JP5295568B2 - Kir結合剤およびその使用方法 - Google Patents
Kir結合剤およびその使用方法 Download PDFInfo
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- JP5295568B2 JP5295568B2 JP2007549896A JP2007549896A JP5295568B2 JP 5295568 B2 JP5295568 B2 JP 5295568B2 JP 2007549896 A JP2007549896 A JP 2007549896A JP 2007549896 A JP2007549896 A JP 2007549896A JP 5295568 B2 JP5295568 B2 JP 5295568B2
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
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Images
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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- C07K2317/00—Immunoglobulins specific features
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Description
本発明に従った「薬剤」には、小分子、ポリペプチド、タンパク質、抗体または抗体断片を含む。本発明に関して、小分子は、一つの態様において1000ダルトン、特に800ダルトン未満、特に500ダルトン未満よりも小さい分子量をもつ化学物質を意味する。
HEGVHRKPSLLAHPGXLVKSEETVILQCWSDVMFEHFLLHREGMFNDTLRLIGEHHDGVSKANFSISRMTQDLAGTYRCYGSVTHSPYQVSAPSDPLDIVIIGLYEKPSLSAQXGPTVLAGENVTLSCSSRSSYDMYHLSREGEAHERRLPAGPKVNGTFQADFPLGPATHGGTYRCFGSFHDSPYEWSKSSDPLLVSVTGNPSNSWPSPTEPSSKTGNPRHLH(配列番号:14)、式中、位置16の「X」は、PまたはRであり、位置114の「X」は、PまたはLであり、対立遺伝子変異体を表す。
HEGVHRKPSLLAHPGRLVKSEETVILQCWSDVRFEHFLLHREGKFKDTLHLIGEHHDGVSKANFSIGPMMQDLAGTYRCYGSVTHSPYQLSAPSDPLDIVITGLYEKPSLSAQPGPTVLAGESVTLSCSSRSSYDMYHLSREGEAHECRFSAGPKVNGTFQADFPLGPATHGGTYRCFGSFRDSPYEWSNSSDPLLVSVIGNPSNSWPSPTEPSSKTGNPRHLH(配列番号:15)、
HEGVHRKPSLLAHPGPLVKSEETVILQCWSDVRFQHFLLHREGKFKDTLHLIGEHHDGVSKANFSIGPMMQDLAGTYRCYGSVTHSPYQLSAPSDPLDIVITGLYEKPSLSAQPGPTVLAGESVTLSCSSRSSYDMYHLSREGEAHERRFSAGPKVNGTFQADFPLGPATHGGTYRCFGSFRDSPYEWSNSSDPLLVSVTGNPSNSWPSPTEPSSETGNPRHLH(配列番号:16)。
れぞれが参照により本明細書に援用される。2つの実質的に同一のアミノ酸配列の「対応する」アミノ酸位置は、本明細書において言及したタンパク質解析ソフトウェア(典型的には、デフォルトパラメーターを使用する)のいずれかによって整列させたものである。
EVQLQQSGPELVKPGASVKISCKASDYSFTGYFMNWVMQSQEKSLEWIGRINPFNGDAFYNQKFKGKATLTVDKSSNTAHMELRSLTSEDSAVYYCARLDYRGYFFDYWGQGTTLTVSS
DIVMTQSQKFMSTTVGDRVSITCKASQSVGSAVGWYQQKPGQSPKLLIYSASTRYTGVPDRFTGSGSGTDFTLTITNMQSDDLADYFCHQYSRYPLSFGSGTKLEMKR。
CDR H1:GYFMN(配列番号:17の残基31〜35)
CDR H2:RINPFNGDAFYNQKFKG(配列番号:17の残基50〜66)
CDR H3:LDYRGYFFDY(配列番号:17の残基99〜108)。
CDR L2:SASTRYT(配列番号:18の残基50〜56)
CDR L3:HQYSRYPLS(配列番号:18の残基89〜97)。
gaggttcagctgcagcagtctggacctgagctggtgaagcctggggcttcagtgaagatatcctgtaagg cttctgattactcatttactggctactttatgaactgggtgatgcagagccaagaaaagagccttgagtg gattggacgtattaatcctttcaatggtgatgctttctacaaccagaagttcaagggcaaggccacattg actgtggacaaatcctctaacacagcccacatggagctccggagcctgacatctgaggactctgcagtct attattgtgcaagattggattaccgcggctacttctttgactactggggccaaggcaccacgctcacagt ctcatca。
gacattgtgatgacccagtctcaaaaattcatgtccacaacagtaggagacagggtcagcatcacctgca aggccagtcagagtgtgggtagcgctgtaggctggtatcaacagaaaccaggacaatctcctaaactact gatttactcagcatccactcggtacactggagtccctgatcgcttcacaggcagtggatctgggacagat ttcactctcaccattaccaatatgcagtctgatgacctggcagattatttctgtcaccaatatagcagat atcctctctcgttcggctcggggacaaagttggaaatgaaacgg。
QVQLKESGPGLVAPSQSLSITCTVSGFSLTDYGVSWVRQPPGKGLEWLGLIWGDGRTNYHSALISRLSISKDNSKSQVFLKLNSLQIDDTATYYCARRGAMDYWGQGTSVTVSS。
CDR H1:DYGVS(配列番号:21の残基31〜35)
CDR H2:LIWGDGRTNYHSALISR(配列番号:21の残基50〜66)
CDR H3:RGAMDY(配列番号:21の残基98〜103)
CDR L1:KASQSVGSAVG(配列番号:18の残基24〜34)
CDR L2:SASTRYT(配列番号:18の残基50〜56)
CDR L3:HQYSRYPLS(配列番号:18の残基89〜97)。
caggtgcagctgaaggagtcaggacctggcctggtggcgccctcacagagcctgtccatcacatgcactg tctcagggttctcactaaccgactatggtgtaagctgggttcgccagcctccaggaaagggtctggagtg gctgggactaatatggggtgacgggcgcacaaattatcattcagctctcatatccagactgagcatcagc aaggataactccaagagccaagttttcttaaaactgaacagtctgcaaattgatgacacagccacatact actgtgccagaaggggtgctatggactactggggtcaaggaacctcggtcaccgtctcctca。
gacattgtgatgacccagtctcaaaaattcatgtccacaacagtaggagacagggtcagcatcacctgca aggccagtcagagtgtgggtagcgctgtaggctggtatcaacagaaaccaggacaatctcctaaactact gatttactcagcatccactcggtacactggagtccctgatcgcttcacaggcagtggatctgggacagat ttcactctcaccattaccaatatgcagtctgatgacctggctgattatttctgtcaccaatatagcagat atcctctctcgttcggctcggggacaaagttggaaatgaaacgg。
a)薬剤を提供すること;および
b)二量体化のために寄与する条件下で、薬剤の存在下における(HLA-Cまたはその他のKIRリガンドを発現する標的細胞の存在下など)KIRの二量体化を試験すること;
c)NK細胞細胞障害性のKIRを媒介した阻害を中和することができる(b)からの薬剤を選択すること、
によってNK細胞細胞障害性のKIRを媒介した阻害を中和することができる薬剤を単離する方法であって、工程(c)および(d)の順序は、任意に逆転される方法に関する。
a)KIRポリペプチドを含む免疫原でヒト以外の動物を免疫する工程;
b)前記免疫された動物から、前記KIRポリペプチドに結合する抗体を製造する工程;
c)KIRの二量体化を遮断する抗体を選択する工程;
d)NK細胞細胞障害性のKIRを媒介した阻害を中和することができる(c)からの抗体を選択する工程、
を含み、
工程(c)および(d)の順序は、任意に逆転される方法に関する。
本発明の抗体は、NK細胞細胞障害性のKIRを媒介した阻害;特にKIR2DL受容体によって媒介される阻害およびより詳細には、少なくともKIR2DL1およびKIR2DL2/3の両方の阻害を中和することができる。したがって、これらの抗体は、これらが少なくとも部分的にKIR受容体によって媒介される阻害性シグナリング経路を遮断するという意味で、二量体化を「減少させ」または「遮断する」。さらに重要なことに、この阻害活性は、阻害性KIR受容体のいくつかのタイプ、特にいくつかのKIR2DL受容体遺伝子産物、およびより詳細には、少なくともKIR2DL1、KIR2DL2およびKIR2DL3に関して示され、その結果、これらの抗体は、種々の被験体において高い有効性で使用されるであろう。NK細胞細胞障害性のKIRを媒介した阻害の阻害は、結合アッセイ法または細胞アッセイ法などの種々のアッセイ法または試験によって評価することができる。mAbが本発明の基準を満たすかどうか、すなわち(1)KIRを媒介した阻害性シグナリングを減少させる能力を有し、(2)KIR-HLAクラスI相互作用を遮断しないことを検査するための例示的方法は、以下のとおりである(また実施例を参照されたい):
(1)薬剤がKIRを媒介したシグナリングを減少させる能力は、KIR2DL1を発現するNK細胞およびHLA-Cw4を発現する標的細胞を使用して、標準的な4時間のインビトロ細胞障害性アッセイ法において試験することができる。KIR2DL1は、HLA-Cw4を認識してKIRの二量体化を引き起こし、これが次にNKを媒介した細胞溶解を妨げる阻害性シグナリングの開始および伝播を引き起こすので、このようなNK細胞は、HLA-Cw4を発現する標的を死滅させない。インビトロ細胞障害性アッセイ法は、当技術分野に周知の標準的方法によって、たとえばColigan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, N.Y., (1992, 1993)に記述されたとおりに行われる。標的細胞をNK細胞の添加の前に51Crで標識し、次いで、死滅の結果として細胞から培地への51Crの放出に比例した死滅を見積もる。KIRの二量体化を妨げる薬剤またはKIRがHLA-Cw4に結合するのを妨げる薬剤を添加すると、KIRを経た阻害性シグナリングの開始および伝播の阻止が生じる。したがって、このような薬剤の添加により、標的細胞のNKを媒介した死滅の増大が生じる。こうして、この工程により、たとえばリガンド結合を遮断すること、またはKIRがリガンドに結合したことを示す、KIRの二量体化もしくは細胞外から細胞内へのシグナル伝達に関与するその他の分子現象を妨げることによってKIRで誘導されるネガティブシグナリングを妨げる薬剤を同定する。特定の51Cr-放出細胞障害性アッセイ法において、KIR2DL1を発現するYTSエフェクター細胞(YTS-2DL1)は、LCL 721.221-Cw3標的細胞を死滅させることができるが、LCL 721.221-Cw4細胞ではできない。対照的に、KIRを欠いているYTSエフェクター細胞(YTS)は、両方の株化細胞を効率的に死滅させる。したがって、YTS-2DL1エフェクター細胞は、KIR2DL1を経たHLA-Cw4で誘導された阻害性シグナリングのために、LCL 721.221-Cw4細胞を死滅させることができない。このような51Cr-放出細胞障害性アッ
セイ法において、YTS-2DL1細胞を本発明に従った遮断抗KIR mAbまたはmAbと共にプレインキュベートすると、LCL 721.221-Cw4細胞は、抗KIR mAb濃度依存的様式で死滅する。
(a)KIRポリペプチドを含む免疫原で非ヒト哺乳類を免疫する工程;
(b)前記免疫された動物から、前記KIRポリペプチドに結合する抗体を製造する工程、
(c)NK細胞細胞障害性のKIRを媒介した阻害を減少させることができる(b)の抗体を選択する工程、
(d)HLA-Cに対するKIR結合を減少させない(c)の抗体を選択する工程、
を含み、工程(c)および(d)の順序は、任意に逆転することができる方法に関する。
本発明によれば、HLA-Cに対するKIR結合で妨害することなくNK細胞細胞障害性の阻害を妨げるための一つの方法は、KIR二量体化を妨げることである。一つの側面において、HLA-Cに対するKIR結合で妨害することなくNK細胞細胞障害性の阻害を妨げるもう一つの方法は、KIRクラスター形成を妨げることである。
(a)KIRポリペプチドを含む免疫原で非ヒト哺乳類を免疫する工程;
(b)前記免疫された動物から、前記KIRポリペプチドに結合する抗体を製造する工程、
(c)KIR遺伝子産物の二量体化を遮断する(b)の抗体を選択する工程、および、
(d)NK細胞細胞障害性のKIRを媒介した阻害を減少させることができる(c)の抗体を選択する工程、
を含み、
工程(c)および(d)の順序は、任意に逆転することができる方法を提供する。
Tによって明らかになるHLA-Cw4の近接、またはクラスター形成、または二量体化は、同じようにKIRが近くに近接することを意味する。抗KIR mAbの有無においてこのアッセイ法を行うことにより、抗KIR mAbがKIRクラスター形成または二量体化に影響を及ぼす能力の測定値が得られる。HLA-Cw4-GFPによるFRETを、標的細胞をNK細胞の非存在下でインキュベートしたときに観察されるレベルに減少させる抗KIR mAbは、KIRクラスター形成または二量体化を妨げるmAbを指し示す。
タンパク質の3次元の構造が、X線実験または相同性モデリングから既知であるときは、機能的有意性をもつ残基を同定するために、少なくとも3つの異なる方法が存在する。保存部位アプローチでは、保存された部位を同定するために、タンパク質構造上の部位を配列整列と比較する。タンパク質-タンパク質ドッキングアプローチでは、機能的に有意な残基を同定するために、タンパク質がそれ自体または別のタンパク質にドッキングされるであろう。結晶パッキングアプローチでは、機能的部位を決定するために、タンパク質を同じかまたは異なる結晶の組成物のその他のタンパク質にパックするかが、X線結晶により調査される。
重鎖の定常ドメインのタイプに応じて、抗体は、5つの主要なクラス:IgA、IgD、IgE、IgGおよびIgMのうちの1つに割り当てられる。これらのいくつかは、IgG1、IgG2、IgG3、IgG4、その他などのサブクラスまたはアイソタイプにさらに分けられる。異なる免疫グロブリンのクラスに対応する重鎖定常ドメインは、それぞれ「α」、「δ」、「ε」、「γ」および「μ」と呼ばれる。異なるクラスの免疫グロブリンのサブユニット構造および三次元配置が周知である。IgGおよび/またはIgMは、これらが生理学的状況において最も一般的抗体であるので、またこれらが研究室状況において最も容易に作製されるので、本発明に使用される抗体の好ましいクラスである。一つの態様において、本発明の抗体は、インビボにおけるNK細胞の枯渇を回避するために、Fc受容体と結合せず、かつ補体を固定しないIgG4サブクラス、またはIgG1もしくはIgG2のモノクローナル抗体である。
本発明の抗体の断片および誘導体は、当該技術分野において既知の技術によって作製することができる。「免疫反応性断片」は、一部の無処置の抗体、一般には抗原結合部位または可変領域を含む。抗体断片の例は、Fab、Fab’、Fab’-SH、F(ab’)2およびFv断片;ダイアボディー;隣接するアミノ酸残基の1つの連続的配列からなる一次構造物を有するポリペプチドであるいずれかの抗体断片(本明細書において、「単鎖抗体断片」または「1本鎖ポリペプチド」と称する)を含み、:(1)単鎖Fv(scFv)分子(2)結合した重鎖部分をもたずに軽鎖可変ドメインの3つのCDRを含む、1つの軽鎖可変ドメインのみを含む1本鎖ポリペプチドか、またはこれらの断片および(3)結合した軽鎖部分をもたずに重鎖可変領域の3つのCDRを含む、1つの重鎖可変領域のみを含む1本鎖ポリペプチドまたはこれらの断片;並びに抗体断片から形成された多特異的抗体を含むが、これらに限定されるわけではない。たとえば、FabまたはF(ab’)2断片は、従来の技術に従って単離した抗体のプロテアーゼ消化によって産生してもよい。
ヒトIgG1定数重鎖領域:GenBankアクセッション#:J00228
ヒトIgG2一定の重鎖領域:GenBankアクセッション#:J00230
ヒトIgG3一定の重鎖領域:GenBankアクセッション#:X04646
ヒトIgG4一定の重鎖領域:GenBankアクセッション#:K01316
ヒトカッパ軽鎖定常領域:GenBankアクセッション#:J00241。
a)試験薬剤のプールを提供すること;および、
b)二量体化に貢献する条件下(HLA-Cまたはその他のKIR-リガンドを発現する標的細胞の存在下など)でKIRの二量体化を減少させるか、または遮断する試験薬剤を選択すること;
c)NK細胞細胞障害性のKIRを媒介した阻害を中和することができる(b)からのいずれかの薬剤を選択することにより、
NK細胞細胞障害性のKIRを媒介した阻害を中和することができる薬剤を単離するための方法であって、
工程(b)および(c)の順序は、任意に逆転される方法に関する。
a)試験薬剤のプールを提供すること;および、
b)HLA-Cに対するKIR結合に貢献する条件下(HLA-Cまたはその他のKIR-リガンドを発現する標的細胞の存在下など)でKIRとHLAとの結合を検出可能におよび/または実質的に減少させないか、または遮断しない試験薬剤を選択すること;
c)(NK細胞細胞障害性のKIRを媒介した阻害を中和することができるb)からのいずれかの薬剤を選択することにより、
NK細胞細胞障害性のKIRを媒介した阻害を中和することができる薬剤を単離するための方法であって、
工程(b)および(c)の順序は、任意に逆転される方法に関する。
また、本発明は、任意の適切な媒体中に、患者における、またはNK細胞を含む生体試料におけるNK細胞細胞障害性を検出可能に増強するために有効な量で、薬剤、たとえば上に記載のような抗体(抗体の断片および誘導体を含む)を含む組成物を提供する。本組成物は、薬学的に許容される担体をさらに含む。
a);淋菌(N. gonorrhoeae)およびN.メニンギチデス(N. meningitides)を含むナイセリア属(Neisseria);F.メニンゴセプチカム(F. meningosepticum)およびF.オドラターン(F. odoraturn)を含むフラボバクテリウム属(Flavobacterium);ブルセラ属(Brucella);百日咳菌(B. pertussis)およびボルデテラブロンキセプチカ(B. bronchiseptica)を含むボルデテラ属(Bordetella);大腸菌(E. coli)を含むエシュリヒア属(Escherichia)、クレブシエラ属(Klebsiella);エンテロバクター属(Enterobacter)、S.マルセセンス(S. marcescens)およびS.リクエファシエンス(S. liquefaciens)を含むセラチア属(Serratia);エドバルシエラ属(Edwardsiella);P.ミラビリス(P. mirabilis)およびP.ブルガリス(P. vulgaris)を含むプロテウス属(Proteus);ストレプトバチルス属(Streptobacillus);R.フィケッツフィ(R. fickettsfi)を含むリケッチア科(Rickettsiaceae)、C.プシッタシ(C. psittaci)およびC.トラコルナティス(C. trachornatis)を含むクラミジア属(Chlamydia);結核菌(M. tuberculosis、M.イントラセルラレ(M. intracellulare)、M.フォルイターン(M. folluiturn)、ライ菌(M. laprae)、M.アビウム(M. avium)、M.ボビス(M. bovis)、M.アフリカヌム(M. africanum)、M. カンサシ(M. kansasii)、M.イントラセルラレ(M. intracellulare)およびM.レプレルヌリウム(M. lepraernurium)を含むマイコバクテリウム属(Mycobacterium);およびノカルジア属(Nocardia)。原生動物には、レーシュマニア、コクジディオア属(kokzidioa)およびトリパノソーマ属(trypanosoma)を含んでもよいが、これに限定されるわけではない。生虫には、クラミジア属(chlamydia)およびリケッチア属(rickettsia)を含むが、これに限定されるわけではない。感染症の完全な一覧は、伝染病予防本部(Center for Disease Control:CDC)(ワールド・ワイド・ウェブ(www)アドレスcdc.gov/ncidod/diseases/)にて国立感染症センター(NCID)のウェブサイトに見いだすことができ、この一覧は、参照により本明細書に援用される。前記疾患の全てが、本発明の阻害性、任意に交差反応性のKIR抗体を使用する治療のための候補である。
上で論議した一般的アプローチを使用して、KIR2DL1の二量体化に関与する可能性のあるドメインが発見された。
本実施例では、Fan et al., 1997, Nature vol. 389: 96-100: Domain 1 comprises residues 6-101 of KIR and Domain 2 comprises amino acids residues 105-200に従ったKIRのために残基およびドメイン命名法を使用する。
交差反応性抗KIR抗体1-7F9のFab’断片との複合体中のKIR2DL1の結晶構造を解いて、X線結晶学で2.35Å分解能に洗練した。結果から、結晶構造においてKIR2DL1-KIR2DL1二量体界面があることを確認した。
細胞外KIR2DL1(配列番号:14のアミノ酸1〜223、残基16はアルギニン(R)であり、残基114はロイシン(L)であり、さらなるN末端メチオニン(M)残基を含む)および1-7F9のヒト抗KIR Fab’(配列番号:24の軽鎖配列と配列番号:25の残基1〜221の重鎖配列をもつ)をわずかに過剰なKIR2DL1と混合して、複合体をゲル濾過カラムで精製した。次いで、複合体を約13.5mg/mLまで濃縮した。結晶は、10%のPEG6000および500mMシトラート緩衝液中で4.2のpHで懸滴技術によって成長させた。結晶を液体N2中で瞬間凍結させて、beam-line BL711I, MAX-lab, Lund, Swedenを使用して2.35Å分解能までの結晶学的データを100Kにて収集した。データをXDSプログラム(Kabsch, J. Appl. Crystallogr. 1993;26:795-800)に取り込んだ。構造決定のために、CCP4セットのMOLREPプログラム(Bailey, Acta Crystallogr. Sect. D-Biol. Crystallogr. 1994;50:760-763)を使用する分子置換およびPDBに寄託された構造1RZJ(Fab part1)および1NKR(KIR)を使用した。位相改善は、ARP/WARPプログラム (Lamzin and Wilson, Acta Crystallogr. Sect. D-Biol. Crystallogr. 1993;49:129-147)行い、X線由来構造モデルに対する手動修正は、QUANTAプログラム(Accelrys Inc., San Diego, CA, USAから入手可能)で行った。洗練は、CCP4セットのREFMAC5コンピュータープログラムで行った。水分子は、ARP/WARPプログラムによって負荷した。モデルは、KIR2DL1の残基6〜114および124〜200、1-7F9軽鎖の1〜212および1-7F9重鎖の143〜224と共に1〜136で構成された。加えて、330個の水分子を配置した。本モデルについてのR-およびR-freeは、それぞれ0.191および0.253であった。
対称な「X、Y、Z」および「Y、X、1/3-Z」をもつKIR2DL1間の接触残基は、CCP4セットのCONTACTコンピュータープログラムによって4.0Åのカットオフ距離を使用して同定した。KIRのドメイン2に生じている二量体界面領域は、KIR2DL1(配列番号:14)の以下の残基を含むことが見いだされた:L110、S111、A112、Q113、L114、D193、P194、L195、L196、V197、S198、V199、およびT200)。また、KIR2DL1二量体界面および水素結合に含まれる残基は、図4のKIR2DL1のアミノ酸配列に示してある。二量体界面領域は、CCP4プログラムのAREAIMAOLが665Å2であることによって算出した。結晶のパッキングにおいて、残基115〜123を含むKIR2DL1のループは整っていない。したがって、生物学的に重要な界面残基には、その範囲内の残基も含むことができる。表1は、1-7F9 Fab’VL鎖との複合体におけるKIR2DL1の結晶構造のKIR2DL1-KIR2DL1相互作用を示す。4.0Åのカットオフを使用した。接触は、CCP4セットのCONTACTコンピュータープログラムによって対称カード(X,Y,Z)および(Y,X,1/3-Z)を使用して同定した。最後の列において、「***」は、CONTACTによって算出されるこの接触(距離<3.3Å)にて水素結合の可能性が強いこと示し、「*」は、可能性が弱いこと(距離>3.3Å)を示す。空白は、プログラムが水素結合の可能性がないとみなしたことを示す。水分子は、算出において無視した。
本実施例は、(1)HLA-C結合を妨害せず、(2)NK細胞細胞障害性を増強することができる抗KIR抗体の産生および同定を記述する。
標準的方法により大腸菌において産生して、インビトロでリフォールディングしたKIR2DL1の完全な細胞外ドメインに対応する20μg可溶性KIR2DL1タンパク質(配列番号:14)で、正常RBFマウスを3回免疫した。マウスを静脈内注射によって20μgの可溶性KIR2DL1追加免疫し、3日後に屠殺した。脾臓を無菌的に除去して、単個細胞浮遊液に分散した。脾細胞およびFOX-NY骨髄腫細胞の融合を電気融合方法によって行った。細胞をマイクロタイタープレートに播種して、73℃、5%のCO2に培養した。選択のためのAATを含む組織培養培地を2週の期間にわたって3回交換した。
KIR2DL1を免疫したRBFマウスに由来するハイブリドーマを、フローサイトメトリーによってKIR2DL1陽性細胞の認識のために上清を試験することによって、KIR2DL1特異的mAbの産生についてスクリーニングした。組織培養上清を1:2希釈のYTS(KIR2DL1陰性)およびYTS-2DL1(KIR2DL1陽性)と共にインキュベートした。氷上で1時間インキュベーション後、細胞をDMEM/2%のFCSで洗浄して、APC縫合ロバ抗マウス二次Ab断片と共に氷上で30’間インキュベートした。PBSでよく洗浄後、生細胞に対するAb結合を、FACSarray(BD Biosciences)を使用して解析した。MAbは、ハイブリドーマ組織培養上清中のマウスmAbがYTS-2DL1に結合するが、YTS細胞に結合しないときに「KIR2DL1陽性」と命名した(図5を参照されたい)。
選択されたマウス交差反応性のmAbが、ヒトmAb 1-7F9とは異なるエピトープでKIR2DL1および-3に結合したかどうかを決定するために、これらがKIR2DL1および/または-3に対する1-7F9の結合と競合する能力を表面プラスモン共鳴解析によって測定した。これは、Biacore 3000装置(Biacore AB, Uppsala, Sweden)で行った。同量の精製した1-7F9を標準的アミン-カップリングキット(Biacore AB)を使用して、CM5 sensorchip(Biacore AB, Uppsala, Sweden)上の全4つのフローセルに固定した。HBS-EP緩衝液(10mM HEPES、150mM NaCl、3mM EDTA、0.005%のPolysorbat 20(v/v))中の精製した組換えKIR2DL3は、10μg/mLの濃度でフローセル1および3内に10μl/分の流速で1分間注入した。その後、HBS-EP緩衝液中の精製した組換えKIR2DL1は、10μg/mLの濃度の濃度でフローセル2および4に10μl/分の流速で1分間注入した。KIR2DL1およびKIR2DL3の注入後、HBS-EP緩衝液に1:1.5希釈した最初のハイブリドーマ組織培養上清の試料をフローセル1および2に10μl/分の流速で1分間注入した。その後、第2の試料を同様の条件下でフローセル3および4に注入した。RU反応>20とき、試料は結合について陽性と記録した。最後に、10mMグリシン-HCl pH 1.8を30μl/分の流速で15秒間注入することによってセンサー-チップの再生を行った。
選択した交差反応性mAbがKIRの機能を阻害する能力をNK細胞障害性アッセイ法において試験した。YTS-2DL1細胞を、選択したmAbを産生するハイブリドーマからの組織培養上清と共に1:2希釈して30分間プレインキュベートした。その後、KIR2DL1-リガンドHLA-Cw4を発現する51Cr標識したLCL 721.221-Cw4細胞を6:1のE:T比にて添加した。湿らせた炭酸ガス恒温器内において37℃にて4時間インキュベーション後、組織培養培地への51Crの放出をγ放射線カウンターで測定した。試料中の標的細胞の特異的死滅は、Triton X-100溶解した細胞からの最大の51Cr放出と比較して、組織培養培地で測定される51Crの割合を算出することによって決定した。試料は、3回解析した。
1-26F117-A3および1-26F117-A4などのKIRシグナリング(実施例5で決定したとおり)を遮断した抗KIR mAbがKIRのそのHLA-リガンドに対する結合を妨げることによってNK溶解を誘導することができるかどうかを決定するために、これらのmAbがKIR2DL1とHLA-Cw4との間の相互作用を妨げる能力を測定した。これのために、可溶性KIR2DL1-Fcタンパク質を、ヒトFcをマウスIgG1 Fcと置き換えたことを除き、記述されたとおりに産生した(Wagtmann et al., Immunity 1995;3(6):801-9)。可溶性KIR-Fcは、KIR2DL1によって認識される特異的HLA-Cアロタイプを発現する細胞と結合させて、この結合を、KIR-Fcタンパク質のマウスFc部分に対して特異的な二次蛍光色素抱合Abを使用してフローサイトメトリーによって視覚化することができる。たとえば、KIR2DL1-Fcは、HLA-Cw*0402を形質導入した細胞(LCL 721.221-Cw4トランスフェクタント)に対して結合するが、トランスフェクトしなかったLCL721.221の細胞には結合しない(Litwin et al., J Exp Med. 1993;178:1321-36)。
抗KIR mAb 1-7F9、1-4F1およびDF200gaHLA-CとKIR分子との間の相互作用を遮断する能力を、HLA-Cを発現する細胞に対する可溶性組換え型KIR-Fc融合タンパク質の結合の競合によって評価した。
本実施例は、選択した抗体またはその他の薬剤が、KIRのドメイン1またはドメイン2と結合するかどうかを決定する方法を記述する。
本明細書で引用した刊行物、特許出願および特許を含む全ての参照文献は、参照により、あたかもそれぞれの参照文献が個々におよび具体的に参照により援用されたことを示し、かつ本明細書にその全体が記載されたのと同じ範囲で、本明細書に援用される。
Claims (53)
- 阻害性ヒトキラーIgG様受容体(KIR)ポリペプチドKIR2DL1、KIR2DL2および/またはKIR2DL3の細胞外部分と結合するか、または相互作用する単離された抗体またはその抗原結合断片であって、前記単離された抗体またはその抗原結合断片は、(i)NK細胞細胞障害性の、KIR2DL1、KIR2DL2および/またはKIR2DL3を媒介した阻害を減少させ、(ii)KIR2DL1、KIR2DL2および/またはKIR2DL3と、KIR2DL1、KIR2DL2および/またはKIR2DL3のHLAクラスIリガンドとの間の結合を検出可能に減少させない抗体またはその抗原結合断片。
- 請求項1の抗体またはその抗原結合断片であって、前記抗体またはその抗原結合断片は、前記KIRのクラスター形成を減少させるか、または遮断することによってNK細胞細胞障害性のKIRを媒介した阻害を減少させる抗体またはその抗原結合断片。
- 請求項1および2のいずれか1項に記載の抗体またはその抗原結合断片であって、前記抗体またはその抗原結合断片は、前記KIRの二量体化を減少させるか、または遮断することによってNK細胞細胞障害性のKIRを媒介した阻害を減少させる抗体またはその抗原結合断片。
- 請求項1〜3のいずれか1項に記載の抗体またはその抗原結合断片であって、前記抗体またはその抗原結合断片は、ドメイン1と会合する相互作用部位間の相互作用を減少させるか、または遮断する抗体またはその抗原結合断片。
- 請求項4に記載の抗体またはその抗原結合断片であって、前記ドメイン1と会合する相互作用部位は、配列番号:14の残基1〜92の1つに対応する少なくとも1つのアミノ酸残基を含む抗体またはその抗原結合断片。
- 請求項5に記載の抗体またはその抗原結合断片であって、前記ドメイン1と会合する相互作用部位は、H1、E2、H5、R6、D31、V32、M33、F34、E35、H36、H50、D57、G58、V59、V83、T84、H85、S86、Q89、L90、S91またはA92に対応する少なくとも1つのアミノ酸残基を含む抗体またはその抗原結合断片。
- 請求項1〜3のいずれか1項に記載の抗体またはその抗原結合断片であって、前記抗体またはその抗原結合断片は、ドメイン2と会合する相互作用部位間の相互作用を減少させるか、または遮断する抗体またはその抗原結合断片。
- 請求項7に記載の抗体またはその抗原結合断片であって、前記ドメイン2と会合する相互作用部位は、配列番号:14の残基108〜200の1つに対応する少なくとも1つのアミノ酸残基を含む抗体またはその抗原結合断片。
- 請求項8に記載の抗体またはその抗原結合断片であって、前記ドメイン2と会合する相互作用部位は、P108、S109、L110、S111、A112、Q113、P114、L114、G115、T125、S127、S129、R131、K155、V156、N157、G158、T159、Q161、A162、D163、S192、D193、P194、L195、L196、V197、S198、V199またはT200に対応する少なくとも1つのアミノ酸残基を含む抗体またはその抗原結合断片。
- 請求項9に記載の抗体またはその抗原結合断片であって、前記KIR2DL1のドメイン2と会合する相互作用部位は、アミノ酸残基L110、S111、A112、Q113、P/L114およびL195を含む抗体またはその抗原結合断片。
- 請求項1〜10のいずれか1項に記載の抗体またはその抗原結合断片であって、前記抗体またはその抗原結合断片は、前記KIRファミリーのメンバーのホモ二量体化、ヘテロ二量体化または両方の少なくとも一つを減少させるか、または遮断する抗体またはその抗原結合断片。
- 請求項11に記載の抗体またはその抗原結合断片であって、前記抗体またはその抗原結合断片は、KIR2DL1のホモ二量体化を減少させるか、または遮断する抗体またはその抗原結合断片。
- 請求項1〜12のいずれか1項に記載の抗体またはその抗原結合断片であって、前記断片は、Fab断片、Fab’断片、Fab’-SH断片、F(ab’)2断片、Fv断片、ダイアボディー、単鎖抗体断片および多特異的抗体から選択される抗体またはその抗原結合断片。
- 請求項1〜13のいずれか1項に記載の抗体またはその抗原結合断片であって、前記抗体は、ヒト抗体、ヒト化抗体またはキメラ抗体である抗体またはその抗原結合断片。
- 請求項1〜14のいずれか1項に記載の抗体またはその抗原結合断片であって、前記抗体またはその抗原結合断片は、交差反応性KIR結合剤である抗体またはその抗原結合断片。
- 請求項15に記載の抗体またはその抗原結合断片であって、前記抗体またはその抗原結合断片は、交差反応性抗KIR抗体またはこれらの断片である抗体またはその抗原結合断片。
- 請求項15および16のいずれか1項に記載の抗体またはその抗原結合断片であって、前記抗体またはその抗原結合断片は、KIR2DL1およびKIR2DL3のそれぞれに結合する抗体またはその抗原結合断片。
- 請求項15〜17のいずれか1項に記載の抗体またはその抗原結合断片であって、前記抗体またはその抗原結合断片は、KIR2DL1およびKIR2DL3の少なくとも一つに結合する際に配列番号:17のアミノ酸配列を有するVH領域と配列番号:18のアミノ酸配列を有するVL領域とを含む抗体または抗体断片と競合する抗体またはその抗原結合断片。
- 請求項18に記載の抗体またはその抗原結合断片であって、前記抗体またはその抗原結合断片は、配列番号:17のアミノ酸配列を有するVH領域と配列番号:18のアミノ酸配列を有するVL領域とを含む抗体またはその抗原結合断片。
- 請求項15〜17のいずれか1項に記載の抗体またはその抗原結合断片であって、前記抗体またはその抗原結合断片は、KIR2DL1およびKIR2DL3の少なくとも一つに結合する際に配列番号:21のアミノ酸配列を有するVH領域と配列番号:18のアミノ酸配列を有するVL領域とを含む抗体または抗体断片と競合する抗体またはその抗原結合断片。
- 請求項20に記載の抗体またはその抗原結合断片であって、前記抗体またはその抗原結合断片は、配列番号:21のアミノ酸配列を有するVH領域と配列番号:18のアミノ酸配列を有するVL領域とを含む抗体またはその抗原結合断片。
- 医薬として使用するための、請求項1〜21のいずれか1項に記載の抗体またはその抗原結合断片。
- 患者におけるNK細胞細胞障害性を検出可能に増強するために有効な量の請求項1〜22に記載の抗体またはその抗原結合断片と、1つまたは複数の薬学的に許容される担体または希釈剤とを含む医薬組成物。
- 免疫調節薬、ホルモン薬、化学療法薬、血管新生阻害薬、アポトーシス薬および阻害性KIR受容体に対するHLA結合を遮断する抗体から選択される治療薬をさらに含む、請求項23に記載の医薬品製剤。
- NK細胞を請求項1〜22のいずれか1項に記載の抗体またはその抗原結合断片の有効量と接触させることを含むNK細胞細胞障害性のKIRを媒介した阻害を減少させるインビトロの方法。
- 請求項25に記載の方法であって、前記抗体またはその抗原結合断片は、KIRの二量体化を減少させるか、または遮断する方法。
- 請求項25または26に記載の方法であって、前記抗体またはその抗原結合断片は、モノクローナル抗KIR抗体またはこれらの抗原結合断片である方法。
- 請求項25〜27のいずれか1項に記載の方法であって、前記抗体またはその抗原結合断片は、KIR2DL1およびKIR2DL3の少なくとも一つに結合する際に配列番号:17のアミノ酸配列を有するVH領域と配列番号:18のアミノ酸配列を有するVL領域とを含む抗体と競合する方法。
- 請求項25〜27のいずれか1項に記載の方法であって、前記抗体またはその抗原結合断片は、KIR2DL1およびKIR2DL3の少なくとも一つに結合する際に配列番号:21のアミノ酸配列を有するVH領域と配列番号:18のアミノ酸配列を有するVL領域とを含む抗体と競合する方法。
- 癌、感染症、ウイルス感染または免疫不全の治療のための医薬の製造のための、請求項1〜21のいずれか1項に記載の抗体またはその抗原結合断片の使用。
- 請求項30に記載の使用であって、前記医薬が癌を治療するためのものである使用。
- 請求項31に記載の使用であって、前記癌は、急性および慢性脊髄性白血病(AMLおよびCML)、急性リンパ性白血病(ALL)、骨髄異形成症候群、非ホジキンリンパ腫(NHL)、多発性骨髄腫、腎細胞癌、悪性黒色腫および結直腸癌から選択される使用。
- 請求項30に記載の使用であって、前記ウイルス感染は、ヒト免疫不全症ウイルス(HIV)、C型肝炎ウイルス(HCV)およびエボラウイルスから選択されるウイルスによって生じる使用。
- 癌、感染症、ウイルス感染または免疫不全の治療のための医薬の製造のための、請求項1〜21のいずれか1項に記載の抗体またはその抗原結合断片の使用。
- 前記医薬が癌の治療のためのものである請求項34に記載の使用。
- 請求項34または35に記載の使用であって、前記抗体またはその抗原結合断片は、ヒト抗体、ヒト化抗体もしくはキメラ交差反応性モノクローナル抗KIR抗体またはこれらの抗原結合断片である使用。
- 請求項34〜36のいずれか1項に記載の使用であって、前記抗体またはその抗原結合断片は、KIR2DL1およびKIR2DL3の少なくとも一つに結合する際に配列番号:17のアミノ酸配列を有するVH領域と配列番号:18のアミノ酸配列を有するVL領域とを含む抗体と競合する使用。
- 請求項34〜37のいずれか1項に記載の使用であって、前記抗体またはその抗原結合断片は、KIR2DL1およびKIR2DL3の少なくとも一つに結合する際に配列番号21:のアミノ酸配列を有するVH領域と配列番号:18のアミノ酸配列を有するVL領域とを含む抗体と競合する使用。
- 免疫調節薬、ホルモン薬、化学療法薬、血管新生阻害薬、アポトーシス薬および阻害性KIR受容体に対するHLA結合を遮断する抗体から選択される治療薬を投与することをさらに含む、請求項34〜38のいずれか1項に記載の使用。
- a)候補となる抗体またはその抗原結合断片のプールを製造することと;
b)阻害性KIRの細胞外部分と結合するか、または相互作用するいずれかの候補となる抗体またはその抗原結合断片を選択することと;
c)それらの中から、前記阻害性KIRとKIRのHLAクラスIリガンドとの間の結合を減少させることなくNK細胞細胞障害性のKIRを媒介した阻害を中和することができる工程b)からのいずれかの候補となる抗体またはその抗原結合断片を選択することと、
によってNK細胞細胞障害性のKIRを媒介した阻害を中和することができる抗体またはその抗原結合断片を同定する方法であって、
工程b)およびc)の順序は、任意に逆転される方法。 - 交差反応性KIR結合抗体またはその抗原結合断片を選択する工程をさらに含む、請求項40に記載の方法。
- 請求項40または41に記載の方法であって、前記抗体またはその抗原結合断片は、モノクローナル抗体またはこれらの断片である方法。
- 以下の工程を含む、NK細胞細胞障害性のKIRを媒介した阻害を減少させることができる抗体またはその抗原結合断片を同定するための方法:
a)ヒト以外の動物を少なくともKIRの細胞外部分を含む免疫原性組成物で免疫することと;
b)前記免疫された動物からKIRに結合する抗体またはその抗原結合断片を製造することと;
c)前記阻害性KIRと前記KIRのHLAクラスIリガンドとの間の結合を減少させることなくNK細胞細胞障害性のKIRを媒介した阻害を中和することができる(b)からのいずれかの抗体またはその抗原結合断片を選択することと;、
d)任意に前記選択された抗体またはその抗原結合断片を製造すること。 - KIR2DL1およびKIR2DL3の少なくとも一つに結合する際に配列番号:17のアミノ酸配列を有するVH領域と配列番号:18のアミノ酸配列を有するVL領域とを含む抗体またはその抗原結合断片と競合する単離された抗体またはその抗原結合断片であって、KIRと前記KIRのHLAクラスIリガンドとの間の結合を検出可能に減少させることなくNK細胞細胞障害性のKIRを媒介した阻害を減少させる抗体またはその抗原結合断片。
- 配列番号:17の残基31〜35に対応するCDR H1領域、配列番号:17の残基50〜66に対応するCDR H2、配列番号:17の残基99〜108に対応するCDR H3;配列番号:18の残基24〜34に対応するCDR L1;配列番号:18の残基50〜56に対応するCDR L2および配列番号:18の残基89〜97に対応するCDR L3を含む、請求項44に記載の抗体またはその抗原結合断片。
- 配列番号:17のアミノ酸配列を有するVH領域と配列番号:18のアミノ酸配列を有するVL領域とを含む、請求項44または45に記載の抗体またはその抗原結合断片。
- KIR2DL1およびKIR2DL3の少なくとも一つに結合する際に配列番号:21のアミノ酸配列を有するVH領域と配列番号:18のアミノ酸配列を有するVL領域とを含む抗体と競合する単離された抗体またはその抗原結合断片であって、KIRと前記KIRのHLAクラスIリガンドとの間の結合を検出可能に減少させることなくNK細胞細胞障害性のKIRを媒介した阻害を減少させる抗体またはその抗原結合断片。
- 配列番号:21の残基31〜35に対応するCDR H1領域、配列番号:21の残基50〜66に対応するCDR H2、配列番号:21の残基98〜103に対応するCDR H3;配列番号:18の残基24〜34に対応するCDR L1;配列番号:18の残基50〜56に対応するCDR L2および配列番号:18の残基89〜97に対応するCDR L3を含む、請求項47に記載の抗体またはその抗原結合断片。
- 配列番号:21のアミノ酸配列を有するVH領域と配列番号:18のアミノ酸配列を有するVL領域とを含む、請求項47または48に記載の抗体またはその抗原結合断片。
- 請求項44〜49のいずれか1項に記載の抗体またはその抗原結合断片をコードするポリヌクレオチド。
- 請求項50に記載のポリヌクレオチドを含む発現ベクター。
- 請求項51に記載のベクターをトランスフェクトした宿主細胞。
- 抗体の発現のために適した条件下で請求項52に記載の宿主細胞を培養することを含む抗体またはその抗原結合断片を製造する方法。
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DK1836225T3 (da) | 2012-02-27 |
SI1836225T1 (sl) | 2012-06-29 |
ATE531733T1 (de) | 2011-11-15 |
US20080305117A1 (en) | 2008-12-11 |
US9708403B2 (en) | 2017-07-18 |
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JP2013100320A (ja) | 2013-05-23 |
JP2008526221A (ja) | 2008-07-24 |
US20090075340A1 (en) | 2009-03-19 |
US20130143269A1 (en) | 2013-06-06 |
PL1836225T3 (pl) | 2012-05-31 |
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US8222376B2 (en) | 2012-07-17 |
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CN104829720B (zh) | 2019-01-01 |
CN104829720A (zh) | 2015-08-12 |
US9018366B2 (en) | 2015-04-28 |
US20160046712A1 (en) | 2016-02-18 |
ES2374603T3 (es) | 2012-02-20 |
CN101103043A (zh) | 2008-01-09 |
CY1112897T1 (el) | 2016-04-13 |
WO2006072626A1 (en) | 2006-07-13 |
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