JP6205621B2 - 抗体を有するインターフェロンλでの標的化は抗腫瘍および抗ウイルス活性を大きく増強する - Google Patents
抗体を有するインターフェロンλでの標的化は抗腫瘍および抗ウイルス活性を大きく増強する Download PDFInfo
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Description
本願は、米国特許法35U.S.C.第119条(e)の下で、2012年1月26日出願の米国特許仮出願第61/591,087号、および2012年3月6日出願の米国特許仮出願第13/412,816号の利益を主張するものである。先に引用された各優先権出願の本文は、全体として参照により本明細書に組み入れられる。
本願は、FES−Webにより寄託され、全体として参照により本明細書に組み入れられる、Sequencing Listingを含む。2013年1月22日に作成された前記ASCIIコピーは、 IBC136WOテキストと称され、サイズが50,753バイトである。
本発明は、抗体または抗原結合抗体フラグメントに結合されたインターフェロンλ(IFN−λ)、より好ましくはIFN−λ1を含むDOCK−AND−LOCK(商標)(DNL(商標))複合体の治療的使用の組成物および方法に関する。好ましい実施形態において、抗体は、抗TROP−2、抗CEACAM5、抗CEACAM6、抗HLA−DR、抗ムチン、抗CD19、抗CD20、抗CD74、抗AFP、または抗CD22抗体であってもよい。しかし当業者は、本発明がそれに限定されず、抗体−インターフェロン複合体をより広く網羅することを認識するであろう。好ましくはDNL(商標)複合体は、米国特許第7,521,056号;同第7,527,787号;同第7,534,866号;同第7,550,143号および同第7,666,400号に例示された組成および技術を用いて作製され、それらの特許それぞれの実施例の節は、参照により本明細書に組み入れられる。抗体コンジュゲートインターフェロンは、インビトロ活性を保持し、実質的に高いインビボ有効性および長い血清半減期を示す。DNL(商標)生成物の追加的利点としては、より低い免疫原性、少ない投薬回数、高い溶解度、高い安定性、および低い腎クリアランスを挙げることができる。
インターフェロンα(IFNα)は、癌の動物モデル(Ferrantini et al.,1994、J Immunol 153:4604−15)およびヒト癌患者(Gutterman et al.,1980、Ann Intern Med 93:399−406)の両方において抗腫瘍活性を有することが報告された。IFNαは、癌遺伝子のダウンレギュレーション、腫瘍抑制因子のアップレギュレーション、腫瘍表面のMHCクラスI蛋白質の発現の増加を介した免疫認識の増強、アポトーシスの増強、および化学療法剤に対する感作をはじめとし、種々の直接的な抗腫瘍効果を発揮し得る(Gutterman et al.,1994,PNAS USA 91:1198−205;Matarrese et al.,2002,Am J Pathol 160:1507−20;Mecchia et al.,2000,Gene Ther 7:167−79;Sabaawy et al.,1999,Int.J.Oncol 14:1143−51;Takaoka et al.,2003,Nature 424:516−23)。一部の腫瘍については、IFNαは、STAT1の活性化により直接的かつ強力な抗増殖効果を有し得る(Grimley et al.,1998,Blood 91:3017−27)。
本発明は、抗体または抗原結合抗体フラグメントに結合されたインターフェロン、好ましくはインターフェロンλ、より好ましくはIFN−λ1を含むDNL(商標)複合体を製造するための方法および組成物を開示する。インターフェロン部分は、ヒトプロテインキナーゼA(PKA)調節サブユニットRIα、RIβ、RIIαもしくはRIIβからの二量体化およびドッキングドメイン(DDD)部分、あるいはA−キナーゼアンカー蛋白質(AKAP)からのアンカードメイン(AD)部分にコンジュゲートされ得る。抗体または抗体フラグメント部分は、相補性ADまたはDDD部分にコンジュゲートされている。DDD部分は、AD部分への高い親和力によって結合する二量体を自発的に形成するため、DNL(商標)複合体は、それぞれがDDD部分またはAD部分に結合されているインターフェロン、抗体または抗体フラグメントなどのエフェクターから組織化されていてもよい。DDD部分に結合されたエフェクターをAD部分に結合されたエフェクターと混合することにより、事実上任意のエフェクターをDNL(商標)複合体に組み込むことができる。
定義
他に断りがなければ「a」または「an」は、「1以上」を意味する。
好ましい実施形態において、インターフェロン−抗体複合体は、DOCK−AND−LOCK(商標)(DNL(商標))複合体として形成される(例えば、米国特許第7,521,056号;同第7,527,787号;同第7,534,866号;7,550,143号、および同第7,666,400号参照。それらそれぞれの実施例の節は、参照により本明細書に組み入れられる)。一般にその技術は、cAMP依存性プロテインキナーゼ(PKA)の調節(R)サブユニットの二量体化およびドッキングドメイン(DDD)配列と、種々のAKAP蛋白質のいずれかから得られたアンカードメイン(AD)配列と、の間に生じる特異的で高親和力の結合相互作用の利益を受けている(Baillie et al,FEBS Letters.2005;579:3264. Wong and Scott,Nat.Rev.Mol.Cell Biol.2004;5:959)。DDDおよびADペプチドは、任意の蛋白質、ペプチドまたは他の分子に結合されていてもよい。DDD配列は自発的に二量体化してAD配列に結合するため、その技術は、DDDまたはAD配列に結合され得る任意の選択された分子の間に複合体を形成させる。
異なるタイプのDNL(商標)構築物の場合、異なるADまたはDDD配列が用いられ得る。例示的DDDおよびAD配列を、以下に示す。
特定の好ましい実施形態において、エフェクター部分は、免疫調整物質である。免疫調整物質は、存在すると、身体の免疫系を変化、抑制または刺激する物質である。使用される免疫調整物質としては、サイトカイン、幹細胞増殖因子、リンフォトキシン、造血因子、コロニー刺激因子(CSF)、インターフェロン(IFN)、エリスロポエチン、トロンボポエチンおよびそれらの組み合わせを挙げることができる。特に有用なものは、腫瘍壊死因子(TNF)などのリンフォトキシン、インターロイキン(IL)などの造血因子、顆粒球コロニー刺激因子(G−CSF)または顆粒球マクロファージコロニー刺激因子(GM−CSF)などのコロニー刺激因子、インターフェロンα、インターフェロンβ、インターフェロンγまたはインターフェロンλなどのインターフェロン、および「S1因子」と称されるものなどの幹細胞増殖因子を挙げることができる。
特定の実施形態において、抗体またはその抗原結合フラグメントは、サイトカインの標的送達のための抗体または抗体フラグメントのインターフェロンまたは他のサイトカインへの結合などにより、DNL(商標)構築物に組み込まれ得る。任意の公知抗体またはその抗原結合フラグメントが、DNL(商標)構築物に組み込まれ得る。好ましい実施形態において、該複合体は、癌治療に使用され、該抗体は、腫瘍関連抗原(TAA)と結合する。非限定的に炭酸脱水酵素IX、CCCL19、CCCL21、CSAp、CD1、CD1a、CD2、CD3、CD4、CD5、CD8、CD11A、CD14、CD15、CD16、CD18、CD19、IGF−1R、CD20、CD21、CD22、CD23、CD25、CD29、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD45、CD46、CD52、CD54、CD55、CD59、CD64、CD66a−e、CD67、CD70、CD74、CD79a、CD80、CD83、CD95、CD126、CD133、CD138、CD147、CD154、AFP、PSMA、CEACAM5、CEACAM−6、B7、フィブロネクチンのED−B、H因子、FHL−1、Flt−3、葉酸受容体、gp41、gp120、GROB、HMGB−1、低酸素誘導因子(HIF)、HM1.24、インスリン様成長因子−1(ILGF−1)、IFN−γ、IFN−α、IFN−β、IL−2、IL−4R、IL−6R、IL−13R、IL−15R、IL−17R、IL−18R、IL−6、IL−8、IL−12、IL−15、IL−17、IL−18、IL−25、IP−10、MAGE、mCRP、MCP−1、MIP−1A、MIP−1B、MIF、MUC1、MUC2、MUC3、MUC4、MUC5ac、PAM4抗原、NCA−95、NCA−90、Ia、HM1.24、EGP−1、EGP−2、HLA−DR、テネイシン、Le(y)、RANTES、T101、TAC、Tn抗原、トムソン−フリーデンライヒ抗原、腫瘍壊死抗原、TNF−α、TRAIL受容体(R1およびR2)、VEGFR、EGFR、P1GF、補体因子C3、C3a、C3b、C5a、C5および癌遺伝子産物をはじめとする、種々の腫瘍関連抗原が、当該技術分野において公知である。他のタイプの標的抗原が、異なる疾患状態の抗体を基にした治療に用いられ、任意のそのような代替抗原を標的とする抗体を組み込んだDNL(商標)構築物が、使用され得る。
キメラ抗体は、ヒト抗体の可変領域が、例えばマウス抗体の相補性決定領域(CDR)を含むマウス抗体の、可変領域によって置き換えられた組換え蛋白質である。キメラ抗体は、対象に投与されると、免疫原性の低下および安定性の上昇を示す。ネズミ免疫グロブリン可変ドメインをクローニングするための一般的な技術は、例えば、Orlandi et al.,Proc.Nat’l Acad.Sci.USA 6:3833(1989)に開示されている。キメラ抗体を構築するための技術は、当業者に周知である。例として、Leung et al.,Hybridoma 13:469(1994)では、抗CD22モノクローナル抗体であるネズミLL2のVKおよびVHドメインをコードするDNA配列を、それぞれのヒトκおよびIgG1定常領域ドメインと組み合わせることによりLL2キメラを生成した。
ヒト化MAbを生成する技術は、当該技術分野で周知である(例えば、Jones et al.,Nature 321:522(1986)、Riechmann et al.,Nature 332:323(1988)、Verhoeyen et al.,Science 239:1534(1988)、Carter et al.,Proc.Nat’l Acad.Sci.USA 89:4285(1992)、Sandhu,Crit.Rev.Biotech.12:437(1992)、およびSinger et al.,J.Immun.150:2844(1993)参照)。キメラまたはネズミモノクローナル抗体は、マウス免疫グロブリンの重および軽鎖可変ドメイン由来のマウスCDRを、ヒト抗体の対応する可変ドメインに転移することにより、ヒト化され得る。キメラモノクローナル抗体におけるマウスフレームワーク領域(FR)も、ヒトFR配列と置き換えられる。マウスCDRをヒトFRに単に転移すると、多くの場合、抗体親和力の低下または喪失も起こるため、ネズミ抗体の本来の親和力を回復するためには、更なる改変が必要とされる。このことは、FR領域における1個以上のヒト残基を、それらのネズミ対応部分と置き換えて、エピトープに対する良好な結合親和力を有する抗体を得ることにより達成され得る。例えば、Tempest et al.,Biotechnology 9:266(1991)およびVerhoeyen et al.,Science 239:1534(1988)を参照されたい。一般にネズミ対応物とは異なっていて、1つ以上のCDRアミノ酸残基に接近して配置されるか、またはそれに接触している、それらのヒトFRアミノ酸残基が、置換の候補物質となろう。
コンビナトリアルアプローチ、またはヒト免疫グロブリン遺伝子座で形質転換されたトランスジェニック動物のいずれかを用いる完全ヒト抗体を生成する方法は、当該技術分野で公知である(例えば、Mancini et al.,2004、New Microbiol.27:315−28;Conrad and Scheller,2005,Comb.Chem.High Throughput Screen.8:117−26;Brekke and Loset,2003,Curr.Opin.Phamacol.3:544−50)。完全ヒト抗体は、遺伝子または染色体トランスフェクション法およびファージディスプレイ技術によっても構築することができ、それらは全てが当該技術分野で公知である。例えば、McCafferty et al., Nature 348:552−553(1990)を参照されたい。そのような完全ヒト抗体は、キメラまたはヒト化抗体よりも更に少ない副作用を示すこと、およびインビボにおいて実質的に内因性ヒト抗体として機能することが予測される。特定の実施形態において、請求された方法および手順は、そのような技術により生成されたヒト抗体を利用し得る。
特異的なエピトープを認識する抗体フラグメントは、公知の技術により生成され得る。抗体フラグメントは、抗体、例えばF(ab’)2、Fab’、F(ab)2、Fab、Fv、sFvなどの抗原結合部分である。F(ab’)2フラグメントは、抗体分子のペプシン消化によって産生され得、Fab’フラグメントは、F(ab’)2フラグメントのジスルフィド架橋を減少させることによって生成され得る。あるいはFab’発現ライブラリが構築されて(Huse et al.,1989,Science,246:1274−1281)、所望の特異性を有するモノクローナルFab’フラグメントの迅速かつ容易な同定を可能にすることができる。F(ab)2フラグメントは、抗体のパパイン消化により生成され得、Fabフラグメントは、ジスルフィドの還元により得られる。
使用される抗体は、非常に様々な公知供給元から商業的に得ることができる。例えば種々の抗体分泌ハイブリドーマ株が、American Type Culture Collection(ATCC、バージニア州マナサス所在)から入手可能である。非限定的に腫瘍関連抗原をはじめとする様々な疾患標的に対する多数の抗体が、ATCCに寄託されており、そして/または可変領域配列を公開しており、請求された方法および組成物における使用に利用可能である。例えば、米国特許第7,312,318号;同第7,282,567号;同第7,151,164号;同第7,074,403号;同第7,060,802号;同第7,056,509号;同第7,049,060号;同第7,045,132号;同第7,041,803号;同第7,041,802号;同第7,041,293号;同第7,038,018号;同第7,037,498号;同第7,012,133号;同第7,001,598号;同第6,998,468号;同第6,994,976号;同第6,994,852号;同第6,989,241号;同第6,974,863号;同第6,965,018号;同第6,964,854号;同第6,962,981号;同第6,962,813号;同第6,956,107号;同第6,951,924号;同第6,949,244号;同第6,946,129号;同第6,943,020号;同第6,939,547号;同第6,921,645号;同第6,921,645号;同第6,921,533号;同第6,919,433号;同第6,919,078号;同第6,916,475号;同第6,905,681号;同第6,899,879号;同第6,893,625号;同第6,887,468号;同第6,887,466号;同第6,884,594号;同第6,881,405号;同第6,878,812号;同第6,875,580号;同第6,872,568号;同第6,867,006号;同第6,864,062号;同第6,861,511号;同第6,861,227号;同第6,861,226号;同第6,838,282号;同第6,835,549号;同第6,835,370号;同第6,824,780号;同第6,824,778号;同第6,812,206号;同第6,793,924号;同第6,783,758号;同第6,770,450号;同第6,767,711号;同第6,764,688号;同第6,764,681号;同第6,764,679号;同第6,743,898号;同第6,733,981号;同第6,730,307号;同第6,720,155号;同第6,716,966号;同第6,709,653号;同第6,693,176号;同第6,692,908号;同第6,689,607号;同第6,689,362号;同第6,689,355号;同第6,682,737号;同第6,682,736号;同第6,682,734号;同第6,673,344号;同第6,653,104号;同第6,652,852号;同第6,635,482号;同第6,630,144号;同第6,610,833号;同第6,610,294号;同第6,605,441号;同第6,605,279号;同第6,596,852号;同第6,592,868号;同第6,576,745号;同第6,572,856号;同第6,566,076号;同第6,562,618号;同第6,545,130号;同第6,544,749号;同第6,534,058号;同第6,528,625号;同第6,528,269号;同第6,521,227号;同第6,518,404号;同第6,511,665号;同第6,491,915号;同第6,488,930号;同第6,482,598号;同第6,482,408号;同第6,479,247号;同第6,468,531号;同第6,468,529号;同第6,465,173号;同第6,461,823号;同第6,458,356号;同第6,455,044号;同第6,455,040号;同第6,451,310号;同第6,444,206号;同第6,441,143号;同第6,432,404号;同第6,432,402号;同第6,419,928号;同第6,413,726号、同第6,406,694号;同第6,403,770号;同第6,403,091号;同第6,395,276号;同第6,395,274号;同第6,387,350号;同第6,383,759号;同第6,383,484号;同第6,376,654号;同第6,372,215号;同第6,359,126号;同第6,355,481号;同第6,355,444号;同第6,355,245号;同第6,355,244号;同第6,346,246号;同第6,344,198号;同第6,340,571号;同第6,340,459号;同第6,331,175号;同第6,306,393号;同第6,254,868号;同第6,187,287号;同第6,183,744号;同第6,129,914号;同第6,120,767号;同第6,096,289号;同第6,077,499号;同第5,922,302号;同第5,874,540号;同第5,814,440号;同第5,798,229号;同第5,789,554号;同第5,776,456号;同第5,736,119号;同第5,716,595号;同第5,677,136号;同第5,587,459号;同第5,443,953号;同第5,525,338号を参照されたい。これらは例示に過ぎず、広範の他の抗体およびこれらのハイブリドーマが当該分野において公知である。当業者は、ほとんどの任意の疾患関連抗原に対する抗体配列または抗体分泌ハイブリドーマが、該当する選択された疾患関連標的への抗体に関するATCC、NCBIおよび/またはUSPTOデータベースの簡単検索によって入手し得ることを認識するであろう。クローニングされた抗体の抗原結合ドメインは、当該分野で周知の標準的な技術を用いて増幅、切除され、発現ベクター内にライゲートされ、適合した宿主細胞内にトランスフェクトされ、蛋白質産生に用いられ得る。
治療抗体の免疫原性は、インヒュージョンリアクションのリスク増大および治療的応答の持続期間短縮に関連する (Baert et al., 2003, N Engl J Med 348:602−08)。治療抗体が宿主における免疫反応を誘導する度合いは、一部として抗体のアロタイプにより決定され得る(Stickler et al.,2011,Genes and Immunity 12:213−21)。抗体のアロタイプは、抗体の定常領域配列における特異的位置のアミノ酸配列変異に関係する。重鎖γ型定常領域を含むIgG抗体のアロタイプは、Gmアロタイプと称される(1976,J Immunol 117:1056−59)。
リツキシマブ重鎖可変領域配列(配列番号:85)
特定の実施形態において、開示された方法および組成物は、1つ以上の置換されたアミノ酸残基を有する蛋白質またはペプチドの製造および使用を包含し得る。非限定的例において、DNL(商標)構築物の作製に用いられるDDDおよび/またはAD配列は、例えばDDD−AD結合親和力を増大させるように、更に最適化されてもよい。
特定の実施形態において、使用される標的部分は、アプタマーであってもよい。アプタマーの結合特性を構築および決定する方法は、当該技術分野で周知である。例えば、そのような技術は、米国特許第5,582,981号、同第5,595,877号および同第5,637,459号に記載され、それぞれの実施例の節は、参照により本明細書に組み入れられる。該当する特定の標的に結合するアプタマーの調製およびスクリーニングの方法は、周知であり、例えば米国特許第5,475,096号および米国特許第5,270,163号であり、それぞれの実施例の節は、参照により本明細書に組み入れられる。
特定の代替的実施形態で、抗体の代わりにAffibodyを使用してもよい。Affibodyは、Affibody AB(スウェーデン、ソルナ所在)から市販される。Affibodyは、抗体模倣体として機能し、標的分子との結合に使用される小蛋白質である。Affibodyは、α−ヘリックス蛋白質スカフォールド上でのコンビナトリアルエンジニアリングにより開発された (Nord et al.,1995,Protein Eng 8:601−8;Nord et al.,1997,Nat Biotechnol 15:772−77)。Affibodyの設計は、プロテインAのIgG結合ドメインを含む3ヘリックスバンドル構造に基づく (Nord et al.,1995;1997)。広範囲の結合親和力を有するAffibodyが、バクテリア蛋白質のFc結合活性に関与する13のアミノ酸の無作為化により製造され得る (Nord et al.,1995; 1997)。無作為化の後、PCR増幅されたライブラリーが、突然変異蛋白質のファージディスプレイによるスクリーニングのために、ファージミドベクターにクローニングされた。ファージディスプレイライブラリーは、標的抗原に対する1種以上のAffibodyを同定するために、ファージディスプレイスクリーニング技術を用いて、任意の公知抗原に対してスクリーニングされ得る(例えば、Pasqualini and Ruoslahti,1996,Nature 380:364−366;Pasqualini,1999,Quart.J Nucl.Med.43:159−162)。
二重特異性抗体は、複数の生物医学的適用例において有用である。例えば腫瘍細胞表面抗原およびT細胞表面受容体に対する結合部位を有する二重特異性抗体は、T細胞による特異性腫瘍細胞の溶解を誘導し得る。神経膠腫およびT細胞上のCD3エピトープを認識する二重特異性抗体を用いて、ヒト患者における脳腫瘍の処置に成功した(Nitta et al.Lancet.1990;355:368−371)。特定の実施形態において、本明細書に開示された治療薬コンジュゲーションのための技術および組成物を、標的部分としての二重特異性または多重特異性抗体と共に用いてもよい。
二重特異性または多重特異性抗体は、プレターゲッティング技術において用いられ得る。プレターゲッティングは元々、骨髄などの正常組織への不適切な毒性に寄与する、直接標的抗体の緩やか血中クリアランスを解決するために開発された多段階の工程である。プレターゲッティングにより、放射性核種または他の治療薬は、血液から数分以内に排出される小さな送達分子(標的化可能な構築物)に結合する。標的化可能な構築物および標的抗原の結合部位を有するプレターゲッティング二重特異性または多重特異性抗体が、最初に投与され、遊離抗体を循環から排出させ、その後、標的化可能な構築物が投与される。
特定の実施形態において、プレターゲッティングにおいて使用される1種以上の治療または診断薬で標識された標識化可能な構築物ペプチドを選択して、標的化可能な構築物ペプチドの1つ以上の結合部位および疾患または状態に関連する標的抗原の1種以上の結合部位を有する二重特異性抗体に結合させることができる。二重特異性抗体は、抗体が最初に対象に投与され得るプレターゲッティング技術において用いることができる。二重特異性抗体が標的抗原に結合して、非結合抗体が循環から排出されるのに十分な時間が与えられ得る。その後、標的化可能な構築物、例えば標識ペプチドが対象に投与され、二重特異性抗体と結合されて、罹患した細胞または組織に局在化され得る。
様々な実施形態において、治療薬、例えば細胞毒性薬、抗血管新生薬、アポトーシス促進剤、抗生物質、ホルモン、ホルモンアンタゴニスト、ケモカイン、薬物、プロドラッグ、毒素、酵素、または他の物質を、本明細書に記載されたインターフェロン−抗体DNL(商標)構築物に付加治療薬として用いられ得る。使用される薬物は、抗有糸分裂剤、抗キナーゼ剤、アルキル化剤、代謝拮抗剤、抗生物質、アルカロイド、抗血管新生薬、アポトーシス促進剤、およびそれらの組み合わせからなる群より選択される医薬特性を有し得る。
診断薬は、好ましくは放射性核種、放射線造影剤、常磁性イオン、金属、蛍光標識、化学発光標識、超音波造影剤、および光活性剤からなる群より選択される。そのような診断薬は周知であり、任意のそのような公知診断薬を使用することができる。診断薬の非限定的な例としては、110In、111In、177Lu、18F、19F、52Fe、62Cu、64Cu、67Cu、67Ga、68Ga、86Y、90Y、89Zr、94mTc、94Tc、99mTc、120I、123I、124I、125I、131I、154−158Gd、32P、11C、13N、15O、186Re、188Re、51Mn、52mMn、55Co、72As、75Br、76Br、82mRb、83Sr、または他のガンマ−、ベータ−、またはポジトロン−放射体などの放射性核種を挙げることができる。使用される常磁性イオンとしては、クロム(III)、マンガン(II)、鉄(III)、鉄(II)、コバルト(II)、ニッケル(II)、銅(II)、ネオジム(III)、サマリウム(III)、イッテルビウム(III)、ガドリニウム(III)、バナジウム(II)、テルビウム(III)、ジスプロシウム(III)、ホルミウム(III)、またはエルビウム(III)を挙げることができる。金属造影剤としては、ランタン(III)、金(III)、鉛(II)、またはビスマス(III)を挙げることができる。超音波造影剤は、ガス封入リポソームなどのリポソームを含んでいてもよい。放射線不透過性診断薬は、化合物、バリウム化合物、ガリウム化合物、およびタリウム化合物から選択されてもよい。非限定的にフルオレセインイソチオシアナート、ローダミン、フィコエリテリン、フィコシアニン、アロフィコシアニン、o−フタアルデヒドおよびフルオレサミンをはじめとする非常に様々な蛍光標識が、公知である。使用される化学発光標識としては、ルミノール、イソルミノール、芳香族アクリジニウムエステル、イミダゾール、アクリジニウム塩、またはシュウ酸エステルを挙げることができる。
特定の実施形態において、DNL(商標)構築物は、1つ以上の治療薬または診断薬にコンジュゲートされていてもよい。例えば、131Iを蛋白質またはペプチドのチロシンに組み込むか、または薬物をリジン残基のεアミノ基に結合することができる。治療薬および診断薬を、例えば還元型SH基に結合させることもできる。治療薬または診断薬と蛋白質またはペプチドとの共有結合または非共有結合性コンジュゲートを生成するための多数の方法が、当該技術分野で公知であり、任意のそのような公知方法を使用することができる。
様々な実施形態は、治療有効量のインターフェロン−抗体DNL(商標)構築物を対象に投与することを含む、ヒト、家畜また愛玩動物、例えばイヌまたはネコをはじめとする哺乳動物などの対象における癌を処置する方法に関する。インターフェロン−抗体DNL(商標)構築物の投与は、標的細胞の表面で抗原と結合または反応する治療有効量の抗体を同時にまたは順次投与することにより、補足することができる。好ましい付加MAbは、CD4、CD5、CD8、CD14、CD15、CD16、CD19、IGF−1R、CD20、CD21、CD22、CD23、CD25、CD30、CD32b、CD33、CD37、CD38、CD40、CD40L、CD45、CD46、CD52、CD54、CD70、CD74、CD79a、CD80、CD95、CD126、CD133、CD138、CD154、CEACAM5、CEACAM6、B7、AFP、PSMA、EGP−1、EGP−2、炭酸脱水酵素IX、PAM4抗原、MUC1、MUC2、MUC3、MUC4、MUC5ac、Ia、MIF、HM1.24、HLA−DR、テネイシン、Flt−3、VEGFR、PlGF、ILGF、IL−6、IL−25、テネイシン、TRAIL−R1、TRAIL−R2、補体因子C5、癌遺伝子産物、またはそれらの組み合わせと反応するMAbからなる群より選択される少なくとも1つのヒト化MAb、キメラMAb、またはヒトMAbを含む。
様々な実施形態が、患者における患部組織の治療または診断に適した成分を含むキットに関し得る。例示的なキットは、本明細書に記載された少なくとも1つまたは複数のインターフェロン−抗体構築物を含み得る。投与のための成分を含有する組成物が、経口送達など、消化管を介した送達のために配合されていない場合、他の何らかの経路を通してキット成分を送達することが可能なデバイスが含まれ得る。非経口送達などの適用のためのデバイスのタイプの1つは、組成物を対象の身体に注入するために使用される注射器である。吸入用デバイスも、使用され得る。特定の実施形態において、治療薬を、滅菌された液剤または凍結乾燥調製物を含むプレフィルドシリンジまたは自己注射ペンの形態で提供し得る。
以下の実施例は、本発明の請求を限定するのでなく、例示するために示されている。
pdHL2哺乳動物発現ベクターが、組換えIgGの発現に用いられてきた(Qu et al.,Methods,2005,36:84−95)。任意のIgG−pdHL2ベクターのCH3−AD2−IgG−pdHL2ベクターへの変換を促進するために、プラスミドシャトルベクターを作製した。Fc(CH2およびCH3ドメイン)の遺伝子を、鋳型としてのpdHL2ベクターおよび以下のオリゴヌクレオチドプライマーを用いて、PCRにより増幅した:
トランスフェクションおよび安定したC H 3−AD2−IgG分泌細胞株の選択
全ての細胞株をハイブリドーマSFM(Invitrogen、カリフォルニア州カールスバッド所在)中で増殖させた。CH3−AD2−IgG−pdHL2ベクター(30μg)をSalI制限エンドヌクレアーゼでの消化により直線化し、エレクトロポレーション(450ボルト、25μF)によりSp2/0−Ag14(2.8×106細胞)内にトランスフェクトした。pdHL2ベクターは、クローン選択およびメソトレキサート(MTX)による遺伝子増幅を可能にする、ジヒドロ葉酸還元酵素の遺伝子を含む。
融合蛋白質製造のために、ローラーボトル培養物を2×105細胞/mlで播種し、細胞生存率が25%を下回るまで(約10日)、ローラーボトルインキュベーター中で5%CO2の下、37℃でインキュベートした。培養ブロスを遠心分離により透明化して濾過し、限外濾過により50倍にまで濃縮した。CH3−AD2−IgGモジュール精製のために、濃縮した上清液をプロテインA(MAB Select)アフィニティーカラムにロードした。カラムをPBSでベースラインまで洗浄し、融合蛋白質をpH2.5の0.1Mグリシンで溶出した。
先の実施例において記載された技術を利用して、表6に示されたIgGおよびFab融合蛋白質を構築して、DNL構築物に組み込んだ。親抗体およびDNL構築物の抗原結合特性を保持した融合蛋白質が、組み込まれた抗体または抗体フラグメントの抗原結合活性を示した。
哺乳動物細胞内で発現するIFN−α2b−DDD2−pdHL2の構築
IFN−α2bのcDNA配列をPCRにより増幅して、以下の特色を含む配列を得た:XbaIおよびBamHIが制限部位であり、シグナルペプチドがIFN−α2b由来であり、6Hisがヘキサヒスチジンタグ:XbaI−シグナルペプチド−IFNα2b−6His−BamHI(6Hisは配列番号:92で開示される)である。得られた分泌蛋白質は、そのC末端で、以下の配列のポリペプチドに融合したIFN−α2bで構成されていた。
IFN−α2b−DDD2−pdHL2をSalIで消化して直線化し、エレクトロポレーションによりSp/ESF骨髄腫細胞内へ安定にトランスフェクトした(実施例の節が参照により本明細書に組み入れられる米国特許出願第11/877,728号参照)。2つのクローンが、ELISA法により検出可能なレベルのIFN−α2bを有することが見出された。2つのクローンのうち95と称する一方のクローンが、実質的に産生能を低下させることなく、無血清培地での増殖に適応した。次いで5週間にわたり、MTX濃度を0.1から0.8μMに増加させて、このクローンを増幅した。この段階で、クローンを限界希釈によりサブクローニングし、最も産生能の高いサブクローン(95−5)を拡大させた。振盪フラスコ中で発育させた95−5の産生能は、市販のrIFN−α2b(Chemicon、IF007、ロット番号06008039084)を標準として用いると2.5mg/Lであると推定された。
クローン95−5を、0.8μMのMTXを含有する無血清ハイブリドーマSFM全20Lを含む34個のローラーボトルに拡大し、最終培養まで培養した。培養ブロスを処理して、IFN−α2b−DDD2を、固定化金属アフィニティークロマトグラフィー(IMAC)により以下の通り精製した。上清液を遠心分離により透明化し、0.2μMで濾過し、1×結合緩衝液(10mMイミダゾール、0.5M NaCl、50mM NaH2PO4、pH 7.5)中へ透析濾過して、310mLに濃縮し、最終濃度0.1%になるまでTween20を添加し、30mL Ni−NTAカラムにロードした。試料ロードの後、カラムを、1×結合緩衝液中の0.02%Tween20 500mL、その後、30mMイミダゾール、0.02%Tween20、0.5M NaCl、50mM NaH2PO4、pH 7.5の溶液290mLで洗浄した。生成物を、250mMイミダゾール、0.02%Tween20、150mM NaCl、50mM NaH2PO4、pH7.5 110mLで溶出した。約6mgのIFNα2b−DDD2を精製した。
IFN−α2b−DDD2は、E.コリにおいても、微生物発酵により、可溶性蛋白質として発現された。コード配列を、IFN−α2b−DDD2−pdHL2 DNAを鋳型として用いたPCRにより増幅した。アンプリマーを、Nde IおよびXhoI制限部位を用いて、pET26b E.コリ発現ベクター内にクローニングした。100μMのIPTGを含むLB振盪フラスコでの18℃で12時間の誘導により、蛋白質をBL21pLysS宿主細胞において細胞内発現させた。可溶性IFN−α2b−DDD2を、上記IMACにより細胞溶解物から精製した。
CH3−AD2−IgGに結合した4つのIFN−α2b−DDD2部分を含むDNL複合体(図1)を、以下の通り作製した。簡潔に述べると、選別したCH3−AD2−IgGを約2モル当量のIFN−α2b−DDD2と混和し、この混合物に1mM EDTAおよび2mM 還元型グルタチオン(GSH)を添加した後、穏やかな条件下、室温で一場還元した。酸化型グルタチオンを2mMになるまで添加し、この混合物を更に12〜24時間、室温で保持した。DNLコンジュゲートをプロテインAアフィニティーカラムで精製した。それぞれCH3−AD2−IgG−hA20(CD20に対する特異性を有する)、CH3−AD2−IgG−hLL2(CD22に対する特異性を有する)、CH3−AD2−IgG−hR1(IGF−1Rに対する特異性を有する)およびCH3−AD2−IgG−hL243(HLA−DRに対する特異性を有する)にアンカーリングされた、4コピーのIFN−α2bを含む、20−2b、22−2b、hR1−2bおよび243−2bと称されるそのような4つのDNLコンジュゲートを調製した。哺乳動物(m)またはE.コリ(e)産生IFN−α2b−DDD2から生成された20−2bのSE−HPLC分析では、それぞれが1つのIgGおよび4つのIFN−α2bグループからなる共有結合性複合体と一致した保持時間を有する主要ピークを示した(図示しない)。同様のSE−HPLCプロファイルが、他の3つのIFN−IgGコンジュゲートに関して観察された。
20−2bのインビトロでのIFNα生物学的活性を、細胞ベースのレポーター、ウイルス防御およびリンパ腫増殖のアッセイを用いて、市販のペグ化IFNα2剤であるPEGASYS(登録商標)およびPEG−Intron(登録商標)の生物学的活性と比較した。インターフェロン刺激応答要素に融合されたレポーター遺伝子を含有するトランスジェニックヒト前単球細胞株を用いる細胞ベースのキットを使用して、比活性を測定した(図2A〜2D)。20−2bの比活性(5300IU/pmol)は、PEGASYS(170IU/pmol)およびPEG−Intron(3400IU/pmol)の両方よりも高かった(図2A)。20−2bと同様に作製された734−2b、1R−2bおよび更に5つのMAb−IFNα構築物(データは示さない)は、それぞれ同様の比活性(4000〜8000IU/pmol)を示しており、そのような構造物を生成するためのDNL法に一貫性があることが実証された(図2A)。4つのIFNα2bグループを有することが、MAb−IFNαの効能増強に寄与した。IFNα当量に正規化すると、比活性/IFNαは、PEGASYSよりも約10倍高く、PEG−INTRONよりも約2倍だけ低かった。
IFNαは、NK細胞およびマクロファージを活性化することにより、抗CD20免疫療法の基本的な作用機序(MOA)であるADCC活性を増強し得る。本発明者らは、末梢血単核細胞(PBMC)をエフェクター細胞として使用して、2つのNHL細胞株で20−2bとv−mabとでADCCを比較した。複数のドナー由来のPBMCを用いた反復アッセイにより、DaudiおよびRaji細胞の両方について示すように、20−2bの方が、v−mabに比較してADCCをより増強することが実証された(図4A)。この作用は、抗CD22MAbであるエピラツズマブを含み、ADCCをわずかに示す、MAb−IFNαである22−2bでも示された(Carnahan et al.,2007,Mol.Immunol.,44:1331−41)。
CDCは、I型抗CD20MAb(v−mabおよびリツキシマブを含む)の重要なMOAであると考えられている。しかし、トシツモマブに代表されるII型MAbには、この機能が欠如している(Cardarelli et al.,2002,Cancer Immunol Immunother 51:15−24)にもかかわらず、抗リンパ腫活性を有する。v−mabとは異なり20−2bは、インビトロでのCDC活性を示さない(図4B)。これらの結果は、補体結合がおそらく立体的干渉により見かけ上、阻害されている、CH3−AD2−IgG−v−mabモジュールに基づく他のDNL構造物の結果(Rossi et al.,2008,Cancer Res 68:8384−92)と一致する。
雄Swiss−Websterマウスにおける20−2bの薬物動態(PK)特性を評価し、PEGASYS、PEG−INTRONおよびα2b−413(DNLにより作製されたペグ化IFN、米国特許出願第11/925,408参照)のものと比較した。様々な時間における血清試料中のIFN−α濃度を、製造業者による使用説明書に従ってELISA法により決定した。簡潔に述べると、血清試料を、キットに備付けのヒトIFN−α標準に従って適切に希釈した。マイクロタイタープレートウェルに結合した抗体は、インターフェロンを捕捉する。その後、二次抗体を用いて、結合したインターフェロンを明らかにし、テトラメチルベンジジン(TMB)を添加後、西洋ワサビペルオキシダーゼ(HRP)とコンジュゲートした抗二次抗体により定量した。プレートを450nmで読み取った。図3は、PK解析の結果を表し、20−2bは他の薬剤と比較して、消失が有意に緩やかで、血中保持時間が有意に長いことを示した。210pmolの注射用量において、時間単位で算出される薬物動態的な血清中半減期は、8.0時間(20−2b)、5.7時間(α2b−413)、4.7時間(PEGASYS)および2.6時間(PEG−INTRON)であった。消失速度(1/h)は、0.087(20−2b)、0.121(α2b−413)、0.149(PEGASYS)および0.265(PEG−INTRON)であった。算出されたMRT0.08→∞(時間)は、22.2(20−2b)、12.5(α2b−413)、10.7(PEGASYS)および6.0(PEG−INTRON)であった。薬物動態パラメーターは、個々の抗体またはサイトカインよりも複合体の性質により決定されるため、サイトカイン−DNL複合体のPK特性は、他のサイトカイン部分および抗体部分に一般化可能であり、先に議論された特定の20−2b構築物に限定されないことが予測される。
血清安定性
20−2bは、37℃ではヒト血清中(≧10日)または全血中(≧6日)で安定であった(図示しない)。20−2b複合体の濃度を、二重特異性ELISAアッセイを用いて決定した。アッセイ時間では、全血または血清中における血中20−2bレベルの検出可能な変化は、本質的に存在しかった。
本発明者らは、20−2b、v−mab、734−2bまたはv−mab+734−2bが、エクスビボ設定で全血からリンパ腫または正常なB細胞を排除する能力を比較した(図5)。裸の抗CD20MAbの治療有効性は、3つの作用機序(MOA)、すなわちシグナル伝達誘導性アポトーシスもしくは増殖停止、ADCCおよびCDCを介して実現されると考えられている(Glennie et al.,2007、Mol Immunol.,44:3823−37)。このアッセイにおいて、v−mabは、3つのMOA全てを利用し得るのに対し、インビトロの知見では、20−2bは、シグナル伝達およびADCCの増強において潜在的に有利となり得るが、CDCは増強されない。この短期モデルにおいて、20−2bおよび734−2bのIFNα2b群は、腫瘍細胞に直接作用し、v−mabのADCC活性を増強して、おそらく若干の免疫刺激作用を有し得る。しかし、インビボで生じ得る自然および適応免疫系の、IFNαを介した活性化の全領域は、この2日間のエクスビボアッセイでは実現されない。
マウスモデルの限界は、ネズミ細胞がヒトIFNα2bに対して非常に低感受性であるということである。ヒトにおいて実現され得る20−2bの全般的な治療利益として、自然および適応免疫の両方の増強を挙げることができる。これらの限界を考慮して、本発明者らは、SCIDマウスにおける播種性のバーキットリンパ腫モデルに対する、20−2bの抗リンパ腫性インビボ有効性を試験した。初めに本発明者らは、高感受性の初期Daudiモデルを試験した(図6A)。接種の1日後に、各群に1低用量の20−2b、v−mabまたは734−2bを投与した。v−mab(ベルツブマブ)または734−2bの1単一用量0.7pmol(170ng)では、生理食塩水と比較した場合の生存率において、v−mabに関しては有意な改善が得られた(P<0.0001)が、無関係な対照MAb−IFNαである734−2bでは得られなかった(図6A)。この改善はわずかであり、生存期間中央値(MST)は生理食塩水での27日からv−mabでの34日に増加した。しかし、20−2bの単一用量0.7pmol(170ng)では、MSTにおいて、生理食塩水およびv−mab群の両方を100日よりも多く上回る改善が得られた(p<O.0001)(図6A)。19週間後にこの実験を終了し、その時点で、0.7pmolの20−2b処置群中の長期生存例7匹を剖検したところ、疾患の目に見える証拠は見出されなかった(治癒した)(図6A)。注目すべきことに、最低用量0.07pmol(17ng)の20−2bでさえも、MSTが2倍を超えて増加させた(図6A)。
結果は、抗CD20MAbを用いたIFNαの標的化により、単独の薬剤または薬剤の組み合わせよりも、免疫サイトカインがより強力で効果的になることを明白に実証している。腫瘍に対するMAbによるIFNα標的化は、単一薬剤の投与計画の頻度を減らし、IFN療法に付随する副作用を低減または除去し、非常に増大した有効性をもたらし得る。更に標的化IFNαは、腫瘍に対する急性免疫応答を誘導し、おそらくは自然および適応免疫の多面的な刺激を介して免疫記憶を誘発することができる(Belardelli et al.,2002、Cytokine Growth Factor Rev.,12:119−34)。別のグループは、化学的コンジュゲーションにより作製されるMAb−IFNαを産生し、そのような構築物の潜在的な臨床利益を明らかにした(Pelham et al.,1983、Cancer Immunol Immunother.,15:210−16;Ozzello et al.,1998、Breast Cancer Res.Treat.,48:135−47)。ネズミIFNαおよび抗HER2/neuMAbを含む組換えMAb−IFNαは、免疫適格性マウスにおいて、トランスジェニック(HER2/neu)ネズミB細胞リンパ腫の強力な阻害を示し、免疫記憶による防御的な適応免疫応答の誘導も可能であった(Huang et al.,2007,J.Immunol.,179:6881−88)。
要約および緒言
インターフェロンλ1(IFN−λ)は、III型インターフェロンであり、近年になり抗ウイルスおよび抗腫瘍活性ならびに免疫系調節に関する治療可能性を有するクラスIIIサイトカインファミリーの1種として記載された。IFN−λは、IFN−αおよびIFN−βの両方を含むI型IFNと同様に、JAK1およびTYK2キナーゼの活性化、STAT蛋白質のリン酸化、およびIFN刺激遺伝子因子3の転写複合体の活性化を含むJAK/STAT経路を介してシグナル伝達を惹起する(Witte et al.,2010,Cytokine Growth Factor Rev 21:237−51;Zhou et al.,2007,J Virol 81:7749−58)。
抗体および試薬ヒト化抗体hA20−IgG(抗CD20)、hRS7−IgG(抗Trop−2)、hMN15−IgG(抗CEACAM6)およびhL243(抗HLA−DR)は、Immunomedics,Incから得た。組換えヒトIFN−λ1、ヒトIFN−λ1に対するマウスmAb 、およびヒトHLA−ABCに対するマウスFITC−IgGlkは、R&D Systems Incから購入した。AD2部分を含む融合蛋白質のアミノ酸配列および突然変異体(C17 IS)または野生型IFNλ1に結合したポリ−His配列を、以下に示す。STAT1、STAT3、pY−STATlおよびpY−STAT3に対するウサギ抗体は、Cell Signaling Technology Incから購入した。STAT2抗体は、 Santa Cruz Biotechnologyから得た。pY−STAT2抗体は、Millipore Corporationから得た。
野生型:AD2−IFN−λ1
(Fab)2−IFN−λ1の生成および特徴づけ 点突然変異(C171S)を、野生型IFN−λ1配列に導入して、DNLモジュールのリフォールディングおよび組織化を有する非対合システイン残基の潜在的干渉を排除した。AD2−IFN−λ1モジュールの組換え形態を、E.コリ内で産生して、固定化金属イオンアフィニティークロマトグラフィー(IMAC)により変性条件下で封入体から精製した。蛋白質をジチオトレイトール(DTE)で還元し、その後、酸化グルタチオンを含むリフォールディング緩衝液中でリフォールディングして、ジスルフィド結合を形成させた。SDS−PAGEにより決定された通り(図示しない)、AD2−IFN−λ1蛋白質が高度に精製されて、主に単量体状態で存在した。最終生成物の収率は、約6mg/mlE.コリ細胞培養物であった。
IFN−λ1、IFN−λ2、およびIFN−λ3を含むIII型インターフェロン(IFN)は、抗ウイルス、抗腫瘍、および抗免疫調整活性の誘発においてIFN−αと同様に挙動する。より制限された細胞標的物のために、IFN−λ1は、IFN−αに基づく既存の治療レジメンの潜在的代替法として興味を集めている。本発明者らは、抗体コンジュゲートIFN−λ1を含むDOCK−AND−LOCK(商標)複合体を生成し、hRS7(ヒト化抗Trop−2)、hMN−15(ヒト化抗CEACAM6)、hL243(ヒト化抗HLA−DR)、およびc225(キメラ抗EGFR)から得られた安定したFab二量体をIFN−λ1に部位特異的につないで、それぞれ(E1)−λ1、(15)−λ1、(C2)−λ1および(c225)−λ1と称される新規な免疫サイトカインを得ることにより、標的癌細胞株においてIFN−λ1の抗増殖能を最大1,000まで改善した。(15)−λ1または(c225)−λ1を介したIFN−λ1の、各抗原発現細胞への標的送達も、脳心筋炎ウイルスに対して(15)−λ1によるヒト肺腺癌上皮細胞株A549(EC50=22.2pM対223pM)、およびC型肝炎ウイルスに対して(c225)−λ1によるヒト肝臓癌細胞株Huh−7(EC50=0.56pM対91.2pM)において実証された通り、非標的(C2)−λ1と比較すると抗ウイルス活性も有意に上昇させた。これらの意外で予測されなかった結果は、マウスにおける(E1)−λ1の好適な薬物動態プロファイル(T1/2 8.6時間)と共に、抗体−標的細胞へのIFN−λ1のより良好な局在化およびより強力な結合に起因する。
アルツハイマー病(AD)は、進行性の記憶障害、錯乱、緩やかな身体機能の悪化、そして最終的に死を迎える変性性脳障害である。世界中でおよそ1500万の人々が、 アルツハイマー病に罹患している。組織学的に該疾患は、主として連合皮質、大脳辺縁系および大脳基底核に見出される、老人斑により特徴づけられる。これらの斑の主要な構成成分は、アミロイドβペプチド(Aβ)であり、それはβアミロイド前駆蛋白質(βAPPまたはAPP)の切断生成物である。
喘息は、刺激物質に対する気管・気管支の過敏反応により特徴づけられる異種起源の疾患群である。臨床的に喘息は、気管・気管支の広範にわたる狭窄、粘稠性分泌物と、呼吸困難、咳および喘鳴の発作により顕在化され、気道抵抗性の上昇、肺およびのどの過膨張、通気および肺血流の異常分布に陥る。該疾患は、無症状期間の間に挟まれた急性症状のエピソード期間において顕在化される。急性エピソードにより低酸素症になり、致命的となる可能性がある。一般的な世界人口のおよそ3%が、該疾患に罹患している。喘息の症状は、 惹起する抗原、環境的要因、職業的要因、身体活動、および情動的ストレスの存在およびレベルにより増悪し得る。喘息は、メチルキサンチン(テオフィリンなど)、βアドレナリン作動薬(カテコラミン、レゾルシノール、サリゲニン、およびエフェドリンなど)、グルココルチコイド(ヒドロコルチゾンなど)、肥満細胞脱顆粒の阻害物質(即ち、クロモリンナトリウムなどのクロモン)、および抗コリン作動薬(ストロピンなど)で処理され得るが、喘息を処置するための改善された方法および組成物が、求められている。
多発性硬化症(MS)は、自己反応性T細胞が血液脳関門を横断して髄鞘を攻撃し、炎症を起こして脱髄および軸索変性に至る、自己免疫疾患である。青少年期の予測不能な神経障害エピソードに続き、離散的攻撃(再発型)により、または時間の経過と共に徐々に、身体的および認知的障害が増えていく。治癒は知られていないが、インターフェロンβ療法が、再発寛解型多発性硬化症の現在の最前線処置であり、再発率の低下に関する有効性が実証されている。しかしIFN療法は、インフルエンザ様症状、骨髄抑制、自己免疫疾患の発症または増悪、好中球減少症、血小板減少症、および神経精神学的作用などの副作用による著しい病的状態を伴う。
Claims (17)
- i)ヒトプロテインキナーゼA(PKA)RI、RIβ、RIIまたはRIIβからの二量体化およびドッキングドメイン(DDD)部分に結合したインターフェロンλを含む第一の融合蛋白質と;
ii)AKAP蛋白質からのアンカードメイン(AD)に結合した抗体または抗原結合抗体フラグメントを含む第二の融合蛋白質と;
を含むインターフェロン−抗体複合体であって、
前記DDD部分の2コピーが、前記AD部分に結合する二量体を形成して、前記複合体を形成しており、
前記AD部分が、前記抗体または抗原結合抗体フラグメントのC末端に結合しており、前記DDD部分が、前記インターフェロンλのC末端又はN末端に結合している複合体を含み、
前記抗体またはその抗体フラグメントが、TROP−2、CEACAM5、CEACAM6、HLA−DR、CD19、CD20、CD22、CD52、CD74、EGFR、ムチン、αフェト蛋白質、CEA、CSAp、TNFおよびMIFからなる群より選択される抗原に結合する、
癌、ウイルス感染、喘息または多発性硬化症の治療剤。 - 前記インターフェロンλが、ヒトインターフェロンλ1、インターフェロンλ2およびインターフェロンλ3からなる群より選択される、請求項1に記載の治療剤。
- 前記抗体フラグメントが、Fab、Fv、scFv、およびdAbからなる群より選択される、請求項1または2に記載の治療剤。
- 追加の治療薬を更に含む、請求項1〜3のいずれか一項に記載の治療剤。
- 前記治療薬が、二次抗体、二次抗体フラグメント、二次インターフェロン、薬物、毒素、酵素、ホルモン、免疫調整物質、サイトカイン、ケモカイン、アンチセンスオリゴヌクレオチド、siRNA、RNAi、放射性核種、ホウ素化合物、光活性剤、抗血管新生薬およびアポトーシス促進剤からなる群より選択される、請求項4に記載の治療剤。
- 前記薬物が、5−フルオロウラシル、アプリジン、アザリビン、アナストロゾール、アントラサイクリン、ベンダムスチン、ブレオマイシン、ボルテゾミブ、ブルトン型キナーゼ阻害剤、ブリオスタチン−1、ブスルファン、カリケアマイシン、カンプトテシン、カルボプラチン、10−ヒドロキシカンプトテシン、カルムスチン、セレコキシブ、クロラムブシル、シスプラチン(CDDP)、Cox−2阻害剤、イリノテカン(CPT−11)、SN−38、カルボプラチン、クラドリビン、カンプトテカン、シクロホスファミド、シタラビン、ダカルバジン、ドセタキセル、ダクチノマイシン、ダウノルビシン、ドキソルビシン、2−ピロリノドキソルビシン(2P−DOX)、シアノモルホリノドキソルビシン、ドキソルビシングルクロニド、エピルビシングルクロニド、エストラムスチン、エピポドフィロトキシン、エストロゲン受容体結合剤、エトポシド(VP16)、エトポシドグルクロニド、リン酸エトポシド、フロクスウリジン(FUdR)、3’,5’−O−ジオレオイルFudR、フルダラビン、フルタミド、ファルネシル−蛋白質トランスフェラーゼ阻害剤、ゲムシタビン、ヒドロキシ尿素、イダルビシン、イフォスファミド、L−アスパラギナーゼ、レノリダミド、ロイコボリン、ロムスチン、メクロレタミン、メルファラン、メルカプトプリン、6−メルカプトプリン、メトトレキサート、ミトキサントロン、ミスラマイシン、マイトマイシン、ミトタン、ナベルビン、ニトロソ尿素、プリカマイシン、プロカルバジン、パクリタキセル、ペントスタチン、PSI−341、ラロキシフェン、セムスチン、ストレプトゾシン、タモキシフェン、パクリタキセル、テマゾロミド、トランス白金、サリドマイド、チオグアニン、チオテパ、テニポシド、トポテカン、チロシンキナーゼ阻害剤、ウラシルマスタード、ビノレルビン、ビンブラスチン、ビンクリスチン、ビンカアルカロイド、LFM−A13、ダサチニブ、イマチニブおよびニロチニブからなる群より選択される、請求項5に記載の治療剤。
- 前記毒素が、リシン、アブリン、α毒素、サポリン、リボヌクレアーゼ(RNase)、オンコナーゼ、DNaseI、ブドウ球菌腸毒素A、ポークウィード抗ウイルス蛋白質、ゲロニン、ジフテリア毒素、緑膿菌外毒素、および緑膿菌内毒素からなる群より選択される、請求項5に記載の治療剤。
- 前記抗血管新生薬が、アンギオスタチン、バキュロスタチン、カンスタチン、マスピン、抗VEGF抗体、抗PIGF抗体、ラミニン、フィブロネクチン、プラスミノーゲン活性化因子阻害剤、組織メタロプロテイナーゼ阻害剤、インターフェロン、インターロイキン12、IP−10、Gro−β、トロンボスポンジン、2−メトキシエストラジオール、プロリフェリン関連蛋白質、カルボキサミドトリアゾール、CM101、マリマスタット、多硫酸ペントサン、アンギオポエチン2、インターフェロンα、ハービマイシンA、PNU145156E、16Kプロラクチンフラグメント、リノミド(ロキニメックス)、サリドマイド、ペントキシフィリン、ゲニステイン、TNP−470、エンドスタチン、バクリタキセル、アクチン(accutin)、アンギオスタチン、シドフォビル、ビンクリスチン、ブレオマイシン、AGM−1470、血小板因子4およびミノサイクリンからなる群より選択される、請求項5に記載の治療剤。
- 前記AD部分のアミノ酸配列が、配列番号:3、配列番号:4、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:32、配列番号:33、配列番号:34、配列番号:35、配列番号:36、配列番号:37、配列番号:38、配列番号:39、配列番号:40、配列番号:41、配列番号:42、配列番号:43、配列番号:44、配列番号:45、配列番号:46、配列番号:47、配列番号:48、配列番号:49、配列番号:50、配列番号:51、配列番号:52、配列番号:53、配列番号:54、配列番号:55、配列番号:56、配列番号:57、配列番号:58、配列番号:59、配列番号:60、配列番号:61、配列番号:62、配列番号:63、配列番号:64、配列番号:65、配列番号:66、配列番号:67、配列番号:68、配列番号:69、配列番号:70、配列番号:71、配列番号:72、配列番号:73、配列番号:74、配列番号:75、配列番号:76、配列番号:77、配列番号:78、配列番号:79、配列番号:80、配列番号:81、配列番号:82、配列番号:83および配列番号:84からなる群より選択される、請求項1〜8のいずれか一項に記載の治療剤。
- 前記DDD部分のアミノ酸配列が、配列番号:1、配列番号:2、配列番号:5、配列番号:6、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、配列番号:14、配列番号:15、配列番号:16、配列番号:17、配列番号:18、配列番号:19、配列番号:20、配列番号:21、配列番号:22、配列番号:23、配列番号:24、配列番号:25、配列番号:26、配列番号:27、配列番号:28、配列番号:29、配列番号:30および配列番号:31からなる群より選択される、請求項1〜9のいずれか一項に記載の治療剤。
- 前記インターフェロン−抗体複合体が、前記インターフェロン単独、前記抗体単独、またはコンジュゲートされていないインターフェロンと抗体との組み合わせよりも効果的である、請求項1〜10のいずれか一項に記載の治療剤。
- 前記癌が、急性リンパ芽球性白血病、急性骨髄性白血病、胆道癌、乳癌、子宮頸癌、慢性リンパ性白血病、慢性骨髄性白血病、大腸癌、子宮内膜癌、食道癌、胃癌、頭頸部癌、ホジキンリンパ腫、肺癌、甲状腺髄様癌、非ホジキンリンパ腫、多発性骨髄腫、腎臓癌、卵巣癌、膵臓癌、神経膠腫、黒色腫、肝臓癌、前立腺癌、および膀胱癌からなる群より選択される、請求項1に記載の治療剤。
- 前記ウイルス感染が、ヒト免疫不全ウイルス(HIV)、ヘルペスウイルス、単純ヘルペスウイルス、ワクシニアウイルス、サイトメガロウイルス、狂犬病ウイルス、インフルエンザウイルス、ライノウイルス、B型肝炎ウイルス、C型肝炎ウイルス、センダイウイルス、ネコ白血病ウイルス、レオウイルス、ポリオウイルス、ヒト血清パルボ様ウイルス、サルウイルス40、呼吸器合胞体ウイルス、マウス哺乳動物腫瘍ウイルス、バリセラ・ゾスターウイルス、デングウイルス、ルベラウイルス、麻疹ウイルス、アデノウイルス、ヒトT細胞白血病ウイルス、エプスタイン・バーウイルス、ネズミ白血病ウイルス、ムンプスウイルス、水疱性口炎ウイルス、シンドビスウイルス、リンパ性脈絡髄膜炎ウイルス、イボウイルス、およびブルータングウイルスからなる群より選択される、請求項1に記載の治療剤。
- 前記ウイルス感染が、慢性C型肝炎感染である、請求項13に記載の治療剤。
- 喘息または多発性硬化症の治療剤である、請求項1に記載の治療剤。
- 喘息の治療剤であり、前記複合体が、鼻腔内投与により投与されるためのものである、請求項15に記載の治療剤。
- 前記抗体または抗体フラグメントが、抗TNF、抗CD74、または抗MIF抗体または抗体フラグメントである、請求項16に記載の治療剤。
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US13/412,816 US8435540B2 (en) | 2005-04-06 | 2012-03-06 | Dimeric alpha interferon PEGylated site-specifically shows enhanced and prolonged efficacy in VIVO |
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PCT/US2013/023093 WO2013112801A1 (en) | 2012-01-26 | 2013-01-25 | Targeting interferon-lambda with antibodies potently enhances anti-tumor and anti-viral activities |
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RU2605390C2 (ru) | 2011-08-23 | 2016-12-20 | Рош Гликарт Аг | Биспецифические антитела, специфичные к антигенам, активирующим т-клетки, и опухолевому антигену, и способы их применения |
CN105745543B (zh) | 2013-09-18 | 2018-02-02 | 阿德莱德研究及创新控股有限公司 | 卵巢癌的自身抗体生物标志物 |
US11497767B2 (en) | 2015-02-18 | 2022-11-15 | Enlivex Therapeutics R&D Ltd | Combination immune therapy and cytokine control therapy for cancer treatment |
US11596652B2 (en) | 2015-02-18 | 2023-03-07 | Enlivex Therapeutics R&D Ltd | Early apoptotic cells for use in treating sepsis |
US11318163B2 (en) | 2015-02-18 | 2022-05-03 | Enlivex Therapeutics Ltd | Combination immune therapy and cytokine control therapy for cancer treatment |
US11000548B2 (en) | 2015-02-18 | 2021-05-11 | Enlivex Therapeutics Ltd | Combination immune therapy and cytokine control therapy for cancer treatment |
US11304976B2 (en) | 2015-02-18 | 2022-04-19 | Enlivex Therapeutics Ltd | Combination immune therapy and cytokine control therapy for cancer treatment |
IL284985B2 (en) | 2015-02-18 | 2023-03-01 | Enlivex Therapeutics R& D Ltd | Combined immunotherapy and cytokine control therapy for cancer treatment |
CN104678099B (zh) * | 2015-03-03 | 2017-06-16 | 南京农业大学 | Cox‑2在制备诊断、检测犬肿瘤的诊断试剂中的应用 |
EP3285877B1 (en) | 2015-04-21 | 2022-10-19 | Enlivex Therapeutics Rdo Ltd | Therapeutic pooled blood apoptotic cell preparations and uses thereof |
CN106366189A (zh) * | 2015-07-22 | 2017-02-01 | 中国医学科学院肿瘤医院 | 一种抗人肺癌干细胞的单克隆抗体 |
CA3014885A1 (en) | 2016-02-18 | 2017-08-24 | Enlivex Therapeutics Ltd. | Combination immune therapy and cytokine control therapy for cancer treatment |
CN106834300B (zh) * | 2017-03-06 | 2019-12-31 | 李斯文 | 一种抗cd33单链抗体及光敏剂复合物及其制备方法 |
CN109422813A (zh) * | 2017-08-22 | 2019-03-05 | 中国科学院深圳先进技术研究院 | HBs-α317ScFv重组蛋白、其编码序列、表达载体及应用 |
CN117957257A (zh) * | 2021-08-04 | 2024-04-30 | 清华大学 | 一种靶向并杀伤病原体和/或肿瘤细胞的多功能融合蛋白药物 |
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