JP2023043118A - Cd47とpd-l1を標的とする組換え融合タンパク質、その調製および使用 - Google Patents
Cd47とpd-l1を標的とする組換え融合タンパク質、その調製および使用 Download PDFInfo
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Abstract
Description
本出願は、2021年9月15日に出願された中国特許出願第202111083819.5号の優先権を主張するものである。
シグナル調節タンパク質(SIRP)は、3つのファミリーメンバ、すなわち、SIRPα(CD172a)、SIRPβ(CD172b)、およびSIRPγ(CD172g)を含む膜貫通糖タンパク質である。3つのタンパク質はすべて、同様の細胞外領域を含むが、細胞内ドメインは異なる。細胞外領域は、3つの免疫グロブリン様ドメイン、1つのIg Vセット、および2つのIg Cセットドメインを含む。SIRPα(CD172a)の細胞内ドメインは、シグナル伝達および対応する細胞機能を阻害できる2つの阻害シグナリング領域を含む。SIRPβ(CD172b)およびSIRPγ(CD172g)は、いかなるシグナル伝達ドメインも有しない非常に短い細胞内領域を有する。しかしながら、SIRPβ(CD172b)は、例えばDAP12などのアダプタタンパク質を通じてシグナル伝達のために機能し得る。SIRPは主に、マクロファージ(Mφ)、樹状細胞(DC)およびニューロンにおいて発現する。
programmed death-ligand 1またはCD274としても知られているPD-L1は、組織同種移植、自己免疫性疾患および癌の発生など、一部の特定のイベントにおいて免疫系を抑制する上で主な役割を担う膜貫通タンパク質である。癌において、STAT3およびNF-κBのような転写因子間のフィードバック抑制の喪失は、局所的なPD-L1発現が増加を引き起こし得、PD-L1を標的にする薬剤を用いる全身治療の効果が制限され得る(Vlahopoulos SA, 2017)。腎細胞癌の患者からの196の腫瘍標本の解析から、PD-L1の高い腫瘍発現は、腫瘍の進行性の増加、および、死亡リスクの4.5倍の増加に関連することが分かった(Thompson RH et al., 2004)。
断片結晶化可能領域(Fc領域)は抗体の尾部領域であり、抗体のエフェクター機能、すなわち、特定の細胞受容体または他の防御タンパク質とどのように係合するかを決定するドメインである。
単一の抗原を標的にする抗体は、治療効率が限定されることが分かっている。例えば、承認されている抗PD-L1抗体、アベルマブ(BAVENCIO)の全奏効率はわずか33%である。近年、二重特異性または三重特異性な融合タンパク質が開発され、前臨床テストおよび臨床テストで有望な効果を示している。
特定の実施形態では、抗PD-L1抗体またはその抗体断片の各パラトープが、パラトープを構成する重鎖可変領域または軽鎖可変領域のN末端でCD47結合ペプチドに連結されている。
特定の実施形態では、抗PD-L1抗体またはその抗体断片の各パラトープが、パラトープを構成する重鎖可変領域のN末端でCD47結合ペプチドに連結されている。
特定の実施形態では、抗PD-L1抗体またはその抗体断片の各パラトープが、パラトープを構成する軽鎖可変領域のN末端でCD47結合ペプチドに連結されている。
まず、本明細書以下に記載されている組換えタンパク質を説明する。
IMM2520およびIMM2521の構造を図1Aおよび図1Bに示した。組換え融合タンパク質IMM2520およびIMM2521のコード配列の全長は人工的に設計された。
組換えタンパク質IMM2520およびIMM2521を製造するために、ネオマイシンの圧力選択を複数回受けたチャイニーズハムスター卵巣(CHO)細胞(ATCC,Cat# CCL-61)へ発現ベクターが電気穿孔で導入された。選択された安定した細胞は、血清を含まないBalan CD CHO Growth A培地(Irvine Scientific,Cat#94120)に適合された。タンパク質発現については、細胞は3リットルバイオリアクタに播種され、フェドバッチプロセスにおいて培養された。細胞の生存率が約80%に低下した時点で、バイオリアクターから細胞培養上清を採取し、親和性クロマトグラフィーによるタンパク質精製を行った。組換えタンパク質の純度は95%より高く、エンドチキシンの含有量は0.5U/gより低かった。
CHO-PD-L1細胞(PD-L1を過剰発現している、自社製)またはJurkat細胞(CD47を自然に発現している)を、それぞれ希釈したIMM2520、IMM2521、対照剤とともに4℃で1時間連続的に希釈した。細胞は冷たいPBSで2回洗浄され、次に、ヒトIgG-Fc(Cat#F9512、Sigma)に対するFITC結合二次抗体と共に45分間希釈された。細胞は2回洗浄され、200mlのPBSにおいて再懸濁された。次に、フローサイトメータ(Merck Millipore,Guava(登録商標) easyCyte 5HT)を使用して、細胞がFACS解析にかけられた。
1μg/mlのビオチン-hPD1-mFcタンパク質(SEQ ID NO:22)を、連続的に希釈したIMM2520、IMM2521、IMM2515およびhIgG1-Fcとそれぞれ混合し、その混合物を、CD47+またはCD47-のCHO-PD-L1細胞を含む96ウェルプレートに添加した。細胞が4℃で45分間希釈され、PBSで洗浄され、次に、4℃でさらに45分間、PE結合マウス抗ヒトCD279(Cat#557946、BD BioScience)と共に希釈した。細胞を洗浄し、200mlのPBSで再懸濁した後、hPD1-mFc-PD-L1の結合/相互作用についてFACS解析を行った。
FITC結合SIRPα-Fc(ヒトIgG1 Fcと結合した野生型ヒトSIRPα、SEQ ID NO:23)80nMを、連続的に希釈したIMM2520、IMM2521、IMM01およびhIgG1-Fcとそれぞれ混合した。この混合物を、PD-L1-またはPD-L1+ CD47-発現Raji細胞を含む96ウェルプレートに添加し、プレートを4℃で45分間希釈した。細胞をPBSで洗浄した後、SIRPα-Fc-CD47の相互作用を調べるためにFACS解析を行った。
CFSE標識Raji-PD-L1細胞(標的細胞として使用される)が、FcγRIIIaを安定的に発現するNK92MI細胞(エフェクター細胞)と、1:2の比で混合され、混合細胞は、連続的に希釈したIMM2515またはIMM2520の存在下で、5%のCO2と共に37℃で4時間培養された。次に、ヨウ化プロピジウム(PI)(Cat#P4170、Sigma)が、5μg/mlの濃度で細胞培養液に添加され、細胞培養液が、PIシグナルについてFACS解析にかけられた。ADCCによる細胞溶解の割合を以下の式に基づいて算出した:
溶解率=(IMM2515またはIMM2520で処理した%PI陽性細胞-陰性対照タンパク質で処理した%PI陽性細胞)/(100-陰性対照タンパク質で処理した%PI陽性細胞)×100
96ウェル細胞培養プレートにAna-1細胞(マウスマクロファージ細胞株、エフェクター細胞として)を1ウェルあたり1×105細胞ずつ播種し、37℃および5%CO2で16~18時間培養した。Raji-PD-L1細胞(標的細胞として)をCFSEで標識した後、それぞれ希釈したIMM2520、IMM2515、IMM01、IMM01とIMM2515との組み合わせ、およびhIgG1-Fcと45分間で連続的に希釈した。標的細胞溶液は、Ana-1細胞を含むプレートに移された(Ana-1細胞とRaji-PD-L1細胞細胞との比は1:1)。混合物は細胞培養インキュベータで2時間培養され、次に、Ana-1細胞におけるCFSEの密度について、FACSによる解析にかけられた。
5~7週齢のSCIDマウス24匹に、CT26-hPDL1/hCD47大腸癌細胞(1匹あたり2×106細胞)を右脇腹に皮下注射した。腫瘍体積が100~150mm3に達した時点で、マウスを無作為に4群に振り分け、各群6匹ずつとし、この日を0日目とした。0日目から、これらのマウスにそれぞれPBS、IMM2505(6.0mg/kg)、IMM2520(6.0mg/kg)、およびIMM01(3.0mg/kg)を週2回、4週間腹腔内注射した。4週目の終わりに投与を中止し、実験終了までマウスを観察した。PBSを投与した群では、平均腫瘍体積が3000mm3に達した時点でテストを終了したが、他の群では60日目にテストを終了した。腫瘍体積および体重は3~4日ごとに測定された。
CD47とPD-L1へのIMM2520の同時結合を検出するために、分子間相互作用装置(Probe Life,Gator)を使用した。抗ヒトIgGプローブを用いて、10μg/mlのIMM2520タンパク質を、シフトが約1.0nmになるまで捕捉した。続いて、プローブをバッファで30秒間リンスした後、結合強度が飽和レベルに達するまで、10μg/mlのPD-L1-His(図11)または10μg/mlのCD47-His溶液(図12)に移した。最後に、プローブを10μg/ml CD47-His(図11)または10μg/ml PD-L1-His溶液(図12)に120秒間移した。
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Claims (15)
- 抗PD-L1抗体またはその抗体断片と、CD47結合ペプチドとを含む、組換え融合タンパク質であって、
前記CD47結合ペプチドが前記抗体またはその抗体断片に結合し、
前記抗PD-L1抗体またはその抗体断片が、SEQ ID NO:19と少なくとも95%の配列同一性を有するアミノ酸配列を有する重鎖可変領域と、前記重鎖可変領域に連結され、FcR結合能力を有する重鎖定常領域と、SEQ ID NO:20と少なくとも95%の配列同一性を有するアミノ酸配列を有する軽鎖可変領域とを含み、
前記CD47結合ペプチドが、SEQ ID NO:2と少なくとも95%の配列同一性を有するアミノ酸配列を有するシグナル調節タンパク質(SIRP)細胞外ドメインを含み、
前記組換え融合タンパク質は、CD47およびPD-L1に同時に結合することができる
組換え融合タンパク質。 - 抗PD-L1抗体またはその抗体断片の少なくとも1つのパラトープが、前記パラトープを構成する前記重鎖可変領域または前記軽鎖可変領域のN末端で前記CD47結合ペプチドに連結されている、請求項1に記載の組換え融合タンパク質。
- 前記抗PD-L1抗体またはその抗体断片の各パラトープが、前記パラトープを構成する前記重鎖可変領域または前記軽鎖可変領域のN末端で前記CD47結合ペプチドに連結されている、請求項2に記載の組換え融合タンパク質。
- 前記重鎖定常領域が、SEQ ID NO:21に対して少なくとも95%の配列同一性を有するアミノ酸配列を含む、請求項1から3のいずれか一項に記載の組換え融合タンパク質。
- 前記抗PD-L1抗体またはその抗体断片が、リンカを介して前記CD47結合ペプチドに連結されている、請求項1から4のいずれか一項に記載の組換え融合タンパク質。
- 前記リンカが、-(Gly-Gly-Gly-Gly-Ser)3-(SEQ ID NO:4)、-(Gly-Gly-Gly-Gly-Ser)2-(SEQ ID NO:17)、または-(Gly-Gly-Gly-Ser)4-(SEQ ID NO:18)である、請求項5に記載の組換え融合タンパク質。
- SEQ ID NO:10と少なくとも95%の配列同一性を有するアミノ酸配列を有するCD47結合ペプチド-リンカ-抗PD-L1重鎖可変領域-重鎖定常領域断片と、SEQ ID NO:20と少なくとも95%の配列同一性を有するアミノ酸配列を有する抗PD-L1軽鎖可変領域とを含む、請求項1から6のいずれか一項に記載の組換え融合タンパク質。
- 前記軽鎖可変領域に連結された軽鎖定常領域をさらに含み、前記組換え融合タンパク質が、SEQ ID NO:10と少なくとも95%の配列同一性を有するアミノ酸配列を有するCD47結合ペプチドリンカ-抗PD-L1重鎖可変領域-重鎖定常領域断片と、SEQ ID NO:8と少なくとも95%の配列同一性を有するアミノ酸配列を有する抗PD-L1軽鎖可変領域-軽鎖定常領域断片とを含む、請求項7に記載の組換え融合タンパク質。
- 前記軽鎖可変領域に連結された軽鎖定常領域をさらに含み、前記組換え融合タンパク質が、SEQ ID NO:6と少なくとも95%の配列同一性を有するアミノ酸配列を有する抗PD-L1重鎖可変領域-重鎖定常領域断片と、SEQ ID NO:16と少なくとも95%の配列同一性を有するアミノ酸配列を有するCD47結合ペプチドリンカ-抗PD-L1軽鎖可変領域-軽鎖定常領域断片とを含む、請求項1から6のいずれか一項に記載の組換え融合タンパク質。
- 請求項1から9のいずれか一項に記載の組換え融合タンパク質をエンコードする核酸分子。
- 請求項10に記載の核酸分子を含む発現ベクター。
- 請求項11に記載の発現ベクターを含む宿主細胞。
- 請求項1から9のいずれか一項に記載の組換え融合タンパク質、請求項10に記載の核酸分子、請求項11に記載の発現ベクター、または請求項12に記載の宿主細胞と、少なくとも1つの薬学的に許容される賦形剤とを含む、医薬組成物。
- CD47および/またはPD-L1の過剰発現に関連する疾患の治療を必要とする対象の治療に使用するための、請求項13に記載の医薬組成物。
- 前記疾患は、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、急性リンパ性白血病(ALL)、非ホジキンリンパ腫(NHL)、多発性骨髄腫(MM)、膀胱癌、卵巣癌、前立腺癌、肺癌、大腸癌、乳癌、膵臓癌、および腎細胞癌から成る群から選択される、請求項14に記載の使用するための医薬組成物。
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RU2727914C2 (ru) * | 2015-11-17 | 2020-07-24 | Сучжоу Санкадия Биофармасьютикалз Ко., Лтд. | Антитело против лиганда 1 запрограммированной гибели клеток (pd-l1), его антигенсвязывающий фрагмент и их медицинское применение |
CN107459578B (zh) * | 2016-05-31 | 2021-11-26 | 泰州迈博太科药业有限公司 | 一种靶向cd47与pd-l1的双功能融合蛋白 |
EP3565839A4 (en) * | 2017-01-05 | 2021-04-21 | Gensun Biopharma Inc. | CHECKPOINT REGULATOR ANTAGONISTS |
CN107857819A (zh) * | 2017-07-03 | 2018-03-30 | 江苏西迪尔生物技术有限公司 | 多功能融合蛋白及其应用 |
JP7035299B2 (ja) * | 2017-10-26 | 2022-03-15 | イミューンオンコ バイオファーマシューティカルズ (シャンハイ) カンパニー リミテッド | 新規組換融合タンパク質、ならびにその調製および使用 |
US20200354458A1 (en) * | 2017-11-20 | 2020-11-12 | Taizhou Mabtech Pharmaceutical Co., Ltd. | Bifunctional Fusion Protein Targeting CD47 and PD-L1 |
KR20210028222A (ko) * | 2018-06-29 | 2021-03-11 | 젠선 바이오파마, 인코포레이티드 | 항종양 면역 체크포인트 조절 길항제 |
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CN111763261B (zh) * | 2019-04-02 | 2022-08-09 | 杭州尚健生物技术有限公司 | 一种融合蛋白及其用途 |
CN112125975B (zh) * | 2019-06-25 | 2024-03-01 | 上海翰森生物医药科技有限公司 | Pd-l1和cd47双特异性融合蛋白及其医药用途 |
CN112442132A (zh) * | 2019-09-05 | 2021-03-05 | 复旦大学 | 靶向肿瘤的重组双功能融合蛋白及其应用 |
CN113321735B (zh) * | 2021-05-20 | 2023-01-06 | 盛禾(中国)生物制药有限公司 | 一种多功能融合蛋白 |
CN113773401B (zh) * | 2021-09-15 | 2023-06-20 | 宜明昂科生物医药技术(上海)股份有限公司 | 靶向cd47和pd-l1的重组融合蛋白及其制备和用途 |
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WO2023040667A1 (zh) | 2023-03-23 |
US20230083670A1 (en) | 2023-03-16 |
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