JP7386796B2 - 抗-her2抗体又はその抗原結合フラグメント、及びこれを含むキメラ抗原受容体 - Google Patents
抗-her2抗体又はその抗原結合フラグメント、及びこれを含むキメラ抗原受容体 Download PDFInfo
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
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- 235000019364 tetracycline Nutrition 0.000 description 1
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- 229940113082 thymine Drugs 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Description
(a)以下の重鎖CDR(complementarity determining region)アミノ酸配列を含む重鎖可変領域:配列番号1のCDRH1、配列番号2のCDRH2及び配列番号3のCDRH3;及び
(b)以下の軽鎖CDRアミノ酸配列を含む軽鎖可変領域:
配列番号4のCDRL1、配列番号5のCDRL2及び配列番号6のCDRL3。
(a)以下の重鎖CDR(complementarity determining region)アミノ酸配列を含む重鎖可変領域:
配列番号7のCDRH1、配列番号8のCDRH2及び配列番号9、71、又は72のCDRH3;及び
(b)次の軽鎖CDRアミノ酸配列を含む軽鎖可変領域:
配列番号10のCDRL1、配列番号11のCDRL2及び配列番号12、73、又は74のCDRL3。
(a)以下の重鎖CDR(complementarity determining region)アミノ酸配列を含む重鎖可変領域:
配列番号13のCDRH1、配列番号14のCDRH2及び配列番号15のCDRH3;及び
(b)以下の軽鎖CDRアミノ酸配列を含む軽鎖可変領域:
配列番号16のCDRL1、配列番号17のCDRL2及び配列番号18のCDRL3。
(a)次の重鎖CDR(complementarity determining region)アミノ酸配列を含む重鎖可変領域:
配列番号19のCDRH1、配列番号20のCDRH2及び配列番号21のCDRH3;及び
(b)以下の軽鎖CDRアミノ酸配列を含む軽鎖可変領域:
配列番号22のCDRL1、配列番号23のCDRL2及び配列番号24のCDRL3。
(a)以下の重鎖CDR(complementarity determining region)アミノ酸配列を含む重鎖可変領域:
配列番号25のCDRH1、配列番号26のCDRH2及び配列番号27のCDRH3;及び
(b)以下の軽鎖CDRアミノ酸配列を含む軽鎖可変領域:
配列番号28のCDRL1、配列番号29のCDRL2及び配列番号30のCDRL3。
FRH1(framework region 1 of Heavy chain)-CDRH1(complementarity determining region 1 of Heavy chain)-FRH2-CDRH2-FRH3-CDRH3-FRH4。
FRL1(framework region 1 of Light chain)-CDRL1(complementarity determining region 1 of Light chain)-FRL2-CDRL2-FRL3-CDRL3-FRL4。
nは1~7の整数であり;
mは0~7の整数であり;
nとmの和は8以下の整数であり;及び
pは1~7の整数である。
軽鎖可変領域-リンカー-重鎖可変領域;又は
重鎖可変領域-リンカー-軽鎖可変領域。
(a)HER2結合ドメイン(HER2 binding domain);
(b)膜貫通ドメイン(transmembrane domain,TM);
(c)共刺激ドメイン(costimulatory domain);及び
(d)細胞内シグナル(信号)伝達ドメイン(intracellular signaling domain,ICD)。
遺伝子伝達のために選択された遺伝子はレトロウイルスベクター内に挿入され、レトロウイルス粒子内にパッケージングされ得る。次いで、組み換えられたレトロウイルスは、インビボ、又はインビトロでターゲットとする宿主細胞に伝達され得る。多くのレトロウイルスベクターが当技術分野において知られており、本発明の特定の例示的な実施形態において前記レトロウイルスベクターは、MLV-ベースのレトロウイルスベクターであるpMTレトロウイルスベクターであるが、これに限定されない。
抗体作製のために、HER2タンパク質の細胞外部ドメイン(extracellular domain,ECD)を動物細胞を用いて作製した。ECDのC-末端にヒトIgG1のヒンジ及びFc部位(CH2-CH3)が結合されたDNAを、pCEP4(Invitrogen,Cat.No.V044-50)にHindIIIとBamHI制限酵素を用いてクローニングした。次いで、FreeStyle 293F(Invitrogen,Cat.No.R790-07)細胞にポリエチレンイミン(Polyscience Inc.,Cat.No.23966)を用いて前記クローニングされたベクターを一時形質転換(transient transfection)させ、Protein-A Ceramic HyperD Fレジン(PALL,Cat No.20078-028)を用いて細胞培養液から精製した。精製されたタンパク質を、タンパク質アッセイ色素(Protein assay dye)(Bio-Rad,Cat.No.500-0006)を用いて定量し、その濃度及び純度をSDS-PAGE後、クマシーブルー染色によって確認した。精製された100μgのタンパク質抗原をフロイントアジュバント(Freund’s adjuvant)(Sigma,Cat.No.F5506)と混合し、BALB/cマウス((株)大韓バイオ)の腹腔に注射した。2週後、抗原100μgをPBSに希釈して追加注射し、3日後にマウスの脾臓を摘出してリンパ球を分離した。分離したリンパ球をミエローマ細胞株であるSP2/0-Ag14(ATCC,Cat.No.CRL-1581)と5:1の比率で混合し、PEG-1500(Roche,Cat.No.783641)を用いて融合(fusion)させた。融合された細胞(ハイブリドーマ、hybridoma)を選択的に選別してHAT補助剤(HAT supplement)(Sigma,Cat.No.H0262)を含む培地に培養した。
選択された5種の抗体(hz2G10、hz39D2、24D3、1G3、hz8G11)のHER2タンパク質の細胞外部ドメイン(extracellular domain,ECD)に対する結合部位をELISA法で確認した。ELISA法の場合、ERBBファミリータンパク質の細胞外部ドメイン(ECD)部位を動物細胞を用いて作製し、抗原として使用した。具体的には、ECDのC-末端にヒトIgG1のヒンジ及びFc部位(CH2-CH3)が結合した形態のDNAを、pCEP4ベクター(Invitrogen,Cat.No.V044-50)にHindIIIとBamHI制限酵素を用いてクローニングした。次いで、FreeStyle TM293F(Invitrogen,Cat.No.R790-07)細胞にポリエチレンイミン(Polyscience Inc.,Cat.No.23966)を用いて前記クローニングされたベクターを一時形質転換(transient transfection)させ、細胞培養液からHER2-ECD DI Fc、HER2-ECD DII Fc、HER2-ECD DIII Fc、HER2-ECD DIV Fc、HER2-ECD Fc融合タンパク質をProtein-A Ceramic HyperD Fレジン(PALL,Cat No.20078-028)を用いて精製した。精製されたタンパク質をタンパク質アッセイ色素(Protein assay dye)(Bio-Rad,Cat.No.500-0006)を用いて定量し、SDS-PAGE後、クマシーブルー染色を用いて濃度及び純度を確認した。
細胞生存率を、HER2が過発現される代表的な乳癌細胞株であるSKBR-3及びHER2未発現乳癌細胞株であるMCF-7を対象に単独又はトラスツズマブと併用処理して分析した。併用処理の場合、作製された抗体とトラスツズマブを1:1比率(重量比)で混合して使用した。96ウェルプレートにSKBR3(韓国細胞株銀行、Cat.No.30030、5,000cells/well)、MCF-7(ATCC,Cat.No.HTB 22、5,000cells/well)細胞を分注し、24時間培養した。精製された抗体を最終的に20μg/mLとなるように処理し、4日間追加培養した。細胞の生存率を測定するために、CCK-8(Dojindo,Cat.No.CK-04-13)を最終濃度が10%となるように添加し、37℃で3時間処理した後、吸光度を測定した。抗体を非処理したウェルの吸光度を生存率100%にして相対的生存率を計算した。
抗体配列を分析するために、各ハイブリドーマのRNAを用いてファージFab抗体ライブラリーを作製し、これからHER2-ECD-Fcと結合するファージを得るために、3次にわたる選別過程(panning)を行った(Phage display:a laboratory manua,Carlos Barbas III,et al.,Cold Spring Harbor Laboratory Press)。ハイブリドーマ培養後、RNAをSV Total RNA Isolation System(Promega,Cat.No.Z3100)を用いて分離し、cDNAを合成した。公知のプライマーセット(参照:Phage display:a laboratory manual,Carlos Barbas III,et al.,Cold Spring Harbor Laboratory Press)を用いて抗体の可変領域を増幅し、ヒトCk(Kappa chain)とCH1を連結してpComb3Xベクター(Barbas laboratory,The Scripps Research Institute)にSfi-I制限酵素を用いてクローニングし、ER2537バクテリア(New England Biolabs,Cat.No.801-N)に形質転換した。形質転換されたバクテリアにVCSM13ヘルパーファージ(Stratagene,Cat.No.200251)を感染させてファージを得て、HER2-ECD-Fcに固定されたイムノチューブを用いてHER2-ECD-Fcに結合するクローンを得た。
作製された本明細書に記載の5種の抗体が、HER2の属したErbBファミリータンパク質のうちHER2に特異的に結合するかどうかをELISA法で確認した。作製された抗体がErbBファミリータンパク質のうちHER2に特異的に結合するかを確認するために、ErbBファミリーに属するEGFR、HER2、HER3及びHER4の細胞外部ドメインを対象にELISA法で確認した。EGFRの細胞外ドメイン(EGFR-ECD-Fc)は、上記の実施例2のHER2-ECD-Fcと同じ方法で生産され、HER3(R&D Systems,#348-RB-050)とHER4(R&D Systems,#1131-ER-050)タンパク質は購入した。セツキシマブ(cetuximab,CET)、トラスツズマブ(trastuzumab,TRA)、パトリツマブ(Patritumab,AMG888,AMG)をそれぞれEGFR、HER2、及びHER3に結合する対照群抗体とした。
HER2に対する抗体トラスツズマブは、HER2 ECDの4個のドメインのうちドメイン-4に結合することが知られている。作製された抗体がトラスツズマブのHER2に対するエピトープと重複するかどうかを確認するために、Octet(Pall ForteBio)機器を用いてエピトープビニング(epitope binning)を行った。AR2Gセンサーチップ(Fortebio,Cat.No.18-5092(tray)、18-5093(pack)、18-5094(case))にトラスツズマブを10μg/mLの濃度で、ECD/NHSを用いたアミンカップリング方法で固定させた。トラスツズマブが固定されたセンサーチップにHER2-ECD-Hisタンパク質を10μg/mLの濃度で10分間結合させ、5分間トラスツズマブとHER2-ECD間の結合を安定化させた。その後、本明細書に記載の抗体5種を10μg/mLの濃度で10分間結合させ、10分間抗原と抗体間の結合を安定化させた。トラスツズマブを固定した後、全ての抗体抗原は動態緩衝液(kinetics buffer)(Fortebio,cat No.18-1092)を用いて希釈したが、安定化させる段階でも同緩衝液を使用した。仮に、追加された抗体がトラスツズマブと結合されたHER2-ECDタンパク質に結合する場合、これはトラスツズマブとエピトープを共有しない抗体と解釈できる。
本発明者は、ヒト化39D2抗体(hz39D2)に基づいて親和度が改善された抗体を作製するために、軽鎖又は重鎖のCDR3を無作為化(randomization)したファージ抗体ライブラリーを作製した(Phage display:a laboratory manual,Carlos Barbas III,et al.,Cold Spring Harbor Laboratory Press)。重鎖のCDR3のうち、Kabatナンバリングよるアミノ酸番号であるD101、Y102に該当するDとY、及び軽鎖のCDRのうち、P95、W96、T97に該当するP、W、Tは、ヒト抗体の各位置で頻繁に発見されるアミノ酸であるので、無作為化から除外した。このとき、使用されたプライマーは、重鎖及び軽鎖のCDR3に該当する部位に対するものであり、無作為化しようとするアミノ酸に該当するコドンの一番目と二番目には、アデニン(A)、シトシン(C)、グアニン(G)及びチミン(T)を同一比率で混合して無作為に入るようにし、三番目の位置はグアニン(G)やシトシン(C)が同一比率で入るように合成して使用した。作製されたライブラリーから親和度の向上したクローンを、HER2-ECD-Hisタンパク質を用いたバイオパンニング(biopanning)によって選択した。最終的に選択された3つの抗体hz39D2.14、hz39D2.22、及びhz39D2.23のCDR配列情報は、表6及び表7にまとめるた。親和度を増進させるために変更されたアミノ酸残基は、太字及び下線で表示した。
Claims (22)
- (a)~(c)のいずれか一つを含むHER2(Human Epidermal Growth Factor Receptor 2)に対する抗体又はその抗原結合フラグメント:
(a)配列番号1のCDRH1、配列番号2のCDRH2及び配列番号3のCDRH3を含む重鎖可変領域;及び配列番号4のCDRL1、配列番号5のCDRL2及び配列番号6のCDRL3を含む軽鎖可変領域;
(b)配列番号7のCDRH1、配列番号8のCDRH2及び配列番号9、71、又は72のCDRH3を含む重鎖可変領域、及び配列番号10配列のCDRL1、配列番号11のCDRL2及び配列番号12、73、又は配列番号74のCDRL3を含む軽鎖可変領域;及び
(c)配列番号13のCDRH1、配列番号14のCDRH2及び配列番号15のCDRH3を含む重鎖可変領域、及び配列番号16のCDRL1、配列番号17のCDRL2及び配列番号18のCDRL3を含む軽鎖可変領域。 - 前記(a)の重鎖可変領域は、配列番号31、又は75のアミノ酸配列を含み;
前記(b)の重鎖可変領域は、配列番号39、83、87、95、又は配列番号103のアミノ酸配列を含み;及び
前記(c)の重鎖可変領域は、配列番号47のアミノ酸配列を含む、請求項1に記載の抗体又はその抗原結合フラグメント。 - 前記(a)の軽鎖可変領域は、配列番号35、又は配列番号77のアミノ酸配列を含み;
前記(b)の軽鎖可変領域は、配列番号43、配列番号85、配列番号91、配列番号99、又は配列番号107のアミノ酸配列を含み;及び
前記(c)の軽鎖可変領域は、配列番号51のアミノ酸配列を含む、請求項1に記載の抗体又はその抗原結合フラグメント。 - 前記(a)を含む抗体又はその抗原結合フラグメントは、配列番号33のアミノ酸配列を含む重鎖を含み;
前記(b)を含む抗体又はその抗原結合フラグメントは、配列番号41、89、97、105のアミノ酸配列を含む重鎖を含み;及び
前記(c)を含む抗体又はその抗原結合フラグメントは、配列番号49のアミノ酸配列を含む重鎖を含む、請求項1に記載の抗体又はその抗原結合フラグメント。 - 前記(a)を含む抗体又はその抗原結合フラグメントは、配列番号37のアミノ酸配列を含む軽鎖を含み;
前記(b)を含む抗体又はその抗原結合フラグメントは、配列番号45、93、101、109のアミノ酸配列を含む軽鎖を含み;及び
前記(c)を含む抗体又はその抗原結合フラグメントは、配列番号53のアミノ酸配列を含む軽鎖を含む、請求項1に記載の抗体又はその抗原結合フラグメント。 - 請求項1~5のいずれか一項の抗体又はその抗原結合フラグメントを含む融合タンパク質。
- 以下を含むキメラ抗原受容体ポリペプチド:
(a)HER2結合ドメイン(HER2 binding domain)であって、前記HER2結合ドメインは、請求項1~5のいずれかに記載の抗体又はその抗原結合フラグメントを含む;
(b)膜貫通ドメイン(transmembrane domain,TM);
(c)共刺激ドメイン(costimulatory domain);及び
(d)細胞内シグナル伝達ドメイン(intracellular signaling domain,ICD) - 前記膜貫通ドメインは、T-細胞受容体のアルファ鎖、ベータ鎖又はゼータ鎖、CD28、CD3エプシロン、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137及びCD154からなる群から選ばれるタンパク質の膜貫通ドメインを含む、請求項7に記載のキメラ抗原受容体ポリペプチド。
- 前記共刺激ドメインは、MHCクラスI分子、TNF受容体タンパク質、イムノグロブリン様タンパク質、サイトカイン受容体、インテグリン、シグナル伝達リンパ球性活性化分子(signaling lymphocytic activation molecule,SLAM)、活性化NK細胞受容体、BTLA(B an T lymphocyte attenuator)、トル様リガンド受容体(Toll-like ligand receptor)、OX40、CD2、CD7、CD27、CD28、CD30、CD40、CDS、ICAM-1、LFA-1(CD11a/CD18)、4-1BB(CD137)、B7-H3、CDS、ICAM-1、ICOS(CD278)、GITR、BAFFR、LIGHT、HVEM(LIGHTR)、KIRDS2、SLAMF7、NKp80(KLRF1)、NKp44、NKp30、NKp46、CD19、CD4、CD8アルファ、CD8ベータ、IL2Rベータ、IL2Rガンマ、IL7Rアルファ、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD11d、ITGAE、CD103、ITGAL、CD11a、LFA-1、ITGAM、CD11b、ITGAX、CD11c、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、NKG2D、NKG2C、TNFR2、TRANCE/RANKL、DNAM1(CD226)、SLAMF4(CD244、2B4)、CD84、CD96(Tactile)、CEACAM1、CRTAM、Ly9(CD229)、CD160(BY55)、PSGL1、CD100(SEMA4D)、CD69、SLAMF6(NTB-A、Ly108)、SLAM(SLAMF1、CD150、IPO-3)、BLAME(SLAMF8)、SELPLG(CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、CD19a、及びCD83と特異的に結合するリガンドからなる群から選択されるタンパク質から得られた機能的シグナル伝達ドメインである、請求項7に記載のキメラ抗原受容体ポリペプチド。
- 前記細胞内シグナル伝達ドメインは、4-1BB、CD28、OX40、CD3ゼータの機能的シグナル伝達ドメイン、又はそれらの組合せを含む、請求項7に記載のキメラ抗原受容体ポリペプチド。
- 請求項1に記載の抗-HER2抗体又はその抗原結合フラグメントをコードする核酸分子。
- 請求項7に記載のキメラ抗原受容体ポリペプチドをコードする核酸分子。
- 請求項11又は12に記載の核酸分子を含む組換えベクター。
- 請求項13に記載の組換えベクターで形質転換された宿主細胞。
- 請求項7に記載のキメラ抗原受容体ポリペプチドを発現するエフェクター細胞。
- 前記エフェクター細胞は、樹状細胞、キラー樹状細胞、マスト細胞、ナチュラルキラー細胞、Bリンパ球、Tリンパ球、マクロファージ及びそれらの前駆細胞からなる群から選ばれることを特徴とする、請求項15に記載のエフェクター細胞。
- 前記Tリンパ球は、炎症性Tリンパ球、細胞毒性Tリンパ球、制御性Tリンパ球又はヘルパーTリンパ球からなる群から選択される、請求項16に記載のエフェクター細胞。
- (a)請求項1~3のいずれか一項に記載の抗-HER2抗体又はその抗原結合フラグメントの薬剤学的有効量;及び(b)薬剤学的に許容される担体を含む癌予防又は治療用の医薬組成物。
- 請求項15に記載のキメラ抗原受容体ポリペプチドを発現するエフェクター細胞を含む、癌の治療用の医薬組成物。
- 前記癌は、乳癌、卵巣癌、胃癌、肺癌、肝癌、気管支癌、鼻咽頭癌、喉頭癌、膵癌、膀胱癌、大腸癌、結腸癌、子宮頸癌、脳癌、前立腺癌、骨癌、頭頸部癌、皮膚癌、甲状腺癌、副甲状腺癌又は尿管癌であることを特徴とする、請求項18又は19に記載の組成物。
- 前記医薬組成物はトラスツズマブ抗体をさらに含む、請求項18又は19に記載の組成物。
- 請求項1~5のいずれか一項に記載の抗-HER2抗体又はその抗原結合フラグメントを含む癌診断用キット。
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- 2018-11-14 JP JP2020544730A patent/JP7386796B2/ja active Active
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KR20190055022A (ko) | 2019-05-22 |
AU2018370195A1 (en) | 2020-06-04 |
WO2019098682A1 (ko) | 2019-05-23 |
US20210179733A1 (en) | 2021-06-17 |
EP3712178A1 (en) | 2020-09-23 |
CA3082328A1 (en) | 2019-05-23 |
KR20190055008A (ko) | 2019-05-22 |
CN111655732B (zh) | 2023-09-12 |
CN111655732A (zh) | 2020-09-11 |
JP2021509288A (ja) | 2021-03-25 |
EP3712178A4 (en) | 2021-08-11 |
AU2018370195B2 (en) | 2022-01-13 |
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