JP2016527187A - 抗b7−h5抗体およびその使用 - Google Patents
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Abstract
Description
本発明は、国立衛生研究所(National Institute of Health)(NIH)による助成金RO1 CA097085およびRO1 A172592、ならびに国立癌研究所(National Cancer Institute)(NCI)による助成金U19 CA113341の下で、政府の支援によりなされた。政府は本発明において一定の権利を有する。
本出願は、紙およびコンピューター読み取り可能な媒体の両方で開示される、37C.F.R.1.821および以下参照に準拠した1つまたは複数の配列表を含み、紙およびコンピューター読み取り可能な開示内容はその全体を援用する。
(A)抗B7−H5抗体2D3の3つの軽鎖CDRおよび3つの重鎖CDR;または
(B)抗B7−H5抗体18C3の3つの軽鎖CDRおよび3つの重鎖CDR
から選択され得る。
(A)抗B7−H5抗体2D3の3つの軽鎖CDRおよび3つの重鎖CDR;または
(B)抗B7−H5抗体18C3の3つの軽鎖CDRおよび3つの重鎖CDR
である、B7−H5結合分子を提供する。
B7−H5アミノ酸配列は、機能が知られていなかった(Flajnik,M.F.et al.(2012)「Evolution Of The B7 Family:Co−Evolution Of B7H6 And Nkp30,Identification Of A New B7 Family Member,B7H7,And Of B7’s Historical Relationship With The MHC,」Immunogenetics 64:571−590)、以前に発見されたヒト遺伝子のHHLA2(human endogenous retrovirus−H long terminal repeat−associating protein 2(HHLA2);Mager,D.L.et al.(1999)「Endogenous Retroviruses Provide The Primary Polyadenylation Signal For Two New Human Genes(HHLA2 And HHLA3,」Genomics 59:255−263)に類似していることが分かった。B7−H5は、本明細書その他において、B7−H7ともいう。したがって、B7−H5およびB7−H7という用語は、本明細書においては、交換可能な用語として使用される。
本明細書その他においてH7CRとも呼ばれるCD28Hは、B7−H5のカウンター受容体である。したがって、CD28HおよびH7CRという用語は、本明細書においては、交換可能な用語として使用される。本明細書で使用する場合、「ネイティブCD28H」という用語は(また「ネイティブH7CR」も)、天然に存在するB7−H7またはその変異体のカウンター受容体をいう。CD28Hは、T細胞、NK細胞および形質細胞様樹状細胞により発現する。ヒトCD28Hポリペプチドは、そうでなければ、文献/データベース中で膜貫通および免疫グロブリンドメイン含有2(TMIGD2)と呼ばれるが(Rahimi,N.et al.(Epub 2012 Mar 14)「Identification Of IGPR−1 As A Novel Adhesion Molecule Involved In Angiogenesis,」Molec.Biol.Cell.23(9):1646−1656)、CD28Hの機能はこれまでに解明されなかった。こうしたネイティブCD28H分子のアミノ酸配列に対する受託番号の非限定例としては、以下のものが挙げられる:Q96BF3−1(ヒト(homo sapiens))、Q96BF3−2(ヒト(homo sapiens))、NP_653216.1(GI:21389429;ヒト(homo sapiens))およびNP_653216.2(GI:281306838;ヒト(homo sapiens))。ネイティブCD28H分子の代表的なアミノ酸配列(Q96BF3−2)を、配列番号7として以下に示す。
本明細書で使用する場合、ある分子が第2の分子に「免疫特異的に結合する」ことができるとされるのは、そうした結合が抗体に対応する抗原に対して抗体の特異性および親和性を示す場合である。抗体が抗原(特に、抗原B7−H5)の標的領域または立体構造(「エピトープ」)に「免疫特異的に結合する」ことができるとされるのは、そうした結合が免疫グロブリン分子の抗原認識部位を含む場合である。特定の抗原に免疫特異的に結合する抗体は、たとえば、イムノアッセイ、BIACORE(登録商標)アッセイまたは当該技術分野において公知の他のアッセイで判定して、他の抗原が抗原認識部位により認識される配列または立体構造に類似性をある程度有する場合、より低い親和性を持つ他の抗原に結合することもあるが、まったく無関係の抗原には結合しないと考えられる。ただし、抗体(およびその抗原結合フラグメント)は、他の抗原と交差反応しないことが好ましい。また、抗体は、Fc領域など、抗原認識部位を含まない分子の他の領域/ドメインの結合ドメインによって、免疫特異的でない形でFcR受容体など他の分子に結合することができる。
本明細書で使用する場合、「調節する」という用語は、ある作用または結果を変化させる能力に関する。特に、本発明は、抗ヒトB7−H5抗体、またはヒトB7−H5に免疫特異的に結合する、抗体の任意の抗原結合フラグメント、もしくはB7−H5に生理学特異的に結合する分子を含むポリペプチドに関し、それらは、B7−H5とその対応するリガンドとの間の結合を調節すること、および/またはB7−H5−対応カウンター受容体結合の結果として生じるシグナル伝達を調節することができる。加えて、多重特異性抗B7−H5抗体、抗B7−H5抗原結合フラグメント、およびCD28Hまたは他の細胞リガンドもしくは受容体に結合する追加の能力を有するそれらそれぞれの融合生成物は、そうしたリガンドまたは受容体を発現する細胞とCD28を発現する細胞との共局在化を促進するのに特に有用である。
本発明によれば、そうした分子はハイブリドーマ株についてヒトB7−H5に免疫特異的な抗体を産生する株をスクリーニングし、次いで、場合によってはそうした株の中で調節活性(たとえば、中和活性、促進活性、変化したシグナルの伝達活性など)を示す株をスクリーニングすることにより作製することができる。本発明は、特に、ハムスター抗ヒトB7−H5クローン:2D3および18C3を提供する。抗体2D3および18C3はヒトB7−H5に結合することができ、かつB7−H5のCD28Hとの相互作用を実質的に遮断することができる。B7−H5のCD28Hとの相互作用を実質的に遮断することができる抗体は、炎症性疾患および自己免疫疾患の治療に特に有用である。B7−H5のCD28Hとの相互作用を実質的に遮断することができない抗体は、B7−H5:CD28H相互作用の存在、場所および発現率を検出するために使用できるため、診断に特に有用である。
抗ヒトB7−H5クローン2D3
重鎖可変領域(配列番号9):
重鎖可変領域をコードするポリヌクレオチド(配列番号10):
軽鎖可変領域(配列番号11):
軽鎖可変領域をコードするポリヌクレオチド(配列番号12):
抗ヒトB7−H5クローン18C3
重鎖可変領域(配列番号13):
重鎖可変領域をコードするポリヌクレオチド(配列番号14):
軽鎖可変領域(配列番号15):
軽鎖可変領域をコードするポリヌクレオチド(配列番号28):
コンセンサスCDR配列と、おそらく類似の結合性を与えると考えられる変異CDR配列とを特定するため、特定された抗体のCDRの解析を行った。そうした変異CDRは、表1に従いBlosum62.iij解析を用いてコンピューター処理した。表1は、Blosum62.iij置換スコアである。スコアが高いほど、置換はより保存的になり、したがって置換が機能に影響を与える可能性が低くなる。
(1)抗ヒトB7−H5抗体2D3/18C3の軽鎖CDR1;
(2)抗ヒトB7−H5抗体2D3もしくは抗ヒトB7−H5抗体18C3の軽鎖CDR2、またはそのような抗体のCDR2のコンセンサス配列;および
(3)抗ヒトB7−H5抗体2D3/18C3の軽鎖CDR3
を含む。
(1)抗ヒトB7−H5抗体2D3/18C3の重鎖CDR1;
(2)抗ヒトB7−H5抗体2D3/18C3の重鎖CDR2;および
(2)抗ヒトB7−H5抗体2D3/18C3の重鎖CDR3
を含む。
CD28H融合タンパク質は、B7−H5とCD28Hの間のシグナル伝達のアンタゴニストであり得る。したがって、CD28H融合タンパク質、および免疫システムの下方調節のためのその使用方法もまた開示される。したがって、受容体融合ポリペプチドは、通常、リガンドの膜貫通CD28Hへの結合能力を遮断し、B7−H5:CD28H仲介シグナル伝達を誘発または維持させる。
受容体融合タンパク質は、完全長CD28Hポリペプチドを含むことができるか、あるいは完全長CD28Hのフラグメントまたは変異体を含むことができる。好ましい実施形態では、第1の融合パートナーは、CD28Hの可溶性フラグメント、たとえば、CD28Hの細胞外ドメインの一部もしくは全部、またはその変異体である。任意の哺乳類の配列CD28Hを使用することができる。一例として、上記配列のヒト配列、ならびに既知のそのアイソフォームおよび変異体が示される。いくつかの実施形態では、他の哺乳類の配列、たとえばマウス配列などが、当該技術分野で知られており、使用することができる。開示された融合タンパク質に有用な、ヒトCD28Hポリペプチドは、配列番号7に対して、少なくとも60%、65%、70%、75%、80%、85%、90%、95%、99%または100%の配列同一性を示すか、または、好ましくは、配列番号7の細胞外ドメインに対して、60%、65%、70%、75%、80%、85%、90%、95%、99%または100%の配列同一性を示すアミノ酸配列を有することができる。開示された融合タンパク質に有用な、ヒトCD28Hポリペプチドは、配列番号8に対して、少なくとも60%、65%、70%、75%、80%、85%、90%、95%、99%または100%の配列同一性を示すか、または、好ましくは、配列番号8の核酸配列によりコードされた細胞外ドメインに対して、60%、65%、70%、75%、80%、85%、90%、95%、99%または100%の配列同一性を示す核酸配列によりコードされ得る。
CD28Hポリペプチドは第2のポリペプチドに融合し得る。第2のポリペプチドの存在は、融合ポリペプチドの可溶性、安定性、親和性および/または結合価を変えることができる。本明細書で使用する場合、「結合価」は、1分子当たり利用できる結合部位の数をいう。一実施形態では、第2のポリペプチドは異なるソースまたは異なるタンパク質からのポリペプチドである。
開示されたCD28H融合タンパク質は、任意選択により、第2のポリペプチドからCD28Hポリペプチドを分離する、ペプチドまたはポリペプチドリンカードメインを含有する。
一実施形態では、リンカードメインは免疫グロブリンのヒンジ領域を含有する。好ましい実施形態では、ヒンジ領域はヒト免疫グロブリンに由来する。ヒンジを得ることができる、適切なヒト免疫グロブリンは、IgG、IgDおよびIgAを含む。好ましい実施形態では、ヒンジ領域はヒトIgGに由来する。免疫グロブリンヒンジ領域および他のドメインのアミノ酸配列は当該技術分野でよく知られている。
他の適切なペプチド/ポリペプチドリンカードメインは、天然に存在するか、または天然には存在しないペプチドまたはポリペプチドを含む。ペプチドリンカーの配列は、少なくとも2アミノ酸長さである。好ましくは、ペプチドまたはポリペプチドのドメインは、柔軟性ペプチドまたはポリペプチドである。本明細書では、「柔軟性リンカー」とは、ペプチド結合で繋がれた2つ以上のアミノ酸残基を含む、ペプチドまたはポリペプチドであって、2つの結合したポリペプチドが柔軟性リンカーの非存在下に有するであろうより、大きな回転自由度をペプチド結合で繋がれた2つのポリペプチドに与えるペプチドまたはポリペプチドをいう。そのような回転自由度は、柔軟性リンカーで繋がれた、2つ以上の抗原結合部位が、それぞれの標的抗原により効率的に接近することを可能にする。柔軟性ペプチド/ポリペプチドの例としては、アミノ酸配列Gly−Ser、Gly−Ser−Gly−Ser(配列番号16)、Ala−Ser、Gly−Gly−Gly−Ser(配列番号17)、(Gly4−Ser)3(配列番号18)、および(Gly4−Ser)4(配列番号19)が挙げられるが、これらに限定されるものではない。さらなる柔軟性ペプチド/ポリペプチド配列は当該技術分野でよく知られている。
代表的なヒトCD28H−Ig融合タンパク質、CD28H−hIg4(CD28H ECD aa23−140、軽鎖カッパシグナルペプチド:CD28H配列は太字で示され;突然変異したヒトIgG4 Fc配列は下線を付して示され、セリン228からプロリンへの突然変異は二重下線で示されている)のアミノ酸配列(配列番号20)は、以下のとおりである:
融合タンパク質は、さらに、N−末端リーダー配列(軽鎖カッパリーダー配列)(配列番号21の残基1〜20)
または、次のような天然に存在するCD28Hリーダー配列(配列番号22):
を含んでもよい。CD28H配列は、本発明においては、ヒトIgG4領域に融合したものが示されているが、そのような配列は代わりに任意のIgアイソタイプに、または、実際のところ、任意の他のタンパク質に融合することができる。配列番号21のシグナル配列を含む、配列番号20のヒトCD28H−IgをコードするDNA配列(配列番号23)は、以下のとおりである(配列番号23)。
本明細書で使用する場合、「処置する」、「処置すること」、「処置」および「治療用途」という用語は、免疫反応の増大または低下から利益を受けるであろう疾患または障害の1つまたは複数の症状が消失、減少または軽減することをいう。本明細書で使用する場合、「治療上有効な量」とは、免疫反応の変化を媒介するのに十分な治療薬のそうした量、一層好ましくは、臨床的意義のある免疫反応の変化であり、疾患または状態の症状の減少または軽減を媒介するのに十分な治療薬のそうした量をいう。ある作用は、その大きさがレシピエント被検体の健康または予後に影響を与えるのに十分である場合、臨床的意義がある。治療上有効な量とは、疾患の進行を遅延させるまたは最小限に抑える、たとえば、自己免疫応答、または炎症反応、または移植による拒絶反応を遅延させるまたは最小限に抑えるのに十分な治療薬の量をいう場合がある。治療上有効な量はまた、疾患の処置または管理において治療上の利益をもたらす治療薬の量をいうこともある。さらに、治療薬、B7−H5抗体、またはB7−H5融合タンパク質もしくはCD28H融合タンパク質に関する治療上有効な量は、疾患の処置または管理に治療上の利益をもたらす、たとえば、治療用抗体の薬効を増強するのに十分で、疾患を処置または管理するのに十分な、治療薬単独または他の療法薬と組み合わせたそうした量を意味する。
様々な送達系、たとえば、リポソーム、微小粒子、マイクロカプセルへの封入、抗体または融合タンパク質を発現することができる組換え細胞、受容体を介したエンドサイトーシス(たとえば、Wu and Wu,1987,J.Biol.Chem.262:4429−4432を参照)、レトロウイルスベクターまたは他のベクターの一部としての核酸の構築等が知られており、治療用または予防用組成物の投与に使用することができる。
組成物は、医薬組成物の製造に有用なバルク薬剤組成物(たとえば、不純物を含むまたは非無菌の組成物)、および単位剤形の調製に使用することができる医薬組成物(すなわち、被検体または患者への投与に好適な組成物)を含む。そうした組成物は、本明細書に開示された予防上または治療上有効な量の予防薬および/または治療薬、またはそうした薬と薬学的に許容されるキャリアとの組み合わせを含む。好ましくは、開示される組成物は、予防上または治療上有効な量の抗体または融合タンパク質および薬学的に許容されるキャリアを含む。
一実施形態は、抗体または融合タンパク質が入った1つまたは複数の容器を含む医療パックまたはキットを提供する。加えて、医療パックまたはキットには、疾患の処置に有用な1つまたは複数の他の予防薬または治療薬がさらに含まれていてもよい。一実施形態は、医薬組成物の成分の1つまたは複数が入った1つまたは複数の容器を含む医療パックまたはキットを提供する。そうした容器には任意に、医薬品または生物学的製剤の製造、使用または販売を規制する政府機関より定められた形式の注意書が添付されていてもよい。注意書には、ヒト投与を目的とした製造、使用または販売に関するその機関の承認が反映される。
B7−H5抗体およびその抗原結合フラグメントは、B7−H5の発現に関連する疾患、障害または感染症を検出、診断またはモニターすることなど、診断目的に使用することができる。本発明は、疾患、障害または感染症、特に自己免疫疾患の検出または診断を提供し、それは、(a)被検体の細胞または組織サンプルにおけるB7−H5の発現を、そうした抗原に免疫特異的に結合する1つまたは複数の抗体(またはそのフラグメント)を使用してアッセイすること;および(b)抗原のレベルを対照レベル、たとえば、正常組織サンプルのレベルと比較することによって実施することができ、抗原の対照レベルと比較した、アッセイされた抗原レベルの上昇または低下から疾患、障害または感染症が示唆される。そうした抗体およびフラグメントは、好ましくはイムノアッセイ、たとえば酵素結合免疫吸着測定(ELISA)、ラジオイムノアッセイ(RIA)および蛍光活性化セルソーティング(FACS)に利用される。
抗ヒトB7−H5抗体の単離および特性評価
ハムスターにB7−H5を接種し、B7−H5免疫反応性抗体を発現するハイブリドーマを単離することによって抗ヒトB7−H5抗体を得た。抗体産生クローン2D3および18C3を単離した。図4A〜4Bに、クローン2D3および18C3によって産生された抗体の、CHOトランスフェクタントによって発現されたヒトB7−H5に結合する能力を示す。
IgG2a配列は以下のとおりであり得る(配列番号27)。
図7に、サイトカイン(IL−2、IFN−γおよびIL−10)を誘発し、それによってB7−H5 Igの能力を示す。これにより、その分子の免疫系を刺激する能力が確認される。抗B7−H5抗体2D3の供給によってそうした刺激が阻害された(図8)。抗体はまた、同種T細胞反応を阻害することができることが分かった(図9)。これらの結果は、B7−H5に結合して、B7−H5がCD28Hと相互作用する能力を遮断することができる、本発明のそれらの抗体が、免疫系の活性化の生理的低下を仲介し得ることを示している。
抗ヒトB7−H5抗体のインビボでの効果を調べるために、2000万個の末梢血単核細胞(PBMC)をNOD scid IL2受容体ガンマ鎖ノックアウト(NSG)マウス(たとえば、Iorns,E.et al.(Epub 2012 Oct 31)「A New Mouse Model For Study Of Human Breast Cancer Metastasis」,PLoS One 7(10):e47995;Misharin,A.V.et al.(2012)「Development Of A New Humanized Mouse Model To Study Acute Inflammatory Arthritis」,J.Transl.Med.10:190;Waldron−Lynch,F.et al.(Epub 2012 Aug 17)「Analysis Of Human Biologics With A Mouse Skin Transplant Model In Humanized Mice」,Amer.J.Transplant.12(10):2652−2662;Volk,A.et al.(2012)「Comparison Of Three Harmonized Mouse Models For Adoptive T Cell Transfer」,J.Gene Med.14(8):540−548;Racki,W.J.et al.(2010)「NOD−scidIL2rgamma(null)Mouse Model Of Human Skin Transplantation And Allograft Rejection」,Transplantation 89(5)527−536を参照)の腹腔内に注入した。リン酸緩衝食塩水(PBS)または抗ヒトB7−H5抗体(2D3)を動物の尾の静脈に注入し、CD45RO+細胞中のCD28H+細胞の割合を測定した。
組換え抗ヒトB7−H5抗体は抗原特異性を保持する
IgG4抗体は特有の構造特性および機能特性を有し、インビボで「半抗体交換(half−antibody exchange)」を受け、2つの異なる結合特異性からなる組換え抗体が形成される(Nirula,A.et al.(2011)「What Is Igg4? A Review Of The Biology Of A Unique Immunoglobulin Subtype」,Curr.Opin.Rheumatol.23(1):119−124;.Aalberse,et al.(2009)「Immunoglobulin G4:An Odd Antibody」,Clin.Exp.Allergy 39(4):469−477)。Ser228がProに変化して腕が安定化する。キメラhIgG4Pは「半抗体交換(half−antibody exchange)」をしない。
B7−H5:CD28H相互作用の遮断は、破傷風トキソイド(TT)特異的T細胞反応を阻害する
メモリー特異的T細胞リコールに対するB7−H5:CD28H相互作用の効果を調べるために、ヒトPBMCと自己樹状細胞で再構成したNSGマウスに破傷風トキソイド(「TT」)ワクチンを接種した。同日に、マウスを対照Igまたは抗ヒトB7−H5抗体2D3で処理した。7日後、腹腔内の細胞を採取し、TT抗原で再刺激した。T細胞の分裂をBrdUを取り込ませることによって分析した。培養上清中のサイトカインをヒトTh1/Th2 CBAキットにより試験した。
B7−H5:CD28H相互作用の遮断は、同種T細胞反応を阻害する
インビボでの同種反応に対するB7−H5:CD28H相互作用の効果を調べるために、ヒト化NSGマウスに同種ヒトマクロファージを注入した。同日に、マウスを対照または2D3 mAbとともにインキュベートした。7日目に、脾細胞を採取し、同種のCD4およびCD8のT細胞の増殖を、細胞内染色によりKi−67の発現を観察することによって評価した。
B7−H5:CD28H相互作用の遮断は、ヒトT細胞におけるAKT活性化を阻害する
そのような試験結果を図18に示す。図18に示すように、内因性B7−H5:CD28H相互作用は、TCRシグナルの存在下でのAKT経路の活性化に重要であると考えられる。TCRとB7−H5融合タンパク質の同時架橋は、刺激後30分にAKTリン酸化反応を誘起したが、TCR単独の架橋ではAKTリン酸化反応の誘起は最小限であった。B7−H5遮断性抗体2D3が含まれることによって、AKT活性化が妨げられ、これによりB7−H5遮断がT細胞AKT経路の活性化を遮断し得ることが示された。
B7−H5:CD28H相互作用の遮断は、癌細胞に対する細胞傷害性Tリンパ球の殺活性を抑制する
そのような試験結果を図19に示す。図19に示すように、おとり受容体融合タンパク質によるB7−H5−CD28H経路の遮断は、いくつかのエフェクター対標的(E:T)比の条件でCTL殺活性を阻害するため、癌に関連するB7−H5と、CD28Hを発現する細胞障害性T細胞との相互作用は細胞障害性殺活性を共刺激する。
B7−H5:CD28H相互作用の遮断は、ナチュラルキラー細胞活性を抑制する
そのような試験結果を図20A〜Bに示す。図20Aに示すように、可溶性組換えヒトIL−2の存在下でのナチュラルキラー細胞(NK)上のCD16およびB7−H5融合タンパク質の同時架橋は、NK活性化および脱顆粒を誘発した(CD107a表面の上方制御)が、CD16結合単独では、さほど顕著なNKの脱顆粒は誘発されなかった。B7−H5抗体2D3によるB7−H5−CD28H経路の遮断は、NKの脱顆粒を抑制し(図20B)、これはB7−H5がNKの活性化を共刺激することを示すものである。
Claims (50)
- 6つの相補性決定領域(CDR)を含む、抗体またはその抗原結合フラグメントであって、
前記CDRが、
(1)3つの配列番号11の軽鎖CDRおよび3つの配列番号9の重鎖CDR;または
(2)3つの配列番号15の軽鎖CDRおよび3つの配列番号13の重鎖CDR
を含み、かつ
前記抗体またはその抗原結合フラグメントがB7−H5に結合する、
抗体またはその抗原結合フラグメント。 - 前記3つの軽鎖CDRが、配列番号11のアミノ酸27〜38を含む第1の軽鎖CDR、配列番号11のアミノ酸56〜58を含む第2の軽鎖CDR、および配列番号11のアミノ酸95〜102を含む第3の軽鎖CDRを含む、請求項1に記載の抗体またはその抗原結合フラグメント。
- 前記3つの重鎖CDRが、配列番号9のアミノ酸26〜33を含む第1の重鎖CDR、配列番号9のアミノ酸51〜58を含む第2の重鎖CDR、および配列番号9のアミノ酸97〜106を含む第3の重鎖CDRを含む、請求項1または2に記載の抗体またはその抗原結合フラグメント。
- 配列番号11のアミノ酸配列を含む軽鎖可変領域を含む、請求項1〜3のいずれか一項に記載の抗体またはその抗原結合フラグメント。
- 配列番号9のアミノ酸配列を含む重鎖可変領域を含む、請求項1〜4のいずれか一項に記載の抗体またはその抗原結合フラグメント。
- 前記3つの軽鎖CDRが、配列番号15のアミノ酸27〜38を含む第1の軽鎖CDR、配列番号15のアミノ酸56〜58を含む第2の軽鎖CDR、および配列番号15のアミノ酸95〜102を含む第3の軽鎖CDRを含む、請求項1に記載の抗体またはその抗原結合フラグメント。
- 前記3つの重鎖CDRが、配列番号13のアミノ酸26〜33を含む第1の重鎖CDR、配列番号13のアミノ酸51〜58を含む第2の重鎖CDR、および配列番号13のアミノ酸97〜106を含む第3の重鎖CDRを含む、請求項1または2に記載の抗体またはその抗原結合フラグメント。
- 配列番号15のアミノ酸配列を含む軽鎖可変領域を含む、請求項1〜3のいずれか一項に記載の抗体またはその抗原結合フラグメント。
- 配列番号13のアミノ酸配列を含む重鎖可変領域を含む、請求項1〜4のいずれか一項に記載の抗体またはその抗原結合フラグメント。
- 配列番号11のアミノ酸配列を含む軽鎖可変領域、および配列番号9のアミノ酸配列を含む重鎖可変領域を含む、請求項1に記載の抗体またはその抗原結合フラグメント。
- 配列番号15のアミノ酸配列を含む軽鎖可変領域、および配列番号13のアミノ酸配列を含む重鎖可変領域を含む、請求項1に記載の抗体またはその抗原結合フラグメント。
- 前記結合したB7−H5が、生細胞の表面に配置されているか、または内因性もしくはトラスフェクトされた濃度で発現されている、請求項1に記載の抗体またはその抗原結合フラグメント。
- 前記生細胞が、マクロファージまたは樹状細胞である、請求項7に記載の抗体またはその抗原結合フラグメント。
- 前記B7−H5が、ヒトB7−H5である、請求項1に記載の抗体またはその抗原結合フラグメント。
- (A)B7−H5のリガンドのCD28Hに対する結合能力を低下させ;
(B)B7−H5のCD28Hへの結合の結果として生じるシグナル伝達を遮断し;
(C)同種T細胞反応を阻害し;
(D)それらの組み合わせである、
請求項1に記載の抗体またはその抗原結合フラグメント。 - 免疫グロブリン定常領域(Fc)の1つまたは複数の定常ドメインを含む、請求項1〜15のいずれか一項に記載の抗体またはその抗原結合フラグメント。
- 前記定常ドメインは、ヒト定常ドメインである、請求項16に記載の抗体またはその抗原結合フラグメント。
- 前記ヒト定常ドメインは、ヒトIgAドメイン、IgDドメイン、IgEドメイン、IgGドメインまたはIgMドメインである、請求項17に記載の抗体またはその抗原結合フラグメント。
- 前記ヒトIgG定常ドメインは、IgG1ドメイン、IgG2ドメイン、IgG3ドメインまたはIgG4ドメインである、請求項18に記載の抗体またはその抗原結合フラグメント。
- 検出可能に標識されるか、またはコンジュゲートされたトキシン、薬剤、受容体、酵素、受容体リガンドを含む、請求項1〜19のいずれか一項に記載の抗体またはその抗原結合フラグメント。
- 前記抗体は、モノクローナル抗体、ヒト抗体、キメラ抗体、またはヒト化抗体である、請求項1〜20のいずれか一項に記載の抗体またはその抗原結合フラグメント。
- 前記抗体は、二重特異性、三重特異性または多重特異性の抗体である、請求項1〜21のいずれか一項に記載の抗体またはその抗原結合フラグメント。
- 1つまたは複数のヒトIgG4定常ドメイン、および
配列番号11のアミノ酸配列を含む軽鎖可変領域、配列番号9のアミノ酸配列を含む重鎖可変領域、または
配列番号15のアミノ酸配列を含む軽鎖可変領域、配列番号13のアミノ酸配列を含む重鎖可変領域
を含む、ヒト化抗体またはその抗原結合フラグメント。 - 請求項1〜23のいずれか一項に記載の抗体またはその抗原結合フラグメント、あるいはCD28H−Ig融合タンパク質、および生理学的に許容されるキャリアまたは賦形剤を含む、医薬組成物。
- 被験体の免疫系を下方調節する方法に使用するための、請求項24に記載の医薬組成物。
- 前記被験体が自己免疫疾患を有する、請求項25に記載の使用のための医薬組成物。
- 自己免疫疾患を治療する方法で使用するための、請求項24に記載の医薬組成物。
- 前記自己免疫疾患は、円形脱毛症、強直性脊椎炎、抗リン脂質症候群、自己免疫性アジソン病、副腎の自己免疫疾患、自己免疫性溶血性貧血、自己免疫性肝炎、自己免疫性卵巣炎および精巣炎、自己免疫性血小板減少症、ベーチェット病、水疱性類天疱瘡、心筋症、セリアックスプルー皮膚炎、慢性疲労免疫機能障害症候群(CFIDS)、慢性炎症性脱髄性多発ニューロパチー、チャーグ・ストラウス症候群、瘢痕性類天疱瘡、クレスト症候群、寒冷凝集素症、クローン病、円板状ループス、本態性混合性クリオグロブリン血症、線維筋痛症−線維筋炎、糸球体腎炎、グレーブス病、ギラン・バレー、橋本甲状腺炎、特発性肺線維症、特発性血小板減少症紫斑病(ITP)、IgAニューロパチー、若年性関節炎、扁平苔癬、ループスエリテマトーデス、メニエール病、混合性結合組織病、多発性硬化症、視神経脊髄炎(NMO)、1型または免疫性糖尿病、重症筋無力症、尋常性天疱瘡、悪性貧血、結節性多発動脈炎、多発性軟骨炎、多腺性症候群、リウマチ性多発筋痛症、多発性筋炎および皮膚筋炎、原発性無ガンマグロブリン血症、原発性胆汁性硬変、乾癬、乾癬性関節炎、レイノー現象、ライター症候群、関節リウマチ、サルコイドーシス、強皮症、シェーグレン症候群、全身硬直症候群、全身性紅斑性狼瘡、紅斑性狼瘡、高安動脈炎、側頭動脈炎/巨細胞性動脈炎、潰瘍性大腸炎、ぶどう膜炎、血管炎、たとえば疱疹状皮膚炎血管炎、白斑、ならびにウェゲナー肉芽腫症からなる群から選択される、請求項26または27に記載の使用のための医薬組成物。
- 前記被験体が炎症性疾患を有する、請求項25に記載の使用のための医薬組成物。
- 炎症性疾患を治療する方法で使用するための、請求項24に記載の医薬組成物。
- 前記炎症性疾患は、喘息、脳炎、炎症性腸疾患、慢性閉塞性肺疾患(COPD)、アレルギー性障害、敗血症性ショック、肺線維症、未分化脊椎関節症、未分化関節症、関節炎、炎症性骨溶解、および慢性のウイルス感染もしくは細菌感染に起因する慢性炎症からなる群から選択される、請求項29または30に記載の使用のための医薬組成物。
- 前記被験体が移植を受けたことがあるか、または受ける予定がある、請求項25に記載の使用のための医薬組成物。
- 移植による拒絶反応を治療または防止する方法で使用するための、請求項24に記載の医薬組成物。
- 被験体の免疫系を下方調節する薬剤の製造における、請求項1〜23のいずれか一項に記載の抗体またはその抗原結合フラグメント、あるいはCD28H−Ig融合タンパク質の使用。
- 被験体の自己免疫疾患を治療するための薬剤の製造における、請求項1〜23のいずれか一項に記載の抗体またはその抗原結合フラグメント、あるいはCD28H−Ig融合タンパク質の使用。
- 被験体の炎症性疾患を治療するための薬剤の製造における、請求項1〜23のいずれか一項に記載の抗体またはその抗原結合フラグメント、あるいはCD28H−Ig融合タンパク質の使用。
- 被験体の移植による拒絶反応を治療または防止するための薬剤の製造における、請求項1〜23のいずれか一項に記載の抗体またはその抗原結合フラグメント、あるいはCD28H−Ig融合タンパク質の使用。
- 疾患、障害または感染症を検出または診断する方法であって、(a)請求項1〜23のいずれか一項に記載の抗体またはその抗原結合フラグメントを用いて被験体の細胞または組織サンプルにおけるB7−H5の発現をアッセイすること、および(b)前記B7−H5のレベルを対照レベルと比較することを含み、前記対照レベルと比較した、前記アッセイされたB7−H5レベルの上昇が、前記疾患、障害または感染症を示唆する、方法。
- 前記B7−H5の発現が、酵素結合免疫吸着測定(ELISA)、ラジオイムノアッセイ(RIA)または蛍光活性化セルソーティング(FACS)によってアッセイされる、請求項38に記載の方法。
- 疾患、障害または感染症の進行をモニターする方法であって、(a)第1の時点で、被験体の細胞または組織サンプルにおけるB7−H5の発現を、請求項1〜23のいずれか一項に記載の抗体またはその抗原結合フラグメントを用いてアッセイすること、および(b)第2の時点で、または経時的に、前記被験体の前記細胞または前記組織サンプルにおけるB7−H5の発現レベルを比較することを含み、前記アッセイされたB7−H5レベルの上昇が、前記疾患、障害または感染症の進行を示唆する、方法。
- 前記B7−H5の発現が、酵素結合免疫吸着測定(ELISA)、ラジオイムノアッセイ(RIA)または蛍光活性化セルソーティング(FACS)によってアッセイされる、請求項30に記載の方法。
- 治療に対する応答をモニターする方法であって、(a)治療前に、被験体の細胞または組織サンプルにおけるB7−H5の発現を、請求項1〜23のいずれか一項に記載の抗体またはその抗原結合フラグメントを用いてアッセイすること、および(b)治療後、1つまたは複数の時点の前に、被験体の細胞または組織サンプルにおけるB7−H5の発現をアッセイして、B7−H5レベルを経時的に比較することを含み、前記治療前のB7−H5レベルと比較した、前記アッセイされたB7−H5レベルの低下が、治療に対する応答を示す、方法。
- 前記B7−H5の発現が、酵素結合免疫吸着測定(ELISA)、ラジオイムノアッセイ(RIA)または蛍光活性化セルソーティング(FACS)によってアッセイされる、請求項42に記載の方法。
- B7−H5の発現の増大を特徴とする疾患の被験体を治療する方法において使用するための医薬組成物であって、前記方法が
(i)前記被験体がB7−H5の発現の増大を特徴とする疾患を有するか否かを
(a)前記被験体の細胞または組織サンプルにおける前記B7−H5の発現を、B7−H5に結合する抗体またはその抗原結合フラグメントを用いてアッセイし;
(b)前記B7−H5レベルを対照レベルと比較する
ことによって決定する工程であって、
前記対照レベルと比較した、前記アッセイされたB7−H5レベルの上昇が、前記被験体がB7−H5の発現の増大を特徴とする疾患を有することを示唆する工程と;
(ii)前記被験体がB7−H5の発現の増大を特徴とする疾患を有する場合、治療上有効な量の請求項24に記載の医薬組成物を前記被験体に投与する工程と
を含む、医薬組成物。 - 前記抗体またはその抗原結合フラグメントは、請求項1〜23のいずれか一項に記載の抗体またはその抗原結合フラグメントである、請求項44に記載の方法。
- B7−H5の発現の増大を特徴とする前記疾患が、自己免疫疾患である、請求項44に記載の使用のための医薬組成物。
- B7−H5の発現の増大を特徴とする前記疾患が、炎症性疾患である、請求項44に記載の使用のための医薬組成物。
- CD28Hの発現の増大を特徴とする疾患の被験体を治療する方法において使用するための医薬組成物であって、前記方法が
(i)前記被験体がCD28Hの発現の増大を特徴とする疾患を有するか否かを
(a)前記被験体の細胞または組織サンプルにおける前記CD28Hの発現を、抗CD28H抗体またはその抗原結合フラグメントを用いてアッセイし;
(b)前記CD28Hレベルを対照レベルと比較する
ことによって決定する工程であって、
前記対照レベルと比較した、前記アッセイされたCD28Hレベルの上昇が、前記被験体がCD28Hの発現の増大を特徴とする疾患を有することを示唆する工程と;
(ii)前記被験体がCD28Hの発現の増大を特徴とする疾患を有する場合、治療上有効な量の請求項24に記載の医薬組成物を前記被験体に投与する工程と
を含む、医薬組成物。 - CD28Hの発現の増大を特徴とする前記疾患が、自己免疫疾患である、請求項48に記載の使用のための医薬組成物。
- CD28Hの発現の増大を特徴とする前記疾患が、炎症性疾患である、請求項48に記載の使用のための医薬組成物。
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US20160096891A1 (en) | 2016-04-07 |
KR20160129698A (ko) | 2016-11-09 |
SG11201509618QA (en) | 2015-12-30 |
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CN106414489A (zh) | 2017-02-15 |
WO2014190356A2 (en) | 2014-11-27 |
WO2014190356A3 (en) | 2015-04-23 |
AU2014268298B2 (en) | 2019-01-17 |
SG10201709715RA (en) | 2017-12-28 |
MX2015016111A (es) | 2016-10-26 |
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AU2014268298A1 (en) | 2016-01-21 |
CA2913312A1 (en) | 2014-11-27 |
BR112015029395A2 (pt) | 2017-09-19 |
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US10316092B2 (en) | 2019-06-11 |
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