JP2018148897A - SIRPアルファ−Fc融合体でのCD47+疾患細胞の治療 - Google Patents
SIRPアルファ−Fc融合体でのCD47+疾患細胞の治療 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
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- Public Health (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Cell Biology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
る。これは、間接的に、まずタンパク質および試験細胞を融合タンパク質とインキュベーションし、そして次いで、融合タンパク質に結合する検出可能な剤で探査する(probing)ことによって間接的に、または標識型で融合タンパク質を提供することによって、直接、達成することも可能である。
表1
以下に示すプライマーを用いて、3段階クローニングプロセスによって、SIRPαFc構築物を生成した:
TTI−602:プライマーP#5863およびP#5929;最初の融解94℃5分間、その後、94℃1分間、56℃2分間、および68℃2分間からなる30周期。
TTI−602:プライマーP#5930およびP#1035;最初の融解94℃5分間、その後、94℃1分間、56℃2分間、および72℃2分間からなる30周期。
TTI−602:プライマーP#5863およびP#1035を用いて、94℃1分間および56℃3分間で10周期、その後、94℃1分間、55℃2.5分間、および72℃3分間の30周期。
CHO−S細胞株(Invitrogen)を用いて、安定トランスフェクタントを生成した。簡潔には、単離したプラスミドDNAを、XbaI(New England BioLabs)によって直線化し、そしてQIAGENカラム(Qiagen)を用いて精製した。8mM L−グルタミンおよび1xHT補充剤を補充した、血清不含で化学的に定義された培地(CD−CHO、Invitrogen)中で増殖させたCHO−S細胞を、Lipofectamine 2000試薬(Invitrogen)を用いて、直線化プラスミドでトランスフェクションした。48時間後、細胞を96ウェルプレートに移し、そして600μg/mLのハイグロマイシンB(Invitrogen)を含有する培地中、異なる濃度(10000、5000、または2000細胞/ウェル)でプレーティングした。混合物にDNAを添加せず、同一の方式で、偽トランスフェクション対照を行った。トランスフェクションの2〜3週後、薬剤耐性オリゴクローンパネルを摘み取り、そして48時間の発現研究由来の上清を、以下のように、ELISAによってスクリーニングした: 96ウェルプレートを、0.1μg/ウェルの捕捉Ab(ヤギ抗ヒトIgGFc)でコーティングし、そして4℃で一晩インキュベーションした。ウェルを洗浄し、そして200μlのPBST中の2%BSAで室温で1時間ブロッキングした。洗浄後、100μlの試料をPBST中の1%BSAで希釈し、ウェルに添加し、1時間インキュベーションし、洗浄し、そして次いで、HRPコンジュゲート化検出Ab(HRPコンジュゲート化ヤギ抗ヒトIgGFc)と室温で1時間インキュベーションした。次いで、ウェルを洗浄し、そしてTMB基質(Moss Inc.)を添加し、そして室温で3〜5分間インキュベーションした。iMarkマイクロプレート読み取り装置(Biorad)を用いて、450nm/655nm波長で吸光度を測定し、そして既知の量の精製融合タンパク質を用いて、標準曲線を構築した。3つの最高発現オリゴクローンの第二の限界希釈を、600μg/mlのハイグロマイシンBを含有する完全CD−CHO培地中、より低い細胞濃度(0.1、0.25、および0.5細胞/ウェル)で行った。2〜3週後、薬剤耐性クローンを、上述のようなELISAによって、組換えタンパク質産生に関して再び評価した。生産性をpg/細胞/日で表し、そしてこれは、ヒトSIRPα融合タンパク質に関しては、1.4〜23.9pg/細胞/日の範囲であった。最高に発現している単一細胞クローンを、WAVEバイオリアクター系において、上清バッチ産生のために用いた。いくつかの例において、単一クローン段階に到達する前に、最適オリゴクローンを産生に用いた。
小ロットタンパク質の迅速産生のため、一過性トランスフェクション293F細胞において、いくつかのSIRPα−Fcバッチを作製した。簡潔には、FreeStyle 293F細胞(Invitrogen)を、293F培地(Invitrogen)中で増殖させ、非直線化プラスミドDNAおよび293Fectin試薬(Invitrogen)でトランスフェクションし、そして体積80〜100mL/フラスコ中、37℃、5%CO2で3〜6日間、振盪装置フラスコバッチ中で増殖させた。細胞生存度が〜90%に低下するまで、細胞密度および生存度を毎日監視した。バッチ採取物の細胞生存度は、85〜90%の範囲であった。
SIRPαは、3つの細胞外免疫グロブリン(Ig)様ドメインからなるが、CD47への結合は、N末端ドメインに局在化される。SIRPαFc融合体のための最適なSIRPα領域を決定するため、本発明者らは、3つすべての細胞外SIRPαドメイン(TTI−602)または単一のN末端ドメイン(TTI−616)のいずれかを取り込むタンパク質を生成した。
単一SIRPαドメインを取り込む融合タンパク質に関する優先性が確立されたため、最適Fc領域を決定するための研究を行った。同じSIRPα領域(31〜148)を含有するが、多様なエフェクター活性を有する異なるFc構成要素上に構築される、3つの異なるヒトSIRPαFc融合体を生成した。設計詳細を以下の表2に要約する。注釈付きのDNAおよびタンパク質配列を付録1に示す。
3つのSIRPαFc融合体を、細胞表面ヒトCD47に対する結合に関して比較した。簡潔には、CD47+ヒトJurkat細胞を、多様な濃度(示す通り)のhSIRPαFcタンパク質と氷上で1時間インキュベーションした。次いで、細胞を洗浄して、いかなる未結合タンパク質も除去し、そして次いで、抗hIgG Fcg特異的(Fab’)2 FITC抗体と氷上で1時間インキュベーションした。次いで、細胞を洗浄し、そして2%パラホルムアルデヒド溶液と一晩インキュベーションすることによって、固定した。次いで、固定溶液を洗い流し、そして細胞をフローサイトメトリー(BD FACScan)によって分析した。次いで、幾何平均を規準化し、そして、一部位結合モデルにデータを適合させる非線形回帰を用いて、Prism(Graphpad)によって、結合曲線およびKd値を生成した。
SIRPαFcによるCD47の遮断は、活性化ヒトマクロファージによるヒト急性骨髄性白血病(AML)腫瘍細胞の食作用を増進する。3つの融合タンパク質の食作用促進活性をin vitroで比較して、Fc領域がAML食作用に影響を及ぼすかどうかを決定した。磁気選択を用いて、Ficoll精製ヒト末梢血単核細胞からCD14+単球をまず単離することによって、ヒトマクロファージを生成した。20ng/mlでヒト単球コロニー刺激因子を含有するX−vivo培地中で、少なくとも1週間、単球を培養して、マクロファージへの発生を促進した。次いで、マクロファージを24ウェル培養プレート中で、ガラススライド上にプレーティングし、そしてヒトインターフェロンガンマと一晩インキュベーションした。翌日、ウェルを洗浄し、そしてLPSを少なくとも1時間添加した。ヒトAML細胞を計数し、そしてCFSEで標識した。標識後、AML細胞を、PBS、SIRPαFcタンパク質またはアイソタイプ対照と、室温(RT)で15分間インキュベーションした。次いで、AML細胞を個々のウェルに添加し、混合し、そして37℃、5%CO2加湿細胞インキュベーター中で、2時間、インキュベーションした。インキュベーション後、ウェルを洗浄し、そしてマクロファージを小麦胚芽凝集素Alexa Fluor(登録商標)555コンジュゲート(Invitrogen、カタログ番号W32464)で、RTで15分間振盪しながら標識した。次いで、ウェルを洗浄し、そして2%パラホルムアルデヒドで、RTで30分間固定した。次いで、ウェルを洗浄し、そして暗所、4℃で一晩維持した。走査型共焦点顕微鏡(Quorum Wave FX−X1回転ディスク共焦点系、Quorum Technologies、カナダ・オンタリオ州グェルフ)によって、ガラススライドを分析した。以下のように、食作用インデックスを用いて、AML細胞の食作用を定量化した:(マクロファージ内部のAML細胞/マクロファージ数)x100;試料あたり少なくとも200のマクロファージを計数。図3に示すように、TTI−621およびTTI−622は、類似の食作用活性を示し、一方、TTI−616は明らかにより弱い(これは特に、10nM用量で明らかである)。これは、マクロファージによる最大SIRPαFc誘発腫瘍細胞殺傷には、野生型IgG4またはIgG1 Fc領域のいずれかが必要であることを示す。
標準的異種移植モデルにおいて、ヒトAML腫瘍細胞の増殖を制御する能力に関して、3つのSIRPαFc融合タンパク質を試験した。NOD/ShiLtJ−Prkdcscid(NOD.SCID)マウス(8〜12週齢)を、137Cs γ−照射装置から275cGyで致死量以下に照射した後、ヒト白血病患者から収集したAML細胞を大腿内注射した。移植3週後から開始して、マウスをSIRPαFc融合タンパク質(週あたり3回の8mg/kg IP)、あるいは等モル用量の対照Fcタンパク質TTI−401(突然変異ヒトIgG4)またはTTI−402(ヒトIgG1)で治療した。治療4週後、マウスを屠殺し、そして注射した大腿、注射していない骨髄および脾臓内のヒト白血病細胞を、ヒトCD45およびヒトCD33マーカーの発現に関して染色してフローサイトメトリー分析によって検出した。AML生着は、各区画におけるヒトCD45+CD33+細胞の割合として表した。
健康なドナー由来のヘパリン処理全血を用いて、ヒト赤血球を調製した。4mLの全血を15mLコニカル試験管中にピペッティングし、リン酸緩衝生理食塩水(PBS)を重層し、そして200xg、室温で10分間遠心分離して、血小板を除去した。血小板分画を吸引した後、試験管に15mLまでPBSを重層し、試験管を反転させることによって、内容物をよく混合し、そしてRBCを1500rpm、5分間の遠心分離によって、充填させた。この洗浄をさらに3回反復した。最終洗浄後、上清を吸引し、そして十分なPBSを添加して、充填された赤血球が10%RBC溶液となるようにした(例えば、1mLの充填RBCが得られた場合、これらを9mL PBSでさらに希釈して、10%RBC溶液を作製した)。4℃で保存した10%RBC溶液は、1週間以内に使用可能であった。赤血球凝集アッセイ直前に、新鮮な1%RBC溶液を作製した。
ヒトJurkat T細胞クローンE6−1をATCC(カタログ番号TB−152)より購入し、そして10%FBS、2mM L−グルタミン、1mMピルビン酸ナトリウム、10mM HEPES、および1.5g/L重炭酸ナトリウムを補充したRPMI1640中で増殖させた。抗CD47 mAbクローンB6H12、2D3、BRIC126、およびCC2C6の細胞表面結合を示すことによって、フローサイトメトリーにより、CD47発現を分析した。アゴニストアッセイの前日、Jurkat細胞を、完全増殖培地中、〜3x105細胞/mLで、T75/T150組織培養フラスコ中に植え付けた。
CD47に基づく療法に関する1つの懸念は、巨大な抗原シンクとして作用し、そして血液学的毒性を引き起こす潜在能力を有する、赤血球(RBC)表面上のターゲットの発現である。実際、高アフィニティSIRPαFc変異体およびCD47特異的抗体で治療した動物において、貧血が報告されてきている。したがって、ヒト赤血球へのSIRPαFc融合タンパク質の結合を、フローサイトメトリーによって評価した。ヘパリン処理全血を用いて、ヒトRBCを調製した。全血を200xg、室温で10分間、遠心分離して、血小板を除去した。血小板分画を吸引した後、試験管に元来の体積までPBSを重層し、試験管を反転させることによって、内容物をよく混合し、そして1500rpmで5分間遠心分離することによって、RBCをペレットにした。この洗浄をさらに3〜5回反復した。最終洗浄後、上清を吸引し、そして試験管に、元来の血液体積までPBSを重層した。血球計算板を用いてRBCを計数し、そしてRBC結合アッセイ前に、5x108細胞/mLで再懸濁した。抗ヒトCD235aを示すフローサイトメトリーによって、赤血球の純度を評価した(eBiosciences カタログ番号12−9978)。
本願は以下の発明を包含する。
[項目1] CD47+疾患細胞の成長および/または増殖を阻害するために有用なヒトSIRPα融合タンパク質であって、無視できるCD47アゴニズムおよび無視できる赤血球結合を有し、ヒトSIRPαの全細胞外領域のアフィニティよりも少なくとも5倍高いアフィニティでヒトCD47に結合するのに有効なヒトSIRPαドメイン、およびエフェクター機能を有するヒトIgG定常領域(Fc)を含み、該融合タンパク質の強度がエフェクター機能を欠くFc領域から形成されるSIRPαFc融合体の強度よりも少なくとも5倍高く、ヒトSIRPαドメインが、ヒトSIRPα変異体2の残基32〜137(配列番号1)を含むIgVドメインである、前記ヒトSIRPα融合タンパク質。
[項目2] ヒトSIRPαドメインが、ヒトSIRPα変異体2の残基31〜148(配列番号22)からなる、項目1記載のヒトSIRPα融合タンパク質。
[項目3] エフェクター機能を有するFcが、(a)ヒトIgG1抗体の定常領域、および(b)ヒトIgG4抗体の定常領域より選択される、項目1または項目2記載のヒトSIRPα融合タンパク質。
[項目4] エフェクター機能を有するFcが、ヒトIgG1抗体の定常領域である、項目3記載のヒトSIRPα融合タンパク質。
[項目5] ヒトIgG1抗体の定常領域が配列番号2を含む、項目4記載のヒトSIRPα融合タンパク質。
[項目6] 配列番号3を含む、項目5記載のヒトSIRPα融合タンパク質。
[項目7] 配列番号25を含む、項目5記載のヒトSIRPα融合タンパク質。
[項目8] エフェクター機能を有するFcが、ヒトIgG4抗体の定常領域である、項目3記載のヒトSIRPα融合タンパク質。
[項目9] FcがSer 228 Pro(EU)突然変異を含む、項目8記載のヒトSIRPα融合タンパク質。
[項目10] Fcが配列番号24を含む、項目9記載の融合タンパク質。
[項目11] 配列番号26を含む、項目10記載の融合タンパク質。
[項目12] 検出可能標識をさらに含む、項目1〜11記載の融合タンパク質。
[項目13] 薬学的に許容されうるキャリアー、およびCD47+疾患細胞の成長または増殖を阻害するために有効な量の項目1〜11のいずれか記載の融合タンパク質を含む、薬学的組成物。
[項目14] 融合タンパク質が配列番号25を含む、項目13記載の薬学的組成物。
[項目15] 融合タンパク質が配列番号26を含む、項目13記載の薬学的組成物。
[項目16] CD47+疾患細胞の増殖を阻害する必要がある被験体において、CD47+疾患細胞の増殖を阻害するための方法であって、項目13〜15のいずれか1項に記載の組成物を投与する工程を含む、前記方法。
[項目17] 疾患細胞がCD47+癌細胞である、項目16記載の方法。
[項目18] 疾患細胞がCD47+血液学的癌細胞である、項目17記載の方法。
[項目19] 疾患細胞がCD47+白血病細胞である、項目18記載の方法。
[項目20] 疾患細胞がCD47+癌細胞を含む固形腫瘍である、項目17記載の方法。
[項目21] 項目1〜10のいずれか1項に記載のヒトSIRPα融合タンパク質をコードするヌクレオチド配列を含む、DNA構築物。
[項目22] 発現可能であるように取り込まれた項目21記載のDNA構築物を含む、タンパク質産生宿主細胞。
[項目23] ヒトSIRPα融合タンパク質を産生するための方法であって、項目1〜11のいずれか1項に記載のヒトSIRPαFc融合タンパク質をコードするポリヌクレオチドを発現のために取り込んだタンパク質産生宿主細胞を培養する工程を含む、前記方法。
Claims (12)
- CD47+疾患細胞の成長および/または増殖を阻害するために有用なヒトSIRPα融合タンパク質であって、配列番号26を含む、前記ヒトSIRPα融合タンパク質。
- 配列番号26からなる、ヒトSIRPα融合タンパク質。
- 検出可能標識をさらに含む、請求項1または2記載のヒトSIRPα融合タンパク質。
- 薬学的に許容されうるキャリアー、およびCD47+疾患細胞の成長または増殖を阻害するために有効な量の請求項1〜3のいずれか1項に記載の融合タンパク質を含む、薬学的組成物。
- CD47+疾患細胞の増殖を阻害する必要がある被験体に投与される、CD47+疾患細胞の増殖の阻害に使用するための、請求項4記載の薬学的組成物。
- 疾患細胞がCD47+癌細胞である、請求項4または5記載の薬学的組成物。
- 疾患細胞がCD47+血液学的癌細胞である、請求項6記載の薬学的組成物。
- 疾患細胞がCD47+白血病細胞である、請求項7記載の薬学的組成物。
- 疾患細胞がCD47+癌細胞を含む固形腫瘍である、請求項6記載の薬学的組成物。
- 請求項1〜3のいずれか1項に記載のヒトSIRPα融合タンパク質をコードするヌクレオチド配列を含む、DNA構築物。
- 発現可能であるように取り込まれた請求項10記載のDNA構築物を含む、タンパク質産生宿主細胞。
- ヒトSIRPα融合タンパク質を産生するための方法であって、請求項1〜3のいずれか1項に記載のヒトSIRPαFc融合タンパク質をコードするポリヌクレオチドを発現のために取り込んだタンパク質産生宿主細胞を培養する工程を含む、前記方法。
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