
- 前記1つ以上の追加の結合ドメインが、T細胞表面マーカーに結合し、前記T細胞表面マーカーが、CD8、またはCD4である、請求項5に記載のPD-1結合ポリペプチド構築物。
- 前記ポリペプチドが、免疫グロブリンFc領域を含む、請求項5または6に記載のPD-1結合ポリペプチド構築物。
- 前記少なくとも1つのPD-1 VHHドメインが、配列番号251~267、284、もしくは312のいずれかに記載される配列、または配列番号251~267、284、もしくは312のいずれかと少なくとも85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、もしくは99%の配列同一性を示すアミノ酸の配列を含み、PD-1に結合する、請求項1~7のいずれかに記載のPD-1結合ポリペプチド構築物。
- a)配列番号268に記載されるアミノ酸配列を含む相補性決定領域1(CDR1);
配列番号278に記載されるアミノ酸配列を含む相補性決定領域2(CDR2);および
配列番号283に記載されるアミノ酸配列を含む相補性決定領域3(CDR3);
b)配列番号272に記載されるアミノ酸配列を含むCDR1;
配列番号278に記載されるアミノ酸配列を含むCDR2;および
配列番号283に記載されるアミノ酸配列を含むCDR3;
c)配列番号273に記載されるアミノ酸配列を含むCDR1;
配列番号278に記載されるアミノ酸配列を含むCDR2;および
配列番号283に記載されるアミノ酸配列を含むCDR3;または
d)配列番号313に記載されるアミノ酸配列を含むCDR1;
配列番号314に記載されるアミノ酸配列を含むCDR2;および
配列番号315に記載されるアミノ酸配列を含むCDR3
を含む少なくとも1つのVHHドメインを含む、PD-1に結合する単離された単一ドメイン抗体。 - 配列番号251~267、284もしくは312のいずれかに記載されるアミノ酸配列、または配列番号251~267、284、もしくは312のいずれかと少なくとも85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%、もしくは99%の配列同一性を示すアミノ酸の配列を含み、PD-1に結合する、請求項9に記載の単離された単一ドメイン抗体。
- 請求項1~8のいずれか一項に記載のPD-1結合ポリペプチドをコードする、ポリヌクレオチド。
- 請求項9または10に記載の単一ドメイン抗体をコードする、ポリヌクレオチド。
- 請求項11または12に記載のポリヌクレオチドを含む、ベクター。
- 請求項11に記載のポリヌクレオチドを含む、細胞。
- ポリペプチドを産生する方法であって、細胞に、請求項11に記載のポリヌクレオチドを導入することと、前記ポリペプチドを産生するための条件下で前記細胞を培養することと、を含む、方法。
- 請求項1~3のいずれか一項に記載のPD-1結合ポリペプチド構築物結合分子を含む結合分子を含む、操作された免疫細胞。
- 前記PD-1結合ポリペプチド構築物結合分子が、前記細胞から分泌可能である、請求項16に記載の操作された免疫細胞。
- 請求項1~8のいずれか一項に記載のPD-1結合ポリペプチド構築物を含む、医薬組成物。
- 対象における免疫応答を刺激または誘発する方法において使用するための、請求項1~8のいずれか一項に記載のPD-1結合ポリペプチド構築物を含む組成物であって、前記方法が、それを必要とする対象に、前記PD-1結合ポリペプチドを投与することを含む、組成物。
- 対象における疾患または状態を治療する方法において使用するための、請求項1~8のいずれか一項に記載のPD-1結合ポリペプチド構築物を含む組成物であって、前記方法が、それを必要とする対象に、治療有効量の前記PD-1結合ポリペプチドを投与することを含む、組成物。
- 請求項12に記載のポリヌクレオチドを含む、細胞。
- 単一ドメイン抗体を産生する方法であって、細胞に、請求項12に記載のポリヌクレオチドを導入することと、前記単一ドメイン抗体を産生するための条件下で前記細胞を培養することと、を含む、方法。
- 請求項9または10に記載の単一ドメイン抗体結合分子を含む結合分子を含む、操作された免疫細胞。
- 前記単一ドメイン抗体結合分子が、前記細胞から分泌可能である、請求項23に記載の操作された免疫細胞。
- 請求項9または10に記載の単一ドメイン抗体を含む、医薬組成物。
- 対象における免疫応答を刺激または誘発する方法において使用するための、請求項9または10に記載の単離された単一ドメイン抗体を含む組成物であって、前記方法が、それを必要とする対象に、前記単離された単一ドメイン抗体を投与することを含む、組成物。
- 対象における疾患または状態を治療する方法において使用するための、請求項9または10に記載の単離された単一ドメイン抗体を含む組成物であって、前記方法が、それを必要とする対象に、治療有効量の前記単離された単一ドメイン抗体を投与することを含む、組成物。
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