JP7336457B2 - 抗体Fc領域を主鎖として用いた融合タンパク質二量体及びその使用 - Google Patents
抗体Fc領域を主鎖として用いた融合タンパク質二量体及びその使用 Download PDFInfo
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Description
サイトカインIL-2またはIL-12を、抗体FcのN末端またはC末端にリンカー配列(Gly4Ser)3(すなわち、(G4S)3)を介して連結させてもよい。同様に、PD-1単一ドメイン抗体をまた、抗体FcのN末端またはC末端にリンカー配列(Gly4Ser)3を介して連結させてもよい。形成した融合タンパク質は、抗体及びサイトカインの二重効果を保持している。作用性IL-12が2つのサブユニット、P35及びP40で構成されていることから、IL-12が抗体Fc上に2つのサブユニットの形態で単独で融合する、または、IL-12の2つのサブユニットが最初に抗体Fcにリンカー配列(Gly4Ser)3を介して融合して単鎖タンパク質を形成してから、単鎖タンパク質が抗体Fc上に融合する。
2.1:細胞ベースの標的親和性実験
本実験では、Biacoreの酵素結合吸着測定法、FACS、及び、類似の方法を用いて、PD-1発現細胞株及び活性化T細胞内における、PD-1受容体に対する抗体/サイトカイン融合タンパク質の標的親和性を測定する。
活性化T細胞を用いた抗体親和性の測定:陽性T細胞スクリーニングキット(BD Bioscience)を用いてヒト末梢血単核球からCD4+T細胞を単離してから、抗CD3抗体で4日間活性化させ、蛍光標識抗体及びFACS法を用いて測定する。CM5感知プローブをヒトPD-1-FC(R&D system)またはFLAGタグ付きサルPD-1タンパク質で標識して、PD-1受容体タンパク質をプローブに通して流し、SPR(Biacore)を用いて親和性を測定することにより、抗体/サイトカイン融合タンパク質とPD-1の間の結合性のパラメータを測定する。
2.2.1:細胞増殖、ならびに、IFN-γ分泌及びIL-2分泌の実験:
IL-2及びIL-12が、ヒトT細胞の増殖を促進し得、様々なリンパ球についても活性化し得ることから、T細胞の増殖及びインターフェロン-ガンマ(IFN-γ)の分泌が促進される。T細胞増殖またはIFN-γ分泌を検出することにより、抗体-サイトカイン融合タンパク質のサイトカイン活性を評価することができる。
概要:ADCCとは、IgGFc受容体を発現し、標的細胞の表面に結合しているIgG抗体のFcセグメントに結合することにより、ウイルス感染細胞及び腫瘍細胞などの標的細胞を殺傷するNK細胞、マクロファージ、好中球、顆粒球などによる作用のことを意味する。IgG抗体はこれらの細胞のADCC作用を媒介することができ、NK細胞は、ADCCの役割を果たすことのできる主な細胞である。
1.標的細胞の調製:Raji細胞をインフルエンザウイルスに48時間感染させて80~95%の感染率に到達させてから、生理食塩水で2回洗浄し、PKH67で標識する。
概要:標準的な手順に従いPD-1阻害実験(Promega)及び混合リンパ球反応実験(Genscript)を実施する。以下はPD-1阻害実験の簡潔な工程である。
1.PD-L1細胞を溶解して96ウェルプレート上に播種し、37℃の温度で維持する。
ヒトIL-12受容体を有する腫瘍モデル、ヒトPD-1を有する腫瘍モデル、及び、ノックインマウスを確立することにより、インビボ抗腫瘍効果を評価する。IL-12受容体及びPD-1のそれぞれのヒト化により、単一ドメイン抗体及びサイトカインを融合させた融合タンパク質のインビボ医薬効果を直接評価することが可能となる。この評価に好適な腫瘍モデルとしては、GL261細胞株またはB16細胞株を挙げることができるがこれらに限定されない。以下の特徴、(1)腫瘍形成の阻害、(2)形成腫瘍の増殖の阻害、及び、(3)用量勾配試験(3つの用量)において、医薬効果を評価する。
1×106のGL261細胞またはB16細胞をマウスの腹部または背部に皮下注射する。平均腫瘍容積が100mm3に到達すると、マウスを、4つの群(それぞれの群に8匹のマウス)、対照群、抗PD-1群、抗PD-1+IL2群、抗PD-1+IL-12群、及び、抗PD-1+IL2+IL12群へと、無作為に分割する。4日間に1回、合計で3回、投与を実施する。毎回、PBS(対照群)、PD-1(sdAb-Fc)単一ドメイン抗体Fc融合(抗PD-1群)、PD-1 sdAb-IL2融合タンパク質(抗PD-1+IL2群)、PD-1 sdAb-IL12融合タンパク質(抗PD-1+IL12群)、及び、PD-1 sdAb-IL2-IL12融合タンパク質(抗PD-1+IL2+IL12群)を用いて、腫瘍内投与または尾静脈投与により、投与を実施する。その後、腫瘍の増殖状態を週に3回モニターする。
解析用にSPSSソフトウェアを採用する。全てのデータは「平均±標準偏差」の形態で表される。one-way ANOVA解析を用い、P<0.05の差異を統計的に有意とする。
1.抗体Fcヘテロ二量体をベースとした免疫サイトカイン融合タンパク質の構築
本試験では、抗体Fcヘテロ二量体をベースとした一連の単一ドメイン抗体-サイトカイン融合タンパク質を構築する。融合タンパク質を構築するために使用する構成要素は、PD-1単一ドメイン抗体、ならびに、サイトカインIL-12、IL-2、及び、IL-2変異体である。
ATGGGCTGGTCCTGCATCATCCTGTTTCTGGTGGCTACCGCTACCGGCGTGCACTCT
CAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGC
QVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSS
GGTGGAGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCT
ATTTGGGAGCTGAAGAAAGACGTGTACGTGGTCGAGCTGGACTGGTACCCTGATGCCCCAGGCGAGATGGTCGTGCTGACCTGCGATACACCAGAGGAAGATGGTATCACCTGGACACTGGATCAGTCCTCAGAGGTGCTGGGCTCTGGTAAAACACTGACCATTCAGGTGAAGGAGTTCGGTGACGCTGGACAGTACACTTGTCATAAGGGCGGGGAGGTGCTGTCTCACTCCCTGCTGCTGCTGCATAAGAAGGAGGATGGAATCTGGTCCACTGACATCCTGAAAGACCAGAAGGAGCCAAAGAACAAAACCTTCCTGCGATGCGAGGCTAAGAACTACAGCGGCCGCTTTACATGCTGGTGGCTGACAACCATCAGCACCGATCTGACCTTTAGCGTGAAGTCATCCAGGGGCAGTTCAGACCCTCAGGGAGTCACATGTGGCGCCGCAACCCTGTCAGCAGAGCGAGTGCGGGGAGACAATAAGGAATACGAGTACAGCGTCGAGTGTCAGGAGGATTCCGCATGTCCAGCTGCAGAAGAATCCCTGCCTATCGAAGTCATGGTGGACGCTGTGCATAAACTGAAGTACGAGAATTACACCAGCAGCTTTTTCATCCGGGACATCATCAAGCCCGATCCACCTAAGAATCTGCAGCTGAAGCCTCTGAAAAATAGCCGACAGGTCGAAGTGTCATGGGAATACCCAGACACCTGGTCAACACCACACTCCTACTTCTCCCTGACCTTCTGTGTGCAGGTCCAGGGAAAAAGCAAGCGGGAAAAGAAAGATCGGGTGTTCACCGACAAGACCAGTGCTACAGTGATTTGCCGGAAGAATGCCAGCATTTCTGTCAGAGCTCAGGACCGGTACTATAGCTCTTCCTGGAGCGAGTGGGCTTCAGTGCCATGTTCTGGaGGCGGtGGATCTGGCGGAGGTGGAAGCGGAGGCGGTGGATCTAGAAACCTGCCCGTCGCAACCCCTGATCCAGGGATGTTCCCCTGTCTGCATCACAGCCAGAATCTGCTGAGGGCTGTCTCCAACATGCTGCAGAAGGCTCGACAGACCCTGGAGTTCTACCCATGTACCAGCGAAGAGATCGACCACGAGGATATCACAAAGGATAAAACCAGCACAGTGGAAGCATGCCTGCCTCTGGAACTGACCAAGAATGAGAGCTGCCTGAATAGCAGGGAGACCTCCTTCATCACCAACGGCTCATGCCTGGCTTCAAGGAAGACCAGCTTCATGATGGCTCTGTGTCTGAGCTCTATCTATGAGGACCTGAAGATGTACCAGGTGGAGTTCAAGACCATGAACGCCAAGCTGCTGATGGATCCAAAGAGGCAGATCTTCCTGGATCAGAATATGCTGGCAGTGATCGATGAGCTGATGCAGGCCCTGAATTTTAACAGTGAGACAGTGCCTCAGAAGAGCTCTCTGGAAGAGCCAGACTTTTACAAAACTAAGATCAAGCTGTGCATTCTGCTGCACGCTTTCCGCATCAGAGCTGTCACTATCGATAGAGTGATGAGCTATCTGAATGCCTCA
IWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
GCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTAAGACCCAGGGACTTAATCAGCAATATCAACGTAATAGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
GCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTCGACCCCAGGGACGTGGTGAGCAATATCAACGTATTCGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHFDPRDVVSNINVFVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
CAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCCCCTTGTCCTGCCCCTGAACTGCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCAAAGCCTAAGGACACCCTGATGATCTCCCGGACCCCCGAAGTGACCTGCGTGGTGGTGGATGTGTCCCACGAGGACCCTGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACGCCTCCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCCCGGGAACCCCAGGTGTACACACTGCCCCCTAGCAGGGACGAGCTGACCAAGAACCAGGTGTCCCTGACCTGTCTCGTGAAAGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTATAAGACCACCCCCCCTGTGCTGGACTCCGACGGCTCATTCTTCCTGTACAGCAAGCTGACAGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGTCCCTGAGCCCCGGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTATTTGGGAGCTGAAGAAAGACGTGTACGTGGTCGAGCTGGACTGGTACCCTGATGCCCCAGGCGAGATGGTCGTGCTGACCTGCGATACACCAGAGGAAGATGGTATCACCTGGACACTGGATCAGTCCTCAGAGGTGCTGGGCTCTGGTAAAACACTGACCATTCAGGTGAAGGAGTTCGGTGACGCTGGACAGTACACTTGTCATAAGGGCGGGGAGGTGCTGTCTCACTCCCTGCTGCTGCTGCATAAGAAGGAGGATGGAATCTGGTCCACTGACATCCTGAAAGACCAGAAGGAGCCAAAGAACAAAACCTTCCTGCGATGCGAGGCTAAGAACTACAGCGGCCGCTTTACATGCTGGTGGCTGACAACCATCAGCACCGATCTGACCTTTAGCGTGAAGTCATCCAGGGGCAGTTCAGACCCTCAGGGAGTCACATGTGGCGCCGCAACCCTGTCAGCAGAGCGAGTGCGGGGAGACAATAAGGAATACGAGTACAGCGTCGAGTGTCAGGAGGATTCCGCATGTCCAGCTGCAGAAGAATCCCTGCCTATCGAAGTCATGGTGGACGCTGTGCATAAACTGAAGTACGAGAATTACACCAGCAGCTTTTTCATCCGGGACATCATCAAGCCCGATCCACCTAAGAATCTGCAGCTGAAGCCTCTGAAAAATAGCCGACAGGTCGAAGTGTCATGGGAATACCCAGACACCTGGTCAACACCACACTCCTACTTCTCCCTGACCTTCTGTGTGCAGGTCCAGGGAAAAAGCAAGCGGGAAAAGAAAGATCGGGTGTTCACCGACAAGACCAGTGCTACAGTGATTTGCCGGAAGAATGCCAGCATTTCTGTCAGAGCTCAGGACCGGTACTATAGCTCTTCCTGGAGCGAGTGGGCTTCAGTGCCATGTTCTGGaGGCGGtGGATCTGGCGGAGGTGGAAGCGGAGGCGGTGGATCTAGAAACCTGCCCGTCGCAACCCCTGATCCAGGGATGTTCCCCTGTCTGCATCACAGCCAGAATCTGCTGAGGGCTGTCTCCAACATGCTGCAGAAGGCTCGACAGACCCTGGAGTTCTACCCATGTACCAGCGAAGAGATCGACCACGAGGATATCACAAAGGATAAAACCAGCACAGTGGAAGCATGCCTGCCTCTGGAACTGACCAAGAATGAGAGCTGCCTGAATAGCAGGGAGACCTCCTTCATCACCAACGGCTCATGCCTGGCTTCAAGGAAGACCAGCTTCATGATGGCTCTGTGTCTGAGCTCTATCTATGAGGACCTGAAGATGTACCAGGTGGAGTTCAAGACCATGAACGCCAAGCTGCTGATGGATCCAAAGAGGCAGATCTTCCTGGATCAGAATATGCTGGCAGTGATCGATGAGCTGATGCAGGCCCTGAATTTTAACAGTGAGACAGTGCCTCAGAAGAGCTCTCTGGAAGAGCCAGACTTTTACAAAACTAAGATCAAGCTGTGCATTCTGCTGCACGCTTTCCGCATCAGAGCTGTCACTATCGATAGAGTGATGAGCTATCTGAATGCCTCA
QVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
CAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCCCCTTGTCCTGCCCCTGAACTGCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCAAAGCCTAAGGACACCCTGATGATCTCCCGGACCCCCGAAGTGACCTGCGTGGTGGTGGATGTGTCCCACGAGGACCCTGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACGCCTCCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCCCGGGAACCCCAGGTGTACACACTGCCCCCTAGCAGGGACGAGCTGACCAAGAACCAGGTGTCCCTGACCTGTCTCGTGAAAGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTATAAGACCACCCCCCCTGTGCTGGACTCCGACGGCTCATTCTTCCTGTACAGCAAGCTGACAGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGTCCCTGAGCCCCGGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTAAGACCCAGGGACTTAATCAGCAATATCAACGTAATAGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
QVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
CAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCCCCTTGTCCTGCCCCTGAACTGCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCAAAGCCTAAGGACACCCTGATGATCTCCCGGACCCCCGAAGTGACCTGCGTGGTGGTGGATGTGTCCCACGAGGACCCTGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACGCCTCCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCCCGGGAACCCCAGGTGTACACACTGCCCCCTTGCAGGGACGAGCTGACCAAGAACCAGGTGTCCCTGTGGTGTCTCGTGAAAGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTATAAGACCACCCCCCCTGTGCTGGACTCCGACGGCTCATTCTTCCTGTACAGCAAGCTGACAGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGTCCCTGAGCCCCGGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTATTTGGGAGCTGAAGAAAGACGTGTACGTGGTCGAGCTGGACTGGTACCCTGATGCCCCAGGCGAGATGGTCGTGCTGACCTGCGATACACCAGAGGAAGATGGTATCACCTGGACACTGGATCAGTCCTCAGAGGTGCTGGGCTCTGGTAAAACACTGACCATTCAGGTGAAGGAGTTCGGTGACGCTGGACAGTACACTTGTCATAAGGGCGGGGAGGTGCTGTCTCACTCCCTGCTGCTGCTGCATAAGAAGGAGGATGGAATCTGGTCCACTGACATCCTGAAAGACCAGAAGGAGCCAAAGAACAAAACCTTCCTGCGATGCGAGGCTAAGAACTACAGCGGCCGCTTTACATGCTGGTGGCTGACAACCATCAGCACCGATCTGACCTTTAGCGTGAAGTCATCCAGGGGCAGTTCAGACCCTCAGGGAGTCACATGTGGCGCCGCAACCCTGTCAGCAGAGCGAGTGCGGGGAGACAATAAGGAATACGAGTACAGCGTCGAGTGTCAGGAGGATTCCGCATGTCCAGCTGCAGAAGAATCCCTGCCTATCGAAGTCATGGTGGACGCTGTGCATAAACTGAAGTACGAGAATTACACCAGCAGCTTTTTCATCCGGGACATCATCAAGCCCGATCCACCTAAGAATCTGCAGCTGAAGCCTCTGAAAAATAGCCGACAGGTCGAAGTGTCATGGGAATACCCAGACACCTGGTCAACACCACACTCCTACTTCTCCCTGACCTTCTGTGTGCAGGTCCAGGGAAAAAGCAAGCGGGAAAAGAAAGATCGGGTGTTCACCGACAAGACCAGTGCTACAGTGATTTGCCGGAAGAATGCCAGCATTTCTGTCAGAGCTCAGGACCGGTACTATAGCTCTTCCTGGAGCGAGTGGGCTTCAGTGCCATGTTCTGGaGGCGGtGGATCTGGCGGAGGTGGAAGCGGAGGCGGTGGATCTAGAAACCTGCCCGTCGCAACCCCTGATCCAGGGATGTTCCCCTGTCTGCATCACAGCCAGAATCTGCTGAGGGCTGTCTCCAACATGCTGCAGAAGGCTCGACAGACCCTGGAGTTCTACCCATGTACCAGCGAAGAGATCGACCACGAGGATATCACAAAGGATAAAACCAGCACAGTGGAAGCATGCCTGCCTCTGGAACTGACCAAGAATGAGAGCTGCCTGAATAGCAGGGAGACCTCCTTCATCACCAACGGCTCATGCCTGGCTTCAAGGAAGACCAGCTTCATGATGGCTCTGTGTCTGAGCTCTATCTATGAGGACCTGAAGATGTACCAGGTGGAGTTCAAGACCATGAACGCCAAGCTGCTGATGGATCCAAAGAGGCAGATCTTCCTGGATCAGAATATGCTGGCAGTGATCGATGAGCTGATGCAGGCCCTGAATTTTAACAGTGAGACAGTGCCTCAGAAGAGCTCTCTGGAAGAGCCAGACTTTTACAAAACTAAGATCAAGCTGTGCATTCTGCTGCACGCTTTCCGCATCAGAGCTGTCACTATCGATAGAGTGATGAGCTATCTGAATGCCTCA
QVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
CAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCCCCTTGTCCTGCCCCTGAACTGCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCAAAGCCTAAGGACACCCTGATGATCTCCCGGACCCCCGAAGTGACCTGCGTGGTGGTGGATGTGTCCCACGAGGACCCTGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACGCCTCCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCCCGGGAACCCCAGGTGTGTACACTGCCCCCTAGCAGGGACGAGCTGACCAAGAACCAGGTGTCCCTGTCCTGTGCCGTGAAAGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTATAAGACCACCCCCCCTGTGCTGGACTCCGACGGCTCATTCTTCCTGGTGAGCAAGCTGACAGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGTCCCTGAGCCCCGGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTAAGACCCAGGGACTTAATCAGCAATATCAACGTAATAGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
QVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
CAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTCAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCCCCTTGTCCTGCCCCTGAACTGCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCAAAGCCTAAGGACACCCTGATGATCTCCCGGACCCCCGAAGTGACCTGCGTGGTGGTGGATGTGTCCCACGAGGACCCTGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACGCCTCCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCCCGGGAACCCCAGGTGTACACACTGCCCCCTTGCAGGGACGAGCTGACCAAGAACCAGGTGTCCCTGTGGTGTCTCGTGAAAGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTATAAGACCACCCCCCCTGTGCTGGACTCCGACGGCTCATTCTTCCTGTACAGCAAGCTGACAGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGTCCCTGAGCCCCGGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTATTTGGGAGCTGAAGAAAGACGTGTACGTGGTCGAGCTGGACTGGTACCCTGATGCCCCAGGCGAGATGGTCGTGCTGACCTGCGATACACCAGAGGAAGATGGTATCACCTGGACACTGGATCAGTCCTCAGAGGTGCTGGGCTCTGGTAAAACACTGACCATTCAGGTGAAGGAGTTCGGTGACGCTGGACAGTACACTTGTCATAAGGGCGGGGAGGTGCTGTCTCACTCCCTGCTGCTGCTGCATAAGAAGGAGGATGGAATCTGGTCCACTGACATCCTGAAAGACCAGAAGGAGCCAAAGAACAAAACCTTCCTGCGATGCGAGGCTAAGAACTACAGCGGCCGCTTTACATGCTGGTGGCTGACAACCATCAGCACCGATCTGACCTTTAGCGTGAAGTCATCCAGGGGCAGTTCAGACCCTCAGGGAGTCACATGTGGCGCCGCAACCCTGTCAGCAGAGCGAGTGCGGGGAGACAATAAGGAATACGAGTACAGCGTCGAGTGTCAGGAGGATTCCGCATGTCCAGCTGCAGAAGAATCCCTGCCTATCGAAGTCATGGTGGACGCTGTGCATAAACTGAAGTACGAGAATTACACCAGCAGCTTTTTCATCCGGGACATCATCAAGCCCGATCCACCTAAGAATCTGCAGCTGAAGCCTCTGAAAAATAGCCGACAGGTCGAAGTGTCATGGGAATACCCAGACACCTGGTCAACACCACACTCCTACTTCTCCCTGACCTTCTGTGTGCAGGTCCAGGGAAAAAGCAAGCGGGAAAAGAAAGATCGGGTGTTCACCGACAAGACCAGTGCTACAGTGATTTGCCGGAAGAATGCCAGCATTTCTGTCAGAGCTCAGGACCGGTACTATAGCTCTTCCTGGAGCGAGTGGGCTTCAGTGCCATGTTCTGGaGGCGGtGGATCTGGCGGAGGTGGAAGCGGAGGCGGTGGATCTAGAAACCTGCCCGTCGCAACCCCTGATCCAGGGATGTTCCCCTGTCTGCATCACAGCCAGAATCTGCTGAGGGCTGTCTCCAACATGCTGCAGAAGGCTCGACAGACCCTGGAGTTCTACCCATGTACCAGCGAAGAGATCGACCACGAGGATATCACAAAGGATAAAACCAGCACAGTGGAAGCATGCCTGCCTCTGGAACTGACCAAGAATGAGAGCTGCCTGAATAGCAGGGAGACCTCCTTCATCACCAACGGCTCATGCCTGGCTTCAAGGAAGACCAGCTTCATGATGGCTCTGTGTCTGAGCTCTATCTATGAGGACCTGAAGATGTACCAGGTGGAGTTCAAGACCATGAACGCCAAGCTGCTGATGGATCCAAAGAGGCAGATCTTCCTGGATCAGAATATGCTGGCAGTGATCGATGAGCTGATGCAGGCCCTGAATTTTAACAGTGAGACAGTGCCTCAGAAGAGCTCTCTGGAAGAGCCAGACTTTTACAAAACTAAGATCAAGCTGTGCATTCTGCTGCACGCTTTCCGCATCAGAGCTGTCACTATCGATAGAGTGATGAGCTATCTGAATGCCTCA
QVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
CAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTCAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCCCCTTGTCCTGCCCCTGAACTGCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCAAAGCCTAAGGACACCCTGATGATCTCCCGGACCCCCGAAGTGACCTGCGTGGTGGTGGATGTGTCCCACGAGGACCCTGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACGCCTCCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCCCGGGAACCCCAGGTGTGTACACTGCCCCCTAGCAGGGACGAGCTGACCAAGAACCAGGTGTCCCTGTCCTGTGCCGTGAAAGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTATAAGACCACCCCCCCTGTGCTGGACTCCGACGGCTCATTCTTCCTGGTGAGCAAGCTGACAGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGTCCCTGAGCCCCGGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTAAGACCCAGGGACTTAATCAGCAATATCAACGTAATAGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
QVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
CAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTCAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCCCCTTGTCCTGCCCCTGAACTGCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCAAAGCCTAAGGACACCCTGATGATCTCCCGGACCCCCGAAGTGACCTGCGTGGTGGTGGATGTGTCCCACGAGGACCCTGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACGCCTCCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCCCGGGAACCCCAGGTGTGTACACTGCCCCCTAGCAGGGACGAGCTGACCAAGAACCAGGTGTCCCTGTCCTGTGCCGTGAAAGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTATAAGACCACCCCCCCTGTGCTGGACTCCGACGGCTCATTCTTCCTGGTGAGCAAGCTGACAGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGTCCCTGAGCCCCGGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTCGACCCCAGGGACGTGGTGAGCAATATCAACGTATTCGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
QVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHFDPRDVVSNINVFVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
CAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTCAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCCCCTTGTCCTGCCCCTGAACTGCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCAAAGCCTAAGGACACCCTGATGATCTCCCGGACCCCCGAAGTGACCTGCGTGGTGGTGGATGTGTCCCACGAGGACCCTGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACGCCTCCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCCCGGGAACCCCAGGTGTACACACTGCCCCCTTGCAGGGACGAGCTGACCAAGAACCAGGTGTCCCTGTGGTGTCTCGTGAAAGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTATAAGACCACCCCCCCTGTGCTGGACTCCGACGGCTCATTCTTCCTGTACAGCAAGCTGACAGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGTCCCTGAGCCCCGGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTAAGACCCAGGGACTTAATCAGCAATATCAACGTAATAGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
QVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
CAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTCAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCCCCTTGTCCTGCCCCTGAACTGCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCAAAGCCTAAGGACACCCTGATGATCTCCCGGACCCCCGAAGTGACCTGCGTGGTGGTGGATGTGTCCCACGAGGACCCTGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACGCCTCCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCCCGGGAACCCCAGGTGTGTACACTGCCCCCTAGCAGGGACGAGCTGACCAAGAACCAGGTGTCCCTGTCCTGTGCCGTGAAAGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTATAAGACCACCCCCCCTGTGCTGGACTCCGACGGCTCATTCTTCCTGGTGAGCAAGCTGACAGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGTCCCTGAGCCCCGGC
QVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
CAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTCAAGTTCAACTGGTGGAAAGCGGTGGTGGTCTGGTTCAGCCGGGCGGTAGCCTGCGTCTGAGCTGCGCGGCGAGCGGTGGTACCCTGGACTACTATGCGATCGGTTGGTTCCGTCAGGCGCCGGGCAAGGAGCGTGAGGCGGTGAGCTGCATTAGCAGCAGCGACGGTAGCACCTACTATGCGGATAGCGTTAAGGGCCGTTTTACCATCAGCCGTGATAACAGCAAAAACACCCTGTACCTGCAAATGAACAGCCTGCGTGCGGAAGACACCGCGGTGTATCACTGCGCGACCGATCGTGCGTGCGGTAGCAGCTGGCTGGGCGCGGAGAGCTGGGCGCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGAACCCAAGTCCTGCGACAAGACCCACACCTGTCCCCCTTGTCCTGCCCCTGAACTGCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCAAAGCCTAAGGACACCCTGATGATCTCCCGGACCCCCGAAGTGACCTGCGTGGTGGTGGATGTGTCCCACGAGGACCCTGAAGTGAAGTTCAATTGGTACGTGGACGGCGTGGAAGTGCACAACGCCAAGACCAAGCCTAGAGAGGAACAGTACGCCTCCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGCCCTGCCTGCCCCCATCGAAAAGACCATCTCCAAGGCCAAGGGCCAGCCCCGGGAACCCCAGGTGTACACACTGCCCCCTAGCAGGGACGAGCTGACCAAGAACCAGGTGTCCCTGACCTGTCTCGTGAAAGGCTTCTACCCCTCCGATATCGCCGTGGAATGGGAGTCCAACGGCCAGCCTGAGAACAACTATAAGACCACCCCCCCTGTGCTGGACTCCGACGGCTCATTCTTCCTGTACAGCAAGCTGACAGTGGACAAGTCCCGGTGGCAGCAGGGCAACGTGTTCTCCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGTCCCTGTCCCTGAGCCCCGGC
QVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSQVQLVESGGGLVQPGGSLRLSCAASGGTLDYYAIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCATDRACGSSWLGAESWAQGTLVTVSSGGGGSGGGGSGGGGSEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
本実験では、NK92細胞を刺激してインターフェロン-ガンマ(IFN-γ)を放出させるサイトカインを採用することにより、融合タンパク質内におけるサイトカインIL-12及びIL-2のインビトロ生物学的活性を検証する。本実験で構築した融合タンパク質がサイトカインを含有することから、異なる融合タンパク質をNK92細胞と共にインキュベートしてから、IFN-γの放出を検出する。
PD-1/PD-L1経路遮断のバイオアッセイは、生物学的に有意味な作用機構に基づいた検出解析法であり、PD-1/PD-L1相互作用を遮断可能な抗体及びその他の生物学的製剤の効果及び安定性を測定するのに使用することができる。この検出システムには、以下の2種の遺伝子組換え細胞株、ヒト由来PD-1を安定的に発現可能な細胞及びヒト由来PD-L1を安定的に発現する細胞が含まれている。
上記の実験結果は、抗体Fcヘテロ二量体をベースとした単一ドメイン抗体-サイトカインの優位性を示している。この技術プラットフォームの応用範囲及び広域スペクトルを更に検証するために、本発明者らは、以下の研究において、分子の異なる更なる単一ドメイン抗体を用いて、抗体Fcヘテロ二量体をベースとした一連の単一ドメイン抗体-サイトカイン融合タンパク質を構築する。それらにおいて、融合タンパク質を構築するのに用いるサイトカインは依然としてIL-12及びIL-2であり、単一ドメイン抗体は、1つの新規PD-1単一ドメイン抗体、または、3つの新規PD-L1単一ドメイン抗体である。ヒトIgG1変異体をベースとした上記の抗体Fcフラグメントとは異なり、新規の抗体FcフラグメントはヒトIgG4変異体をベースとしている。
本実験で構築したプラスミドの情報について、以下の表2に示す。
抗PD1a単一ドメイン抗体のアミノ酸配列(配列番号:71):
EVQLVESGGGLVQPGGSLRLSCAVSGNIYNRNFMGWFRQAPGKGLEGVSAIYTGTSRTYYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAADLRDGFWDTGVWNTWGQGTLVTVSS
抗PD-L1a単一ドメイン抗体のアミノ酸配列(配列番号:72):
EVQLVESGGGLVQPGGSLRLSCAASGRTFVTYGMGWFRQAPGKGREFVSAISWSGSMTSYGDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAALGAVVYTTREPYTYWGQGTLVTVSS
抗PD-L1b単一ドメイン抗体のアミノ酸配列(配列番号:73):
EVQLVESGGGLVQPGGSLRLSCAASGRTFVTYGMGWFRQAPGKGREFVSAISWSGSSTSYGDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAALGAVVYTTREPYTYWGQGTLVTVSS
抗PD-L1c単一ドメイン抗体のアミノ酸配列(配列番号:74):
EVQLVESGGGLVQPGGSLRLSCAASGRTFITYAIGWFRQAPGKGREFVSAISWSGSMTSYADSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAHRGAIAPIAQSVYTNWGQGTLVTVSS
GAAGTGCAGCTGGTTGAGTCCGGCGGCGGCCTGGTGCAGCCTGGCGGTTCTCTGCGGCTGTCTTGCGCCGTGAGCGGAAATATCTACAACCGGAACTTCATGGGCTGGTTTCGGCAGGCTCCAGGCAAAGGACTGGAAGGCGTGTCCGCCATCTACACCGGCACCTCTCGGACCTACTACGCCGACTCTGTCAAAGGCAGATTCACCATCTCCCGCGACAACAGCAAAAACACCGTGTACCTGCAGATGAACAGCCTGAGAGCTGAAGATACAGCTGTGTACTATTGCGCCGCCGATCTGAGAGACGGCTTCTGGGACACAGGCGTGTGGAACACCTGGGGCCAGGGCACACTTGTGACCGTGTCCTCTGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTACACCCTGCCTCCCTgTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtggTGCCTGGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGTACTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGCtcaGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTATTTGGGAGCTGAAGAAAGACGTGTACGTGGTCGAGCTGGACTGGTACCCTGATGCCCCAGGCGAGATGGTCGTGCTGACCTGCGATACACCAGAGGAAGATGGTATCACCTGGACACTGGATCAGTCCTCAGAGGTGCTGGGCTCTGGTAAAACACTGACCATTCAGGTGAAGGAGTTCGGTGACGCTGGACAGTACACTTGTCATAAGGGCGGGGAGGTGCTGTCTCACTCCCTGCTGCTGCTGCATAAGAAGGAGGATGGAATCTGGTCCACTGACATCCTGAAAGACCAGAAGGAGCCAAAGAACAAAACCTTCCTGCGATGCGAGGCTAAGAACTACAGCGGCCGCTTTACATGCTGGTGGCTGACAACCATCAGCACCGATCTGACCTTTAGCGTGAAGTCATCCAGGGGCAGTTCAGACCCTCAGGGAGTCACATGTGGCGCCGCAACCCTGTCAGCAGAGCGAGTGCGGGGAGACAATAAGGAATACGAGTACAGCGTCGAGTGTCAGGAGGATTCCGCATGTCCAGCTGCAGAAGAATCCCTGCCTATCGAAGTCATGGTGGACGCTGTGCATAAACTGAAGTACGAGAATTACACCAGCAGCTTTTTCATCCGGGACATCATCAAGCCCGATCCACCTAAGAATCTGCAGCTGAAGCCTCTGAAAAATAGCCGACAGGTCGAAGTGTCATGGGAATACCCAGACACCTGGTCAACACCACACTCCTACTTCTCCCTGACCTTCTGTGTGCAGGTCCAGGGAAAAAGCAAGCGGGAAAAGAAAGATCGGGTGTTCACCGACAAGACCAGTGCTACAGTGATTTGCCGGAAGAATGCCAGCATTTCTGTCAGAGCTCAGGACCGGTACTATAGCTCTTCCTGGAGCGAGTGGGCTTCAGTGCCATGTTCTGGaGGCGGtGGATCTGGCGGAGGTGGAAGCGGAGGCGGTGGATCTAGAAACCTGCCCGTCGCAACCCCTGATCCAGGGATGTTCCCCTGTCTGCATCACAGCCAGAATCTGCTGAGGGCTGTCTCCAACATGCTGCAGAAGGCTCGACAGACCCTGGAGTTCTACCCATGTACCAGCGAAGAGATCGACCACGAGGATATCACAAAGGATAAAACCAGCACAGTGGAAGCATGCCTGCCTCTGGAACTGACCAAGAATGAGAGCTGCCTGAATAGCAGGGAGACCTCCTTCATCACCAACGGCTCATGCCTGGCTTCAAGGAAGACCAGCTTCATGATGGCTCTGTGTCTGAGCTCTATCTATGAGGACCTGAAGATGTACCAGGTGGAGTTCAAGACCATGAACGCCAAGCTGCTGATGGATCCAAAGAGGCAGATCTTCCTGGATCAGAATATGCTGGCAGTGATCGATGAGCTGATGCAGGCCCTGAATTTTAACAGTGAGACAGTGCCTCAGAAGAGCTCTCTGGAAGAGCCAGACTTTTACAAAACTAAGATCAAGCTGTGCATTCTGCTGCACGCTTTCCGCATCAGAGCTGTCACTATCGATAGAGTGATGAGCTATCTGAATGCCTCA
EVQLVESGGGLVQPGGSLRLSCAVSGNIYNRNFMGWFRQAPGKGLEGVSAIYTGTSRTYYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAADLRDGFWDTGVWNTWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPCQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGSGGGGSGGGGSGGGGSIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
GAAGTGCAGCTGGTTGAGTCCGGCGGCGGCCTGGTGCAGCCTGGCGGTTCTCTGCGGCTGTCTTGCGCCGTGAGCGGAAATATCTACAACCGGAACTTCATGGGCTGGTTTCGGCAGGCTCCAGGCAAAGGACTGGAAGGCGTGTCCGCCATCTACACCGGCACCTCTCGGACCTACTACGCCGACTCTGTCAAAGGCAGATTCACCATCTCCCGCGACAACAGCAAAAACACCGTGTACCTGCAGATGAACAGCCTGAGAGCTGAAGATACAGCTGTGTACTATTGCGCCGCCGATCTGAGAGACGGCTTCTGGGACACAGGCGTGTGGAACACCTGGGGCCAGGGCACACTTGTGACCGTGTCCTCTGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTgCACCCTGCCTCCCTCTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtCCTGCgctGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGgttTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGCtcaGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTAAGACCCAGGGACTTAATCAGCAATATCAACGTAATAGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
EVQLVESGGGLVQPGGSLRLSCAVSGNIYNRNFMGWFRQAPGKGLEGVSAIYTGTSRTYYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAADLRDGFWDTGVWNTWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVCTLPPSQEEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGSGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
GAAGTGCAGCTGGTTGAGTCCGGCGGCGGCCTGGTGCAGCCTGGCGGTTCTCTGCGGCTGTCTTGCGCCGTGAGCGGAAATATCTACAACCGGAACTTCATGGGCTGGTTTCGGCAGGCTCCAGGCAAAGGACTGGAAGGCGTGTCCGCCATCTACACCGGCACCTCTCGGACCTACTACGCCGACTCTGTCAAAGGCAGATTCACCATCTCCCGCGACAACAGCAAAAACACCGTGTACCTGCAGATGAACAGCCTGAGAGCTGAAGATACAGCTGTGTACTATTGCGCCGCCGATCTGAGAGACGGCTTCTGGGACACAGGCGTGTGGAACACCTGGGGCCAGGGCACACTTGTGACCGTGTCCTCTGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTgCACCCTGCCTCCCTCTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtCCTGCgctGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGgttTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGC
EVQLVESGGGLVQPGGSLRLSCAVSGNIYNRNFMGWFRQAPGKGLEGVSAIYTGTSRTYYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAADLRDGFWDTGVWNTWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVCTLPPSQEEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG
GAAGTGCAGCTGGTTGAGTCCGGCGGCGGCCTGGTGCAGCCTGGCGGTTCTCTGCGGCTGTCTTGCGCCGTGAGCGGAAATATCTACAACCGGAACTTCATGGGCTGGTTTCGGCAGGCTCCAGGCAAAGGACTGGAAGGCGTGTCCGCCATCTACACCGGCACCTCTCGGACCTACTACGCCGACTCTGTCAAAGGCAGATTCACCATCTCCCGCGACAACAGCAAAAACACCGTGTACCTGCAGATGAACAGCCTGAGAGCTGAAGATACAGCTGTGTACTATTGCGCCGCCGATCTGAGAGACGGCTTCTGGGACACAGGCGTGTGGAACACCTGGGGCCAGGGCACACTTGTGACCGTGTCCTCTGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTACACCCTGCCTCCCTgTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtggTGCCTGGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGTACTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGCtcaGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTAAGACCCAGGGACTTAATCAGCAATATCAACGTAATAGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
EVQLVESGGGLVQPGGSLRLSCAVSGNIYNRNFMGWFRQAPGKGLEGVSAIYTGTSRTYYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAADLRDGFWDTGVWNTWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPCQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGSGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTCCAGCCTGGCGGCTCTCTGCGGCTGTCCTGCGCCGCTTCTGGCAGAACCTTCGTGACCTACGGCATGGGCTGGTTCCGGCAGGCTCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCCATGACCTCTTACGGCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGATAACGCCAAGAACACACTGTACCTGCAGATGAACTCCCTGCGGCCTGAGGACACCGCCGTGTACTACTGCGCCGCTGCCCTGGGCGCTGTCGTGTACACCACCAGAGAACCCTATACCTACTGGGGACAGGGCACCCTGGTGACCGTGTCCTCTGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTACACCCTGCCTCCCTgTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtggTGCCTGGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGTACTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGCtcaGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTATTTGGGAGCTGAAGAAAGACGTGTACGTGGTCGAGCTGGACTGGTACCCTGATGCCCCAGGCGAGATGGTCGTGCTGACCTGCGATACACCAGAGGAAGATGGTATCACCTGGACACTGGATCAGTCCTCAGAGGTGCTGGGCTCTGGTAAAACACTGACCATTCAGGTGAAGGAGTTCGGTGACGCTGGACAGTACACTTGTCATAAGGGCGGGGAGGTGCTGTCTCACTCCCTGCTGCTGCTGCATAAGAAGGAGGATGGAATCTGGTCCACTGACATCCTGAAAGACCAGAAGGAGCCAAAGAACAAAACCTTCCTGCGATGCGAGGCTAAGAACTACAGCGGCCGCTTTACATGCTGGTGGCTGACAACCATCAGCACCGATCTGACCTTTAGCGTGAAGTCATCCAGGGGCAGTTCAGACCCTCAGGGAGTCACATGTGGCGCCGCAACCCTGTCAGCAGAGCGAGTGCGGGGAGACAATAAGGAATACGAGTACAGCGTCGAGTGTCAGGAGGATTCCGCATGTCCAGCTGCAGAAGAATCCCTGCCTATCGAAGTCATGGTGGACGCTGTGCATAAACTGAAGTACGAGAATTACACCAGCAGCTTTTTCATCCGGGACATCATCAAGCCCGATCCACCTAAGAATCTGCAGCTGAAGCCTCTGAAAAATAGCCGACAGGTCGAAGTGTCATGGGAATACCCAGACACCTGGTCAACACCACACTCCTACTTCTCCCTGACCTTCTGTGTGCAGGTCCAGGGAAAAAGCAAGCGGGAAAAGAAAGATCGGGTGTTCACCGACAAGACCAGTGCTACAGTGATTTGCCGGAAGAATGCCAGCATTTCTGTCAGAGCTCAGGACCGGTACTATAGCTCTTCCTGGAGCGAGTGGGCTTCAGTGCCATGTTCTGGaGGCGGtGGATCTGGCGGAGGTGGAAGCGGAGGCGGTGGATCTAGAAACCTGCCCGTCGCAACCCCTGATCCAGGGATGTTCCCCTGTCTGCATCACAGCCAGAATCTGCTGAGGGCTGTCTCCAACATGCTGCAGAAGGCTCGACAGACCCTGGAGTTCTACCCATGTACCAGCGAAGAGATCGACCACGAGGATATCACAAAGGATAAAACCAGCACAGTGGAAGCATGCCTGCCTCTGGAACTGACCAAGAATGAGAGCTGCCTGAATAGCAGGGAGACCTCCTTCATCACCAACGGCTCATGCCTGGCTTCAAGGAAGACCAGCTTCATGATGGCTCTGTGTCTGAGCTCTATCTATGAGGACCTGAAGATGTACCAGGTGGAGTTCAAGACCATGAACGCCAAGCTGCTGATGGATCCAAAGAGGCAGATCTTCCTGGATCAGAATATGCTGGCAGTGATCGATGAGCTGATGCAGGCCCTGAATTTTAACAGTGAGACAGTGCCTCAGAAGAGCTCTCTGGAAGAGCCAGACTTTTACAAAACTAAGATCAAGCTGTGCATTCTGCTGCACGCTTTCCGCATCAGAGCTGTCACTATCGATAGAGTGATGAGCTATCTGAATGCCTCA
EVQLVESGGGLVQPGGSLRLSCAASGRTFVTYGMGWFRQAPGKGREFVSAISWSGSMTSYGDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAALGAVVYTTREPYTYWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPCQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGSGGGGSGGGGSGGGGSIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTCCAGCCTGGCGGCTCTCTGCGGCTGTCCTGCGCCGCTTCTGGCAGAACCTTCGTGACCTACGGCATGGGCTGGTTCCGGCAGGCTCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCCATGACCTCTTACGGCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGATAACGCCAAGAACACACTGTACCTGCAGATGAACTCCCTGCGGCCTGAGGACACCGCCGTGTACTACTGCGCCGCTGCCCTGGGCGCTGTCGTGTACACCACCAGAGAACCCTATACCTACTGGGGACAGGGCACCCTGGTGACCGTGTCCTCTGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTgCACCCTGCCTCCCTCTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtCCTGCgctGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGgttTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGCtcaGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTAAGACCCAGGGACTTAATCAGCAATATCAACGTAATAGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
EVQLVESGGGLVQPGGSLRLSCAASGRTFVTYGMGWFRQAPGKGREFVSAISWSGSMTSYGDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAALGAVVYTTREPYTYWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVCTLPPSQEEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGSGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTCCAGCCTGGCGGCTCTCTGCGGCTGTCCTGCGCCGCTTCTGGCAGAACCTTCGTGACCTACGGCATGGGCTGGTTCCGGCAGGCTCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCCATGACCTCTTACGGCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGATAACGCCAAGAACACACTGTACCTGCAGATGAACTCCCTGCGGCCTGAGGACACCGCCGTGTACTACTGCGCCGCTGCCCTGGGCGCTGTCGTGTACACCACCAGAGAACCCTATACCTACTGGGGACAGGGCACCCTGGTGACCGTGTCCTCTGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCGAGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTGCACCCTGCCTCCCTCTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGTCCTGCGCTGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGGTTTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGC
EVQLVESGGGLVQPGGSLRLSCAASGRTFVTYGMGWFRQAPGKGREFVSAISWSGSMTSYGDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAALGAVVYTTREPYTYWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVCTLPPSQEEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTCCAGCCTGGCGGCTCTCTGCGGCTGTCCTGCGCCGCTTCTGGCAGAACCTTCGTGACCTACGGCATGGGCTGGTTCCGGCAGGCTCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCCATGACCTCTTACGGCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGATAACGCCAAGAACACACTGTACCTGCAGATGAACTCCCTGCGGCCTGAGGACACCGCCGTGTACTACTGCGCCGCTGCCCTGGGCGCTGTCGTGTACACCACCAGAGAACCCTATACCTACTGGGGACAGGGCACCCTGGTGACCGTGTCCTCTGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTACACCCTGCCTCCCTgTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtggTGCCTGGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGTACTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGCtcaGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTAAGACCCAGGGACTTAATCAGCAATATCAACGTAATAGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
EVQLVESGGGLVQPGGSLRLSCAASGRTFVTYGMGWFRQAPGKGREFVSAISWSGSMTSYGDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAALGAVVYTTREPYTYWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPCQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGSGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTCCAGCCTGGCGGCTCTCTGCGGCTGTCCTGCGCCGCTTCTGGCAGAACCTTCGTGACCTACGGCATGGGCTGGTTCCGGCAGGCTCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCCAgcACCTCTTACGGCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGATAACGCCAAGAACACACTGTACCTGCAGATGAACTCCCTGCGGCCTGAGGACACCGCCGTGTACTACTGCGCCGCTGCCCTGGGCGCTGTCGTGTACACCACCAGAGAACCCTATACCTACTGGGGACAGGGCACCCTGGTGACCGTGTCCTCTGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTACACCCTGCCTCCCTgTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtggTGCCTGGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGTACTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGCtcaGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTATTTGGGAGCTGAAGAAAGACGTGTACGTGGTCGAGCTGGACTGGTACCCTGATGCCCCAGGCGAGATGGTCGTGCTGACCTGCGATACACCAGAGGAAGATGGTATCACCTGGACACTGGATCAGTCCTCAGAGGTGCTGGGCTCTGGTAAAACACTGACCATTCAGGTGAAGGAGTTCGGTGACGCTGGACAGTACACTTGTCATAAGGGCGGGGAGGTGCTGTCTCACTCCCTGCTGCTGCTGCATAAGAAGGAGGATGGAATCTGGTCCACTGACATCCTGAAAGACCAGAAGGAGCCAAAGAACAAAACCTTCCTGCGATGCGAGGCTAAGAACTACAGCGGCCGCTTTACATGCTGGTGGCTGACAACCATCAGCACCGATCTGACCTTTAGCGTGAAGTCATCCAGGGGCAGTTCAGACCCTCAGGGAGTCACATGTGGCGCCGCAACCCTGTCAGCAGAGCGAGTGCGGGGAGACAATAAGGAATACGAGTACAGCGTCGAGTGTCAGGAGGATTCCGCATGTCCAGCTGCAGAAGAATCCCTGCCTATCGAAGTCATGGTGGACGCTGTGCATAAACTGAAGTACGAGAATTACACCAGCAGCTTTTTCATCCGGGACATCATCAAGCCCGATCCACCTAAGAATCTGCAGCTGAAGCCTCTGAAAAATAGCCGACAGGTCGAAGTGTCATGGGAATACCCAGACACCTGGTCAACACCACACTCCTACTTCTCCCTGACCTTCTGTGTGCAGGTCCAGGGAAAAAGCAAGCGGGAAAAGAAAGATCGGGTGTTCACCGACAAGACCAGTGCTACAGTGATTTGCCGGAAGAATGCCAGCATTTCTGTCAGAGCTCAGGACCGGTACTATAGCTCTTCCTGGAGCGAGTGGGCTTCAGTGCCATGTTCTGGaGGCGGtGGATCTGGCGGAGGTGGAAGCGGAGGCGGTGGATCTAGAAACCTGCCCGTCGCAACCCCTGATCCAGGGATGTTCCCCTGTCTGCATCACAGCCAGAATCTGCTGAGGGCTGTCTCCAACATGCTGCAGAAGGCTCGACAGACCCTGGAGTTCTACCCATGTACCAGCGAAGAGATCGACCACGAGGATATCACAAAGGATAAAACCAGCACAGTGGAAGCATGCCTGCCTCTGGAACTGACCAAGAATGAGAGCTGCCTGAATAGCAGGGAGACCTCCTTCATCACCAACGGCTCATGCCTGGCTTCAAGGAAGACCAGCTTCATGATGGCTCTGTGTCTGAGCTCTATCTATGAGGACCTGAAGATGTACCAGGTGGAGTTCAAGACCATGAACGCCAAGCTGCTGATGGATCCAAAGAGGCAGATCTTCCTGGATCAGAATATGCTGGCAGTGATCGATGAGCTGATGCAGGCCCTGAATTTTAACAGTGAGACAGTGCCTCAGAAGAGCTCTCTGGAAGAGCCAGACTTTTACAAAACTAAGATCAAGCTGTGCATTCTGCTGCACGCTTTCCGCATCAGAGCTGTCACTATCGATAGAGTGATGAGCTATCTGAATGCCTCA
EVQLVESGGGLVQPGGSLRLSCAASGRTFVTYGMGWFRQAPGKGREFVSAISWSGSSTSYGDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAALGAVVYTTREPYTYWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPCQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGSGGGGSGGGGSGGGGSIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTCCAGCCTGGCGGCTCTCTGCGGCTGTCCTGCGCCGCTTCTGGCAGAACCTTCGTGACCTACGGCATGGGCTGGTTCCGGCAGGCTCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCCAgcACCTCTTACGGCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGATAACGCCAAGAACACACTGTACCTGCAGATGAACTCCCTGCGGCCTGAGGACACCGCCGTGTACTACTGCGCCGCTGCCCTGGGCGCTGTCGTGTACACCACCAGAGAACCCTATACCTACTGGGGACAGGGCACCCTGGTGACCGTGTCCTCTGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTgCACCCTGCCTCCCTCTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtCCTGCgctGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGgttTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGCtcaGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTAAGACCCAGGGACTTAATCAGCAATATCAACGTAATAGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
EVQLVESGGGLVQPGGSLRLSCAASGRTFVTYGMGWFRQAPGKGREFVSAISWSGSSTSYGDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAALGAVVYTTREPYTYWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVCTLPPSQEEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGSGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTCCAGCCTGGCGGCTCTCTGCGGCTGTCCTGCGCCGCTTCTGGCAGAACCTTCGTGACCTACGGCATGGGCTGGTTCCGGCAGGCTCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCCAgcACCTCTTACGGCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGATAACGCCAAGAACACACTGTACCTGCAGATGAACTCCCTGCGGCCTGAGGACACCGCCGTGTACTACTGCGCCGCTGCCCTGGGCGCTGTCGTGTACACCACCAGAGAACCCTATACCTACTGGGGACAGGGCACCCTGGTGACCGTGTCCTCTGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTgCACCCTGCCTCCCTCTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtCCTGCgctGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGgttTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGC
EVQLVESGGGLVQPGGSLRLSCAASGRTFVTYGMGWFRQAPGKGREFVSAISWSGSSTSYGDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAALGAVVYTTREPYTYWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVCTLPPSQEEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTCCAGCCTGGCGGCTCTCTGCGGCTGTCCTGCGCCGCTTCTGGCAGAACCTTCGTGACCTACGGCATGGGCTGGTTCCGGCAGGCTCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCCAgcACCTCTTACGGCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGATAACGCCAAGAACACACTGTACCTGCAGATGAACTCCCTGCGGCCTGAGGACACCGCCGTGTACTACTGCGCCGCTGCCCTGGGCGCTGTCGTGTACACCACCAGAGAACCCTATACCTACTGGGGACAGGGCACCCTGGTGACCGTGTCCTCTGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTACACCCTGCCTCCCTgTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtggTGCCTGGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGTACTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGCtcaGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTAAGACCCAGGGACTTAATCAGCAATATCAACGTAATAGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
EVQLVESGGGLVQPGGSLRLSCAASGRTFVTYGMGWFRQAPGKGREFVSAISWSGSSTSYGDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAALGAVVYTTREPYTYWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPCQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGSGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTGCAGCCTGGCGGCTCTCTGAGACTGTCCTGCGCCGCTTCTGGCCGGACCTTCATCACCTACGCCATCGGCTGGTTCAGACAGGCCCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCTATGACCAGCTACGCCGACTCTGTGAAGGGCAGATTCACCATCTCCCGGGATAACGCCAAGAACACCCTGTACCTGCAGATGAATTCCCTGAGACCTGAGGACACAGCTGTGTATTACTGCGCCGCTCACCGGGGCGCCATCGCTCCCATCGCTCAGAGCGTGTACACCAACTGGGGCCAGGGAACCCTGGTCACCGTGTCCAGCGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTACACCCTGCCTCCCTgTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtggTGCCTGGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGTACTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGCtcaGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTATTTGGGAGCTGAAGAAAGACGTGTACGTGGTCGAGCTGGACTGGTACCCTGATGCCCCAGGCGAGATGGTCGTGCTGACCTGCGATACACCAGAGGAAGATGGTATCACCTGGACACTGGATCAGTCCTCAGAGGTGCTGGGCTCTGGTAAAACACTGACCATTCAGGTGAAGGAGTTCGGTGACGCTGGACAGTACACTTGTCATAAGGGCGGGGAGGTGCTGTCTCACTCCCTGCTGCTGCTGCATAAGAAGGAGGATGGAATCTGGTCCACTGACATCCTGAAAGACCAGAAGGAGCCAAAGAACAAAACCTTCCTGCGATGCGAGGCTAAGAACTACAGCGGCCGCTTTACATGCTGGTGGCTGACAACCATCAGCACCGATCTGACCTTTAGCGTGAAGTCATCCAGGGGCAGTTCAGACCCTCAGGGAGTCACATGTGGCGCCGCAACCCTGTCAGCAGAGCGAGTGCGGGGAGACAATAAGGAATACGAGTACAGCGTCGAGTGTCAGGAGGATTCCGCATGTCCAGCTGCAGAAGAATCCCTGCCTATCGAAGTCATGGTGGACGCTGTGCATAAACTGAAGTACGAGAATTACACCAGCAGCTTTTTCATCCGGGACATCATCAAGCCCGATCCACCTAAGAATCTGCAGCTGAAGCCTCTGAAAAATAGCCGACAGGTCGAAGTGTCATGGGAATACCCAGACACCTGGTCAACACCACACTCCTACTTCTCCCTGACCTTCTGTGTGCAGGTCCAGGGAAAAAGCAAGCGGGAAAAGAAAGATCGGGTGTTCACCGACAAGACCAGTGCTACAGTGATTTGCCGGAAGAATGCCAGCATTTCTGTCAGAGCTCAGGACCGGTACTATAGCTCTTCCTGGAGCGAGTGGGCTTCAGTGCCATGTTCTGGaGGCGGtGGATCTGGCGGAGGTGGAAGCGGAGGCGGTGGATCTAGAAACCTGCCCGTCGCAACCCCTGATCCAGGGATGTTCCCCTGTCTGCATCACAGCCAGAATCTGCTGAGGGCTGTCTCCAACATGCTGCAGAAGGCTCGACAGACCCTGGAGTTCTACCCATGTACCAGCGAAGAGATCGACCACGAGGATATCACAAAGGATAAAACCAGCACAGTGGAAGCATGCCTGCCTCTGGAACTGACCAAGAATGAGAGCTGCCTGAATAGCAGGGAGACCTCCTTCATCACCAACGGCTCATGCCTGGCTTCAAGGAAGACCAGCTTCATGATGGCTCTGTGTCTGAGCTCTATCTATGAGGACCTGAAGATGTACCAGGTGGAGTTCAAGACCATGAACGCCAAGCTGCTGATGGATCCAAAGAGGCAGATCTTCCTGGATCAGAATATGCTGGCAGTGATCGATGAGCTGATGCAGGCCCTGAATTTTAACAGTGAGACAGTGCCTCAGAAGAGCTCTCTGGAAGAGCCAGACTTTTACAAAACTAAGATCAAGCTGTGCATTCTGCTGCACGCTTTCCGCATCAGAGCTGTCACTATCGATAGAGTGATGAGCTATCTGAATGCCTCA
EVQLVESGGGLVQPGGSLRLSCAASGRTFITYAIGWFRQAPGKGREFVSAISWSGSMTSYADSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAHRGAIAPIAQSVYTNWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPCQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGSGGGGSGGGGSGGGGSIWELKKDVYVVELDWYPDAPGEMVVLTCDTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHSLLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTISTDLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACPAAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSRQVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVICRKNASISVRAQDRYYSSSWSEWASVPCSGGGGSGGGGSGGGGSRNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTSEEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKTSFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDELMQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYLNAS
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTGCAGCCTGGCGGCTCTCTGAGACTGTCCTGCGCCGCTTCTGGCCGGACCTTCATCACCTACGCCATCGGCTGGTTCAGACAGGCCCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCTATGACCAGCTACGCCGACTCTGTGAAGGGCAGATTCACCATCTCCCGGGATAACGCCAAGAACACCCTGTACCTGCAGATGAATTCCCTGAGACCTGAGGACACAGCTGTGTATTACTGCGCCGCTCACCGGGGCGCCATCGCTCCCATCGCTCAGAGCGTGTACACCAACTGGGGCCAGGGAACCCTGGTCACCGTGTCCAGCGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTgCACCCTGCCTCCCTCTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtCCTGCgctGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGgttTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGCtcaGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTAAGACCCAGGGACTTAATCAGCAATATCAACGTAATAGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
EVQLVESGGGLVQPGGSLRLSCAASGRTFITYAIGWFRQAPGKGREFVSAISWSGSMTSYADSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAHRGAIAPIAQSVYTNWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVCTLPPSQEEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGSGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTGCAGCCTGGCGGCTCTCTGAGACTGTCCTGCGCCGCTTCTGGCCGGACCTTCATCACCTACGCCATCGGCTGGTTCAGACAGGCCCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCTATGACCAGCTACGCCGACTCTGTGAAGGGCAGATTCACCATCTCCCGGGATAACGCCAAGAACACCCTGTACCTGCAGATGAATTCCCTGAGACCTGAGGACACAGCTGTGTATTACTGCGCCGCTCACCGGGGCGCCATCGCTCCCATCGCTCAGAGCGTGTACACCAACTGGGGCCAGGGAACCCTGGTCACCGTGTCCAGCGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTgCACCCTGCCTCCCTCTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtCCTGCgctGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGgttTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGC
EVQLVESGGGLVQPGGSLRLSCAASGRTFITYAIGWFRQAPGKGREFVSAISWSGSMTSYADSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAHRGAIAPIAQSVYTNWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVCTLPPSQEEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTGCAGCCTGGCGGCTCTCTGAGACTGTCCTGCGCCGCTTCTGGCCGGACCTTCATCACCTACGCCATCGGCTGGTTCAGACAGGCCCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCTATGACCAGCTACGCCGACTCTGTGAAGGGCAGATTCACCATCTCCCGGGATAACGCCAAGAACACCCTGTACCTGCAGATGAATTCCCTGAGACCTGAGGACACAGCTGTGTATTACTGCGCCGCTCACCGGGGCGCCATCGCTCCCATCGCTCAGAGCGTGTACACCAACTGGGGCCAGGGAACCCTGGTCACCGTGTCCAGCGAGTCTAAGTACGGCCCTCCCTGTCCTCCTTGCCCTGCTCCTGAGTTCgaGGGCGGCCCCTCCGTGTTTCTCTTCCCACCCAAGCCTAAGGACACCCTGATGATCTCCAGAACCCCTGAGGTGACCTGCGTGGTGGTTGACGTGTCTCAGGAGGATCCCGAAGTGCAGTTTAATTGGTACGTGGACGGCGTCGAAGTGCACAATGCTAAAACCAAGCCTCGGGAGGAACAGTTCAATAGCACCTACAGAGTGGTGAGCGTTCTGACAGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGCAAGGTGTCCAACAAGGGCCTGCCATCCTCCATCGAGAAGACCATCTCCAAGGCCAAGGGACAACCTAGAGAGCCTCAGGTGTACACCCTGCCTCCCTgTCAGGAGGAGATGACCAAGAACCAGGTGTCTCTGtggTGCCTGGTGAAGGGCTTCTACCCTTCCGACATCGCCGTGGAATGGGAAAGCAACGGCCAACCTGAGAACAACTACAAGACCACCCCTCCTGTGCTGGACTCCGATGGATCTTTCTTCCTGTACTCTCGGCTGACCGTCGACAAGTCTAGATGGCAGGAGGGCAACGTGTTCAGCTGCTCCGTCATGCACGAGGCCCTGCATAACCACTACACCCAGAAGTCCCTGTCCTTATCTCTGGGCtcaGGTGGaGGCGGTAGTGGCGGAGGCGGTTCAGGCGGAGGCGGATCTGCACCTACTTCAAGTTCTACAAAGAAAACACAGCTACAACTGGAGCATTTACTGCTGGATTTACAGATGATTTTGAATGGAATTAATAATTACAAGAATCCCAAACTCACCAGGATGCTCACATTTAAGTTTTACATGCCCAAGAAGGCCACAGAACTGAAACATCTTCAGTGTCTAGAAGAAGAACTCAAACCTCTGGAGGAAGTGCTAAATTTAGCTCAAAGCAAAAACTTTCACTTAAGACCCAGGGACTTAATCAGCAATATCAACGTAATAGTTCTGGAACTAAAGGGATCTGAAACAACATTCATGTGTGAATATGCTGATGAGACAGCAACCATTGTAGAATTTCTGAACAGATGGATTACCTTTTGTCAAAGCATCATCTCAACACTGACT
EVQLVESGGGLVQPGGSLRLSCAASGRTFITYAIGWFRQAPGKGREFVSAISWSGSMTSYADSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAHRGAIAPIAQSVYTNWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPCQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGSGGGGSGGGGSGGGGSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT
GAAGTGCAGCTGGTTGAGTCCGGCGGCGGCCTGGTGCAGCCTGGCGGTTCTCTGCGGCTGTCTTGCGCCGTGAGCGGAAATATCTACAACCGGAACTTCATGGGCTGGTTTCGGCAGGCTCCAGGCAAAGGACTGGAAGGCGTGTCCGCCATCTACACCGGCACCTCTCGGACCTACTACGCCGACTCTGTCAAAGGCAGATTCACCATCTCCCGCGACAACAGCAAAAACACCGTGTACCTGCAGATGAACAGCCTGAGAGCTGAAGATACAGCTGTGTACTATTGCGCCGCCGATCTGAGAGACGGCTTCTGGGACACAGGCGTGTGGAACACCTGGGGCCAGGGCACACTTGTGACCGTGTCCTCTGAGAGCAAGTACGGACCACCTTGCCCACCATGTCCAGCTCCTGAGTTTGAGGGAGGACCATCCGTGTTCCTGTTTCCTCCAAAGCCTAAGGACACCCTGATGATCAGCCGGACACCTGAGGTGACCTGCGTGGTGGTGGACGTGTCTCAGGAGGATCCAGAGGTGCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCACAATGCTAAGACCAAGCCAAGAGAGGAGCAGTTTAATTCCACATACCGCGTGGTGAGCGTGCTGACCGTGCTGCATCAGGATTGGCTGAACGGCAAGGAGTATAAGTGCAAGGTGTCCAATAAGGGCCTGCCCAGCTCTATCGAGAAGACAATCAGCAAGGCTAAGGGACAGCCTAGGGAGCCACAGGTGTACACCCTGCCCCCTTCTCAGGAGGAGATGACAAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTATCCAAGCGACATCGCTGTGGAGTGGGAGTCTAATGGCCAGCCCGAGAACAATTACAAGACCACACCACCCGTGCTGGACTCTGATGGCTCCTTCTTTCTGTATTCTAGGCTGACAGTGGATAAGTCCCGGTGGCAGGAGGGCAACGTGTTTAGCTGCTCTGTGATGCACGAGGCCCTGCACAATCATTATACCCAGAAGTCCCTGAGCCTGTCTCTGGGCAAG
EVQLVESGGGLVQPGGSLRLSCAVSGNIYNRNFMGWFRQAPGKGLEGVSAIYTGTSRTYYADSVKGRFTISRDNSKNTVYLQMNSLRAEDTAVYYCAADLRDGFWDTGVWNTWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTCCAGCCTGGCGGCTCTCTGCGGCTGTCCTGCGCCGCTTCTGGCAGAACCTTCGTGACCTACGGCATGGGCTGGTTCCGGCAGGCTCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCCATGACCTCTTACGGCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGATAACGCCAAGAACACACTGTACCTGCAGATGAACTCCCTGCGGCCTGAGGACACCGCCGTGTACTACTGCGCCGCTGCCCTGGGCGCTGTCGTGTACACCACCAGAGAACCCTATACCTACTGGGGACAGGGCACCCTGGTGACCGTGTCCTCTGAGAGCAAGTACGGACCACCTTGCCCACCATGTCCAGCTCCTGAGTTTGAGGGAGGACCATCCGTGTTCCTGTTTCCTCCAAAGCCTAAGGACACCCTGATGATCAGCCGGACACCTGAGGTGACCTGCGTGGTGGTGGACGTGTCTCAGGAGGATCCAGAGGTGCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCACAATGCTAAGACCAAGCCAAGAGAGGAGCAGTTTAATTCCACATACCGCGTGGTGAGCGTGCTGACCGTGCTGCATCAGGATTGGCTGAACGGCAAGGAGTATAAGTGCAAGGTGTCCAATAAGGGCCTGCCCAGCTCTATCGAGAAGACAATCAGCAAGGCTAAGGGACAGCCTAGGGAGCCACAGGTGTACACCCTGCCCCCTTCTCAGGAGGAGATGACAAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTATCCAAGCGACATCGCTGTGGAGTGGGAGTCTAATGGCCAGCCCGAGAACAATTACAAGACCACACCACCCGTGCTGGACTCTGATGGCTCCTTCTTTCTGTATTCTAGGCTGACAGTGGATAAGTCCCGGTGGCAGGAGGGCAACGTGTTTAGCTGCTCTGTGATGCACGAGGCCCTGCACAATCATTATACCCAGAAGTCCCTGAGCCTGTCTCTGGGCAAG
EVQLVESGGGLVQPGGSLRLSCAASGRTFVTYGMGWFRQAPGKGREFVSAISWSGSMTSYGDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAALGAVVYTTREPYTYWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTCCAGCCTGGCGGCTCTCTGCGGCTGTCCTGCGCCGCTTCTGGCAGAACCTTCGTGACCTACGGCATGGGCTGGTTCCGGCAGGCTCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCCAgcACCTCTTACGGCGACTCTGTGAAGGGCAGATTCACCATCAGCCGGGATAACGCCAAGAACACACTGTACCTGCAGATGAACTCCCTGCGGCCTGAGGACACCGCCGTGTACTACTGCGCCGCTGCCCTGGGCGCTGTCGTGTACACCACCAGAGAACCCTATACCTACTGGGGACAGGGCACCCTGGTGACCGTGTCCTCTGAGAGCAAGTACGGACCACCTTGCCCACCATGTCCAGCTCCTGAGTTTGAGGGAGGACCATCCGTGTTCCTGTTTCCTCCAAAGCCTAAGGACACCCTGATGATCAGCCGGACACCTGAGGTGACCTGCGTGGTGGTGGACGTGTCTCAGGAGGATCCAGAGGTGCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCACAATGCTAAGACCAAGCCAAGAGAGGAGCAGTTTAATTCCACATACCGCGTGGTGAGCGTGCTGACCGTGCTGCATCAGGATTGGCTGAACGGCAAGGAGTATAAGTGCAAGGTGTCCAATAAGGGCCTGCCCAGCTCTATCGAGAAGACAATCAGCAAGGCTAAGGGACAGCCTAGGGAGCCACAGGTGTACACCCTGCCCCCTTCTCAGGAGGAGATGACAAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTATCCAAGCGACATCGCTGTGGAGTGGGAGTCTAATGGCCAGCCCGAGAACAATTACAAGACCACACCACCCGTGCTGGACTCTGATGGCTCCTTCTTTCTGTATTCTAGGCTGACAGTGGATAAGTCCCGGTGGCAGGAGGGCAACGTGTTTAGCTGCTCTGTGATGCACGAGGCCCTGCACAATCATTATACCCAGAAGTCCCTGAGCCTGTCTCTGGGCAAG
EVQLVESGGGLVQPGGSLRLSCAASGRTFVTYGMGWFRQAPGKGREFVSAISWSGSSTSYGDSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAALGAVVYTTREPYTYWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
GAGGTGCAGCTGGTGGAATCCGGCGGAGGCCTGGTGCAGCCTGGCGGCTCTCTGAGACTGTCCTGCGCCGCTTCTGGCCGGACCTTCATCACCTACGCCATCGGCTGGTTCAGACAGGCCCCTGGCAAGGGCAGAGAGTTCGTGTCCGCCATCTCCTGGTCCGGCTCTATGACCAGCTACGCCGACTCTGTGAAGGGCAGATTCACCATCTCCCGGGATAACGCCAAGAACACCCTGTACCTGCAGATGAATTCCCTGAGACCTGAGGACACAGCTGTGTATTACTGCGCCGCTCACCGGGGCGCCATCGCTCCCATCGCTCAGAGCGTGTACACCAACTGGGGCCAGGGAACCCTGGTCACCGTGTCCAGCGAGAGCAAGTACGGACCACCTTGCCCACCATGTCCAGCTCCTGAGTTTGAGGGAGGACCATCCGTGTTCCTGTTTCCTCCAAAGCCTAAGGACACCCTGATGATCAGCCGGACACCTGAGGTGACCTGCGTGGTGGTGGACGTGTCTCAGGAGGATCCAGAGGTGCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCACAATGCTAAGACCAAGCCAAGAGAGGAGCAGTTTAATTCCACATACCGCGTGGTGAGCGTGCTGACCGTGCTGCATCAGGATTGGCTGAACGGCAAGGAGTATAAGTGCAAGGTGTCCAATAAGGGCCTGCCCAGCTCTATCGAGAAGACAATCAGCAAGGCTAAGGGACAGCCTAGGGAGCCACAGGTGTACACCCTGCCCCCTTCTCAGGAGGAGATGACAAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTATCCAAGCGACATCGCTGTGGAGTGGGAGTCTAATGGCCAGCCCGAGAACAATTACAAGACCACACCACCCGTGCTGGACTCTGATGGCTCCTTCTTTCTGTATTCTAGGCTGACAGTGGATAAGTCCCGGTGGCAGGAGGGCAACGTGTTTAGCTGCTCTGTGATGCACGAGGCCCTGCACAATCATTATACCCAGAAGTCCCTGAGCCTGTCTCTGGGCAAG
EVQLVESGGGLVQPGGSLRLSCAASGRTFITYAIGWFRQAPGKGREFVSAISWSGSMTSYADSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAAHRGAIAPIAQSVYTNWGQGTLVTVSSESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
本実験では、NK92細胞を刺激してインターフェロン-ガンマ(IFN-γ)を放出させるサイトカインを採用することにより、融合タンパク質内におけるサイトカインIL-12及びIL-2のインビトロ生物学的活性を検証する。本実験で構築した融合タンパク質がサイトカインを含有することから、異なる融合タンパク質をNK92細胞と共にインキュベートしてから、IFN-γの放出を検出する。
PD-1/PD-L1経路遮断のバイオアッセイは、生物学的に有意味な作用機構に基づいた検出解析法であり、PD-1/PD-L1相互作用を遮断可能な抗体及びその他の生物学的製剤の効果及び安定性を測定するのに使用することができる。この検出システムには、以下の2種の遺伝子組換え細胞株、ヒト由来PD-1を安定的に発現可能な細胞及びヒト由来PD-L1を安定的に発現する細胞が含まれている。
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Claims (23)
- 第1のポリペプチド鎖と、第2のポリペプチド鎖と、を含む、抗体Fc領域を主鎖として用いた融合タンパク質二量体であって、前記第1のポリペプチド鎖は、第1の抗体Fc領域と、前記第1の抗体Fc領域に融合した1つまたは複数の単一ドメイン抗体と、を含み、前記第2のポリペプチド鎖は、第2の抗体Fc領域と、前記第2の抗体Fc領域に融合した1つまたは複数の単一ドメイン抗体と、を含み、前記第1のポリペプチド鎖及び/または前記第2のポリペプチド鎖は、前記それぞれの抗体の前記Fc領域に融合したサイトカインを更に含み、
前記第1のポリペプチド鎖に含有されるサイトカインがIL-12であり、前記第2のポリペプチド鎖に含有されるサイトカインがIL-2またはIL-2変異体である、前記融合タンパク質二量体。 - 前記単一ドメイン抗体は免疫チェックポイント分子に対する単一ドメイン抗体である、請求項1に記載の融合タンパク質二量体。
- 前記単一ドメイン抗体は抗PD-1単一ドメイン抗体または抗PD-L1単一ドメイン抗体である、請求項1または請求項2に記載の融合タンパク質二量体。
- 前記IL-12の2つのサブユニットであるP35及びP40は、リンカー配列を介して連結してIL-12単鎖タンパク質を形成し、その結果、前記第1のポリペプチド鎖内に存在する、請求項1~3のいずれか1項に記載の融合タンパク質二量体。
- 前記第1の抗体Fc領域と前記第2の抗体Fc領域は異なり、互いに対して非対称的な相補的構造を有する、請求項1~4のいずれか1項に記載の融合タンパク質二量体。
- 前記第1の抗体Fc領域は変異部位組み合わせT366W/S354Cを有し、前記第2の抗体Fc領域は変異部位組み合わせT366S/L368A/Y407V/Y349Cを有する、請求項5に記載の融合タンパク質二量体。
- 前記第1のポリペプチド鎖及び/または前記第2のポリペプチド鎖は、連続的に配列された2つの抗PD-1単一ドメイン抗体または抗PD-L1単一ドメイン抗体を含む、請求項1~6のいずれか1項に記載の融合タンパク質二量体。
- 前記抗PD-1単一ドメイン抗体は、配列番号:3または配列番号:71で表されるアミノ酸配列を有する、請求項3~7のいずれか1項に記載の融合タンパク質二量体。
- 前記抗PD-L1単一ドメイン抗体は、配列番号:72~74で表されるアミノ酸配列を有する、請求項3~8のいずれか1項に記載の融合タンパク質二量体。
- 前記IL-12単鎖タンパク質は、配列番号:6で表されるアミノ酸配列を有する、請求項4~9のいずれか1項に記載の融合タンパク質二量体。
- 前記第1のポリペプチド鎖は配列番号:20で表されるアミノ酸配列を有し、前記第2のポリペプチド鎖は配列番号:22、24または28で表されるアミノ酸配列を有する、
前記第1のポリペプチド鎖は配列番号:26で表されるアミノ酸配列を有し、前記第2のポリペプチド鎖は配列番号:28で表されるアミノ酸配列を有する、
前記第1のポリペプチド鎖は配列番号:16で表されるアミノ酸配列を有し、前記第2のポリペプチド鎖は配列番号:18で表されるアミノ酸配列を有する、
前記第1のポリペプチド鎖は配列番号:32で表されるアミノ酸配列を有し、前記第2のポリペプチド鎖は配列番号:34、36で表されるアミノ酸配列を有する、または、
前記第1のポリペプチド鎖は配列番号:36で表されるアミノ酸配列を有し、前記第2のポリペプチド鎖は配列番号:38で表されるアミノ酸配列を有する、
請求項1~10のいずれか1項に記載の融合タンパク質二量体。 - 前記第1のポリペプチド鎖は配列番号:40で表されるアミノ酸配列を有し、前記第2のポリペプチド鎖は配列番号:42、44で表されるアミノ酸配列を有する、
前記第1のポリペプチド鎖は配列番号:44で表されるアミノ酸配列を有し、前記第2のポリペプチド鎖は配列番号:46で表されるアミノ酸配列を有する、
前記第1のポリペプチド鎖は配列番号:48で表されるアミノ酸配列を有し、前記第2のポリペプチド鎖は配列番号:50、52で表されるアミノ酸配列を有する、
前記第1のポリペプチド鎖は配列番号:52で表されるアミノ酸配列を有し、前記第2のポリペプチド鎖は配列番号:54で表されるアミノ酸配列を有する、
前記第1のポリペプチド鎖は配列番号:56で表されるアミノ酸配列を有し、前記第2のポリペプチド鎖は配列番号:58、60で表されるアミノ酸配列を有する、または、
前記第1のポリペプチド鎖は配列番号:60で表されるアミノ酸配列を有し、前記第2のポリペプチド鎖は配列番号:62で表されるアミノ酸配列を有する、
請求項1~10のいずれか1項に記載の融合タンパク質二量体。 - 前記融合タンパク質二量体内における前記単一ドメイン抗体、前記抗体Fc領域、及び、前記サイトカインは、リンカー配列を介して連結している、または、直接連結している、請求項1~12のいずれか1項に記載の融合タンパク質二量体。
- 前記リンカー配列は、(G4S)1~3、KRVAPELLGGPS、ASTKG、及び、NSPPAAから選択される、請求項13に記載の融合タンパク質二量体。
- 前記1つまたは複数の単一ドメイン抗体は、前記抗体Fc領域のN末端にリンカー配列を介して連結しているまたは直接連結しており、前記サイトカインは、前記抗体Fc領域のC末端にリンカー配列を介して連結している、あるいは、前記1つまたは複数の単一ドメイン抗体は、前記抗体Fc領域のC末端にリンカー配列を介して連結しているまたは直接連結しており、前記サイトカインは、前記抗体Fc領域のN末端にリンカー配列を介して連結している、請求項1~14のいずれか1項に記載の融合タンパク質二量体。
- 前記第1の抗体Fc領域及び前記第2の抗体Fc領域は野生型抗体Fc領域であり、その結果、抗体Fc融合タンパク質ホモ二量体を形成する、請求項1に記載の融合タンパク質二量体。
- 請求項1~16のいずれか1項に記載の融合タンパク質二量体の前記第1のポリペプチド鎖及び前記第2のポリペプチド鎖をコードする単離ポリヌクレオチド。
- 配列番号:15、17、19、21、23、25、27、29、31、33、35、または、37で表されるヌクレオチド配列を有する、あるいは、配列番号:39、41、43、45、47、49、51、53、55、57、59、及び、61で表されるヌクレオチド配列を有する、請求項17に記載のポリヌクレオチド。
- 請求項17または請求項18に記載のポリヌクレオチドを含む発現ベクター。
- 請求項19に記載の発現ベクターを含む宿主細胞。
- 抗腫瘍薬剤の調製における、請求項1から請求項16のいずれか1項に記載の融合タンパク質二量体、請求項17または請求項18に記載のポリヌクレオチド、請求項19に記載の発現ベクター、または、請求項20に記載の宿主細胞の使用。
- 前記腫瘍は黒色腫または肺癌である、請求項21に記載の使用。
- 請求項1から請求項16のいずれか1項に記載の融合タンパク質二量体と、薬学的に許容される担体と、を含む、抗腫瘍医薬組成物。
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