JP2017510249A - 新規組換え二機能性融合タンパク質、それらの調製および使用 - Google Patents
新規組換え二機能性融合タンパク質、それらの調製および使用 Download PDFInfo
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- JP2017510249A JP2017510249A JP2016548031A JP2016548031A JP2017510249A JP 2017510249 A JP2017510249 A JP 2017510249A JP 2016548031 A JP2016548031 A JP 2016548031A JP 2016548031 A JP2016548031 A JP 2016548031A JP 2017510249 A JP2017510249 A JP 2017510249A
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- fusion protein
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Abstract
Description
1.SIRPαD1−Fc−VEGFR1D2発現ベクターの構築
Plg−Tail(R&D systems)が用いられた。クローニング前に、プライマー1および2によってFcコード配列を増幅させて、Fcのカルボキシル末端の停止コドンを欠失させ、PCR産物をPlg−Tail中のEcoRI/XhoI部位にクローニングすることで、plg−Tailが改変された。SIRPαD1のコード配列は、THP−1(ATCC(登録商標)TIB−202(商標))細胞からのプライマー3および4によって増幅され、VEGFR1D2のコード配列は、HUVEC(ATCC(登録商標)PCS−100−010(商標))細胞からのプライマー5および6によって増幅された。2つのPCR産物は、改変plg−Tailベクター中のHindIII/EcoRIおよびXhoI/XbaI部位にそれぞれクローン化され、このようにしてベクターpSIRPαD1−Fc−VEGFR1D2が作成された。
CHO細胞を含有する完全細胞培養液DMEM(10%FBS)が、ウェルあたり0.5mlで24ウェルプレートに添加され、プレートはインキュベーター内で24時間保たれた。形質移入のために、0.5μgのプラスミドDNAおよび2μlのリポフェクタミン2000(カタログ番号11668−027、Invitrogen)が50μlの無血清培養液に別々に溶解され、次に室温で20分間混合されて、ウェルに緩慢に添加され、インキュベーター内に24時間戻された。翌日、100μlの血清が採取されて、酵素結合免疫吸着測定法(ELISA)によるタンパク質発現試験のために使用された。
タンパク質発現試験は、以下の工程によってELISAによって実施された:抗ヒトIgGヤギ抗体F(ab')2フラグメント(Biosource International Inc)がPBSリン酸緩衝液に溶解されて、次にウェルあたり20ngで、96ウェルELISAプレート内に添加された。ELISAプレートは、4℃の冷蔵庫に一晩入れられた。試験では、プレートがブロッキング溶液(PBS、0.05%ツイーン20、3%脱脂乳)で1時間ブロックされ、次に希釈血清が添加されて室温で1時間インキュベートされた。洗浄溶液(PBS、0.05%ツイーン20)で5回の洗浄後、西洋ワサビペルオキシダーゼ(HRP)標識抗ヒトIgGウサギ抗体(Jackson ImmunoResearch Lab)が添加され、プレートが室温で1時間インキュベートされた。5回の洗浄後、HRPの基質が添加されて、2分後に停止液(1NH2SO4)を使用して、発色反応が停止された。光学濃度は、450nmで測定された。
形質移入細胞は、濃度増大圧縮抗生物質スクリーニング(Geneticin、カタログ番号10131035、Invitrogen)を受けた。不安定細胞は徐々に死滅して、生存した細胞は、ウェルあたり0.5〜1個の細胞に希釈にして、5枚の96ウェルプレートに添加された。プレートは、インキュベーターに10〜15日間入れられた。単一クローンを含有するウェルがELISAで試験され、次に陽性細胞が増殖され、無血清Ex−細胞CDCHO培養液(カタログ番号14361C−1000ML、SIGMA)を用いて習慣的に培養された。さらなるスクリーニング後、最大発現レベルに相当する細胞が選択されて、使用のために冷凍された。
安定発現細胞株(3×105/ml)が、300ml無血清培養液を含有する2L振盪フラスコに接種され、振盪フラスコは培養のために振盪床に入れられた。細胞密度が5×106/mlに達した後、本発明者らは上清を得た。上清は、プロテインAカラムによって精製された。精製タンパク質は、透析(pH7.0)によってPBSで置換された。タンパク質電気泳動分析を用いて、少なくとも98%の純度が確証された。
標的CD47およびVEGFに対するSIRPαD1−Fc−VEGFR1D2の結合親和性は、フローサイトメトリーおよびELISA法を使用して試験された。
VEGF−165をコーティング緩衝液CBS(Sigma−Aldrich Co.,製品コード:1001329288 C3041−100CAP)で1000ng/mlに希釈する;100μlの溶液をELISAプレート(カタログ番号442404、Nunc(商標))に添加する(ウェルあたり100ng);被覆プレートを4℃の冷蔵庫に一晩入れる;試験中に、被覆プレートを0.05%のPBS−Tで1回洗浄し、次に被覆プレートを3%の脱脂乳で1時間封止する;希釈SIRPαD1−Fc−VEGFR1D2(20、10、5、…0.01nM)を被覆プレートに添加する(ウェルあたり100μl);室温で1時間インキュベートした後、サンプルを廃棄し、溶液を0.05%のPBS−Tで5回洗浄する;100μlの希釈HRP−ウサギ抗ヒトIgGFcを添加する(1:20000)(カタログ番号:309−036−008、Jackson ImmunoResearch Lab);溶液を室温で1時間インキュベートする;プレートを洗浄溶液で5回洗浄する;HRP基質を添加する;暗所で発色反応を10〜20分間実施し、1NH2SO4を使用して反応を停止させる;マイクロプレートリーダー上でOD450値を得る。
SIRPαD1−Fc−VEGFR1D2が、CD47−SIRPαの結合によって誘導される食作用阻害活性をブロックし得るかどうかを試験するために、FITCCFSE標識SEM−K2細胞およびRAW264.7細胞を2:1のRAW264.7:SEM−K2比で混合する;次に混合物を6枚の新しい細胞培養プレート内で、異なる濃度を有するSIRPαD1−Fc−VEGFR1D2、SIRPαD1−Fc、およびヒトIgG−Fcと共にインキュベートする;4時間後にプレートを注意深く振盪して、懸濁SEM−K2細胞を吸引し、プレートをPBSで2回洗浄して全ての懸濁細胞を除去する;プレート壁上のRAW264.7細胞をトリプシン−EDTAにより消化して、プレートをPBSで2回洗浄する;RAW264.7細胞によるSEM−K2細胞の食作用比率をフローサイトメトリーを通じて定量的に分析する。
SIRPαD1−Fc−VEGFR1D2の生体内抗腫瘍活性が、HL−60皮下腫瘍モデルにおいて試験された。HL−60細胞株は、急性前骨髄球性白血病がある1人の患者に由来する、特徴がよく分かっている生体外ヒト白血病モデルであり[6]、薬物の治療効果のための異種移植片マウスモデルで幅広く使用されている[7−9]。20匹のBalb/cヌードマウスに、白血病(HL60)細胞(マウスあたり4×106個の細胞)が皮下注射された。腫瘍が100〜150mm3にまで増殖したら、マウスは4群に分割された:第1群には、PBSが腹腔内注射され;第2群には、VEGFR1D2−Fcが腹腔内注射され;第3群には、SIRPαD1−Fcが腹腔内注射され;第4群には、SIRPαD1−Fc−VEGFR1D2が腹腔内注射された。各グループの用量は3mg/kgであり、週2回で連続的に6回投与された。腫瘍の体積および重量は、週2回測定された。
1.SIRPαD1−Fc−VEGFR1D2発現ベクターの構築
SIRPαD1−Fc−VEGFR1D2は、ヒトIgG1のFc断片によって連結する、SIRPαの第1の細胞外ドメイン(D1)およびVEGFR1の第2の細胞外ドメイン(D2)からなる組換えFc融合タンパク質であり、MAC−01と命名される。それは、図2のAに示されるような構造を有する。SIRPαD1およびVEGFR1D2は、分子クローニングによって、それぞれN末端およびC末端に連結される。SIRPαD1−Fc−VEGFR1D2の配列は、1503ヌクレオチドを含有し(図3のA)、その中でシグナルペプチドコード配列は63ヌクレオチド(赤色)を有し、SIRPαD1は426ヌクレオチド(青色)を有し、IgG1−Fcは696ヌクレオチド(黒色)を有し、VEGFR1D2は306ヌクレオチド(緑色)を有し、EcoRI配列は6ヌクレオチドを有し、XhoI配列は6ヌクレオチドを有する。図3のBは、対応するアミノ酸配列を示す。
タンパク質電気泳動法(SDS−PAGE)を使用することで、本発明者らは、タンパク質分子量が、非還元条件下で170kDaよりも大きいことを見出し(図4)、これは理論的な値(100kDa)とかなり異なる。これは、タンパク質のグリコシル化に起因するかもしれない。
フローサイトメトリーおよびELISAを使用することで、本発明者らは、VEGF−Aに対する、SIRPαD1−Fc−VEGFR1D2の結合親和性を解析した。結果は、SIRPαD1−Fc−VEGFR1D2が、CD47(図5のA)およびVEGF−A(図5のB)のどちらでも優れており、それぞれ0.1〜1.0nM(CD47)および0.08〜0.15nM(VEGF−A)のEC50を有することを示した。
標識急性リンパ芽球性白血病細胞SEM−K2、およびマウスのマクロファージ(RAW264.7)を使用することで、本発明者らは、腫瘍細胞の食作用に対する、SIRPαD1−Fc−VEGFR1D2の効果を解析した。結果は、SIRPαD1−Fc−VEGFR1D2が、腫瘍細胞のマクロファージによる食作用を有意に強化したことを示した(図6)。効果は用量依存的であった。
HL60皮下腫瘍モデルを使用することで、本発明者らは、生体内SIRPαD1−Fc−VEGFR1D2タンパク質の抗腫瘍活性を試験した。図7に示されるように、VEGFR1D2−Fc処置群は、腫瘍増殖に対する非常に限定的な阻害効果を示し、SIRPαD1−Fc処置群は、腫瘍増殖に対する明白な阻害効果を示したが、腫瘍を排除するには十分でなかった。対照的に、SIRPαD1−Fc−VEGFR1D2による処置後、マウスは、治療開始時の100mm3からの腫瘍サイズの低下を示しながら、治療の終わりには、腫瘍はほとんど消滅していた。陰性対照群では、マウスの腫瘍体積は経時的に徐々に増大し、最終的に1000mm3に達した。実験結果は、VEGFの活性阻害だけでは、HL60腫瘍に対して有意な治療効果をもたらさないことを示し、HL60腫瘍の増殖が、VEGFにほとんど依存しないことが示唆された。腫瘍によって誘導されるマクロファージによる食作用阻害のブロックは、マクロファージによる腫瘍細胞の食作用を強化し、それによって腫瘍細胞の増殖が有意に阻害された。しかし、VEGFおよびCD47−SIRPαの双方の機能が阻害されれば、腫瘍は、完全に除外されるであろう。
上記組換えFc融合タンパク質SIRPAD1−Fc−VEGFR1D2(MAC−01)が、A549肺がん異種移植モデル上で試験された。A549細胞株は、58才の白人男性のがん性肺組織の除去と外植腫瘍中での培養を通じて、D.J.Giard,et al.によって1972年に最初に開発された[10][11]。A549異種移植マウスモデルは、多数の薬剤候補の有効性評価のために広範に利用されている[12−15]。実験データは、MAC−01が、VEGFおよびCD47の双方に同時に結合し得て、したがってそれぞれの分子媒介シグナルをブロックし得ること示した。生体内肺がん異種移植モデルで検討された場合、MAC−01は強力な抗腫瘍活性を示し、それは単一分子の組み合わせの活性よりも明確により良い。
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Claims (21)
- リンカーを介して、VEGF受容体(VEGFR)の細胞外ドメインのIg領域と連結する、シグナル調節タンパク質(SIRP)の細胞外ドメインのIg領域を含んでなる、組換え二機能性融合タンパク質であって、その中で前記タンパク質が、CD47およびVEGFに結合して、前記CD47とマクロファージ細胞表面の前記SIRPとの結合をブロックし、前記マクロファージによる腫瘍細胞の食作用を刺激して、前記VEGFによって誘導される血管内皮細胞増殖を阻害し得る、組換え二機能性融合タンパク質。
- 前記シグナル調節タンパク質がSIRPαである、請求項1に記載の組換え二機能性融合タンパク質。
- 前記シグナル調節タンパク質の細胞外ドメインのIg領域がSIRPαD1である、請求項2に記載の組換え二機能性融合タンパク質。
- 前記VEGFRがVEGFR1である、請求項1に記載の組換え二機能性融合タンパク質。
- VEGFR1のIg領域が、VEGFR1の細胞外ドメインの第2のIg領域(VEGFR1D2)である、請求項4に記載の組換え二機能性融合タンパク質。
- 前記リンカーがIgのFc断片である、請求項1に記載の組換え二機能性融合タンパク質。
- 前記Fc断片がIgG1のFc断片である、請求項6に記載の組換え二機能性融合タンパク質。
- ヒトIgG1のFc断片を介して、SIRPαの細胞外ドメインの第1のIg領域(SIRPαD1)と連結する、ヒトVEGFR1の細胞外ドメインの第2のIg領域(SIRPαD1−Fc−VEGFR1D2)を含んでなる、請求項1に記載の組換え二機能性融合タンパク質。
- 配列番号8と少なくとも80%、85%、90%、95%、98%または99%同一性のアミノ酸配列を含んでなる、請求項1に記載の組換え二機能性融合タンパク質。
- 配列番号8のアミノ酸配列を含んでなる、請求項9に記載の組換え二機能性融合タンパク質。
- 請求項9に記載の組換え二機能性融合タンパク質をコードする、ポリヌクレオチド。
- 請求項10に記載の組換え二機能性融合タンパク質をコードする、ポリヌクレオチド。
- 請求項11に記載のポリヌクレオチドを含んでなる、発現ベクター。
- 請求項12に記載のポリヌクレオチドを含んでなる、発現ベクター。
- 請求項13に記載の発現ベクターを含んでなる、宿主細胞。
- 請求項1に記載の組換え二機能性融合タンパク質と、少なくとも1つの薬剤アジュバントとを含んでなる、医薬組成物。
- 請求項に16記載の医薬組成物の治療有効量を患者または対象に投与するステップを含んでなる、CD47の過剰発現によって引き起こされる疾患を治療する方法。
- 前記疾患が、急性骨髄性白血病(AML)、慢性骨髄性白血病(CML)、急性リンパ芽球性白血病(ALL)、非ホジキンリンパ腫(NHL)、多発性骨髄腫(MM)、膀胱がん、卵巣がん、前立腺がん、肺がん、結腸がん、乳がん、膵臓がん、および腎細胞がんの群から選択される、請求項17に記載の方法。
- 前記疾患が、クローン病、アレルギー性喘息、および関節リウマチの群から選択される、請求項18に記載の方法。
- 請求項16に記載の医薬組成物の治療有効量を患者または対象に投与するステップを含んでなる、VEGF機能および活性の亢進によって引き起こされる疾患を治療する方法。
- 前記疾患が、加齢黄斑変性、AMD、糖尿病性網膜症、肝臓線維症、および血管肉腫から選択される、請求項20に記載の方法。
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JP6355032B2 (ja) | 2018-07-11 |
WO2015148416A1 (en) | 2015-10-01 |
EP3122783B1 (en) | 2019-09-04 |
US9527901B2 (en) | 2016-12-27 |
US20150266942A1 (en) | 2015-09-24 |
KR102314088B1 (ko) | 2021-10-15 |
CN106459218A (zh) | 2017-02-22 |
CN106459218B (zh) | 2021-03-02 |
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