JP6244301B2 - 可溶性ポリペプチド - Google Patents
可溶性ポリペプチド Download PDFInfo
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- JP6244301B2 JP6244301B2 JP2014525261A JP2014525261A JP6244301B2 JP 6244301 B2 JP6244301 B2 JP 6244301B2 JP 2014525261 A JP2014525261 A JP 2014525261A JP 2014525261 A JP2014525261 A JP 2014525261A JP 6244301 B2 JP6244301 B2 JP 6244301B2
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Classifications
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- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/46—Hybrid immunoglobulins
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- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/44—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material not provided for elsewhere, e.g. haptens, metals, DNA, RNA, amino acids
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
- G01N33/6845—Methods of identifying protein-protein interactions in protein mixtures
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6854—Immunoglobulins
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- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
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- C07K2317/00—Immunoglobulins specific features
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- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/565—Complementarity determining region [CDR]
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- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
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- C07K2317/82—Immunoglobulins specific features remaining in the (producing) cell, i.e. intracellular antibodies or intrabodies functional in the cytoplasm, the inner aspect of the cell membrane, the nucleus or the mitochondria
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- C40B40/04—Libraries containing only organic compounds
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Description
脊椎動物抗体のレパートリーは、免疫グロブリン(Ig)フォールドのヘテロダイマーの先祖遺伝子の重複及び多様性によって形成された。免疫システムによって産まれる多様性は、Ig遺伝子の生殖細胞系列の遺伝子ファミリーに依存するだけでなく、Igタンパク質の表面が露出したループで生じるエクソン境界での追加の多様性とともに、多くの独特な系統を形成するB細胞及びT細胞の成長中に、生体内でサブドメインエクソンの組換えにも依存している。この組換えのプロセスは、抗体の軽鎖及び重鎖のそれぞれのN末端抗体結合領域を形成するために再結合する2つの軽鎖可変エクソン(VL)と重鎖可変エクソン(VH)に因んで、V(D)J組換えと呼ばれている。しかしながら、祖先型ペアから枝分かれした複製遺伝子のように、突然変異の蓄積は、可変領域のヘテロダイマーユニット間の不完全な界面接合をもたらす。淘汰圧は、いずれか1つの遺伝子に適用されるのではなく、全体としてのファミリーに適用される。このため、免疫システムにとって良いものである最大多様性は、個々のファミリーのメンバーに理想とは言えない折りたたみ安定性をもたらすこともある。さらに、結合領域それ自体は、異なる折りたたみ安定性を有するかもしれない。たくさんの枝分かれしたサブユニットから機能的ヘテロダイマーを形成する要件は、領域のβシートの間に一定のジスルフィド結合があることによって補われる。しかしながら、接合部分は、ERでの折りたたみのチェックポイントを必要とする安定な接合ではないかもしれない。
i)SEQ ID NO:3に記載のIGLV3−23の骨格領域に90%以上一致する骨格領域を含む重鎖抗体可変領域(VH)、及び、
ii)SEQ ID NO:18に記載のIGLV1−40、SEQ ID NO:21に記載のIGLV1−44、SEQ ID NO:24に記載のIGLV1−47、SEQ ID NO:15に記載のIGLV1−51、SEQ ID NO:6に記載のIGLV3−1、SEQ ID NO:27に記載のIGLV3−19、SEQ ID NO:9に記載のIGLV3−21、SEQ ID NO:12に記載のIGLV6−57、のいずれか1の骨格領域に90%以上一致する骨格領域を含む軽鎖抗体可変領域(VL)、を含み、
VH及びVLは、抗体結合を形成することができ、
ポリペプチドの2以上は、VH可変領域及び/又はVL可変領域中の1以上の相補性決定領域に存在するアミノ酸配列が互いに異なる。
複数の異なるポリペプチドは、
i)SEQ ID NO:3に記載のIGLV3−23の骨格領域に90%以上一致する骨格領域を含む重鎖抗体可変領域(VH)、及び、
ii)SEQ ID NO:18に記載のIGLV1−40、SEQ ID NO:21に記載のIGLV1−44、SEQ ID NO:24に記載のIGLV1−47、SEQ ID NO:15に記載のIGLV1−51、SEQ ID NO:6に記載のIGLV3−1、SEQ ID NO:27に記載のIGLV3−19、SEQ ID NO:9に記載のIGLV3−21、SEQ ID NO:12に記載のIGLV6−57、のいずれか1の骨格領域に90%以上一致する骨格領域を含む軽鎖抗体可変領域(VL)、を含み、
VH及びVLは、抗体結合を形成することができ、ポリペプチドの2以上は、VH可変領域及び/又はVL可変領域中の1以上の相補性決定領域に存在するアミノ酸配列が互いに異なる。
i)SEQ ID NO:3に記載のIGLV3−23の骨格領域に90%以上一致する骨格領域を含む重鎖抗体可変領域(VH)、及び、
ii)SEQ ID NO:18に記載のIGLV1−40、SEQ ID NO:21に記載のIGLV1−44、SEQ ID NO:24に記載のIGLV1−47、SEQ ID NO:15に記載のIGLV1−51、SEQ ID NO:6に記載のIGLV3−1、SEQ ID NO:27に記載のIGLV3−19、SEQ ID NO:9に記載のIGLV3−21、SEQ ID NO:12に記載のIGLV6−57、のいずれか1の骨格領域に90%以上一致する骨格領域を含む軽鎖抗体可変領域(VL)、
を含むポリペプチドをコード化するものであり、
ポリヌクレオチドの2以上は、VH可変領域及び/又はVL可変領域中の1以上の異なる相補性決定領域を含むポリペプチドをコード化することによって互いに異なる。
i)SEQ ID NO:3に記載のIGLV3−23の骨格領域に90%以上一致する骨格領域を含む重鎖抗体可変領域(VH)、及び、
ii)SEQ ID NO:18に記載のIGLV1−40、SEQ ID NO:21に記載のIGLV1−44、SEQ ID NO:24に記載のIGLV1−47、SEQ ID NO:15に記載のIGLV1−51、SEQ ID NO:6に記載のIGLV3−1、SEQ ID NO:27に記載のIGLV3−19、SEQ ID NO:9に記載のIGLV3−21、SEQ ID NO:12に記載のIGLV6−57、のいずれか1の骨格領域に90%以上一致する骨格領域を含む軽鎖抗体可変領域(VL)、を含み、
VH及びVLは、抗体結合を形成することができ、
ポリヌクレオチドの2以上は、VH可変領域及び/又はVL可変領域中の1以上の異なる相補性決定領域を含むポリペプチドをコード化することによって互いに異なる。
i)SEQ ID NO:3に記載のIGLV3−23の骨格領域に90%以上一致する骨格領域を含む重鎖抗体可変領域(VH)、及び、
ii)SEQ ID NO:18に記載のIGLV1−40、SEQ ID NO:21に記載のIGLV1−44、SEQ ID NO:24に記載のIGLV1−47、SEQ ID NO:15に記載のIGLV1−51、SEQ ID NO:6に記載のIGLV3−1、SEQ ID NO:27に記載のIGLV3−19、SEQ ID NO:9に記載のIGLV3−21、SEQ ID NO:12に記載のIGLV6−57、のいずれか1の骨格領域に90%以上一致する骨格領域を含む軽鎖抗体可変領域(VL)、を含み、
VH及びVLは、抗体結合を形成することができる。
a)ポリペプチドが作製されるように、本発明のポリペプチドをコード化するポリヌクレオチドを含む細菌細胞を培養する工程と、
b)細菌細胞を透過化する工程であって、前記ポリヌクレオチド及び前記ポリペプチドが、透過化した細菌細胞内に保持される工程と、
c)標的分子が透過化した細菌細胞内で拡散するように、透過化した細菌細胞を標的分子に接触させる工程と、
d)本発明のポリペプチドが標的分子に結合するかどうかを決定する工程と、を含む。
SEQ ID NO:1−IGHV3-23をコード化するポリヌクレオチド配列(NCBI Ref. NT_026437.12)
SEQ ID NO:2−イントロンを排除する、IGHV3-23をコード化するポリヌクレオチド配列
SEQ ID NO:3−IGHV3-23のアミノ酸配列
SEQ ID NO:4−IGLV3-1をコード化するポリヌクレオチド配列(NCBI Ref. NT_011520.12)
SEQ ID NO:5−イントロンを排除する、IGLV3-1をコード化するポリヌクレオチド配列
SEQ ID NO:6−IGLV3-1のアミノ酸配列
SEQ ID NO:7−IGLV3-21をコード化するポリヌクレオチド配列(NCBI Ref. NT_011520.12)
SEQ ID NO:8−イントロンを排除する、IGLV3-21をコード化するポリヌクレオチド配列
SEQ ID NO:9−IGLV3-21のアミノ酸配列
SEQ ID NO:10−IGLV6-57をコード化するポリヌクレオチド配列(NCBI Reference: NW_001838745.1)
SEQ ID NO:11−イントロンを排除する、IGLV6-57をコード化するポリヌクレオチド配列
SEQ ID NO:12−IGLV6-57のアミノ酸配列
SEQ ID NO:13−IGLV1-51をコード化するポリヌクレオチド配列(NCBI Reference Sequence: NT_011520.12)
SEQ ID NO:14−イントロンを排除する、IGLV1-51をコード化するポリヌクレオチド配列
SEQ ID NO:15−IGLV1-51のアミノ酸配列
SEQ ID NO:16−IGLV1-40をコード化するポリヌクレオチド配列(NCBI Reference Sequence: NT_011520.12)
SEQ ID NO:17−イントロンを排除する、IGLV1-40をコード化するポリヌクレオチド配列
SEQ ID NO:18−IGLV1-40のアミノ酸配列
SEQ ID NO:19−IGLV1-44をコード化するポリヌクレオチド配列(NCBI Reference Sequence: NT_011520.12)
SEQ ID NO:20−イントロンを排除する、IGLV1-44をコード化するポリヌクレオチド配列
SEQ ID NO:21−IGLV1-44のアミノ酸配列
SEQ ID NO:22−IGLV1-47をコード化するポリヌクレオチド配列(NCBI Reference Sequence: NT_011520.12)
SEQ ID NO:23−イントロンを排除する、IGLV1-47をコード化するポリヌクレオチド配列
SEQ ID NO:24−IGLV1-47のアミノ酸配列
SEQ ID NO:25−IGLV3-19をコード化するポリヌクレオチド配列(NCBI Reference Sequence: NT_011520.12)
SEQ ID NO:26−イントロンを排除する、IGLV3-19をコード化するポリヌクレオチド配列
SEQ ID NO:27−IGLV3-19のアミノ酸配列
SEQ ID NO:28−好ましいペプチドリンカー
SEQ ID NO:29−CDR変異体配列
SEQ ID NO:30−選択的CDR変異体配列
SEQ ID NO:31−プライマーHVK1 F1
SEQ ID NO:32−プライマーHVK1 F2
SEQ ID NO:33−プライマーHVK2 F
SEQ ID NO:34−プライマーHVK3 F
SEQ ID NO:35−プライマーHVK4 F
SEQ ID NO:36−プライマーHVK5 F
SEQ ID NO:37−プライマーHVK6 F
SEQ ID NO:38−プライマーHVKCL R
SEQ ID NO:39−プライマーHVL1 F1
SEQ ID NO:40−プライマーHVL1 F2
SEQ ID NO:41−プライマーHVL2 F
SEQ ID NO:42−プライマーHVL3 F1
SEQ ID NO:43−プライマーHVL3 F2
SEQ ID NO:44−プライマーHVL4 F1
SEQ ID NO:45−プライマーHVL4 F2
SEQ ID NO:46−プライマーHVL5 F
SEQ ID NO:47−プライマーHVL6 F
SEQ ID NO:48−プライマーHVL7/8 F
SEQ ID NO:49−プライマーHVL9/10 F
SEQ ID NO:50−プライマー01115 HVLCL R
SEQ ID NO:51−プライマー01116 HVLCL R2
SEQ ID NO:52−プライマーHVK1 2F1
SEQ ID NO:53−プライマーHVK1 2F2
SEQ ID NO:54−プライマーHVK2 2F
SEQ ID NO:55−プライマーHVK3 2F
SEQ ID NO:56−プライマーHVK4 2F
SEQ ID NO:57−プライマーHVK5 2F
SEQ ID NO:58−プライマーHVK6 2F
SEQ ID NO:59−プライマーHVKCL 2R
SEQ ID NO:60−プライマーHVL1 2F1
SEQ ID NO:61−プライマーHVL1 2F2
SEQ ID NO:62−プライマーHVL2 2F
SEQ ID NO:63−プライマーHVL3 2F1
SEQ ID NO:64−プライマーHVL3 2F2
SEQ ID NO:65−プライマーHVL4 2F1
SEQ ID NO:66−プライマーHVL4 2F2
SEQ ID NO:67−プライマーHVL5 2F
SEQ ID NO:68−プライマーHVL6 2F
SEQ ID NO:69−プライマーHVL7/8 2F
SEQ ID NO:70−プライマーHVL9/10 2F
SEQ ID NO:71−プライマーHVLCL 2R
SEQ ID NO:72−ラムダJ領域J1
SEQ ID NO:73−ラムダJ領域J2
SEQ ID NO:74−ラムダJ領域J3
SEQ ID NO:75−ラムダJ領域J4
SEQ ID NO:76−ラムダJ領域J5
SEQ ID NO:77−ラムダJ領域J6
SEQ ID NO:78−ラムダJ領域J7
SEQ ID NO:79−ハイブリッドJ領域配列
SEQ ID NO:80−PCRプライマー
SEQ ID NO:81−転換配列
SEQ ID NO:82−PCRプライマー
SEQ ID NO:83−転換配列
SEQ ID NO:84−可変CDR3領域とIGLV3-1:IGHV3-23スカフォールドをコード化するポリヌクレオチド配列
SEQ ID NO:85−SEQ ID NO:84のポリヌクレオチドによってコード化されたアミノ酸配列
SEQ ID NO:86−転換CDR3配列
SEQ ID NO:87−選択的転換CDR3配列
SEQ ID NO:88−IGLV3-1のフレームワーク配列及びIGHV3-23のJ領域
SEQ ID NO:89−介在配列
SEQ ID NO:90−縮重プライマー1
SEQ ID NO:91−縮重プライマー2
SEQ ID NO:92−CDR3ループL1
SEQ ID NO:93−CDR3ループH1
SEQ ID NO:94−CDR3ループL2
SEQ ID NO:95−CDR3ループH2
SEQ ID NO:96−CDR3ループL3
SEQ ID NO:97−CDR3ループH3
SEQ ID NO:98−CDR3ループL4
SEQ ID NO:99−CDR3ループH4
SEQ ID NO:100−CDR3ループL5
SEQ ID NO:101−CDR3ループH5
SEQ ID NO:102−CDR3ループL6
SEQ ID NO:103−CDR3ループH6
SEQ ID NO:104−CDR3ループL8
SEQ ID NO:105−CDR3ループH8
SEQ ID NO:106−CDR3ループL9
SEQ ID NO:107−CDR3ループH9
SEQ ID NO:108−CDR3ループL10
SEQ ID NO:109−CDR3ループH10
SEQ ID NO:110−mAG-BioHis6タンパク質
SEQ ID NO:111−Anti-mAG-BioHis6 scFv配列
SEQ ID NO:112−gpD:α-mAG scFv 融合構造ポリヌクレオチド配列
SEQ ID NO:113−gpD::α-mAG scFv 融合タンパク質配列
SEQ ID NO:114−野生型ヒトIGLV 3-1
SEQ ID NO:115−可溶性クローン8.93
SEQ ID NO:116−可溶性クローン8.184
SEQ ID NO:117−可溶性クローン8.174
SEQ ID NO:118−可溶性ヒトIGLV 3-21クローン8.186
SEQ ID NO:119−可溶性ヒトIGLV 3-21クローン8.39
SEQ ID NO:120−野生型ヒトIGLV 3-21
SEQ ID NO:121−可溶性ヒトIGLV 3-21クローン9.19
SEQ ID NO:122−野生型ヒトIGLV 6-57
SEQ ID NO:123−可溶性クローン16.26
SEQ ID NO:124−可溶性クローン16.1
SEQ ID NO:125−可溶性クローン16.121
別段の明確に定義されない限り、本明細書中で用いる全ての専門用語及び科学用語は、(例えば、タンパク質化学、生化学、細胞培養、分子遺伝学、微生物学及び免疫学における)当業者により通常理解されるのと同じ意味を有すると解される。
本発明者らは、保有カプセル化ディスプレイ(Retained Encapsulated Display, RED)を使用して、細胞質内を可溶形で発現し、驚くべきレベルの可溶性、熱安定性、CDR多様性に対する耐性を示すポリペプチドを同定した。REDは、WO2011/075761(この内容は参照により本明細書に組み込まれる)で報告されたグラム陰性菌に対するタンパク質ディスプレイプラットフォームである。REDでは、ディスプレイされるタンパク質は、細胞のペリプラズムか細胞質のいずれかで発現する。細胞壁が無傷で残っている間に、細胞膜を洗剤又は有機溶媒で透過処理する。ディスプレイタンパク質は、細胞壁の空隙限界を超えて自身の分子径を増すタンパク質への融合(例えば、四量体モノマーへの融合)、又は、DNA若しくは細胞壁自身のいずれか一方若しくはその両方と結合するタンパク質ドメインへの融合のいずれかを通して細胞壁に保持される。ディスプレイシステムに必要な表現型と遺伝子型の連鎖は、透過処理細胞の細胞壁内のプラスミドとゲノムDNAの共同保持を通して供給される。
ヒト抗体レパートリーは、機能的可変領域と偽遺伝子可変領域を含む(Lefranc, 2000)。抗体の発現に利用できる遺伝子構造物の準備のために、これらは非免疫系統のゲノムDNA、又はV(D)J組み換えを経た免疫細胞起源のmRNAのいずれかからのエクソンとしてクローン化される。その過程の間、軽鎖と重鎖の可変領域は、モノマーscFvとして、又は二価かそれ以上の価数を形成する配列でクローン化される。定常領域もまた、可変ドメインの下流でクローン化され、Fab又は完全長抗体を作る。
本発明のポリペプチドは、当技術分野において公知の任意の適した方法を使用し、1以上の成分に接合している。ポリペプチドが接合できる成分の例は、放射性同位体からなる検出可能ラベル、治療成分、コロイド、毒素、核酸、ペプチド、タンパク質、被験体とその混合物中のタンパク質の半減期を増やす成分のグループから選ばれる。典型的な治療薬は、血管新生阻害剤に限られず、血管新生阻害や他の血管新生剤、抗増殖剤、アポトーシス促進剤、化学療法剤、又は治療核酸を含む。
本発明のポリペプチドは、好ましくは、ポロペプチドを本明細書で言及するRED分析の使用に特に適した1以上の化合物に接合する。例えば、ポリペプチドをジスルフィド架橋などの共有結合、又は非共有結合により、第2ポリペプチド(以下において、「第2ポリペプチド」と言う)と結合させ得る。「非共有結合」とは、原子間結合が関与しない分子相互作用を指す。例えば、非共有相互作用は、イオン結合、水素結合、疎水性相互作用及びファンデルワールス力が関与する。非共有結合力を用いて、別個のポリペプチド鎖をタンパク質又はタンパク質複合体中に一緒に保持することができる。このため、ポリペプチド及び第2ポリペプチドを同じか若しくは異なるベクターのいずれかから別のポリペプチドとして発現することができるか、又はポリペプチドの一方若しくは両方を、細菌細胞ゲノム中に組み入れられたポリペプチドをコード化するDNAから発現することができる。
第2ポリペプチドは、所望の活性に対してスクリーニングされるポリペプチドで形成された複合体の少なくともいくつかが、透過処理された細菌細胞から拡散することができないような十分な分子サイズ(すなわち十分な分子量又は十分な分子半径)の任意のポリペプチドであり得る。このため、タンパク質複合体は、細胞の透過処理後に細菌細胞内に保持される。分子量及び球状又は桿状(糸状)タンパク質であるかどうかを含む第2ポリペプチドの性質が、細菌細胞壁を通過するタンパク質複合体の拡散を防止又は阻害する第2ポリペプチドの能力を決めることを当業者は理解するだろう。一実施形態において、第2ポリペプチドの分子量は、少なくとも約30kDa、又は約40以上、50以上、60以上、70以上、80以上、90以上、100以上、120以上、130以上、140以上、150kDa以上若しくはそれ以上である。一実施形態において、第2ポリペプチドは約120kDa以上である。
本発明者らは、透過処理後の細菌細胞内にDNAが保持されることを見出した。このため、一実施形態において、ポリペプチドをDNA結合タンパク質と結合させて、DNAと結合するタンパク質複合体を形成し、それは細菌細胞の内部に保持される。本明細書中で用いる「DNA結合タンパク質」は、2本鎖又は1本鎖DNAを認識する1以上のモチーフを含むDNA結合領域を含む任意のタンパク質を意味する。DNA結合領域は、当業者に公知であるように、ヘリックス・ターン・ヘリックス、亜鉛フィンガー、ロイシンジッパー、翼状ヘリックス、翼状ヘリックス・ターン・ヘリックス、ヘリックス・ループ・ヘリックス、DNAを認識する免疫グロブリンフォールド、又はB3ドメインが挙げられる。DNA結合タンパク質とポリペプチドを結合により、本発明のスクリーニング法においてポリペプチドをコード化するプラスミド等のDNAの回収が有意に増大する。
細菌細胞壁結合タンパク質とポリペプチドを結合させてもよい。異なる細菌は異なる細胞壁組成を有するので、当業者は、細胞壁結合タンパク質の選択が宿主細胞種に依存することを理解するであろう。細菌は、ペプチドグリカン(PG)から構成される細胞壁を有するが、種間の化学修飾は、異種間結合に影響を及ぼし得る。当業者は、特定の細菌種における使用に適した細胞壁結合タンパク質を容易に決定することができる。
本発明は、本発明のポリペプチドをコード化するポリヌクレオチドを提供するものでもある。好ましくは、ポリヌクレオチドは、単離及び/又は組換ポリヌクレオチドである。
本明細書で開示されるポリペプチドは、当該技術分野で公知の任意の方法、例えば、組み換えポリペプチドの生成及び回収、そしてポリペプチドの化学合成等によって合成することができる。したがって、本発明はまた、本発明のポリペプチドを生成する方法をも提供する。
これまで、細胞内抗体(細胞質内で生産的にフォールドされるようなより高い安全性のために操作又は進化してきた配列を持つ抗体分子)の構造領域の配列、つまり非CDR配列は、同族生殖細胞系列のゲノム配列とは大きく異なる。本明細書で明らかにしたように、本発明者は、同族生殖細胞系列のゲノム配列と同一であるか、又は密接に関連した、そして非酸化環境においての発現時に正確にフォールドし、安定性が増すヒト抗体可変領域の配列をスクリーニングして決定した。本発明での使用に対する好ましい配列は、下記に記載する。本発明に記載した任意の可変領域配列に対して、当業者がCDR(例えば、その多くはNCBIデータベースで同定される)と残りの骨格領域を同定できることが理解される。本発明に記載した各可変領域のCDRの特定の例は図7に示す。
好ましい実施形態において、本発明のポリペプチドは、免疫グロブリン可変ドメインのVH3ファミリーの重鎖可変領域(VH)を含む。VHは、IGHV3-23(SEQ ID NO: 3)であることが好ましい。
本発明者は、scFv融合がREDプラットフォームに可溶であるという基準のみを適用することにより、(生体内で抗体標的への抗体の結合が必要で、従ってそれぞれの生殖系列配列から十分に突然変異した抗体を、以前に実施した機能的スクリーニングとは対照的にスクリーニングした)V領域内で突然変異したナイーブ軽鎖をスクリーニングすることができた。従って、IGHV3-23 scFv融合に安定性をもたらす生殖細胞系列配列を同定することができた。これは、VLとVHドメインで構築された人工的な骨格ライブラリーが豊富なヒト抗体タンパク質の配列において同一であることを保証し、それにより任意の誘導体に長期間さらすことで免疫認識及び拒絶を最小化するという大きな利点を有する。
ポリペプチド配列のライブラリーは、所望の標的に対する親和性タンパク質のために選択できる様々なタンパク質ディスプレイプラットフォームでクローン化してもよいし、発現してもよい。従って、本発明は、本発明の複数のポリペプチドを含むライブラリーを提供する。好ましい実施形態において、ライブラリーは、"親(parent)"ポリペプチド及び/又はポリヌクレオチド配列を同定し、そしてライブラリーを形成するための複数の可変配列を作り出すためにその配列を改変させることによって作成することができる。改変は、任意の適した手段、例えば、部位特異的変異誘発又はランダム突然変異誘発によって行うことができる。ライブラリー構築の適する方法は、当技術分野で公知である。
- SEQ ID NO: 3に記載のIGHV3-23の骨格領域と90%以上同一の骨格領域を含む抗体重鎖可変領域(VH)、及び(SEQ ID NO: 6に記載の)IGLV3-1の骨格領域と90%以上同一の骨格領域を含む抗体軽鎖可変領域(VL)を含む1以上のポリペプチドであって、VH及びVLは抗原結合部位を形成することができるもの。及び
- SEQ ID NO: 3に記載のIGHV3-23の骨格領域と90%以上同一の骨格領域を含む抗体重鎖可変領域(VH)、及び(SEQ ID NO: 18に記載の)IGLV1-40、(SEQ ID NO: 21に記載の)IGLV1-44、(SEQ ID NO: 24に記載の)IGLV1-47、(SEQ ID NO: 15に記載の)IGLV1-51、(SEQ ID NO: 27に記載の)IGLV3-19、(SEQ ID NO: 9に記載の)IGLV3-21、又は(SEQ ID NO: 12に記載の)IGLV6-57の骨格領域と90%以上同一の骨格領域を含む抗体軽鎖可変領域(VL)を含む1以上のポリペプチドであって、VH及びVLは抗原結合部位を形成することができるもの。
このため、本発明のライブラリーは、本発明で明らかにした重鎖及び軽鎖可変領域骨格の任意の組み合わせを有する1以上のポリペプチドを含んでいてもよい。
同定されている任意の骨格のペア(IGHV3-23と、IGLV1-40、IGLV1-44、IGLV1-47、IGLV1-51、IGLV3-1、IGLV3-19、IGLV3-21又はIGLV6-57)は、親の骨格の可溶性が乏しいことを示すであろう温度での細胞質スクリーニングを行なう目的で単一骨格上の変異体のさらなるライブラリーの鋳型として使用できる。
本発明で明らかにしたポリペプチド(又は抗体)ライブラリーは、標的分子に結合したポリペプチドをスクリーニングするために使用することができる。ポリペプチドは、それぞれが異なるポリペプチド又はポリペプチド変異体を発現する細胞のライブラリーに関連して、又は単一ポリペプチドを発現する単一タイプの細胞に関連して、スクリーニング又は選択されるということが理解されるだろう。"標的分子(target molecule)"という用語は、ポリペプチドに結合した、及び/又はポリペプチドで修飾された分子を指し、例えば、抗原、酵素、抗体、受容体などである。従って、"標的分子(target molecule)"は、結合に対して評価される酵素基質のような基質又は分子(例えば、配位子、エピトープ、抗原、ホモ若しくはヘテロ二量体パートナーのような多量体化パートナーなど、又はそれらの任意の組み合わせ)を表示することにも使用できる。
本発明の方法の実施に必要な成分は、キットの形態で好適に提供することができる。当業者に理解されるように、キット中の種々の成分は、個々の容器中若しくはアリコートで供給することができるか、又は溶液成分を異なる組み合わせ、異なる濃度で組み合わせて、本発明の方法の最適な実施を達成することができる。使用するまで成分が安定な形態で維持されるように、キットのどの成分を組み合わせることができるかを決定することは、当業者の知識の範囲内である。
本発明のポリペプチドは、研究、診断及び治療への応用を含む、様々な用途で有用である。ポリペプチドが結合する抗原に応じて、それは、例えば、細胞を殺す又は成長を阻害するために及び/又はイメージング及び/又は生体外試験のために、細胞に化合物を送るのに有用であってもよい。1つの実施例では、ポリペプチドは、イメージング及び細胞毒性薬の細胞への送達の両方に有用である。すなわち、それは検出可能ラベル及び細胞毒性薬に結合する。あるいは、組成物は、いくつかが細胞毒性薬に結合し、いくつかが検出可能ラベルに結合したタンパク質の混合物を含む。
本発明のポリペプチド(同義語、有効成分)は、予防的又は治療的処置のための非経口、局所、経口、若しくは局所投与、エアロゾル投与、又は経皮投与に有用である。医薬組成物は、投与方法に応じて、様々な単位の投薬形態で投与できる。例えば、経口投与に適する単位投薬形態としては、粉末、錠剤、丸薬、カプセル剤及びトローチ剤が挙げられる。又は非経口投与による。本発明の医薬組成物は、経口投与される時、消化から保護されるべきであると認識されている。これは、酸加水分解及び酵素加水分解に対する耐性を得るためにタンパク質と組成物と複合体を作るか、又はリポソームのような適切な耐性キャリアに化合物を詰め込むことのどちらかによって一般的に達成される。消化からタンパク質を保護する手段は当技術分野で公知である。
大腸菌細胞質において十分に発現し可溶性のあるIGHV3-23のヒト軽鎖パートナーをスクリーンするために、本発明者は10λと5κの機能的な軽鎖ファミリー全てを、IGHV3-23へのscFv融合としてクローン化した。scFvライブラリーは、アラビノースによって誘導され、かつ細胞壁結合(ペプチドグリカン(PG)結合ドメイン)、発現レポータードメイン(SNAP、ニューイングランドバイオラボ)、DNA結合ドメイン(DBP)をこの順番で与える下流ドメインにさらに溶解される発現構造物へとクローン化された。これらの下流ドメインは、外部及び内部の細菌宿主の細胞膜が、融合タンパク質をDNAと細胞壁の両方に固定することで、洗浄剤又は有機溶剤によって透過処理されるとき、scFv部分の保持を可能にする。
可溶性の最初のスクリーンのように、各々のライブラリープレートは10mLのLB/グリセロール(10%)の中で破砕され懸濁された。懸濁液の小片(~50uL)は、1時間37℃の1mLのLB媒質(1リットルにつき10gのトリプトン、5gの酵母エキス、10gのNaCl)の中で成長し、次に0.2%のアラビノースによって誘導され、さらに25℃2時間で成長した。この時点で細胞は、10分間25℃のLB媒質における0.5%のn-オクチル-β-チオグリコシド(8TGP)において、細菌ペレットの再懸濁によって透過処理された。透過処理された細胞はLB媒質におけるペレット形成と再懸濁によって一度洗浄され、その後、誘導されたscFv融合タンパク質は、SNAPサーフェス488試薬(S9124S、New England Biolabs)を加えることによって、また20分25℃の培養によってラベルされた。ラベルされた細胞は次にペレット形成とPBSにおける再懸濁によって再び洗浄され、その後、サンプルが蛍光顕微鏡検査によって検視するために固定された。
クローンは単離と配列決定によって調べられた。
25℃での誘導と発現を伴ったVLサブライブラリーの初めのスクリーンの後で、scFvクローンはクローンとファミリーとを熱安定性に応じて等級付けするためにさらなるスクリーンを受けた。
表2でリスト化されている、VLドメインを増幅するために使用された変性オリゴヌクレオチドの配列は、ヒトゲノム(表3)における7の異なるλJ領域を下塗りしなければならなかった。したがって、スクリーンから単離されたクローンは、フォールディングの安定性を低減させていたであろう非カノニカル配列を表すハイブリッドλJ領域をもっていた。
scFvが親和性ライブライーのフレームワークとして役に立つためには、CDR3領域における交換に対して耐性がある必要がある。このことは特に、安定化内部ドメインのジスルフィド結合を欠いた、大腸菌細胞質基質のような還元環境において発現するscFvに当てはまる。
GATCAGGGTCTGAGACGAGACCGTCACTTTCGTACCGGTGCCGAACACCACAGTANNANNANNTCCGCCANNANNANNGTCCCACGCCTGACAGTAATAGTCAGC (SEQ ID NO: 80)
…ADYYCQAWD(91) NNNGGNNN TVVFGTGTKVTVSS (SEQ ID NO: 81)
GATCAGGGTCTGAGACCCGCTGCTCACGGTAACCATGGTACCTTGACCCCAAATATCAAACGCANNANNANNGCCANNANNANNTTTCGCACAGTAGTAAACAGC (SEQ ID NO: 82)
この配列の(逆/順)翻訳(ここで“N”はTrp, Gln, Lys, Glu, Met以外のアミノ酸全てである)は、NNNGNNN AFDIWGQGTMVT (SEQ ID NO: 83)を与える。
IGLV3-1::IGHV3-23スカフォールドは、実施例5で記述された、アミノ酸配列‘NNNGGNNN’(SEQ ID NO:86)と‘NNNGNNN’(SEQ ID NO:87)を、それぞれVLとVHのCDR3領域に導入するという方法を使用することで多様化された。
フレームワーク配列;
ATG GGA GAC GGT CAG TCT GTG CTG ACT CAG CCA CCC TCAGTGTCCGTGTCCCCAGGACAGACAGCCAGCATCACCTGCTCTGGAGATAAATTGGGGGATAAATATGCTTGCTGGTATCAGCAGAAGCCAGGCCAGTCCCCTGTGCTGGTCATCTATCAAGATAGCAAGCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACAGCCACTCTGACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTACTGTCAGGCG TGG GAC tgagacctagacggtctct gcg TTT GAT ATT TGG GGT CAA GGT ACC ATG GTT ACC GTG AGC AGC TCG TCT CaG ACC (SEQ ID NO: 88).
ACT GTG GTG TTC GGC acc ggt acg aaa gtg acT gtc TCA TCT CAG ACC
GGTGGTTCTGGTGGTGGTGGTTCTGGCGGCGGCGGCTCCGGTGGTGGTGGATCCGAAGTCCAACTGCTGGAGTCCGGCGGTGGCCTGGTGCAGCCAGGTGGCAGCCTGCGCCTGAGCTGCGCCGCATCCGGTTTTACTTTCAGCAGCTACGCGATGTCGTGGGTGCGCCAGGCACCGGGCAAGGGCCTGGAGTGGGTCAGCGCCATCAGCGGTAGCGGCGGTTCTACGTATTATGCGGACAGCGTCAAGGGCCGTTTCACCATCAGCCGTGACAATTCCAAAAACACCCTGTACTTGCAGATGAACAGCTTGCGTGCGGAAGATACGGCTGTTTACTACTGTGCGAAA (SEQ ID NO: 89)
gatcag ggtctca ggac NNT NNT NNT ggc gga NNT NNT NNT ACT GTG GTG TTC GGC acc ggt acg aaa gtg (SEQ ID NO: 90)
縮重プライマー2:
GATCAGGGTCTCAACGCANNANNANNGCCANNANNANNTTTCGCACAGTAGTAAACAGCCGTATCTTC (SEQ ID NO: 91)
標的タンパク質mAGに結合するクローンのために多様化したライブラリーをスクリーンした。アザミグリーン(AG)は、Aequorea victoria緑色蛍光体タンパク質(GFP)の遠位オーソログである。配列の同一性が低い(5%)にもかかわらず、それは同様に、492nmの吸収ピークと510nmの放出ピークを有する緑色蛍光である。モノマー体型が(mAG)Karasawa et al.(2003)に報告され、DNA2.0(USA)に大腸菌における最適の発現のために再コード化された。C末端の大腸菌BirAビオチン化モチーフと6xHisタグは、精製とmAGマトリックス付着における支援に含められた。mAG-BioHis6タンパク質のアミノ酸配列は、SEQ ID NO:110のようにリスト化される。
MVSVIKPEMKIKLCMRGTVNGHNFVIEGEGKGNPYEGTQILDLNVTEGAPLPFAYDILTTVFQYGNRAFTKYPADIQDYFKQTFPEGYHWERSMTYEDQGICTATSNISMRGDCFFYDIRFDGTNFPPNGPVMQKKTLKWEPSTEKMYVEDGVLKGDVNMRLLLEGGGHYRCDFKTTYKAKKEVRLPDAHKIDHRIEILKHDKDYNKVKLYENAVARYSMLPSQAKSGGLNDIFEAQKIEWHEDTGGSHHHHHH (SEQ ID NO: 110)
MGDGQSVLTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDSKRP SGIPERFSGSNSGNTATLTISGTQAMDEADYYCQAWDFNLGGCGDTVVFGTGTKVTVSSQ TGGSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAP GKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHID GPVAAFDIWGQGTMVTVSSSSQTSILVA (SEQ ID NO: 111)
細胞質という還元環境における強化された安定性と生産的なフォールディングを示すスカフォールドの有用性を表すために、ラムダバクテリオファージgpDカプシドタンパク質へのC末端融合として、α-mAG IGLV3-1::IGHV3-23 scFvをクローン化した。ラムダバクテリオファージは繊維状ファージに対して多くの長所を持つため、それはタンパク質ディスプレイの典型的な伝達手段であるとこれまで報告されていた。ラムダカプシドタンパク質、gpDは、ファージ頭部につき〜400のコピーにおいて提示され、またそれは頑丈で耐性のあるディスプレイパートナーであるが、これはカプシドによってロードされた>80%のgpDが組み換え融合タンパク質であることを可能にする一方、伝染の実行可能性を維持する(Vaccaro et al., 2006)。さらにそれは、N末端又はC末端への融合に対して耐性を有する。
ATGACGAGCAAAGAAACCTTTACCCATTACCAGCCGCAGGGCAACAGTGACCCGGCTCATACCGCAACCGCGCCCGGCGGATTGAGTGCGAAAGCGCCTGCAATGACCCCGCTGATGCTGGACACCTCCAGCCGTAAGCTGGTTGCGTGGGATGGCACCACCGACGGTGCTGCCGTTGGCATTCTTGCGGTTGCTGCTGACCAGACCAGCACCACGCTGACGTTCTACAAGTCCGGCACGTTCCGTTATGAGGATGTGCTCTGGCCGGAGGCTGCCAGCGACGAGACGAAAAAACGGACCGCGTTTGCCGGAACGGCAATCAGCATCGTTGGAGGTAGCGGCGGATCGGATGACGACGATAAGTCTAGAAATGGCGGAGACGGTCAGTCTGTGCTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAGGACAGACAGCCAGCATCACCTGCTCTGGAGATAAATTGGGGGATAAATATGCTTGCTGGTATCAGCAGAAGCCAGGCCAGTCCCCTGTGCTGGTCATCTATCAAGATAGCAAGCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACAGCCACTCTGACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTACTGTCAGGCGTGGGACTTTAATCTTGGCGGATGTGGTGATACTGTGGTGTTCGGCACCGGTACGAAAGTGACTGTCTCATCTCAGACCGGTGGTTCTGGTGGCGGTGGTTCTGGCGGCGGCGGCTCCGGTGGTGGTGGATCCGAAGTCCAACTGCTGGAGTCCGGTGGTGGCCTGGTGCAGCCAGGTGGCAGCCTGCGCCTGAGCTGCGCCGCATCCGGTTTTACTTTCAGCAGCTACGCGATGTCGTGGGTGCGCCAGGCACCGGGCAAGGGCCTGGAGTGGGTCAGCGCCATCAGCGGTAGCGGCGGTTCTACGTATTATGCGGACAGCGTCAAGGGCCGTTTCACCATCAGCCGTGACAATTCCAAAAACACCCTGTACTTGCAGATGAACAGCTTGCGTGCGGAAGATACGGCTGTTTACTACTGTGCGAAACATATTGATGGCCCTGTTGCTGCGTTTGATATTTGGGGTCAAGGTACCATGGTTACCGTGAGCAACTCGAGCGATTACAAGGACGATGATGACAAATAA (SEQ ID NO: 112)
MTSKETFTHYQPQGNSDPAHTATAPGGLSAKAPAMTPLMLDTSSRKLVAWDGTTDGAAVG ILAVAADQTSTTLTFYKSGTFRYEDVLWPEAASDETKKRTAFAGTAISIVGGSGGSDDDD KSRNGGDGQSVLTQPPSVSVSPGQTASITCSGDKLGDKYACWYQQKPGQSPVLVIYQDSK RPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQAWDFNLGGCGDTVVFGTGTKVTVS SQTGGSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQ APGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKH IDGPVAAFDIWGQGTMVTVSNSSDYKDDDDK* (SEQ ID NO: 113)
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Claims (27)
- 複数の異なるポリペプチドを含むポリペプチドライブラリーであって、
前記ポリペプチドは、
i)SEQ ID NO:3に記載のIGHV3−23の骨格領域に90%以上一致する骨格領域を含む重鎖抗体可変領域(VH)及び、
ii)SEQ ID NO:18に記載のIGLV1−40、SEQ ID NO:21に記載のIGLV1−44、SEQ ID NO:24に記載のIGLV1−47、SEQ ID NO:6に記載のIGLV3−1、SEQ ID NO:27に記載のIGLV3−19、SEQ ID NO:12に記載のIGLV6−57、のいずれか1の骨格領域に90%以上一致する骨格領域を含む軽鎖抗体可変領域(VL)、を含み、
前記VH及び前記VLは、抗体結合を形成することができ、
前記ポリペプチドの2以上は、前記VH可変領域及び/又は前記VL可変領域中の1以上の相補性決定領域に存在するアミノ酸配列が互いに異なり、前記ポリペプチドは還元条件下で溶解性である、ポリペプチドライブラリー。 - 前記VH可変領域及び/又は前記VL可変領域中の1以上の相補性決定領域のアミノ酸配列は、ランダム又はセミランダムであるか、又はヒト抗体に由来する、請求項1のライブラリー。
- ポリペプチドライブラリーを構成する方法であって、
前記方法は、複数の異なるポリペプチドを準備する工程を含み、
前記複数の異なるポリペプチドは、
i)SEQ ID NO:3に記載のIGHV3−23の骨格領域に90%以上一致する骨格領域を含む重鎖抗体可変領域(VH)、及び、
ii)SEQ ID NO:18に記載のIGLV1−40、SEQ ID NO:21に記載のIGLV1−44、SEQ ID NO:24に記載のIGLV1−47、SEQ ID NO:6に記載のIGLV3−1、SEQ ID NO:27に記載のIGLV3−19、SEQ ID NO:12に記載のIGLV6−57、のいずれか1の骨格領域に90%以上一致する骨格領域を含む軽鎖抗体可変領域(VL)、を含み、
前記VH及び前記VLは、抗体結合を形成することができ、
前記ポリペプチドの2以上は、前記VH可変領域及び/又は前記VL可変領域中の1以上の相補性決定領域に存在するアミノ酸配列が互いに異なり、前記ポリペプチドは還元条件下で溶解性である、ポリペプチドライブラリーを構成する方法。 - 複数の異なるポリヌクレオチドを含むポリヌクレオチドライブラリーであって、
各ポリヌクレオチドは、
i)SEQ ID NO:3に記載のIGHV3−23の骨格領域に90%以上一致する骨格領域を含む重鎖抗体可変領域(VH)、及び、
ii)SEQ ID NO:18に記載のIGLV1−40、SEQ ID NO:21に記載のIGLV1−44、SEQ ID NO:24に記載のIGLV1−47、SEQ ID NO:6に記載のIGLV3−1、SEQ ID NO:27に記載のIGLV3−19、SEQ ID NO:12に記載のIGLV6−57、のいずれか1の骨格領域に90%以上一致する骨格領域を含む軽鎖抗体可変領域(VL)、を含むポリペプチドをコード化するものであり、
前記ポリヌクレオチドの2以上は、前記VH可変領域及び/又は前記VL可変領域中の1以上の異なる相補性決定領域を含むポリペプチドをコード化することによって互いに異なり、前記ポリペプチドは還元条件下で溶解性である、ポリヌクレオチドライブラリー。 - 前記ポリヌクレオチドは、前記VH可変領域及び/又は前記VL可変領域の1以上の相補性決定領域のアミノ酸配列をコード化し、
前記アミノ酸配列は、ランダム又はセミランダムであるか、又はヒト抗体に由来する、請求項4のライブラリー。 - ポリヌクレオチドライブラリーを構成する方法であって、
前記方法は、ポリペプチドをコード化する複数の異なるポリヌクレオチドを準備する工程を含み、
前記ポリペプチドは、
i)SEQ ID NO:3に記載のIGHV3−23の骨格領域に90%以上一致する骨格領域を含む重鎖抗体可変領域(VH)、及び、
ii)SEQ ID NO:18に記載のIGLV1−40、SEQ ID NO:21に記載のIGLV1−44、SEQ ID NO:24に記載のIGLV1−47、SEQ ID NO:6に記載のIGLV3−1、SEQ ID NO:27に記載のIGLV3−19、SEQ ID NO:12に記載のIGLV6−57、のいずれか1の骨格領域に90%以上一致する骨格領域を含む軽鎖抗体可変領域(VL)、を含み、
前記VH及び前記VLは、抗体結合を形成することができ、
前記ポリヌクレオチドの2以上は、前記VH可変領域及び/又は前記VL可変領域中の1以上の異なる相補性決定領域を含むポリペプチドをコード化することによって互いに異なり、前記ポリペプチドは還元条件下で溶解性である、ポリペプチドライブラリーを構成する方法。 - i)SEQ ID NO:3に記載のIGHV3−23の骨格領域に90%以上一致する骨格領域を含む重鎖抗体可変領域(VH)、及び、
ii)SEQ ID NO:18に記載のIGLV1−40、SEQ ID NO:21に記載のIGLV1−44、SEQ ID NO:24に記載のIGLV1−47、SEQ ID NO:6に記載のIGLV3−1、SEQ ID NO:27に記載のIGLV3−19、SEQ ID NO:12に記載のIGLV6−57、のいずれか1の骨格領域に90%以上一致する骨格領域を含む軽鎖抗体可変領域(VL)、を含み、
前記VH及び前記VLは、抗体結合を形成することができ、前記ポリペプチドは還元条件下で溶解性である、単離及び/又は組換ポリペプチド。 - 前記VLは、SEQ ID NO:6に記載のIGLV3−1の骨格領域に90%以上一致する骨格領域を含む、請求項7のポリペプチド。
- 可変のフラグメント(Fv)である、請求項7又は8のポリペプチド。
- Fabフラグメント、Fab’フラグメント、F(ab’)フラグメント、scFv、二重特異性抗体、三重特異性抗体、四重特異性抗体、又はより高次のポリペプチド複合体である、請求項7〜9のいずれか一項に記載のポリペプチド。
- 前記ポリペプチドは、scFvであり、前記VH及び前記VLは、リンカーペプチドを通じて互いに結合している、請求項10のポリペプチド。
- 前記VH可変領域及び前記VL可変領域の骨格領域は、与えられたいずれかの配列の骨格領域に95%以上、96%以上、97%以上、98%以上、又は99%以上一致する、請求項7〜11のいずれか一項に記載のポリペプチド。
- 還元条件下で作製されたときに、溶解性であり、かつ抗体結合部を安定して形成することができる、請求項7〜12のいずれか一項に記載のポリペプチド。
- 化合物に接合している、請求項7〜13のいずれか一項に記載のポリペプチド。
- 前記化合物は、放射性同位体、検出可能な標識、治療化合物、コロイド、毒素、核酸、ペプチド、タンパク質、対象物中のポリペプチドの半減期を増加させる化合物、及びそれらの混合物からなる群より選択される、請求項14のポリペプチド。
- 請求項7〜15のいずれか一項のポリペプチドをコード化する単離及び/又は外因性ポリヌクレオチド、又は、それらの重鎖可変領域又は軽鎖可変領域。
- 請求項16のポリヌクレオチドを含むベクター。
- 請求項7〜15のいずれか一項に記載のポリペプチド、請求項16のポリヌクレオチド、又は請求項17のベクターを含む宿主細胞。
- 標的分子に結合するポリペプチドをスクリーニングする方法であって、
前記方法は、請求項7〜15のいずれか一項のポリペプチド又は請求項1、2、4及び5のいずれか一項のライブラリーを標的分子に接触させる工程と、
請求項7〜15のいずれか一項のポリペプチドが、標的分子に結合するかどうかを決定する工程と、を含む、標的分子に結合するポリペプチドをスクリーニングする方法。 - 請求項7〜15のいずれか一項に記載のポリペプチドをコード化するポリヌクレオチドは、宿主細胞中で発現されるか、又は、請求項7〜15のいずれか一項のポリペプチドを作製するための無細胞発現系中で発現される、請求項19の方法。
- 前記宿主細胞は、細菌細胞、酵母細胞、又は哺乳類細胞である、請求項20に記載の方法。
- 前記宿主細胞は、細菌細胞であり、
前記方法は、
a)ポリペプチドが作製されるように、請求項7〜15のいずれか一項のポリペプチドをコード化するポリヌクレオチドを含む細菌細胞を培養する工程と、
b)細菌細胞を透過化する工程であって、前記ポリヌクレオチド及び前記ポリペプチドが、透過化した細菌細胞内に保持される工程と、
c)標的分子が透過化した細菌細胞内で拡散するように、透過化した細菌細胞を標的分子に接触させる工程と、
d)請求項7〜15のいずれか一項のポリペプチドが標的分子に結合するかどうかを決定する工程と、を含む請求項21の方法。 - 前記無細胞発現系は、リボソームディスプレイシステム、mRNAディスプレイシステム、又はシスディスプレイシステムを含む、請求項22の方法。
- 複数の宿主細胞を含む宿主細胞ライブラリーであって、
前記複数の宿主細胞は、請求項7〜15のいずれか一項記載のポリペプチドを含み、
1以上の宿主細胞は、VH可変領域及び/又はVL可変領域中の1以上の相補性決定領域に存在するアミノ酸配列のライブラリーにおいて、別の宿主細胞に存在するポリペプチドと異なるポリペプチドを含む、複数の宿主細胞を含む宿主細胞ライブラリー。 - 請求項7〜15のいずれか一項のポリペプチド、請求項16のポリヌクレオチド、及び/又は請求項17のベクター、並びに、薬学的に許容されるキャリア。
- 請求項7〜15のいずれか一項のポリペプチド、請求項16のポリヌクレオチド、及び/又は、請求項17のベクター、並びに、細菌細胞を透過処理することができる薬剤を含むキット。
- 治療器具又は診断器具における、請求項7〜15のいずれか一項のポリペプチドの使用。
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