JP6905492B2 - ニューロピリン1:セマフォリン軸を介した、制御性t細胞の安定性および機能の制御に基づく療法 - Google Patents
ニューロピリン1:セマフォリン軸を介した、制御性t細胞の安定性および機能の制御に基づく療法 Download PDFInfo
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Description
本出願は、すべてについてその全体を本明細書に援用する2013年3月14日に出願された米国仮特許出願第61/784,607号明細書、2012年10月11日に出願された米国仮特許出願第61/712,679号明細書、および2012年10月8日に出願された米国仮特許出願第61/711,193号明細書の利益を主張する。
連邦政府による資金提供を受けた研究開発の記載
米国政府は、米国国立衛生研究所(National institutes of Health)からのGrant Nos.AI091977、AI039480およびAI098383、ならびにNCI Comprehensive Cancer Center Support CORE助成金CA21765から準備された資金に基づき、本発明に一定の権利を有する。
「Treg」または「制御性T細胞」という用語は、CD4+CD25−およびCD8+T細胞の増殖および/またはエフェクター機能を抑制する、またはその他の方法で免疫反応を抑制的に調節するCD4+T細胞をいう。とりわけ、Tregは、ナチュラルキラー細胞、ナチュラルキラーT細胞のほか、他の免疫細胞により媒介される免疫反応をダウンレギュレートすることができる。好ましい実施形態では、本発明のTregはFoxp3+である。
一実施形態では、本発明は、Tregの機能を阻害するまたは安定性を低下させる方法であって、前記TregにおけるNrp1:セマフォリン軸の阻害剤に前記Tregを曝露することを含む方法を提供する。一実施形態では、Nrp1:セマフォリン軸のこうした阻害剤は、通常型T細胞上の膜貫通型セマフォリン(たとえばクラスIVセマフォリン、たとえばSema4a)とTreg上のNrp1との間の相互作用を阻害する。1つの特定の実施形態では、Nrp1:セマフォリン軸の阻害剤は、前記TregにおけるNrp1−VEGF相互作用に影響を与えない。Nrp1:セマフォリン軸の阻害剤は、被検体(たとえばヒト)に、たとえば癌または感染症に罹患している被検体に直接投与してもよい。関連する実施形態では、本発明は、疾患の処置を必要とする被検体(たとえば、ヒト)の疾患(たとえば、癌または感染症)を処置する方法であって、被検体のTreg内のNrp1:セマフォリン軸を選択的に阻害する方法を提供する。
上記の方法に関連して、本発明は、Tregに対するNrp1:セマフォリン相互作用を阻害または増大する単離された抗体を提供する。一実施形態では、セマフォリンはクラスIVセマフォリン(たとえば、Sema4a)である。一実施形態では、抗体は、TregにおけるNrp1−VEGF相互作用またはNrp1−セマフォリンクラスIII相互作用に影響を与えない。
本発明のタンパク質/ペプチド阻害剤およびアゴニスト
上記に明記したように、本発明の方法に有用なNrp1:セマフォリン軸の阻害剤は、様々なセマフォリン分子、たとえば、可溶型の膜貫通型セマフォリンタンパク質(たとえば、Sema4a)のほか、その様々な阻害性フラグメント、誘導体およびアナログを含む。さらに、Nrp1:セマフォリン軸の競合阻害剤として働き得るNrp1の可溶性細胞外ドメインのほか、その様々な阻害性フラグメント、誘導体およびアナログも本発明内に含まれる。1つの特定の実施形態では、阻害性セマフォリン分子は、Sema4a細胞外ドメイン(GenBank受託番号NP_038686のMet1−His683フラグメント)と、ヒトまたはマウスIgG1のFc領域との融合体(C末端で)であるSema4a−Ig融合タンパク質である。1つの特定の実施形態では、阻害性セマフォリン分子は、C末端アミノ酸配列SEAを含むNrp1細胞質ドメインの全部または一部を含むNrp1タンパク質のフラグメント(またはその誘導体もしくはアナログ)であり、この分子はNrp1タンパク質の細胞質ドメインとPTENタンパク質との間のシグナル伝達経路を阻害する。
本発明は、Treg上のNrp1:セマフォリン軸の小分子阻害剤およびアゴニストをさらに包含する。小分子は、一般に低分子量(好ましくは約2000ダルトン未満、約1000ダルトン未満、または約500ダルトン未満)を有する様々なグループの合成物質および天然物質である。小分子は、以下に限定されるものではないが、たとえば、核酸、ペプチド、ポリペプチド、ペプチド核酸、ペプチド模造物、糖質、脂質または他の有機(炭素を含む)分子または無機分子であってもよく、合成でも、あるいは天然に存在しても、あるいは任意選択的に誘導体化されていてもよい。こうした小分子は、治療送達が可能な物質であってもよいし、あるいは送達または標的化しやいすいようにさらに誘導体化してもよい。こうした小分子は、天然の供給源(たとえば、植物、真菌、微生物および同種のもの)から単離しても、あるいは合成もしくは天然化合物のランダムまたはコンビナトリアル化学ライブラリーから単離しても、あるいは合成してもよい。Werner et al.,(2006)Brief Funct.Genomic Proteomic 5(1):32−6を参照されたい。使用できる多くのランダムまたはコンビナトリアルライブラリーが、当該技術分野において公知である。現在、糖類、ペプチドおよび核酸を用いた化合物のランダム合成および指向性合成(directed synthesis)用に、多くの手段が使用されている。合成化合物のライブラリーは、Maybridge Chemical Co.(Trevillet,Cornwall,UK)、Comgenex(Princeton,N.J.)、Brandon Associates(Merrimack,N.H.)およびMicrosource(New Milford,Conn.)から市販されている。希少な化学ライブラリーは、Aldrich(Milwaukee,Wis.)から入手可能である。あるいは、細菌抽出物、真菌抽出物、植物抽出物および動物抽出物の形態の天然化合物のライブラリーは、たとえばPan Laboratories(Bothell,Wash.)またはMycoSearch(N.C.)から入手可能であるか、または容易に作製可能である。加えて、天然および人工的に作成されたライブラリーおよび化合物は、従来の化学的手段、物理的手段および生化学的手段により容易に修飾できる(Blondelle et al.,(1996)Tib Tech 14:60)。
上記に記載したように、本発明は、TregにおけるNrp1発現を阻害する、または通常型T細胞上のセマフォリン発現を局所的に(たとえば、腫瘍において)阻害する、またはNrp1がその下流のシグナル伝達経路に関与するのを防止するTregにおけるNrp1:セマフォリン軸の阻害剤をさらに包含する。
本発明の阻害剤またはアゴニスト組成物を投与するための方法
ある種の実施形態では、本発明の阻害剤およびアゴニストは、薬学的に許容されるキャリアまたは賦形剤と共に医薬組成物として製剤化される。本化合物は、ヒトまたは動物医学に使用するのに都合のよい任意の方法で投与されるように製剤化してもよい。本組成物中には、湿潤剤、乳化剤および滑沢剤、たとえばラウリル硫酸ナトリウムおよびステアリン酸マグネシウムのほか、着色剤、放出剤(release agent)、コーティング剤、防腐剤および酸化防止剤がさらに存在してもよい。
材料および方法
マウス。C57/BL6マウスおよびdnTGFβRIIマウスは、Jackson Laboratoriesから購入した。Foxp3YFP−iCre、Foxp3−マウスおよびFoxp3DTR−gfpマウスは、A.Y.Rudensky(HHMI/Washington University;Rubtsov et al.,Immunity,2008,28:546−558;Fontenot et al.,Nat Immunol.,2003,4(4):330−336;Kim et al.,Nat Immunol.,2007,8(2):191−197を参照されたい)から入手した。Il10−/−マウスは、T.Geiger(St.Jude Children’s Research Hospital;Selvaraj and Geiger,J Immunol.,2008,180(5):2830−2838を参照されたい)から入手した。Nrp1f/fマウスは、D.Cheresh(UCSD;Acevedo et al.,Blood,2008,111(5):2674−2680を参照されたい)から入手した。Foxp3−×CD45.1マウスは、ヘテロ接合交雑から繁殖させた。動物実験は、St.Jude Animal Resource CenterのAmerican Association for the Accreditation of Laboratory Animal Care公認の特定病原体の感染していない(specific−pathogen−free)施設で行った。動物プロトコルは、St Jude Animal Care and Use Committeeにより承認された。
セマフォリン4aは、Treg活性を刺激する、Tconvに発現するリガンドである
本発明者および共同研究者らは以前に、共培養した通常型CD4+T細胞(Tconv)の存在下または非存在下で刺激したTregの転写および機能的プロファイルが著しく異なることを示唆したことがある12,13。Tregは、上部チャンバーに入れたTconvと直接接触した場合のみ、透過性トランスウェル膜を通過するTconvを抑制することができる(本明細書でトランスウェル抑制という)ことから、Treg機能を強化する接触依存性メカニズムが示唆される12。本発明者らは、この特徴的なTreg活性および転写プロファイルを誘導するシグナルを決定しようとした。本発明者らは、Tregが「自己ブーストする」ことができないことから、この活性を媒介するリガンドがTregではなくTconvに発現し得るとの仮説を立てた。実際、単独、または追加の生もしくは固定したFoxp3+TregもしくはB220+B細胞との共培養で刺激したTregは、上部ウェルにて制御性T細胞(Treg)を刺激した際に下部ウェルにて抗CD3/抗CD28コートビーズで刺激したTconvのトランスウェル抑制アッセイにおいて、トランスウェル膜通過の抑制を媒介できなかった(図1A)。一方、固定したCD4+またはCD8+T細胞と共培養したTregは、トランスウェル抑制を増強できたことから、リガンドが細胞表面に発現することが示唆された12。Foxp3.GFPマウスから選別し、抗CD3抗体の存在下または非存在下で照射APCと共にまたは別にインキュベートしたTconv集団およびTreg集団のAffymetrix解析を用いて、休止および活性化Treg細胞とCD4+Tconv細胞との間の遺伝子発現を比較した(48時間後、CD4およびGFP発現に基づき再選別した細胞抽出されたRNAをAffymetrix解析に供した)。このリストは、Tconvに主に発現する細胞表面発現タンパク質をコードする遺伝子に着目して作成した。このリストから、さらに研究するため上位3種の遺伝子、Sema4a(セマフォリン−4a)、Tgfbr3(トランスフォーミング増殖因子、β受容体III)およびItgb3(インテグリンβ3;CD61)を、免疫調節におけるそれらの役割、およびqPCRによるCD4+Tconv細胞とTregおよびB220+B細胞におけるそれらの差次的発現を結び付けるこれまでの研究に基づき、選択した。Sema4aおよびTgfbr3はCD8+T細胞でも強化されたが、Itgb3は強化されなかった。次いで本発明者らは、これらの分子がTreg機能を増強する能力を評価するのに使用できる細胞株を同定しようとした。3T3線維芽細胞は、多量のTgfbr3およびItgb3を発現するが、Tregのブーストを媒介できないことが明らかになった。一方、3T3細胞はSema4aを発現しなかった。総合すると、これらのデータから、軸索活性および免疫制御を調節することが示されている14Sema4aについて、さらに調査することが妥当であることが示唆された。
ニューロピリン1(Nrp1)は、クラスIIIセマフォリン、Sema3aの共受容体であり、軸索のガイダンスの制御に重要な役割を有する15。Nrp1は、軸索成長円錐の崩壊を誘導し、特権を有する組織への浸潤を防ぎ、マウスで遺伝子を欠損させると、胚性致死が引き起こされる16。Nrp1は、血管内皮増殖因子(VEGF)、血小板由来増殖因子β(PDGFβ)およびトランスフォーミング増殖因子β(TGFβ)と相互作用することが示されている17,18。Nrp1は、Tregに高発現することが示されており、特に胸腺由来の「天然の」Tregの有用なマーカーである(Foxp3CreおよびNrp1f/fFoxp3CreマウスのCD4+T細胞におけるFoxp3およびニューロピリン発現のフローサイトメトリー解析により判定された)19−21。T細胞におけるNrp1の役割は示唆されてきたが22、TregにおけるNrp1の役割は特定されていない。
Nrp1:Sema4a軸を破壊すると、インビトロでTreg活性が減弱することを考慮して、本発明者らは、Treg機能がインビボで、特に高度炎症部位で低下し得ると仮定した。Foxp3−欠損マウスは、ヒト疾患IPEXを想起させる強い自己免疫状態を発症する。これは、広範囲な免疫浸潤および3〜6週で死に至る組織炎症を特徴とする2,27。したがってインビボでのTreg機能の破壊は、炎症性疾患の発症につながる可能性がある。Nrp1f/fFoxp3Creマウスとその年齢および性別の一致した同腹仔Foxp3Cre対照とを10ヶ月間観察し、Treg欠乏マウスで通常対象となるすべての器官の詳細な組織学的解析を行った。盲検解析から、Nrp1f/fFoxp3Creマウスは、外観、および皮膚、肺、肝臓、腸、膵臓、腎臓、唾液腺および脾臓の組織学的解析を含むあらゆる点で正常範囲内にあることが立証された。フローサイトメトリー解析により判定したT細胞亜集団の大きさ、割合または表現型における変化は、観察されなかった。したがって、免疫ホメオスタシスにおける変化、炎症性疾患または自己免疫の発症は、Nrp1の欠失がTreg上に限定された高齢マウスにおいて検出できなかった。
Tregは、多くの癌において効果的な抗腫瘍免疫の大きな障害となる28,29。抗CD25処理またはFoxp3DTR−gfpマウス(Foxp3+Tregはジフテリア毒素受容体を発現し、DT投与によりその条件付き枯渇を行うことができる)の使用によるTregの枯渇は、抗腫瘍免疫を大きく強化することが示されている30,31。一方で、Tregの枯渇は、Foxp3欠乏マウスに見られるのと同様の広範囲なリンパ球増殖および自己免疫疾患も引き起こす32。腫瘍は高度炎症環境であるので、Nrp1欠乏Tregが、腫瘍誘導性寛容を媒介し、効果的な抗腫瘍免疫を妨げる能力を評価した。3つの移植可能な腫瘍モデル:MC38(免疫原性を有する結腸癌株)、EL4(中程度の免疫原性を有する胸腺腫)およびB16(免疫原性に乏しいメラノーマ)を使用した33,34。腫瘍接種Foxp3DTR−gfpマウスのDT処理によるTregの完全な消失の結果、腫瘍は排除されたが、マウスは、DT処理から約3週間後に自己免疫により媒介される死亡に至る(図4A〜C)。
VEGFまたはクラスIIIセマフォリンによるライゲーション後の、腫瘍系、ニューロンおよび内皮におけるNrp1の下流のシグナル伝達は、研究されてきたけれども15,17、TregにおいてクラスIVセマフォリンにより誘導されるNrp1シグナル伝達経路は、知られていない。興味深いことに、Nrp1は、一部の系でAkt(プロテインキナーゼB)活性を調節することが示されている37,38。Akt−mTOR活性はTreg機能にとって有害であることが示されているので39,40、本発明者らは、Nrp1ライゲーションがAkt活性化を阻害し得るとの仮説を立てた。Foxp3CreおよびNrp1f/fFoxp3CreTregをSema4a−IgまたはIgGコートビーズの存在下で刺激し、Akt−mTOR活性化をフローサイトメトリーにより評価した。Nrp1ライゲーションは、Akt S473のリン酸化のほか、Tregにおいてその活性化に必要とされるS6K1 T389のリン酸化を限定した(図5A)。Aktリン酸化については、全反射照明蛍光(TIRF)顕微鏡を用いて免疫シナプス(IS)でも調べた。Foxp3CreおよびNrp1f/fFoxp3CreTregを、抗TCRmAbおよびSema4a−IgあるいはIgGアイソタイプコントロールを含む脂質二重層で刺激した。ISへのNrp1の強いリクルートメントはSema4aが存在したときに観察され、これはISでのグローバルホスホチロシン(global phosphotyrosine)染色が同じであるにもかかわらず、Nrp1依存性のAkt活性の消失と同時に起こった(図5Bおよび6A〜B)。
本明細書に提供されたデータから、Treg機能の細胞接触依存性増強は、PTEN:Akt:Foxo軸を介したSema4a媒介性Nrp1ライゲーションにより媒介されることが立証される(図8)。とりわけ、Nrp1は、T細胞においてAkt活性を限定することが示唆されてきた限られた数の細胞表面受容体(たとえば、PD−148およびCTLA−449)の1つのようである。Nrp1は、特定の状況下でAktシグナル伝達を調節あるいはさらには活性化することもできる(Banerjee et al.,Biochemistry 47,3345−3351(2008);Cao et al.,Cancer Res 68,8667−8672(2008);Fukasawa et al.,Cancer Biol Ther 6,1173−1180(2007);Kim et al.,J Immunol 177,5727−5735(2006))一方、Nrp1がTregにおいて機能する特定の状況(たとえば、IS、独特の細胞型、膜貫通と可溶性リガンドへのリクルートメント)では、PTENのリクルートメントおよびAkt活性の消失を促進する異なる環境が整えられる。この経路は、安定性を強め、生存を促進することにより間接的にTreg機能を強化するが、これは、炎症部位、たとえば腫瘍および大腸炎腸粘膜において最も明らかである。Tregの安定性/可塑性の問題は非常に議論が分かれており、Tregの安定性を維持する細胞外因性刺激およびメカニズムは、依然として分かっていない8−11。FoxoファミリーメンバーがFoxp3機能を強化し、Tregのホメオスタシスおよび機能を促進することを踏まえると45、Nrp1シグナル伝達がFoxoの核局在に対するAktのマイナスの影響を相殺することは、注目に値する。実際、Foxoシグナル伝達およびNrp1シグナル伝達により誘導される転写プロファイル間には、かなりの重複が存在する45。さらに、Nrp1シグナル伝達が、細胞静止状態に関与することが知られている、いくつかのKLF(Klf2、Klf1)の発現を調節することも興味深い46。5つの転写因子(transcription factor quintet)が、Tregの転写シグニチャー「をロックインする(lock-in)」ことも最近示された4。興味深いことに、これらの転写因子の一部は、Nrp1シグナル伝達により調節される(たとえば、Ikzf2、Irf4、Gata1)ことから、Sema4aにより媒介されるNrp1ライゲーションが、このプログラムの細胞外因性レギュレーターになり得ることが示唆される。全体として、本明細書に提供される観察結果から、Sema4a:Nrp1軸は、炎症部位でのTregの安定性を維持するのに必要とされる。さらに、Nrp1:Sema4a経路は特定の病理学的または遺伝的状況下で撹乱されることがあり、これがまた、種々の正常状態および病的状態におけるTregの安定性と可塑性という見たところ相反する認識の根拠ともなり得る可能性がある。メモリーCD4+およびCD8+T細胞がNrp1を発現することが示されていることを踏まえると、Akt−mTOR活性化の制限がメモリーT細胞表現型の維持を促進し得る可能性がある(Powell et al.,Annu Rev Immunol 30,39−68(2012))。
他の実施態様
1.制御性T細胞(Treg)の機能を阻害するまたはその安定性を低下させる方法であって、前記Tregにおけるニューロピリン1(Nrp1):セマフォリン軸の阻害剤に、前記Tregを曝露することを含む方法。
2.前記Nrp1:セマフォリン軸の阻害剤は、膜貫通型セマフォリンを発現する細胞上の膜貫通型セマフォリンと、前記Treg上のNrp1との間の相互作用を阻害する、実施態様1記載の方法。
3.前記膜貫通型セマフォリンはクラスIVセマフォリンである、実施態様2記載の方法。
4.前記クラスIVセマフォリンはSema4aである、実施態様3記載の方法。
5.前記膜貫通型セマフォリンを発現する細胞は、通常型T細胞(Tconv)、通常型樹状細胞(cDC)および形質細胞様樹状細胞(pDC)からなる群より選択される、実施態様2記載の方法。
6.前記Nrp1:セマフォリン軸の阻害剤は、前記TregにおけるNrp1−VEGF相互作用に影響を与えない、実施態様1記載の方法。
7.前記Tregは被検体内にあり、前記Nrp1:セマフォリン軸の阻害剤が該被検体に投与される、実施態様1記載の方法。
8.前記被検体は癌を有する、実施態様7記載の方法。
9.前記癌はメラノーマまたは膠芽細胞腫である、実施態様8記載の方法。
10.前記被検体は、Tregが殺菌免疫(sterilizing immunity)を阻止する感染症を有する、実施態様7記載の方法。
11.前記感染症は慢性感染症である、実施態様10記載の方法。
12.前記被検体はヒトである、実施態様7記載の方法。
13.前記Nrp1:セマフォリン軸の阻害剤は抗体である、実施態様1〜12いずれか1項記載の方法。
14.前記抗体は、前記TregにおけるNrp1−VEGF相互作用に影響を与えない、実施態様13記載の方法。
15.前記Nrp1:セマフォリン軸の阻害剤はセマフォリン分子である、実施態様1〜12いずれか1項記載の方法。
16.前記セマフォリン分子は、可溶型の膜貫通型セマフォリンタンパク質またはそのフラグメントもしくは誘導体もしくはアナログであり、該可溶型の膜貫通型セマフォリンタンパク質、フラグメント、誘導体またはアナログは、TregにおいてNrp1:セマフォリン軸を増強することなく、Treg上のNrp1に高い親和性および特異性で結合することができる、実施態様15記載の方法。
17.前記膜貫通型セマフォリンはクラスIVセマフォリンである、実施態様16記載の方法。
18.前記クラスIVセマフォリンはSema4aである、実施態様17記載の方法。
19.前記セマフォリン分子は、C末端でIgG1のFc領域に融合したSema4a細胞外ドメインを含む、実施態様15記載の方法。
20.前記Nrp1:セマフォリン軸の阻害剤は、Nrp1タンパク質の可溶性細胞外ドメインまたはそのフラグメントもしくは誘導体もしくはアナログであり、該Nrp1タンパク質の可溶性細胞外ドメイン、フラグメント、誘導体またはアナログは、膜貫通型セマフォリンに高い親和性および特異性で結合し、それにより前記膜貫通型セマフォリンが前記TregにおいてNrp1:セマフォリン軸を増強するのを防止することができる、実施態様1〜12いずれか1項記載の方法。
21.前記膜貫通型セマフォリンはクラスIVセマフォリンである、実施態様20記載の方法。
22.前記クラスIVセマフォリンはSema4aである、実施態様21記載の方法。
23.前記Nrp1:セマフォリン軸の阻害剤は、前記TregにおいてNrp1タンパク質の発現を阻害する、実施態様1〜12いずれか1項記載の方法。
24.前記Nrp1:セマフォリン軸の阻害剤は、siRNAまたはアンチセンスオリゴヌクレオチドである、実施態様23記載の方法。
25.前記Nrp1:セマフォリン軸の阻害剤は、Nrp1がその下流のシグナル伝達経路に関与するのを防止する、実施態様1〜12いずれか1項記載の方法。
26.前記Nrp1:セマフォリン軸の阻害剤は小分子である、実施態様1〜12いずれか1項記載の方法。
27.制御性T細胞(Treg)の機能を強化するまたはその安定性を増加させる方法であって、前記Tregにおけるニューロピリン1(Nrp1):セマフォリン軸のアゴニストに、前記Tregを曝露することを含む方法。
28.前記Nrp1:セマフォリン軸のアゴニストは、膜貫通型セマフォリンを発現する細胞上の膜貫通型セマフォリンと、前記Treg上のNrp1との間の相互作用を強化する、実施態様27記載の方法。
29.前記膜貫通型セマフォリンはクラスIVセマフォリンである、実施態様28記載の方法。
30.前記クラスIVセマフォリンはSema4aである、実施態様29記載の方法。
31.前記膜貫通型セマフォリンを発現する細胞は、通常型T細胞(Tconv)、通常型樹状細胞(cDC)および形質細胞様樹状細胞(pDC)からなる群より選択される、実施態様28記載の方法。
32.前記Nrp1:セマフォリン軸のアゴニストは、インビトロで前記Tregに投与される、実施態様27記載の方法。
33.前記Tregは、被検体から抽出され、前記Nrp1−セマフォリン軸のアゴニストの存在下、エキソビボで増幅され、次いで(i)前記被検体に再導入されるか、あるいは(ii)別の被検体に投与される、実施態様32記載の方法。
34.前記増幅されたTregを投与される被検体は、自己免疫性疾患または炎症性疾患を有する、実施態様33記載の方法。
35.前記被検体はヒトである、実施態様33記載の方法。
36.前記Tregは被検体内にあり、前記Nrp1:セマフォリン軸のアゴニストは該被検体に投与される、実施態様27記載の方法。
37.前記被検体は、自己免疫性疾患または炎症性疾患を有する、実施態様36記載の方法。
38.前記被検体はヒトである、実施態様36記載の方法。
39.前記Nrp1:セマフォリン軸のアゴニストはセマフォリン分子である、実施態様27〜38いずれか1項記載の方法。
40.前記セマフォリン分子は多量体セマフォリン分子である、実施態様39記載の方法。
41.前記セマフォリン分子は、表面またはビーズ上に固定化されている、実施態様39記載の方法。
42.前記セマフォリン分子は、クラスIVセマフォリンまたはそのフラグメントもしくは誘導体もしくはアナログである、実施態様39記載の方法。
43.前記クラスIVセマフォリンはSema4aである、実施態様42記載の方法。
44.前記Nrp1:セマフォリン軸のアゴニストは抗体である、実施態様27〜38いずれか1項記載の方法。
45.前記Nrp1:セマフォリン軸のアゴニストは小分子である、実施態様27〜38いずれか1項記載の方法。
46.前記Nrp1:セマフォリン軸のアゴニストは、前記TregにおいてNrp1発現を高める、実施態様27〜38いずれか1項記載の方法。
47.前記Nrp1:セマフォリン軸のアゴニストは、Nrp1のその下流のシグナル伝達経路への関与を高める、実施態様27〜38いずれか1項記載の方法。
48.疾患の処置を必要とする被検体の疾患を処置する方法であって、前記被検体の制御性T細胞(Treg)におけるニューロピリン1(Nrp1):セマフォリン軸を阻害すること含む方法。
49.膜貫通型セマフォリンを発現する細胞上の膜貫通型セマフォリンと、前記被検体のTreg上のNrp1との間の相互作用を阻害することを含む、実施態様48記載の方法。
50.前記膜貫通型セマフォリンはクラスIVセマフォリンである、実施態様49記載の方法。
51.前記クラスIVセマフォリンはSema4aである、実施態様50記載の方法。
52.前記膜貫通型セマフォリンを発現する細胞は、通常型T細胞(Tconv)、通常型樹状細胞(cDC)および形質細胞様樹状細胞(pDC)からなる群より選択される、実施態様49記載の方法。
53.前記疾患は癌である、実施態様48記載の方法。
54.前記癌は、メラノーマまたは膠芽細胞腫である、実施態様53記載の方法。
55.前記疾患は、Tregが殺菌免疫を阻止する感染症である、実施態様48記載の方法。
56.前記感染症は慢性感染症である、実施態様55記載の方法。
57.前記被検体はヒトである、実施態様48記載の方法。
58.前記被検体のTregにおけるニューロピリン1(Nrp1):セマフォリン軸の阻害剤の治療有効量を、前記被検体に投与することを含む、実施態様48〜57いずれか1項記載の方法。
59.前記Nrp1:セマフォリン軸の阻害剤は抗体である、実施態様58記載の方法。
60.前記抗体は、前記被検体のTregにおけるNrp1−VEGF相互作用に影響を与えない、実施態様59記載の方法。
61.前記Nrp1:セマフォリン軸の阻害剤はセマフォリン分子である、実施態様58記載の方法。
62.前記セマフォリン分子は、可溶型の膜貫通型セマフォリンタンパク質またはそのフラグメントもしくは誘導体もしくはアナログであり、該可溶型の膜貫通型セマフォリンタンパク質、フラグメント、誘導体またはアナログは、前記TregにおけるNrp1:セマフォリン軸を増強することなく、Treg上のNrp1に高い親和性および特異性で結合することができる、実施態様61記載の方法。
63.前記膜貫通型セマフォリンはクラスIVセマフォリンである、実施態様62記載の方法。
64.前記クラスIVセマフォリンはSema4aである、実施態様63記載の方法。
65.前記セマフォリン分子は、C末端でIgG1のFc領域に融合したSema4a細胞外ドメインを含む、実施態様61記載の方法。
66.前記Nrp1:セマフォリン軸の阻害剤は、Nrp1タンパク質の可溶性細胞外ドメインまたはそのフラグメントもしくは誘導体もしくはアナログであり、該Nrp1タンパク質の可溶性細胞外ドメイン、フラグメント、誘導体またはアナログは、膜貫通型セマフォリンに高い親和性および特異性で結合することができ、それにより前記膜貫通型セマフォリンが前記被検体のTregにおいてNrp1:セマフォリン軸を増強することを妨げる、実施態様58記載の方法。
67.前記膜貫通型セマフォリンはクラスIVセマフォリンである、実施態様66記載の方法。
68.前記クラスIVセマフォリンはSema4aである、実施態様67記載の方法。
69.前記Nrp1:セマフォリン軸の阻害剤は、前記被検体のTregにおいてNrp1タンパク質の発現を阻害する、実施態様58記載の方法。
70.前記Nrp1:セマフォリン軸の阻害剤は、siRNAまたはアンチセンスオリゴヌクレオチドである、実施態様69記載の方法。
71.前記Nrp1:セマフォリン軸の阻害剤は、Nrp1がその下流のシグナル伝達経路に関与するのを防止する、実施態様58記載の方法。
72.前記Nrp1:セマフォリン軸の阻害剤は小分子である、実施態様58記載の方法。
73.追加の免疫調節治療を前記被検体に行うことをさらに含む、実施態様58記載の方法。
74.前記追加の免疫調節治療は、治療ワクチン、チェックポイント阻害剤またはアクチベーターを投与することを含む、実施態様73記載の方法。
75.化学療法または放射線療法を前記被検体に行うことをさらに含む、実施態様53記載の方法。
76.抗生物質を前記被検体に投与することをさらに含む、実施態様55記載の方法。
77.疾患の処置を必要とする被検体の疾患を処置する方法であって、前記被検体の制御性T細胞(Treg)においてニューロピリン1(Nrp1):セマフォリン軸を活性化することを含む方法。
78.膜貫通型セマフォリンを発現する細胞上の膜貫通型セマフォリンと、前記被検体のTreg上のNrp1との間の相互作用を強化することを含む、実施態様77記載の方法。
79.前記膜貫通型セマフォリンはクラスIVセマフォリンである、実施態様78記載の方法。
80.前記クラスIVセマフォリンはSema4aである、実施態様79記載の方法。
81.前記膜貫通型セマフォリンを発現する細胞は、通常型T細胞(Tconv)、通常型樹状細胞(cDC)および形質細胞様樹状細胞(pDC)からなる群より選択される、実施態様78記載の方法。
82.前記被検体は、自己免疫性疾患または炎症性疾患を有する、実施態様77記載の方法。
83.前記被検体はヒトである、実施態様77記載の方法。
84.前記被検体のTregにおけるニューロピリン1(Nrp1):セマフォリン軸のアゴニストの治療有効量を、前記被検体に投与することを含む、実施態様77〜83いずれか1項記載の方法。
85.前記Nrp1:セマフォリン軸のアゴニストはセマフォリン分子である、実施態様84記載の方法。
86.前記セマフォリン分子は多量体セマフォリン分子である、実施態様85記載の方法。
87.前記セマフォリン分子は、表面またはビーズ上に固定化されている、実施態様85記載の方法。
88.前記セマフォリン分子は、クラスIVセマフォリンまたはそのフラグメントもしくは誘導体もしくはアナログである、実施態様85記載の方法。
89.前記クラスIVセマフォリンはSema4aである、実施態様88記載の方法。
90.前記Nrp1:セマフォリン軸のアゴニストは抗体である、実施態様84記載の方法。
91.前記Nrp1:セマフォリン軸のアゴニストは小分子である、実施態様84記載の方法。
92.前記Nrp1:セマフォリン軸のアゴニストは、前記被検体のTregにおいてNrp1発現を高める、実施態様84記載の方法。
93.前記Nrp1:セマフォリン軸のアゴニストは、Nrp1のその下流のシグナル伝達経路への関与を高める、実施態様84記載の方法。
94.Tregを強化するまたは炎症を阻止する別の治療を前記被検体に行うことをさらに含む、実施態様84記載の方法。
95.被検体におけるワクチンの有効性を高めるための方法であって、前記被検体のTregにおけるニューロピリン1(Nrp1):セマフォリン軸の阻害剤の有効量を前記被検体に投与することを含む方法。
96.前記Nrp1:セマフォリン軸の阻害剤は抗体である、実施態様95記載の方法。
97.前記抗体は、前記被検体のTregにおけるNrp1−VEGF相互作用に影響を与えない、実施態様96記載の方法。
98.前記Nrp1:セマフォリン軸の阻害剤はセマフォリン分子である、実施態様95記載の方法。
99.前記セマフォリン分子は、可溶型の膜貫通型セマフォリンタンパク質またはそのフラグメントもしくは誘導体もしくはアナログであり、該可溶型の膜貫通型セマフォリンタンパク質、フラグメント、誘導体またはアナログは、前記TregにおけるNrp1:セマフォリン軸を増強することなく、Treg上のNrp1に高い親和性および特異性で結合することができる、実施態様98記載の方法。
100.前記膜貫通型セマフォリンはクラスIVセマフォリンである、実施態様99記載の方法。
101.前記クラスIVセマフォリンはSema4aである、実施態様100記載の方法。
102.前記セマフォリン分子は、C末端でIgG1のFc領域に融合したSema4a細胞外ドメインを含む、実施態様98記載の方法。
103.前記Nrp1:セマフォリン軸の阻害剤は、Nrp1タンパク質の可溶性細胞外ドメインまたはそのフラグメントもしくは誘導体もしくはアナログであり、該Nrp1タンパク質の可溶性細胞外ドメイン、フラグメント、誘導体またはアナログは、膜貫通型セマフォリンに高い親和性および特異性で結合することができ、それにより前記膜貫通型セマフォリンが前記被検体のTregにおいてNrp1:セマフォリン軸を増強することを妨げる、実施態様95記載の方法。
104.前記膜貫通型セマフォリンはクラスIVセマフォリンである、実施態様103記載の方法。
105.前記クラスIVセマフォリンはSema4aである、実施態様104記載の方法。
106.前記Nrp1:セマフォリン軸の阻害剤は、前記被検体のTregにおいてNrp1タンパク質の発現を阻害する、実施態様95記載の方法。
107.前記Nrp1:セマフォリン軸の阻害剤は、siRNAまたはアンチセンスオリゴヌクレオチドである、実施態様106記載の方法。
108.前記Nrp1:セマフォリン軸の阻害剤は、Nrp1がその下流のシグナル伝達経路に関与するのを防止する、実施態様95記載の方法。
109.前記Nrp1:セマフォリン軸の阻害剤は小分子である、実施態様95記載の方法。
110.前記被検体はヒトである、実施態様95記載の方法。
111.前記ワクチンは、癌または感染症の処置または予防用である、実施態様95記載の方法。
112.前記Nrp1:セマフォリン軸の阻害剤は、前記ワクチンが前記被検体に投与される前に前記被検体に投与される、実施態様95記載の方法。
113.前記Nrp1:セマフォリン軸の阻害剤は、前記ワクチンと一緒に前記被検体に投与される、実施態様95記載の方法。
114.制御性T細胞(Treg)上のニューロピリン1(Nrp1):セマフォリン相互作用を阻害する単離抗体。
115.前記セマフォリンはクラスIVセマフォリンである、実施態様114記載の抗体。
116.前記クラスIVセマフォリンはSema4aである、実施態様115記載の抗体。
Claims (11)
- 制御性T細胞(Treg)の機能を阻害するまたはその安定性を低下させることによってヒト対象における癌または感染症の治療するための医薬組成物であって、(i)セマフォリンを発現している細胞上の膜貫通型セマフォリンと(ii)制御性T細胞上のニューロピリン−1との間の相互作用を阻害する抗ニューロピリン−1抗体またはその抗原結合フラグメントを有効成分として含む、医薬組成物。
- 前記対象における免疫ホメオスタシスを維持しつつ前記制御性T細胞の機能を阻害するまたはその安定性を低下させる、請求項1に記載の医薬組成物。
- 制御性T細胞の機能を阻害するまたはその安定性を低下させることによってヒト対象におけるワクチンの効果を高めるための医薬組成物であって、膜貫通型セマフォリンと制御性T細胞上のニューロピリン−1との間の相互作用を阻害する抗ニューロピリン−1抗体またはその抗原結合フラグメントを有効成分として含む、医薬組成物。
- 免疫ホメオスタシスを維持しつつ対象におけるワクチンの効果が高められる、請求項3に記載の医薬組成物。
- 前記ワクチンが、癌または感染症の治療または予防のためのものであり、前記抗体またはフラグメントが前記ワクチンが投与される前または前記ワクチンとともに前記対象に投与される、請求項3または4に記載の医薬組成物。
- 前記セマフォリンが、クラスIV膜貫通型セマフォリンまたはセマフォリン−4aである、請求項1〜5のいずれかに記載の医薬組成物。
- 前記抗ニューロピリン−1抗体またはその抗原結合フラグメントが、前記Tregにおけるニューロピリン−1:血管内皮増殖因子(VEGF)相互作用に影響しない、請求項1〜6のいずれかに記載の医薬組成物
- 前記抗ニューロピリン−1抗体またはその抗原結合フラグメントが、Tregにおけるニューロピリン−1:クラスIIIセマフォリン相互作用に影響を与えない、請求項1〜7のいずれかに記載の医薬組成物。
- 前記セマフォリンが、通常型T細胞(Tconv)、通常型樹状細胞(cDC)または形質細胞様樹状細胞(pDC)により発現される、請求項1〜8のいずれかに記載の医薬組成物。
- 前記抗体が、モノクロナール抗体、ヒト化抗体、またはヒト抗体である、請求項1〜9のいずれかに記載の医薬組成物。
- 前記抗ニューロピリン−1抗体またはその抗原結合フラグメントを、対象に投与した時ニューロピリン−1と前記セマフォリンとの間の相互作用を阻害するのに有効な量で含む、請求項1〜10のいずれかに記載の医薬組成物。
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AU2018228501A1 (en) | 2018-09-27 |
EP2903692A2 (en) | 2015-08-12 |
US9540439B2 (en) | 2017-01-10 |
AU2018228501B2 (en) | 2021-07-22 |
AU2013329372A1 (en) | 2015-04-02 |
JP2018172436A (ja) | 2018-11-08 |
WO2014058915A2 (en) | 2014-04-17 |
AU2013329372B2 (en) | 2018-07-12 |
ES2776029T3 (es) | 2020-07-28 |
EP2903692B1 (en) | 2019-12-25 |
EP2903692A4 (en) | 2016-06-08 |
US20150266959A1 (en) | 2015-09-24 |
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