JP6861418B2 - ヒトt細胞免疫グロブリン及びitimドメイン(tigit)に特異的な抗体 - Google Patents
ヒトt細胞免疫グロブリン及びitimドメイン(tigit)に特異的な抗体 Download PDFInfo
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- JP6861418B2 JP6861418B2 JP2018511264A JP2018511264A JP6861418B2 JP 6861418 B2 JP6861418 B2 JP 6861418B2 JP 2018511264 A JP2018511264 A JP 2018511264A JP 2018511264 A JP2018511264 A JP 2018511264A JP 6861418 B2 JP6861418 B2 JP 6861418B2
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Description
又は(ii)QVQLLQPGAELVKPGASVKLSCKASGYTFTIYCIHWVKQRPGQGLEWIGEISPSNGRTIYNEKFKNKATLTIDKSSTTAYMQLSSLTSEDSAVYCCAISDGYDGYYFDYWGQGTTLTVSS(配列番号18)を有する重鎖可変領域を含むモノクローナル抗体又はその断片を含む。
又は(ii)DIQMTQSPSSLSASLGERVSLTCRASQEISGYLNWLQQKPDGTIKRLIYAASTLDSGVPKRFSGSRSGSDYSLTISRLESEDFADYYCLQYASYPRTFGGGTKLEIK(配列番号19)を有する軽鎖可変領域を含むモノクローナル抗体又はその断片を含む。
i.TIGITに特異的な抗体又は少なくとも抗原結合部分を含むその抗体断片と試料をインキュベートする工程;
ii.検出可能なプローブを用いて結合したTIGITを検出する工程
を含み、TIGITの存在を検出又は定量化する方法が提供される。
iii.既知量のTIGITを含有する参照試料から得られた標準曲線と(ii)の量とを比較する工程;
iv.標準曲線から試料中のTIGITの量を計算する工程
を含む。
抗体断片の生成のための様々な技術が開発されている。伝統的に、これらの断片は、無傷の抗体のタンパク質分解消化によるものである(例えば、Morimotoら、Journal of Biochemical and Biophysical Methods 24:107−117(1992)及びBrennanら,Science,229:81(1985)を参照されたい)。しかし、これらの断片は、現在は組換え宿主細胞により直接生成することができる。例えば、抗体断片は、上述の抗体ファージライブラリーから単離することができる。もう1つの方法として、Fab’−SH断片は、大腸菌から直接回収し、化学的に結合させて、F(ab’)2断片を形成することができる(Carterら,Bio/Technology 10:163−167(1992))。別のアプローチによれば、F(ab’)2断片は、組換え宿主細胞培養から直接単離することができる。抗体断片の生成のための他の技術は、当業者には明らかであろう。他の実施形態において、選択抗体は一本鎖Fv断片(scFv)である。
1)アラニン(A)、セリン(S)、スレオニン(T);
2)アスパラギン酸(D)、グルタミン酸(E);
3)アスパラギン(N)、グルタミン(Q);
4)アルギニン(R)、リジン(K);
5)イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V);及び
6)フェニルアラニン(F)、チロシン(Y)、トリプトファン(W)。
ヒト化抗体は、典型的には、非ヒトCDRを移植されたヒトFRを有する。したがって、ヒト化抗体は、非ヒトである供給源からそれに導入された1以上のアミノ酸配列を有する。これらの非ヒトアミノ酸残基は、典型的には「移入(import)」可変ドメインから得られる「移入」残基と呼ばれる場合が多い。ヒト化は、本質的に、ヒト抗体の対応する配列をげっ歯類のCDR又はCDR配列と置換することによる、Winter及び共同研究者の方法に従って行うことができる(Jonesら,Nature,321:522−525(1986);Riechmannら,Nature,332:323−327(1988;Verhoeyenら,Science,239:1534−1536(1988))。従って、そのような「ヒト化」抗体は、非ヒト種由来の対応する配列によって置換されている無傷のヒトVドメインが実質的により少ないキメラ抗体である(米国特許第4,816,567号)。実際には、ヒト化抗体は、典型的にはヒト抗体であり、その中のいくつかのCDR残基及びおそらくいくつかのFR残基は、齧歯類抗体の類似部位からの残基によって置換されている。
医薬品及び医薬製剤において、活性剤は、好ましくは、1以上の薬学的に許容される担体(複数可)及び必要に応じて、任意の他の治療成分と共に利用される。担体(複数可)は、製剤の他の成分と適合し、そのレシピエントに対して過度に有害でないという意味で、薬学的に許容されなければならない。活性剤は、上記のように、所望の薬理学的効果を達成するのに有効な量で提供され、所望の日用量を達成するのに適切な量である。
実験手順
様々な腫瘍のNK細胞の細胞毒性は、全てのヒトNK細胞及び様々なT細胞上に存在するTIGITタンパク質へのリガンド結合により抑制される。抗hTIGIT mAbを作製し、hTIGITとのリガンド相互作用によって与えられる死滅抑制に拮抗する能力について試験した。
表面プラズモン共鳴(SPR)バイオセンサービアコア(商標)T100(GE Healthcare)を用いて、Koff、Kon、及び抗体とTIGITとの間のKDを決定した。
ヒトTIGITに対するモノクローナル抗体を、TIGIT−Fc融合タンパク質で免疫化することにより、一例に従って作製した。ヒトTIGITのコード配列は、IgG1のFc断片との融合体としてクローニングすることによって生成した。作製した組換え融合タンパク質をマウスに注射し、ハイブリドーマ上清を、TIGITを発現するYTS NK細胞株形質移入体の特異的認識について試験した。
生成したヒトTIGITに特異的な2つの例示的モノクローナル抗体を、#4(又は258−cs1#4)及びVSIG9#1(又はVsig9.01)と命名した。これらのmAbは、図1Aに示されているように、ヒトTIGITで形質転換したYTS細胞を認識する。
mAbによるTIGITの認識を調べるために、発現細胞上の2×105個のYTS−TIGIT(Stanietskyらによって以前記載されているように、前出)を、30分間、氷上で0.2マイクログラムの抗TIGIT mAbクローンVSIG9#1又は#4とインキュベートした。FACS緩衝液での2回の洗浄後に、ヤギ抗マウスIgG(H+L)二次抗体アレクサフルオロ(登録商標)647コンジュゲート(BioLegend)を、氷上でさらに30分間添加した。図1Aに示すように、mAbは、YTS細胞上ではなく、発現細胞上のYTS−TIGIT上のTIGITタンパク質を認識する(右の曲線)。mIgGを対照として使用した。次に、VSIG−9#1を、2人の健康なドナーからの活性化NK細胞について調べた。図1Bに示すように、mAbは、NK細胞(FACSヒストグラムプロット中の右の曲線)を認識した。mIgGを対照として使用した(左の曲線)。
腫瘍細胞へのTIGIT−Fc結合に対するVSIG9#1の効果を調べるために、2.5×105個のHepG2細胞(高レベルのPVR、ネクチン−2及びネクチン−3を発現する)を、氷上で30分間、mAbを含めず(図2A、矢印1)、示した濃度のmIgG(図2A、矢印2)又は抗TIGIT−VSIG9#1(図2A、矢印3及び4)を含めて、25マイクログラム/ウェルのhTIGIT−Fcとインキュベートし、アレクサフルオロ(登録商標)647抗ヒトIgG(BioLegend)を用いて検出を行った。HepG2細胞上のTIGITリガンド、PVR、ネクチン−2及びネクチン−3の発現を、図2Bに示している。
エフェクター細胞の死滅活性に対する抗TIGIT mAbの効果を調べるために、YTS−TIGIT NK細胞を、2.5マイクログラム/mlの対照mIgG(左のバー)又は抗TIGIT VSIG9#1(右のバー)の存在下で35S標識721.221−PVR細胞とインキュベートした(*p<0.02)。前述のように、特異的死滅を計算した(Stanietskyら、前出)。死滅率を5時間後に調べた。図3Aに示すように、抗TIGIT mAb VSIG9#1は死滅活性を高める。次に、特異的な死滅活性を、35Sで標識し、対照mIgG(左のバー)又はVSIG9#1(右のバー)の存在下で健康なドナーからのNK細胞とインキュベートしたMDA−MB−231ヒト乳癌細胞について調べた。死滅率を、5時間後に測定した(**p<0.002)。図3Bに示すように、VSIG9#1は死滅効果を高める。2つの抗体の特異的な死滅活性も、MEL562黒色腫細胞を用いて調べた。図3Cに示すように、2つのmAbの258−CS1#4(中央のバー)及びVSIG9#1(左のバー)は、対照抗体mIgGと比較して、これらの細胞の死滅効果を有意に(**p<0.05)高める(右のバー)。最後に、VSIG9#1の抗体依存性細胞媒介性細胞傷害(ADCC)を、抗EGFR mAb(アービタックス(登録商標))とインキュベートし、それぞれ、10:1のエフェクター細胞:標的細胞の割合で対照mAb(左のバー)又はVSIG9#1(右のバー)とプレインキュベートしたNK細胞に添加した35Sで標識したヒト肝細胞HepG2細胞上で調べた(***p<0.0007)。図3Dに示すように、VSIG9#1は死滅効果を高めることができる。
TIGITのそのリガンドとの相互作用を阻止するmAb258−CS1#4及びVSIG9#1の能力を調べるために、PVR、ネクチン−2及びネクチン−3を発現するHepG2細胞を、TIGIT−Fcとインキュベートするか、又はmAb VSIG−9#1(図4A)若しくはmAb 258−CS1#4(図4B)とプレインキュベートした後にTIGIT−Fcとインキュベートした。結果は、VSIG−9#1とTIGIT−FcのプレインキュベーションがTIGIT−Fc結合を完全に阻止するが(図4A)、mAb 258−CS1#4とのプレインキュベーションは、部分的にTIGIT−Fc結合を阻止した(図4B)ことを示した。
2つの供給源からのヒトTIGITに対するmAbの完全結合動態分析を、ビアコアを用いて行った。図5A及び5Bに示す結果は、2つのmAbがヒトTIGITに高い親和性を示すことを示す。258−CS1#4(#4)と命名したmAbは、約1×10−7Mの平均Kdを有してるが(平均9.96×10−8M及び1.07×10−7M)、mAb VSIG−9#1は、4.5×10−10M(平均5.13×10−10M及び3.87×10−10M)のKdを有するヒトTIGITに非常に高い親和性で結合する。
TIGITに対する抗体VSIG9#1及びMBSA43の結合親和性を比較した。75×103個のTIGIT発現YTS細胞を、FACSによる決定後に、250nMから65fMの連続希釈濃度で、2つの抗体で染色した。図6A及び6Bに示すように、VSIG#9は62.5fMのような低濃度で細胞を染色したが、MBSA43は、1950fM(1.95pM)を超えた時だけ細胞を染色し、最後の4つの希釈で染色を示さなかった。2つの抗体間での明瞭な染色の違いは、250pMの濃度まで見られる。MBSA43抗体と比較したVSIG9#1抗体の優位性も、図6Bに示している。
PVR−TIGIT結合に対する抗TIGIT抗体阻止効果を調べるために、PVR−FcでのTIGIT発現YTS細胞の染色アッセイを行った。75×103個のYTS−TIGIT細胞を2倍希釈系列で、27から0.014pmoleの濃度範囲で、VSIG9#1又はMBSA43の存在下で、2.5pmoleのPVR−Fcとインキュベートした。
単独で又は他の免疫調節剤と組み合わせたmAb VSIG9#1(Vsig9.01)の、TIGITの阻止によるT細胞増殖の誘導に対する効力を調べた。健康なドナーからのPBMCを、5(6)−カルボキシフルオレセインN−ヒドロキシスクシンイミジルエステル(CFSE)で標識し、抗CD3抗体で活性化した後、単独で又は組み合わせた4μg/mlのmAb VSIG9#1、抗PD−1(Keytruda)及び抗CTLA4(イピリムマブ)の存在下で、hCD80を過剰発現しているMDA−MB−231細胞と5〜9日間インキュベーションした。増殖をCFSE希釈により測定した。
抗体の抗腫瘍効果は、インビボで研究されている。ヒト癌の阻害における本明細書に記載の抗体の有効性を推定するために、該抗体は、腫瘍とヒト由来のリンパ球の両方を組み合わせたモデルにおいて研究されている。免疫能力を回復するために、重症複合免疫不全マウス(SCID)にhPBLを移植する。マウスにヒト癌細胞を負荷し、腫瘍負荷の数日後に単回又は複数回の血管内用量で投与する抗ヒトTIGIT抗体で濃度を増加して治療する。
ヒト癌の阻害における抗TIGIT抗体の有効性を推定するために、腫瘍とヒト由来のリンパ球の両方を組み合わせたモデルにおいて該改変抗体を調べる。免疫能力を回復するために、重症複合免疫不全マウス(SCID)にhPBLを移植する。マウスに、ヒト黒色腫細胞(SK−28)を負荷し、腫瘍接種後11日目に、単一のi.v.用量で投与する抗体で濃度を増加して治療する。
LIM6及びHM7は、高いムチン合成及び転移能について選択されたヒトCRC細胞株LS174Tの2つのサブクローンである。腫瘍細胞を、麻酔したヌードマウスの露出した脾臓に注入する。数分後、脾臓を除去し、切除部を塞ぐ。低用量の本発明の抗TIGIT抗体を10日後に投与し、マウスを腫瘍接種後35日目に屠殺する。肝臓は秤量し、転移性結節の数を計数し、組織学及び免疫組織化学研究のために肝臓組織を処理する。
骨髄穿刺液をフィコール分離後にAML患者から得、免疫細胞及び芽細胞を12日間様々な抗体(4μg/mlで)と共培養し、12日後にT細胞の量を確立した。
Claims (14)
- ヒトT細胞免疫グロブリン及びITIMドメイン(TIGIT)に結合する単離モノクローナル抗体、又は少なくとも抗原結合部分を含むその抗体断片であって、前記単離抗体又は抗体断片は、
(i)重鎖可変領域の3つの重鎖(HC)相補性決定領域(CDR)と軽鎖可変領域の3つの軽鎖(LC)CDRとを含む単離抗体若しくは抗体断片であって、HC CDR1が配列GYTFTSYGIS(配列番号1)もしくはTSYGIS(配列番号11)を含み、HC CDR2が配列EIYPRSGNTYYNEKFKG(配列番号2)を含み、HC CDR3が配列KGPYYTKNEDY(配列番号3)を含み、LC CDR1が配列RASEHIYYSLA(配列番号4)を含み、LC CDR2が配列NANSLED(配列番号5)を含み、LC CDR3が配列KQAYDVPRT(配列番号6)を含む、単離抗体若しくは抗体断片;及び
(ii)重鎖可変領域の3つの重鎖CDRと軽鎖可変領域の3つの軽鎖CDRとを含む単離抗体若しくは抗体断片であって、HC CDR1が配列IYCIH(配列番号12)を含み、HC CDR2が配列EISPSNGRTIYNEKFKN(配列番号13)を含み、HC CDR3が配列SDGYDGYYFDY(配列番号14)を含み、LC CDR1が配列RASQEISGYLN(配列番号15)を含み、LC CDR2が配列AASTLDS(配列番号16)を含み、LC CDR3が配列LQYASYPRT(配列番号17)を含む、単離抗体若しくは抗体断片、
からなる群から選択される、単離モノクローナル抗体又は抗体断片。 - 配列番号7を含む重鎖と配列番号8を含む軽鎖とを含む;又は
配列番号18を含む重鎖と配列番号19を含む軽鎖とを含む;
請求項1に記載の単離モノクローナル抗体又は抗体断片。 - 前記抗体が、二重特異性抗体、ヒト化抗体、抗体コンジュゲート、又は少なくとも抗体結合部分を含む断片からなる群から選択される、請求項1または2に記載の単離モノクローナル抗体。
- 前記二重特異性抗体が二組のCDR配列を含み、一組が、配列GYTFTSYGIS(配列番号1)若しくはTSYGIS(配列番号11)を有するHC CDR1と、配列:EIYPRSGNTYYNEKFKG(配列番号2)を有するHC CDR2と、配列:KGPYYTKNEDY(配列番号3)を有するHC CDR3と、配列:RASEHIYYSLA(配列番号4)を有するLC CDR1と、配列:NANSLED(配列番号5)を有するLC CDR2と、配列:KQAYDVPRT(配列番号6)を有するLC CDR3と、を含み、二つ目の組が、配列:IYCIH(配列番号12)を有するHC CDR1と、配列:EISPSNGRTIYNE KFKN(配列番号13)を有するHC CDR2と、配列:SDGYDGYYFDY(配列番号14)を有するHC CDR3と、配列:RASQEISGYLN(配列番号15)を有するLC CDR1と、配列:AASTLDS(配列番号16)を有するLC CDR2と、配列:LQYASYPRT(配列番号17)を有するLC CDR3と、を含む、請求項3に記載の単離モノクローナル抗体。
- PVR(CD155)、PVRL2(CD112)、PVRL3(CD113)及びそれらの任意の組み合わせからなる群から選択される少なくとも1つのリガンドへのTIGITの結合を阻害することができる、請求項1〜4のいずれか一項に記載の単離モノクローナル抗体。
- 細胞傷害性部分、放射性部分、又は識別可能な部分に付着した、請求項1〜5のいずれか一項に記載のモノクローナル抗体。
- 請求項1に記載のモノクローナル抗体をコードするポリヌクレオチドであって、
モノクローナル抗体の重鎖可変領域をコードする配列番号9およびモノクローナル抗体の軽鎖可変領域をコードする配列番号10;または
モノクローナル抗体の重鎖可変領域をコードする配列番号20およびモノクローナル抗体の軽鎖可変領域をコードする配列番号21;
を含む配列を含むポリヌクレオチド。 - 請求項7に記載のポリヌクレオチドを含むベクター。
- 請求項1に記載のモノクローナル抗体を産生することが可能なハイブリドーマ細胞。
- 有効成分として少なくとも1種の請求項1〜6のいずれか一項に記載の単離抗体又はその断片と、薬学的に許容される賦形剤、希釈剤、塩又は担体と、を含む医薬組成物。
- 癌の治療に使用するための、請求項1〜6のいずれかに記載のモノクローナル抗体又は請求項10に記載の医薬組成物。
- さらに手術、化学療法、放射線療法、及び免疫療法から選択される追加の抗癌療法を含むか、または
PD−1、CTLA−4、PDL−1、CEACAM1、リンパ球活性化遺伝子3(LAG3)、CD137、OX40(CD134とも呼ばれる)、キラー細胞免疫グロブリン様受容体(KIR)及びそれらの任意の組み合わせからなる群から選択される免疫チェックポイント分子の投与をさらに含み、
前記抗癌療法が上皮成長因子受容体(EGFR)阻害剤の投与を含む、
請求項11に記載の医薬組成物。 - TIGITの発現を測定又は定量する方法であって、請求項1〜6のいずれか一項に記載の抗体又は抗体断片と生体試料を接触させることと、複合体形成のレベルを測定することと、を含む方法。
- 生体試料中のTIGITの発現を測定するためのキットであって、少なくとも1種の請求項1〜6のいずれか一項に記載の抗体又は抗体断片を含むキット。
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