JP2013091644A - Gitr結合分子およびその使用 - Google Patents
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Abstract
【解決手段】刺激剤、例えば、CD3の存在下で、hGITRに高いアフィニティーで結合することを特徴とし、アゴニスト的であり、Treg細胞によるTeff細胞の抑制を取り消す結合分子。種々のアスペクトは、結合分子、およびその医薬組成物、ならびにそのような結合分子を作製するための核酸、組換え発現ベクターおよび宿主細胞に関する。インビトロまたはインビボでヒトGITRを検出し、またはヒトGITR活性を調節する方法も包含される。
【選択図】なし
Description
本願は、2005年3月25日に出願された、「GITR結合分子およびその使用」という発明の名称の米国仮特許出願第60/665322号、および2005年6月3日に出願された、「GITR結合分子およびその使用」という発明の名称の米国仮特許出願第60/687265号の優先権を主張する。それぞれの内容を本明細書において引用によって援用する。
腫瘍壊死因子およびTNFレセプター(TNFR)スーパーファミリーのメンバーは、細胞増殖、分化および生存といった、多様な生物学的機能を調節する。全身性グルココルチコイドホルモンデキサメサゾンによって誘発されるT細胞mRNAを同定するためにディファレンシャルディスプレイを用いて、Nocentini et al. ((1997) Proc. Natl. Acad. Sci., USA 94:6216-6221997)は、TNFRファミリーの新規のメンバーをコードするマウスcDNAを同定した。対応する遺伝子は、glucocorticoid -induced
TNFR(グルココルチコイド誘発性TNFR)ファミリー関連遺伝子を表して、GITR(TNFRSF18としても知られている)と名づけられた。他のTNFRと同様に、予測されるGITRタンパク質は、システインリッチの繰り返し部分を細胞外ドメインに含有する。さらに、GITRの細胞内ドメインは、マウスおよびヒトTNFR、4−1BBおよびCD27のそれと有意なホモロジーを共有している。Nocentini et al. ((1997) Proc. Natl. Acad. Sci., USA 94:6216-6221997)は、GITR遺伝子がデキサメサゾンおよび他の細胞活性化刺激によって、T細胞中において誘発されることを証明した。GITR発現は、抗CD3抗体を用いた処置によって誘発されるアポトーシス(但し、他のアポトーシス物質によるものではない)からT細胞を保護している。
本発明は、T細胞や樹状細胞などの細胞上で、GITR、例えば、ヒトGITR(hGITR)に特異的に結合する結合分子を提供する。本発明の結合分子は、hGITRに高アフィニティーで結合し、刺激剤、例えば、CD3の存在下でアゴニストとなり、Tエフェクター(Teff)細胞のT調節(Treg)細胞による抑制を取り消すことを特徴とする。
本明細書において用いられている用語「グルココルチコイド誘発TNFレセプター」(「GITR」と略される)は、TNFレセプタースーパーファミリー18(TNFRSF18)としても知られており、腫瘍壊死因子/神経成長因子レセプターファミリーのメンバーである。それは、細胞外ドメインにある3つのシステイン・シュードリピートを特徴とする241アミノ酸タイプI膜貫通タンパク質であり、T細胞レセプター誘発アポトーシスを特異的に保護するが、Fasトリガー、デキサメサゾン処置、またはUV照射を含む他のアポトーシスシグナルから細胞を保護しない(Nocentini, G, et al. (1997) Proc. Natl. Acad. Sci., USA 94:6216-622)。ヒトGITR(hGITR)の核酸配列を配列番号:17に示し、アミノ酸配列を配列番号:18に示す。
in Methods in Molecular Biology, Vol. 66, G. E. Morris, Ed. (1996)を参照されたい。
Enzymology 9:242 (1983)参照);固相直接ビオチン−アビジンEIA(Kirkland et al., J. Immunol. 137:3614 (1986));固相直接標識アッセイ、固相直接標識サンドイッチアッセイ(HarlowとLane、Antibody: A
Laboratory Manual, Cold Spring Harbor Press (1988)); I-125標識を用いた固相直接標識RIA(Morel et al., Mol. Immunol.
25(1):7 (1988)参照); 固相直接ビオチン−アビジンEIA(Cheung et al., Virology 176:546 (1990));および直接標識RIA(Moldenhauer et al., Scand. J. Immunol.
32:77 (1990))など、多くのタイプの競合的結合アッセイが知られている。典型的に、そのようなアッセイは、固体表面に結合した精製された抗原またはこれらのいずれか、非標識試験結合分子および標識参照結合分子を保有する細胞を使用する。競合的阻害は、試験結合分子の存在下で固体表面もしくは細胞に結合する標識の量を測定することによって測定される。通常、試験結合分子は、過剰に存在する。通常、競合結合分子が過剰に存在する場合、それは、参照結合分子の共通抗原に対する特異的結合を、少なくとも50〜55%、55〜60%、60〜65%、65〜70%、70〜75%、またはそれ以上阻害するであろう。
256:495 (1975)に最初に記載されたハイブリドーマ法で作製してもよいし、組換えDNA法(例えば、米国特許第4,816,567号参照)を用いて作製してもよい。「モノクローナル結合分子」はまた、例えば、Clackson, et al., Nature
352:624-628 (1991) およびMarks et al., J. Mol Biol. 222:581-597 (1991)に記載の技法を用いて、ファージ抗体ライブラリーから単離してもよい。
Sci. USA 81:6851-6855 (1984))。
Chem. 252, 6609-6616 (1977)およびKabat, et al., Sequences of
protein of immunological interest. (1991)、ならびにChothia, et al., J. Mol.
Biol. 196:901-917 (1987)およびMacCallum, et al., J. Mol. Biol.
262:732-745 (1996)に記載されている。そこでは、それぞれ比較すると、アミノ酸残基のオーバーラッピングまたはサブセットを含んでいる。それにもかかわらず、いずれの定義の提供も、結合分子のCDRまたは移植された結合分子またはそれらの異型も本明細書において定義され、用いられている用語の範囲に包含される。
321:522-525 (1986); Riechmann, et al., Nature
332:323-329 (1988);およびPresta, Curr. Op. Struct. Biol. 2:593-596 (1992)を参照されたい。
145-173; PaulとSeder, 1994, Cell 76,
241-251; ArthurとMason, 1986, J. Exp. Med.
163, 774-786; Paliard, et al., 1988, J. Immunol. 141, 849-855; Finkelman, et
al., 1988, J. Immunol. 141, 2335-2341)。
本発明は、単離されたGITR結合分子を提供する。本発明の結合分子の例としては、6C8抗体および2F8抗体がある。6C8抗体は、T細胞および樹状細胞、例えば、ヒトT細胞および樹状細胞上で、GITRに高アフィニティーで結合する抗GITR抗体である。 好ましくは、そのような結合分子は、T調節細胞によるTエフェクター細胞の抑制を取り消し、そして、部分的に活性化されたT細胞に対して インビトロ
で刺激剤、例えば、CD3の存在下で、アゴニスト性を示す。
ADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNE(配列番号:20);
AKTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPESVTVTWNSGSLSSSVHTFPALLQSGLYTMSSSVTVPSSTWPSQTVTCSVAHPASSTTVDKKLEPSGPISTINPCPPCKECKCPAPNLEGGPSVFIFPPNIKDVLMISLTPKVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTIRVVSTLPIQHQDWMSGKEFKCKVNNKDLPSPIERTISKIKGLVRAQVYILPPPAEQLSRKDVSLTCLVVGFNPGDISVEWTSNGHTEENYKDTAPVLDSDGSYFIYSKLNMKTSKWEKTDSFSCNVRHEGLKNYYLKKTISRSPGK(配列番号:20)。
36:35; Queen et al., Proc. Natl. Acad. Sci. USA, (1989),
86:10029-10033; Jones et al., Nature, (1986),
321:522-25; Riechmann et al., Nature, (1988), 332:323-27; Verhoeyen et al., Science, (1988), 239:1534-36; Orlandi et al., Proc. Natl. Acad. Sci. USA, (1989), 86:3833-37; 米国特許第5,225,539号;5,530,101号;5,585,089号;5,693,761号;5,693,762号;6,180,370号、Selick et al., PCT国際公開公報WO90/07861号、およびWinter, 米国特許第5,225,539号を参照されたい(それらの全てを全ての目的のために、引用によって援用する)。定常領域は、もし存在すれば、ヒトイムノグロブリンに由来することが好ましい。
EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWP(配列番号:25)である。
EIVLTQSPATLSLSPGERATLSCRASQGVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGPGTDFTLTISSLEPEDFAVYYCQQRSNWH(配列番号:26)である。
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWP(配列番号:27)である。
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGRDFTLTISSLEPEDFAVYYCQQRSNWP(配列番号:28)である。
AIRMTQSPFSLSASVGDRVTITCWASQGISSYLAWYQQKPAKAPKLFIYYASSLQSGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQYYSTP(配列番号:29)である。
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYSTP(配列番号:30)である。
DIQMTQSPSFLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQCGYSTP(配列番号:31)である。
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYDNLP(配列番号:32)である。
DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWYQQKPGKVPKLLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQKYNSAP(配列番号:33)である。
DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYP(配列番号:34)である。
DIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISNLQPEDFATYYCLQHNSYP(配列番号:35)である。
DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYP(配列番号:36)である。
DIQMTQSPSSLSASVGDRVTITCRARQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYP(配列番号:37)である。
DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWFQQKPGKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYP(配列番号:38)である。
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFP(配列番号:39)である。
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFP(配列番号:40)である。
DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNSYP(配列番号:41)である。
AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQDYNYP(配列番号:42)である。
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYS(配列番号:43)である。
QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGWIRQPPGKALEWLALIYWNDDKRYSPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYY(配列番号:45)である。
QVTLKESGPVLVKPTETLTLTCTVSGFSLSNARMGVSWIRQPPGKALEWLAHIFSNDEKSYSTSLKSRLTISKDTSKSQVVLTMTNMDPVDTATYYCARI(配列番号:46)である。
QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMCVSWIRQPPGKALEWLALIDWDDDKYYSTSLKTRLTISKDTSKNQVVLTMTNMDPVDTATYYCARI(配列番号:47)である。
QLQLQESGSGLVKPSQTLSLTCAVSGGSISSGGYSWSWIRQPPGKGLEWIGYIYHSGSTYYNPSLKSRVTISVDRSKNQFSLKLSSVTAADTAVYYCAR(配列番号:48)である。
QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGDYYWSWIRQPPGKGLEWIGYIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAR(配列番号:49)である。
QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSTYYNPSLKSLVTISVDTSKNQFSLKLSSVTAADTAVYYCAR(配列番号:50)である。
QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGSIYYSGSTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAR(配列番号:51)である。
QVQLQESGPGLVKPSETLSLTCTVSGGSVSSGSYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAR(配列番号:52)である。
Protein Engineering 4:773 (1991); Kolbinger et al., Protein
Engineering 6:971 (1993) およびCarter et al., PCT国際公開WO92/22653号を参照されたい。
Protein Engineering 4:773 (1991); Kolbinger et al., Protein
Engineering 6:971 (1993) and Carter et al., PCT国際公開WO92/22653を参照されたい。
(QVTLKESGPGILQPSQTLSLTCSFSGFSLSTSGMGVGWIRQPSGKGLEWLAHIWWDDDKYNPSLKSRLTISKDTSSNQVFLKITSVDTRDTATYYCARTRRYFPFAYWGEGTSVTVTS(配列番号:67;フレームワーク残基を太字で示している)。別の態様において、配列番号:68に記載のフレームワーク配列は、
(QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYNPSLKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTRRYFPFAYWGQGTLVTVSS(配列番号:68;フレームワーク残基を太字で示している))。
(1987))によって定義されるCDRに非常に隣接した位置におけるアミノ酸残基が挙げられる。これらのアミノ酸は、CDR中のアミノ酸と特に相互作用しやすく、アクセプターから選択される場合、ドナーCDRをゆがめ、アフィニティーを減少させるかもしれない。さらに、隣接したアミノ酸は、抗原と直接的に相互作用するかもしれない(Amit et al., Science,
233:747 (1986)、本明細書においは引用によって援用する)。また、これらのアミノ酸をドナーから選択することは、もともとの結合分子におけるアフィニティーを提供する抗原接触を維持するために望ましい。
16:548 (1983)、ならびにLee とRichards, J. Mol. Biol. 55:379 (1971)、この両方を本明細書において引用によって援用する)。フレームワークアミノ酸はまた、別のフレームワークアミノ酸の高次構造に影響を及ぼし、ひいてはCDRと接触することによって、間接的にCDRと相互作用する場合もある。
215:175 (1990)、この全てを本明細書において、引用によって援用する)。明らかに、軽鎖の2、48および71位置および重鎖の26〜30、71および94位置のアミノ酸は、多くの結合分子でCDRと相互作用することが可能であることが知られている。軽鎖の35位置のアミノ酸および重鎖の93および103のアミノ酸もCDRと相互作用する可能性が高い。これらすべての、番号付けされた位置において、(アクセプターアミノ酸とドナーアミノ酸が異なる場合)アクセプターアミノ酸よりむしろドナーアミノ酸が、ヒト化イムノグロブリンとして選択されることが好ましい。一方、CDR領域と相互作用する特定の残基、例えば、軽鎖の第1の5アミノ酸は、時として、アクセプターイムノグロブリンから、ヒト化結合分子におけるアフィニティーの損失なしに選択される。
82:4592-66 (1985)に定義されているように、VLとVHの間の界面にそれらの残基を含む。
Biol. 215:175 (1990)、それらの全てを全ての目的のために、引用によって援用する)。正準残基は、軽鎖の2、25、27B、28、29、30、33、48、51、52、64、71、90、94および95、重鎖の24、26、27、29、34、54、55、71および94の残基を含む。さらなる残基(例えば、CDR構造決定残基)は、Martin とThorton (1996) J. Mol. Biol. 263:800の方法に従って同定することができる。
III.結合分子の作製
et al., 米国特許第5,658,570号(1995年1月25日出願、本明細書において引用によって援用する)に記載のように、結合分子の製造のための、定常および可変領域配列へクローンニングを行う。基本的に、これは、選択された細胞からのRNAの抽出、cDNAの変換、Ig特異性プライマーを用いたPCRによる増幅を必然的に伴う。この目的にとって好適なプライマーについても米国特許第5,658,570号に記載がある。所望の抗体を発現する形質転換するされた細胞を、比較的大量に作製し、臨床および市販用の結合分子を提供することができるかもしれない。
H.R. とChames.
2000. Immunol. Today 21:371; Nagy et al. 2002. Nat.
Med. 8:801; Huie et al. 2001.
Proc. Natl. Acad. Sci. USA
98:2682; Lui et al. 2002.
J. Mol. Biol.
315:1063に記載されている。そのそれぞれを本明細書においては引用によって援用する。いくつかの出版物(例えば、Marks
et al. Bio/Technology
10:779-783 (1992))は、大きなファージライブラリーを構築するためのストラテジーとして、高アフィニティーヒト結合分子の鎖シャフリングによる作製、ならびにコンビナトリアル感染およびインビボ 組換えについて記載している。別の態様において、リボソーム性の表示を行って、バクテリオファージを表示プラットフォームに置き換える(例えば、Hanes
et al. 2000. Nat.
Biotechnol. 18:1287; Wilson
et al. 2001. Proc.
Natl. Acad. Sci. USA 98:3750; or Irving et al. 2001 J.
Immunol. Methods 248:31)。さらに別の態様において、細胞表面ライブラリーをスクリーニングして結合分子を得ることができる(Boder
et al. 2000. Proc. Natl. Acad. Sci. USA
97:10701; Daugherty et al.
2000 J. Immunol. Methods 243:211)。そのような処置は、単離およびそれに続くモノクローナル結合分子のクローニングのための伝統的なハイブリドーマ技法にとって変わるものである。
Coligan et al., Eds., Green Publishing Associates and Wiley-Interscience, John
Wiley and Sons, New York (1991) に記載がある。その内容全体を補足も含めて、本明細書に引用によって援用する。
(1982); 欧州特許第120,694号;欧州特許第125,023号;Morrison, J. Immun. 123:793 (1979); Kohler
et al., Proc. Natl. Acad. Sci. USA 77:2197 (1980); Raso et
al., Cancer Res. 41:2073 (1981);
Morrison et al., Ann. Rev. Immunol. 2:239 (1984); Morrison, Science
229:1202 (1985); Morrison et al., Proc. Natl. Acad.
Sci. USA 81:6851 (1984);欧州特許第255,694号;欧州特許第266,663号;ならびにPCT国際公開公報WO88/03559に記載されている。再配列されたイムノグロブリン鎖も公知である。例えば、米国特許第4,444,878;PCT国際公開公報WO88/03565;および欧州特許第68,763号および、そこに引用されている引例を参照されたい。
Natl. Acad. Sci. USA 85:5879)がある。他の結合ペプチドは、当該技術分野において公知である。
al. 1991. Biochemistry 30:10117; Milenic et al. 1991. Cancer Research 51:6363;
Takkinen et al. 1991. Protein
Engineering 4:837を参照されたい。
14:52)。.
Rockford, ILから入手可能である。
IV.結合分子の発現
Maniatis (eds), Molecular Cloning; A Laboratory
Manual, Second Edition, Cold Spring Harbor, N.Y., (1989), Ausubel, F.M. et al. (eds.) Current Protocols in Molecular Biology, Greene Publishing Associates, (1989) and in 米国特許第. 4,816,397 by Boss, et al.に記載されているように行う。
Technology: Methods in Enzymology
185, Academic Press, San Diego, CA (1990)に記載されている。当業者は、調節配列の選択を含めた発現ベクターのデザインが、形質転換されるべき宿主細胞、所望のタンパク質の発現レベルなどの因子によって決定されることを理解するであろう。哺乳動物宿主細胞の発現のための好ましい調節配列としては、哺乳動物細胞において高いレベルのタンパク質発現を導くウイルスエレメント、例えば、サイトメガロウイルス(CMV)(例えば、CMVプロモーター/エンハンサー)、サルウイルス40(SV40)(例えば、SV40プロモーター/エンハンサー)、アデノウイルス(例えば、アデノウイルスメジャーレートプロモーター(AdMLP))、およびポリオーマ由来のプロモーターおよび/またはエンハンサーが挙げられる。ウイルス調節エレメントについてのさらなる詳細、およびその配列については、例えば、米国特許第5,168,062号(Stinskiによる)、米国特許第4,510,245号(Bell et al.による)および米国特許第4,968,615号(Schaffner, et al.による)を参照されたい。
Clones, VCH Publishers, N.Y., N.Y. (1987)を参照されたい。真核生物細胞が実際には好ましい。なぜなら、異種のタンパク質(例えば、未処理の結合分子)を分泌することが可能な、多くの好適な宿主細胞系列が当該技術分野において開発されており、CHO細胞系列、種々のCos細胞系列、HeLa細胞、骨髄腫細胞系列、または形質転換されたB細胞もしくはハイブリドーマなどがあるからである。好ましくは、該細胞は、非ヒト細胞である。これらの細胞のための発現ベクターは、複製のオリジン、プロモーターおよびエンハンサーなどの発現制御配列、および、リボソーム結合部位、RNAスプライシング部位、ポリアデニル化部位、および転写終始配列といった必要なプロセシング情報部位を含むことができる(Queen et al., Immunol. Rev.
89:49 (1986))。好ましい発現制御配列は、イムノグロブリン遺伝子、SV40、アデノウイルス、ウシパピローマウイルス、サイトメガロウイルスなどに由来するプロモーターである。Co et al., J. Immunol.
148:1149 (1992)を参照されたい。
(1982) Mol. Biol. 159:601-621に記載されているようにDHFR選択可能マーカーとともに用いられる)、NS0骨髄腫細胞、COS細胞およびSP2細胞が挙げられる。結合分子遺伝子をコードする組換え発現ベクターを哺乳動物宿主細胞に導入したとき、宿主細胞中の結合分子の発現、より好ましくは、宿主細胞が成長する培養培地への結合分子の分泌を可能にするのに十分な時間の間、宿主細胞を培養することによって、結合分子を作製する。結合分子は、標準的な精製方法を用いて培養培地から回収することができる。.
Cloning: A Laboratory Manual (Cold Spring Harbor Press, 2nd ed., 1989参照)(その全体を全ての目的のために引用によって援用する)。哺乳動物細胞を形質転換するために用いられる他の方法としては、ポリブレン、プロトプラスト融合、リポソーム、エレクトロポレーションおよびマイクロインジェクション(一般的に、Sambrook et al., 上掲文献参照)。トランスジェニック動物を作製するために、トランスジーンを受精卵にマイクロインジェクションすることができる。または、胚性幹細胞のゲノムに組み込み、そのような細胞の核を摘出された卵子に移植することがる。
Purification (Springer-Verlag, N.Y., (1982))。少なくとも約90〜95%の相同性を示す、本質的に純粋な結合分子が好ましい。医薬品として使用するためには、相同性が98〜99%の相同性が最も好ましい。
a)配列番号2のアミノ酸配列を含む可変領域を有する結合分子軽鎖;および
b)配列番号1のアミノ酸配列を含む可変領域を有する結合分子重鎖。
a)配列番号2のアミノ酸配列を含む可変領域を有する結合分子軽鎖;および
b)配列番号66のアミノ酸配列を含む可変領域を有する結合分子重鎖。
GITRに対して結合する能力があれば、本発明の結合分子は、GITR(例えば、血清もしくは血漿などの生物学的サンプル中)を、従来のイムノアッセイ、例えば、酵素結合抗体免疫アッセイ(ELISA)、ラジオイムノアッセイ(RIA)もしくは組織免疫組織化学的手法を用いて検出するために用いることができる。本発明は、生物学的サンプル中のhGITRを検出するための方法であって、生物学的サンプルを本発明の結合分子に接触させ、およびhGITRに結合した結合分子または未結合の結合分子のいずれかを検出し、それによって、生物学的サンプル中のhGITRを検出することを含む方法を提供する。該方法は、インビトロまたはインビボのいずれで行うこともできる。該結合分子は、検出可能な物質を用いて、直接的または間接的に標識し、結合した結合分子または未結合の結合分子の検出を容易にすることができる。好適な検出可能な物質としては、種々の酵素、補欠分子団、蛍光物質、発光性物質、および放射性物質が挙げられる。好適な酵素の例には、西洋ワサビペルオキシダーゼ、アルカリ性ホスファターゼ、β−ガラクトシダーゼ、またはアセチルコリンエステラーゼが含まれる。好適な補欠分子団の例には、ストレプトアビジン/ビオチンおよびアビジン/ビオチンが含まれ、好適な蛍光物質の例には、ウンベリフェロン、フルオレセイン、フルオレセインイソチオシアネート、ローダミン、ジクロロトリアジニルアミンフルオレセイン、ダンシルクロリドもしくはフィコエリトリンが含まれ、発光性物質の例にはルミノールが含まれる;好適な放射性物質の例には、125I、131I、35Sもしくは3Hが含まれる。
添付の実施例に記載しているように、本発明の結合分子は、免疫促進性組成物(またはワクチン)として、例えば、抗原と組み合わせて使用して、対象となる抗原(例えば、被験体におけるタンパク質抗原)に対する免疫応答を促進させるために使用することができる。すなわち、本発明の結合分子は、免疫応答を高めるためのアジュバントとして機能することができる。例えば、対象となる抗原に対する抗体または細胞免疫応答を刺激するために(例えば、ワクチン接種の目的)、本発明の抗原および結合分子を併用して投与する(例えば、同じもしくは別個の組成物で同時に併用投与する、または連続的に併用投与する)ことができ、その結果、免疫応答が上昇する。対象となる抗原および結合分子はいっしょに、単一の医薬組成物として製剤することもできるし、または別個の組成物として製剤することもできる。ある態様において、対象となる抗原および結合分子を被験体に同時に投与する。別法として、いくつかの状況においては、まず抗原を投与し、その後結合分子を投与する、またはその逆が望ましいかもしれない(例えば、反応を引き起こすためにまず抗原のみを投与し、その後結合分子を癌毒もしくは抗原の追加免疫とともに、投与することが好ましいかもしれない)。好ましい態様において、本発明のGITR結合分子を、抗原によるプライミングと同時に、すなわち、最初の抗原投与と同時に、例えば、−3、−2、−1、0、+1、+2、+3日目に投与する。本発明のGITR結合分子の特に好ましい投与日は、抗原投与の前日である。
当該結合分子は、免疫応答を高める方法にも使用することができる。免疫応答のアップレギュレーションは、存在する免疫応答を高める、もしくは最初の免疫応答を惹起するのいずれの形態であってもよい。例えば、GITRの調節によって免疫応答を高めることは、ウイルス性感染症の場合に有用であるかもしれない。抗GITR結合分子は、免疫応答を高めるように作用するので、それらは、より急速もしくはより徹底的な病原性物質(例えば、細菌およびウイルス)の排除が有益な場合に、治療的に有用である。したがって、本発明の抗GITR結合分子は、単独または抗原もしくは免疫促進性の物質との組み合わせのいずれかにおいて、治療的に用いて、感染症や悪性腫瘍などの疾患や状態(例えば、上記参照)をもつ被験体を治療することができる。
本発明の結合分子は、被験体へ好適に投与される医薬組成物に組み込む。典型的に、医薬組成物は、本発明の結合分子 および薬学的に許容される担体を含む。本明細書において用いられている用語「薬学的に許容される担体」には、薬学的投与に適合する、溶媒、分散媒、コーティング、抗菌剤および抗カビ剤、等張剤および吸収遅延剤等が含まれる。薬学的に活性な物質のためのこのような媒質および薬剤の使用は、当業で公知である。従来の媒質または薬剤が当該活性化合物に対して不適合でない限り、治療用組成物中へのその使用は考慮される。補助的な活性化合物も本組成物中に取り入れることができる。
本発明の結合分子は、インビボまたはインビトロでの医薬投与に適した生物学的に適合性ある形で被験体に投与される。「生物学的に適合性ある形」とは、毒性の効果が、当該作用薬の治療効果よりも小さいような作用薬の形を意味する。
Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New
York, 1978を参照されたい。
いくつかの実施例において、以下の材料と方法を用いる。
分化細胞系列を、ヒト臍帯血または末梢血CD4+CD45RA+未処置のT細胞から、フローサイトメトリーおよび磁気ビーズ分離法を含む種々の方法により調製された細胞から作製した。開始集団の純度は>95%だった。次に細胞を、10%FCSおよび1%ヒトAB血清と、サイトカインおよび抗サイトカイン中和化抗体との規定された混合液を含むCD3およびCD28抗体のRPMI1640溶液で刺激して、分化細胞種を作製した。Th1細胞をIL12(62U/ml)および抗IL4(0.2ug/ml)との培養で産生させ;Th2細胞を、IL4(145U/ml)および抗IL12(10ug/ml)および抗IFNγ(10ug/ml)中での培養で産生させ;そして制御性T細胞をTGFβ(32U/ml)、IL9(42U/ml)、抗IL4(10ug/ml)および抗IL12(10ug/ml)および抗IFNγ(10ug/ml)中での培養で産生させた。(注:抗IL12はすべての実験で用いられたわけではない)。培養物すべてに、IL2(65U/ml)およびIL15(4500U/ml)を添加した。細胞を、細胞分裂で可能な場合に、より大型の培養皿に分け取った。
6C8抗体は、IgG2bカッパである。この抗体を精製することによって、二重の重鎖の存在が明らかになった(図1)。これは、グリコシル化または他のAbの混在のいずれかによるものであろう。立体排除クロマトグラフィーによって、1つのピークの存在が示された。
1)20mlのプロテインG(Protein G、Pharmacia HR 10/30)を5CVのdPBSで洗浄した。
2)1L(ラン1)または2L(ラン2)のhGITR(6C8)上清を入れた。
3)10CVのdPBSで洗浄した。
4)100mMクエン酸塩、pH2.8を直接1Mトリス(20−25%、v:v)に溶出させた。
5)100mMクエン酸塩、pH2.8、0.3MのNaClで除去した。
6C8抗体は、GITR−L−Mトランスフェクトされた細胞および活性化されたPBL(図4)に結合する(図3)。および活性化されたリンパ球上のビオチン標識された抗GITRの飽和曲線は、良好な相対的アフィニティーを示唆している(図5)。
6C8抗体は、T調節細胞によって誘発された抑制をブロックすることができる(図9)。CD4+/CD25+細胞をCD4+/CD25−細胞に、種々の比率で添加した。該細胞をプレートに結合した抗CD3および抗CD28で刺激した。1:1の比率で、CD4+/CD25+細胞はCD4+/CD25−細胞の増殖を取り消すことができる。6C8の培養物への添加によって、容量依存的に抑制をブロックすることができた。
I−κBリン酸化(図12および14)およびそれに続く分解(図11および13)の双方によって評価されるように、T細胞のCD3またはCD3とCD28を介しての活性化の結果、I−κBシグナリング経路の活性化が起こる。
B16メラノーマ腫瘍モデルは、癌細胞におけるT調節細胞の役割を研究するために用いられてきた攻撃的なメラノーマモデルである。枯渇作用をする抗CD25抗体もしくは抗CTLA−4を用いてマウスを治療することで、有望な結果がこのモデルにおいて認められる。双方のケースにおいて、治療は、腫瘍の開始および腫瘍サイズを遅らせることができる。GITRは、CD25+細胞において発現し、T調節細胞の抑制を止めることに関与するかもしれない。B16腫瘍を持つマウスを抗GITR結合分子で治療して、腫瘍の開始または腫瘍細胞に影響を及ぼすかどうかを測定した。マウスに腫瘍を注入した1日後に、抗GITR結合分子を用いた治療を行ったところ、腫瘍の発生およびサイズが遅延した(図17)。さらに、実験終了時、腫瘍がなかったGITR治療群にはまだマウスが存在していた。
抗mGITR抗体が卵白アルブミン(Ova)もしくは赤血球凝集素(HA)に対する体液反応のアジュバントをさらに調べた。1日前、0日目、1日目に、マウスを抗体なし、YAML(アイソタイプ対照)、または2F8(ラット抗mGITR)を用いて、0.4mg/日で治療した。結合分子の作用機序におけるFcレセプターの関与の重要性を評価するために、さらに別の群の動物を6mg/日の2F8F(ab’)2を用いて、1日前、0日目、1日目に治療した。この投与量は、抗体全体と比較して短い半減期のF(ab’)2に基づいて選択された。マウスを0日目に、Ova(100μg)またはHA(10μg)で免疫した。Ova治療マウスに対して、100μgのOvaを14日目に攻撃感染し、21日目および28日目に採血してELISAアッセイのための血清サンプルを取得した。HA治療マウスにもを14日目に攻撃感染し、21日目および28日目に採血した。
6C8可変軽鎖領域を、従来の生物学的技法を用いて、ヒト軽鎖定常領域に移植した。IgG1軽鎖定常領域を用いた。完全キメラ軽鎖GITR結合分子のアミノ酸配列を以下に示す:
DIVMTQSQKFMSTSVGDRVSVTCKASQNVGTNVAWYQQKPGQSPKALIYSASYRYSGVPDRFTGSGSGTDFTLTINNVHSEDLAEYFCQQYNTDPLTFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号:22)。
QVTLKESGPGILKPSQTLSLTCSFSGFSLSTSGMGVGWIRQPSGKGLEWLAHIWWDDDKYYNPSLKSQLTISKDTSRNQVFLKITSVDTADAATYYCARTRRYFPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号:23)。
QVTLKESGPGILKPSQTLSLTCSFSGFSLSTSGMGVGWIRQPSGKGLEWLAHIWWDDDKYYNPSLKSQLTISKDTSRNQVFLKITSVDTADAATYYCARTRRYFPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号:24)。
Hwang et al. (2005) Methods (36) 35-42に記載されているCDRホモロジーベースのストラテジーを用いて6C8をヒト化した。重鎖および軽鎖アミノ酸配列を、公開されている利用可能なデータベースを用いてブラストした。その結果によれば、6C8は、3−1重鎖正準構造および2−1−1軽鎖正準構造を持つことが示された。これにより、IMGTデータベース中の2−1−1正準構造を持つ全ての生殖細胞系列κ鎖V遺伝子を6C8抗体配列と比較した。同じことを重鎖についても行い、そこでは、全ての3−1生殖細胞系列重鎖V遺伝子を6C8アミノ酸配列と比較した。CDR配列のみを比較し、フレームワークは、CDRにおいてどの生殖細胞系列配列が最も多くのマッチングを示すかに基づいて選択した(下のアライメントを参照されたい)。
EIVMTQSPATLSVSPGERATLSCKASQNVGTNVAWYQQKPGQAPRLLIYSASYRYSGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNTDPLTFGGGTKVEIK(配列番号:44)(CDRをイタリック体で示している)。
QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYNPSLKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTRRYFPFAYWGQGTLVTVSS (配列番号:53)(「N」とも称する)。
QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYQPSLKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTRRYFPFAYWGQGTLVTVSS(配列番号:54)(「Q」とも称する)。
全長バージョン2(HuN6C8−Agly)−ヒト化(Hu)6C8軽鎖(L)/ヒト化重鎖、CDR2にNをもち(「N」)、Aをもつ定常領域を含む(「Agly」)。
全長バージョン3(HuN6C8−Gly)−ヒト化(Hu)6C8軽鎖(L)/ヒト化重鎖、CDR2にQをもち(「Q」)、Nをもつ定常領域を含む(「Gly」)。
全長バージョン4(HuN6C8−Agly)−ヒト化(Hu)6C8軽鎖(L)/ヒト化重鎖、CDR2にNをもち(「N」)、Aをもつ定常領域を含む(「Agly」)。
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号:55)。
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号:56)。
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号:57)。
EIVMTQSPATLSVSPGERATLSCKASQNVGTNVAWYQQKPGQAPRLLIYSASYRYSGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNTDPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号:58)。
QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYNPSLKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTRRYFPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号:60);
QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYNPSLKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTRRYFPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号:61);
QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYQPSLKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTRRYFPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号:62)
QVTLRESGPALVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYQPSLKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARTRRYFPFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号:63)。
当業者は、ルーチンの実験以上のことをすることなく、本明細書に記載した本発明の具体的な実施形態に対する多くの均等物を認識、または確認することができるであろう。そのような均等物は、添付の請求項に包含されることが意図されている。
Claims (30)
- グルココルチコイド誘発性TNFRファミリー関連レセプター(GITR)に特異的に結合する、抗体またはその抗原結合フラグメントを含む組成物であって、該組成物は、被験体において抗原に対する免疫応答を誘発する、または高める方法に使用され、該方法は、GITR結合抗体または抗原結合フラグメント、および抗原を前記被験体に投与することを含む、組成物。
- 前記被験体が、前記免疫応答が誘導される抗原のソースを含む、請求項1に記載の組成物。
- 前記抗原のソースが、腫瘍または感染性微生物を含む、請求項2に記載の組成物。
- 前記免疫応答が、体液性免疫応答を含む、請求項1、2、及び3のいずれかに記載の組成物。
- 前記GITR結合抗体または抗原結合フラグメントのT細胞への結合によって、T調節細胞によるTエフェクター細胞の抑制を取り消す、請求項1、2、3、及び4のいずれかに記載の組成物。
- 前記GITR結合抗体または前記抗原結合フラグメントが、Tエフェクター細胞の増殖を高める、請求項1、2、3、及び4のいずれかに記載の組成物。
- 前記GITR結合抗体または前記抗原結合フラグメントのTエフェクター細胞への結合によって、前記Tエフェクター細胞の増殖を高める、請求項1、2、3、及び4のいずれかに記載の組成物。
- 前記GITR結合抗体または前記抗原結合フラグメントのT細胞への結合によって、前記T細胞中のI−κBを調節する、請求項1、2、3、及び4のいずれかに記載の組成物。
- 前記GITR結合抗体または前記抗原結合フラグメントのT細胞への結合によって、前記T細胞中のGITR活性を調節する、請求項1、2、3、及び4のいずれかに記載の組成物。
- 前記GITR結合抗体または前記抗原結合フラグメントのT細胞への結合によって、Tエフェクター細胞中でT細胞レセプター誘発性シグナリングを調節する、請求項1、2、3、及び4のいずれかに記載の組成物。
- グルココルチコイド誘発性TNFRファミリー関連レセプター(GITR)に特異的に結合する、抗体またはその抗原結合フラグメントを含む組成物であって、該組成物は、被験体において抗原に対する免疫応答を誘発する、または高める方法に使用され、該方法は、GITR結合抗体または抗原結合フラグメント、および抗原を前記被験体に投与することを含む、組成物。
- 前記抗原が、腫瘍抗原または感染性微生物抗原である、請求項11に記載の組成物。
- 前記GITR結合抗体または抗原結合フラグメントのT細胞への結合によって、T調節細胞によるTエフェクター細胞の抑制を取り消す、請求項11に記載の組成物。
- 前記GITR結合抗体または抗原結合フラグメントの投与が、Tエフェクター細胞の増殖を高める、請求項11に記載の組成物。
- 前記GITR結合抗体または前記抗原結合フラグメントのTエフェクター細胞への結合によって、前記Tエフェクター細胞の増殖を高める、請求項11に記載の組成物。
- 前記GITR結合抗体または前記抗原結合フラグメントのT細胞への結合によって、T細胞中のI−κBを調節する、請求項11に記載の組成物。
- 前記GITR結合抗体または前記抗原結合フラグメントのT細胞への結合によって、前記T細胞中のGITR活性を調節する、請求項11に記載の組成物。
- 前記GITR結合抗体または前記抗原結合フラグメントのT細胞への結合によって、Tエフェクター細胞中でT細胞レセプター誘発性シグナリングを調節する、請求項11に記載の組成物。
- 前記使用は、前記GITR結合抗体または前記抗原結合フラグメントの投与の前、またはそれとの併用投与の前における前記抗原の投与を含む、請求項11に記載の組成物。
- 前記免疫応答が、体液性免疫応答を含む、請求項11乃至19のいずれか1項に記載の組成物。
- 前記被験体が、癌に罹患している、請求項1乃至20のいずれか1項に記載の組成物。
- 前記癌は、膵臓癌、メラノーマ、乳癌、肺癌、気管支癌、結直腸癌、前立腺癌、胃癌、卵巣癌、膀胱癌、脳または中枢神経系癌、末梢神経系の癌、食道癌、子宮頚癌、子宮癌または子宮体癌、口腔または咽頭の癌、肝臓癌、腎臓癌、睾丸の癌、胆道癌、小腸または虫垂の癌、唾液腺の癌、甲状腺癌、副腎癌、骨肉腫、軟骨肉腫および血液学的組織の癌からなる群から選択される、請求項21に記載の組成物。
- 前記被験体が、病原性物質によって引き起こされる感染症、障害、または状態に罹患している、請求項1乃至22のいずれかに記載の組成物。
- 前記病原性物質が、エボラウイルス、HIV、ヒトヘルペスウイルス、サイトメガロウイルス、ロタウイルス、エプスタイン・バーウイルス、水痘−帯状疱疹ウイルス、B型肝炎、A型肝炎、C型肝炎、およびE型肝炎などの肝炎ウイルス、パラミキソウイルス:呼吸系発疹ウイルス、パラインフルエンザウイルス、麻疹ウイルス、おたふくかぜウイルス、ヒトパピローマウイルス、フラビウイルスならびにインフルエンザウイルスからなる群から選択されるウイルスである、請求項23に記載の組成物。
- 前記病原性物質が、ナイセリア種、連鎖球菌種、S.ミュータンス菌、ヘモフィルス種、モラクセラ種、ボルデテラ種、マイコバクテリウム種、レジオネラ種、エシェリキア種、ビブリオ種、エルシニア種、カンピロバクター種、サルモネラ種、リステリア種、ヘリコバクター種、シュードモナス種、ブドウ球菌種、腸球菌種、クロストリジウム種、バシラス種、コリネバクテリウム種、ボレリア種,エールリッヒア種、リケッチア種、クラミジア種、レプトスピラ種、およびトレポネーマ種からなる群から選択される細菌である、請求項23に記載の組成物。
- 前記方法は、(a)少なくとも1つのさらなる作用物質を投与すること、または(b)少なくとも1つのさらなる治療を行うことを含む、請求項1乃至25のいずれかに記載の組成物。
- 前記少なくとも1つのさらなる作用物質が、被験体においてエフェクター細胞の数を増加させる働きをし、前記少なくとも1つのさらなる作用物質が、さらなる抗体またはその抗原結合フラグメント、リンフォカイン、もしくは造血成長因子の1以上を含む、請求項26に記載の組成物。
- 前記少なくとも1つのさらなる治療が、被験体における感染性微生物の感染の治療、または被験体における腫瘍の治療に役立つ、請求項26に記載の組成物。
- 前記少なくとも1つのさらなる治療が、放射線療法、化学療法、ホルモン療法、免疫療法、抗腫瘍薬を用いた治療、および抗生物質を用いた治療からなる群から選択される治療である、請求項26に記載の組成物。
- 前記組成物は、前記抗原を含む、請求項11に記載の組成物。
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JP2019058181A (ja) * | 2014-06-06 | 2019-04-18 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | グルココルチコイド誘導腫瘍壊死因子受容体(gitr)に対する抗体およびその使用 |
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JP7320555B2 (ja) | 2014-06-06 | 2023-08-03 | ブリストル-マイヤーズ スクイブ カンパニー | グルココルチコイド誘導腫瘍壊死因子受容体(gitr)に対する抗体およびその使用 |
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