JP2017507931A - がん及び感染症の治療方法並びに治療用組成物 - Google Patents
がん及び感染症の治療方法並びに治療用組成物 Download PDFInfo
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Abstract
Description
本書に引用したすべての参考文献は、完全に説明されたものとして、参照することによりそれらが全体として組み込まれる。別段の定義のない限り、本書で用いた技術的及び科学的用語は、本発明が属する当業者によって通常理解されるものと同じ意味を有する。Allen et al.,Remington:The Science and Practice of Pharmacy 22nd ed.,Pharmaceutical Press (September 15,2012);Hornyak et al.,Introduction to Nanoscience and Nanotechnology,CRC Press (2008);Singleton and Sainsbury,Dictionary of Microbiology and Molecular Biology 3rd ed.,revised ed.,J. Wiley & Sons(New York,NY 2006);Smith, March's Advanced Organic Chemistry Reactions,Mechanisms and Structure 7th ed.,J. Wiley & Sons(New York,NY 2013);Singleton,Dictionary of DNA and Genome Technology 3rd ed.,Wiley−Blackwell(November 28, 2012);及び、Green and Sambrook, Molecular Cloning:A Laboratory Manual 4th ed.,Cold Spring Harbor Laboratory Press (Cold Spring Harbor, NY 2012)は、本出願に用いた用語の多くへの一般的な指針を当業者に与える。抗体の製造方法の参照用には、Greenfield,Antibodies A Laboratory Manual 2nd ed.,Cold Spring Harbor Press(Cold Spring Harbor NY,2013);Kohler and Milstein,Derivation of specific antibody−producing tissue culture and tumor lines by cell fusion,Eur. J. Immunol.1976 Jul,6(7):511−9;Queen and Selick,Humanized immunoglobulins,U.S.Patent No.5,585,089(1996 Dec);及びRiechmann et al.,Reshaping human antibodies for therapy,Nature 1988 Mar 24,332(6162):323−7を参照されたい。
様々な実施形態において、本発明は、対象の疾患を治療し、予防し、その重篤度を軽減し、及び/またはその進行を遅延させる方法を提供する。該方法は、CD4リンパ球除去剤を含む組成物を与えること、並びに治療有効量の該組成物を該対象に投与することによって該対象の該疾患を治療し、予防し、その重篤度を軽減し、及び/またはその進行を遅延させることを含む。いくつかの実施形態では、該疾患はがんまたは感染症である。いくつかの実施形態では、該対象はがんと診断されている。いくつかの実施形態では、該対象は、感染症と診断されている。様々な実施形態において、該対象は、CD4リンパ球除去剤を含む該組成物の投与の前に、免疫系を準備するのに十分長い期間疾病に罹患している。様々な実施形態において、該対象の罹患期間は、1日以上、2日以上、3日以上、4日以上、5日以上、6日以上、7日以上、8日以上、9日以上、10日以上、15日以上、20日以上、1か月以上、2か月以上、3か月以上、4か月以上、5か月以上、6か月以上、1年以上、またはこれらの組合せである。
様々な実施形態において、本発明は、CD4リンパ球除去剤を含む組成物を提供する。様々な実施形態において、本発明は、免疫チェックポイント阻害薬、養子免疫治療剤、免疫アジュバント、及び免疫調節剤のうちの少なくとも1つを含む組成物を提供する。免疫チェックポイント阻害薬、養子免疫治療剤、免疫アジュバント、及び免疫調節剤の例を本書に記載する。様々な実施形態において、CD4リンパ球除去剤を含む組成物と追加薬剤を含む組成物は、2つの別々の組成物である。
様々な実施形態において、本発明は、対象の疾患の治療、予防、その重篤度の軽減、及び/またはその進行の遅延用のキットを提供する。該キットは、CD4リンパ球除去剤を含む組成物、並びに該対象の該疾患を治療し、予防し、その重篤度を軽減し、及び/またはその進行を遅延させるための該組成物の使用説明書を含む。
いくつかの実施形態において、請求項にかかる方法、組成物、及び/またはキットにおける該CD4リンパ球除去剤の有効量は、約100〜200mg/日、200〜300mg/日、300〜400mg/日、400〜500mg/日、500〜600mg/日、600〜700mg/日、700〜800mg/日、800〜900mg/日、900〜1000mg/日、1000〜1100mg/日、1100〜1200mg/日、1200〜1300mg/日、1300〜1400mg/日、1400〜1500mg/日、1500〜1600mg/日、1600〜1700mg/日、1700〜1800mg/日、1800〜1900mg/日、または1900〜2000mg/日の範囲でありうる。本発明の1つの実施形態では、該CD4リンパ球除去剤は、ヒト化抗CD4抗体(例えば、ザノリムマブ)である。
マウス及び腫瘍細胞
6〜8週齢、雌のC57BL/6J、BALB/cマウス及びPmel−1マウスをJackson研究所(メイン州バーハーバー)から入手し、無菌状態で飼育した。FoxP3−GFP遺伝子導入マウスは、マウスFoxp3(フォークヘッドボックスP3)プロモーターの支配下で緑色蛍光タンパク質を発現する。DEREG(制御性T細胞除去)遺伝子導入マウスは、T.S.Lahl K,Loddenkemper C,Drouin C,Freyer J,Arnason J,Eberl G, et al.J Exp Med.2007;204:57−63によって生成、記載された。動物を使ったすべての実験は、連邦動物福祉法並びに実験動物の管理及び利用に関するNIH指針を含む、連邦及び州の基準に準拠して行われた。
蛍光複合体を伴うまたは伴わない、以下のモノクローナル抗体(mAb)を、Biolegend(サンディエゴ)から入手した。抗CD4(GK1.5及びRM4−5)、抗CD8(53−6.7)、抗CD16/CD32(9.3)、抗CD90.1(OX−7)、抗CD11c(N418)、抗Bcl2(BCL/10C4)、抗T−bet(4B10)、抗CD62L(MEL−14)、抗CD279(PD−1、29F.1A12)、抗FoxP3(FJK−16s)、抗IFN−γ(XMG1.2)、抗IL−2(JES6.5H4)、抗IL−4(11B11)、IL−17A(eBio1787)。CellTrace 5−(及び6−)カルボキシフルオレセインジアセテートスクシンイミジルエステル(CFSE)細胞増殖キットは、Molecular Probes(オレゴン州ユージーン)より入手した。テムシロリムスは、LC Laboratory(マサチューセッツ州ウォバーン)より入手した。
マウスの脾臓及びリンパ節を採取し、単細胞懸濁液に加工処理した。CD8及びCD4T細胞は、マウスCD8またはCD4回収カラムキット(Cedarlane Labs、ノースカロライナ州バーリントン)を用いてネガティブ濃縮した。ネガティブ選択の後のCD8及びCD4細胞の純度は、85%を超えた。FoxP3−GFP細胞または抗体染色CD4+CD25+細胞は、MoFlo Cell Sorter(コロラド州フォートコリンズ)で選別した。
DCの製造は、説明されている(Wang Y,Wang XY,Subjeck JR,Shrikant PA,Kim HL.Br J Cancer.2011;104:643−52)。簡潔に言えば、マウスの骨髄を大腿骨及び脛骨から採取し、その後、12ウェルのプレートに、ウェル当たり1x106の細胞密度で、10%FBS及び10ng/mlのマウスGM−CSFとともに入れた。該細胞は2日おきに供給され、7〜9日後に採取された。75〜90%の細胞がCD11c陽性であった。マウス処置用のDCワクチンの製造のため、DCを腫瘍細胞溶解物でパルスし、10ug/mlのCpGで活性化した。DCをマウスに皮下注射した。Pmel−1細胞のインビトロ活性化のため、DCを10ng/mlのマウスgp100ペプチド(アミノ酸25〜33、H2−DbクラスI分子によって作り出される。Alpha Diagnostic International、テキサス州サンアントニオ)でパルスし、10ug/mlのCpGで2時間活性化した。DCはPBSで洗浄し、CFSEで標識化したPmel−1細胞とともに共培養した。Pmel−1細胞の増殖は、FACscanで分析した。
Pmel−1リンパ球は、未感作Pmel−1マウスのリンパ節及び脾臓から単離した。CD8リンパ球は、Cedarlane精製カラムを用いて、ネガティブ選択により濃縮した。得られた細胞の少なくとも85%がCD8+であった。5x105の細胞をB57BL/6マウスに移入した。養子移入の翌日、マウスは腫瘍溶解物でパルスしたDCワクチンを投与された。CD4細胞を除去するため、αCD4をおよそ7日後及び9日後に投与した;マウスに250ugのCD4mAb(クローンGK1.5)を腹腔内投与した。CD8細胞を除去するため、マウスは250ugのCD8mAb(クローン2.43)を投与された。DEREGマウスのFoxP3細胞を除去するため、5μgのDTを注射した。フローサイトメトリーを用いて、標的細胞の除去を確認した。mTor阻害剤処置については、2週間毎日、15μgのテムシロリムスを腹腔内注射した。フローサイトメトリーを用いて、記憶細胞及びTreg細胞を分析した。
生体内CTL分析は、説明されている(Wang Y,Wang XY,Subjeck JR,Shrikant PA,Kim HL.Br J Cancer.2011;104:643−52)。簡潔に言えば、脾細胞の単細胞懸濁液(1x107細胞/ml)を未感作マウスから得、FBS10%を含むDMEM中、10μMのペプチドを用いてまたは用いずに、37℃で30分間パルスした。各細胞集団は、次に異なる濃度のCFSE(0.5または12.5μM)により、2x107細胞/mlにて、PBS/0.1%BSA中で標識化した。CFSEによる標識化は、等体積のFBSを1分間添加することにより停止し、RPMI完全培地で3回洗浄した。ペプチドでパルスした、またはパルスしていない集団の各々から5x106の細胞を混合し、免疫化及び免疫化されていないマウスに静脈注射した。移入の16時間後、マウスを殺処分し、脾細胞を採取した。脾細胞の単細胞懸濁液を調製し、フローサイトメトリーで分析した。蛍光ドナー脾細胞の特異的溶解割合は次の通りに算出した:[(パルスされていない標的数×A−パルスされた標的数)/パルスされていない標的数×A]×100、ただし、A=免疫化されていないレシピエントマウスにおける[パルスされた標的数/パルスされていない標的数]。
腫瘍増殖の違いは、反復測定ANOVAを用いて評価した。肺転移の数、生体内CTL殺滅率、及びフローサイトメトリーからの平均割合の統計的差異は、両側スチューデントT検定によって評価した。すべての統計的分析は、Stata8.0(StataCorp、テキサス州カレッジステーション)を用いて行った。P値<0.05を有意と見なした。
動物モデルでは、薬理学的mTOR阻害は、免疫記憶の形成を促進することができ、これは、感染の除去及び腫瘍増殖の減少に役立つ。これは、mTOR阻害剤が、固形臓器移植を受けた患者の免疫系を抑制するのに使われることから、驚くべき発見であった。テムシロリムスは、ラパマイシンアナログであり、がん治療として米国食品医薬品局(FDA)によって認可された最初のmTOR阻害剤の1つである。本発明者らの前臨床モデルでは、テムシロリムスでのmTOR阻害は、腫瘍溶解物でパルスしたDC(ここではDCワクチンと言う)の抗腫瘍免疫を高めた(図1a)。テムシロリムスは、腫瘍の一部の成長を直接阻害することができ、そのため、テムシロリムスの免疫効果を評価するために腫瘍予防研究が行われた。腫瘍投与試験の13日前にDCワクチン及びテムシロリムスを投与することによって、直接の抗腫瘍効果が存在する可能性はなく、免疫刺激が全ての腫瘍増殖減少に起因しうると考えられる。DCワクチンのみの投与は、マウスのB16腫瘍細胞の増殖を減少させたが、ほとんどのマウスは、結局腫瘍増殖のために死亡した。対照的に、DCワクチンとテムシロリムスの組合せは、100%の生存という結果をもたらし、B16腫瘍細胞の増殖を完全に抑えた。
テムシロリムスは、Tregの増加にもかかわらず、正味の抗腫瘍免疫反応を引き起こした。さらに、腫瘍の存在自体が、Tregを増加させた(図8)。従って、本発明者らは、mTOR阻害によって誘導された抗腫瘍免疫は、Tregを標的にすることによってさらに高められうるという仮説を立てた。現在のところ、Tregを選択的に除去する臨床戦略はないが、すべてのCD4リンパ球を除去することは可能である。しかしながら、CD4エフェクター細胞は、免疫活性化に必要である。従って、本発明者らのマウスモデルでは、CD4リンパ球を、注入された腫瘍による免疫刺激の6日後から、αCD4抗体(αCD4)で除去し始めた(図2)。図1は、黒色腫のマウスモデルでの結果を示す。本発明者らは、別の古典的な免疫感受性腫瘍である胃細胞がんの第二のモデルでこの手法を試験した。腫瘍処置モデルでは、触知可能なRENCA腫瘍がBalb/cマウスで認められた。テムシロリムスは、RENCA腫瘍細胞の増殖をインビトロで直接阻害することが示されており(Wang Y,Wang XY,Subjeck JR,Shrikant PA,Kim HL.Br J Cancer.2011;104:643−52)、本発明者らのマウスモデルでの腫瘍増殖の減少にも有効であった(図2a)。αCD4単独では効果がなかったが、テムシロリムス処置にαCD4を追加すると、腫瘍増殖をさらに減少させた。興味深いことに、がんワクチンを使用せず、注入された腫瘍が唯一の特異的免疫刺激源であった場合でさえ、αCD4とテムシロリムスの組合せは腫瘍増殖を減少させた。
テムシロリムスは直接の抗腫瘍効果を有しうるため、αCD4とテムシロリムスの組合せが、CD8リンパ球に依存する有効な抗腫瘍免疫を作り出していたことを確証することが重要であった。RENCA腫瘍を担うBalb/cマウスは、テムシロリムス単独で10日間処置され、その後第二のRENCA腫瘍で投与試験された(図3a)。CD8エフェクター細胞を除去するためにαCD8抗体(αCD8)を注射されたマウスは、該第二のRENCA腫瘍の増殖を増加させ、このことは、テムシロリムス単独でさえ、免疫反応を刺激することで、少なくとも部分的に作用することを示した。テムシロリムスとαCD4の組合せは、第二のRENCA腫瘍の増殖を完全に予防したが、αCD8は、該第二の腫瘍に対する抗腫瘍効果を除去し、このことは、腫瘍制御にとっての細胞性免疫の重要性を示した(図3b)。
テムシロリムスが腫瘍増殖を阻害する重要な機構は、特異的CD8記憶の質を高めることである。従って、本発明者らは、αCD4が、さらに、mTOR阻害の存在下で形成された特異的CD8記憶を高めるかどうかを評価することを目的に、CD8記憶細胞の質を特徴決定した。担がんマウスの実験期間が、コントロール群での急速な腫瘍増殖のために限られることから、本発明者らは、腫瘍自体ではなく、DCワクチンが免疫応答を刺激したモデルを用いた。DCワクチンを用いることで、リコール反応を含めて、長期記憶が評価できる。Thy1.1 Pmel−1リンパ球をB6マウスに養子移入し、これらマウスはその後B16−DCワクチンを投与され、αCD4とテムシロリムスで処置された(図4a)。
本発明者らの元の仮説は、テムシロリムスによって正常に誘導されたTregの除去は、抗腫瘍免疫を高めるであろうということであった。CD4除去が患者で実行可能なため、本発明者らは、Treg除去の方法として、CD4除去を選んだ。しかしながら、本発明者らは、CD4除去の影響が、Tregの除去に直接起因しうるかどうかを試したかった。従って、本発明者らは、DEREG(制御性T細胞除去)形質導入マウスを用いたが、これらマウスは、Foxp3プロモーターの支配下でDTR−eGFPを担い、ジフテリア毒素(DT)の投与によって、特異的なTregの除去を可能にする(Lahl K,Loddenkemper C,Drouin C,Freyer J,Arnason J,Eberl G,et al.J Exp Med.2007;204:57−63.)。図2に示したものと類似の実験で、αCD4の代わりに、DTを6日目と10日目に投与した(図5a)。免疫系をDCワクチンで刺激し、特異的免疫記憶を35日目に生体内CTLで評価した(図5c)。DTの投与は、ほぼすべてのCD4+FoxP3+リンパ球を除去した(図5b)。コントロール群と比較した場合、特異的殺滅は、DT及びテムシロリムスで処置されたマウスで有意に増加した(図5c、右端のパネル)。従って、Tregの除去はCD4除去と同様の免疫効果を示した。
DCワクチン、αCD4、及びテムシロリムスでの処置後、Treg集団は最終的に回復する(図7a)。実験群間で、脾臓におけるTregの絶対数の差は統計的に有意ではなかった。しかしながら、該処置はTreg機能に長期的な影響をもたらした可能性がある。従って、本発明者らは、回復したTregの免疫抑制機能を評価した。CD4リンパ球は、CD25の状態によって分類した(図7b)。CD4+CD25+細胞の大部分はFoxP3陽性であったのでTregと見なされ、CD4+CD25−細胞の大部分はFoxP3陰性であったのでCD4エフェクター細胞と見なされた。機能的研究において、コントロールのCD4+CD25+細胞はCD8リンパ球の増殖を抑制した。しかしながら、CD4除去後に回復したCD4+CD25+は、おそらくそれらが腫瘍特異的Tregである可能性が低いため、免疫抑制性が低かった(図7d)。興味深いことに、IFNγ及びIL4分泌が低いことで示される通り、CD4除去後、回復したCD4エフェクター細胞も効果が弱かった(図7c)。CD4エフェクター細胞及びTregの両方が腫瘍特異的である可能性が低かったと考えられる。
B16腫瘍細胞を、FoxP3プロモーターの下でジフテリア毒素受容体を発現するように操作されたB6マウスであるDREGマウスに注入した。マウスは、2日目に腫瘍溶解物でパルスしたDCワクチンを投与された。Tregは、ジフテリア毒素で特異的に除去し、CD4細胞は6日目と10日目にαCD4抗体で除去した。腫瘍増殖を観察した。*p=0.05、**p=0.0009。図11に示すように、CD4リンパ球除去とDCワクチンの組合せは、DCワクチンのみの場合と比べて、抗腫瘍効果を高める。
B16腫瘍細胞をB6マウスに注入した。0日目。CD4細胞は、6日目と10日目にαCD4抗体で除去した。マウスは、10日目と24日目にαPD−1抗体で処置した。腫瘍増殖を観察した。*p=0.02。図12に示すように、CD4リンパ球除去と抗PD−1抗体の組合せは、抗PD−1抗体のみの場合と比べて、抗腫瘍効果を高める。
RENCA−CA9腫瘍細胞を0日目にBalb/Cマウス(n=5/群)に注入した。CD4リンパ球は、6日目と10日目にαCD4抗体で除去した(図13A)。45日目にリンパ球を採取し、CA9ペプチドで再刺激し、CD8及びIFNγについて染色した。結果は、2つ組の実験の代表例である(図13B)。インビトロCTL分析用に、脾細胞を45日目に採取し、IL2、RENCA溶解物、及びCA9ペプチドとともに培養した。標的細胞はRENCA細胞をCFSEで標識化して得た。エフェクター及び標的細胞は、50:1の比率で共培養し、7−AAD陽性でアネキシンV陰性のCFSE+細胞の割合についてFACSで分析した(図13C)。ヒストグラムは平均+SEMを示す。*p<0.05。B16腫瘍増殖曲線は、抗CD4抗体が抗腫瘍効果を有することを示す(図13D)。図13に示すように、CD4除去は、腫瘍抗原の存在下で活性化及び腫瘍細胞の殺滅が可能な腫瘍特異的CD8細胞を製造する。
B16腫瘍細胞を0日目にB6マウス(n=5/群)の脇腹に皮下注射した。マウスは、3日目に腫瘍溶解物でパルスしたDCワクチンを投与され、6日目と9日目にCD4リンパ球除去(抗CD4抗体を用いて)を行った。テムシロリムスを9日目から20日目まで毎日腹腔内注射した。B16腫瘍細胞曲線をSEMとともに示す。**p<0.001。図14に示すように、CD4リンパ球除去剤、樹状細胞ワクチン、及びmTOR阻害剤(テムシロリムス)の組合せは、腫瘍増殖を効果的に制御した。
Claims (33)
- 疾患の治療、予防、その重篤度の軽減、及び/またはその進行の遅延を必要とする対象の疾患を治療し、予防し、その重篤度を軽減し、及び/またはその進行を遅延させる方法であって、
CD4リンパ球除去剤を与えること;
免疫チェックポイント阻害薬、養子免疫治療剤、免疫アジュバント、及び免疫調節剤からなる群から選ばれた少なくとも1つの追加薬剤を与えること;並びに、
治療有効量の前記CD4リンパ球除去剤及び前記追加薬剤を前記対象に投与することによって、前記対象の前記疾患を治療し、予防し、その重篤度を軽減し、及び/またはその進行を遅延させること
を含む、前記方法。 - 対象の疾患を治療し、予防し、その重篤度を軽減し、及び/またはその進行を遅延させる方法であって、
CD4リンパ球除去剤を含む組成物を与えること;並びに、
治療有効量の前記組成物を前記対象に投与することによって、前記対象の前記疾患を治療し、予防し、その重篤度を軽減し、及び/またはその進行を遅延させることを含む、前記方法。 - 前記疾患が、感染症またはがんである、請求項1または2に記載の方法。
- 前記がんが、腎臓がん、黒色腫、前立腺がん、乳がん、膠芽細胞腫、肺がん、結腸がん、または膀胱がんである、請求項3に記載の方法。
- 前記対象がヒトである、請求項2または1に記載の方法。
- 前記対象が、がんまたは感染症と診断されたことがある、請求項2に記載の方法。
- 前記CD4リンパ球除去剤が、小分子、ペプチド、抗体もしくはその断片、及び核酸分子からなる群から選ばれる、請求項2または1に記載の方法。
- 前記CD4リンパ球除去剤が、モノクローナル抗体もしくはその断片、ポリクローナル抗体もしくはその断片、キメラ抗体、ヒト化抗体、ヒト抗体もしくはその断片、または一本鎖抗体である、請求項2または1に記載の方法。
- 前記CD4リンパ球除去剤が、ヒト化抗CD4抗体である、請求項2または1に記載の方法。
- 前記CD4リンパ球除去剤が、ザノリムマブである、請求項2または1に記載の方法。
- 前記CD4リンパ球除去剤が、100〜200mg/日、200〜300mg/日、300〜400mg/日、400〜500mg/日、500〜600mg/日、600〜700mg/日、700〜800mg/日、800〜900mg/日、900〜1000mg/日、1000〜1100mg/日、1100〜1200mg/日、1200〜1300mg/日、1300〜1400mg/日、1400〜1500mg/日、1500〜1600mg/日、1600〜1700mg/日、1700〜1800mg/日、1800〜1900mg/日、または1900〜2000mg/日で投与される、請求項2または1に記載の方法。
- 養子免疫治療薬が、樹状細胞ワクチンである、請求項1または2に記載の方法。
- 前記免疫チェックポイント阻害薬が、抗PD1抗体である、請求項1または2に記載の方法。
- 前記組成物が、mTOR阻害剤をさらに含む、請求項1または2に記載の方法。
- 前記組成物が、静脈内に、筋肉内に、皮下に、腹腔内に、経口に、または吸入を介して投与される、請求項2または1に記載の方法。
- 前記CD4リンパ球除去剤及び前記追加薬剤が同時に投与される、請求項1に記載の方法。
- 前記CD4リンパ球除去剤が、前記追加薬剤の投与前、投与中、または投与後に投与される、請求項1に記載の方法。
- 前記追加薬剤が、0.1〜0.5mg/日、0.5〜1.0mg/日、1.0〜1.5mg/日、1.5〜2.0mg/日、2.0〜2.5mg/日、2.5〜5mg/日、5〜10mg/日、10〜15mg/日、15〜20mg/日、20〜25mg/日、25〜30mg/日、30〜35mg/日、35〜40mg/日、40〜45mg/日、45〜50mg/日、50〜55mg/日、55〜60mg/日、60〜65mg/日、65〜70mg/日、70〜75mg/日、75〜80mg/日、80〜85mg/日、85〜90mg/日、90〜95mg/日、または95〜100mg/日で投与される、請求項1に記載の方法。
- 前記追加薬剤が、免疫チェックポイント阻害薬である、請求項1に記載の方法。
- 前記免疫チェックポイント阻害薬が、PD−1に対する抗体、PD−L1に対する抗体、PD−L2に対する抗体、CTLA−4に対する抗体、KIRに対する抗体、IDO1に対する抗体、IDO2に対する抗体、TIM−3に対する抗体、LAG−3に対する抗体、OX40Rに対する抗体、及びPSに対する抗体、またはこれらの組合せからなる群から選ばれる、請求項19に記載の方法。
- 前記追加薬剤が養子免疫治療剤である、請求項1に記載の方法。
- 前記養子免疫治療剤が、樹状細胞ワクチン、ペプチドワクチン、キメラT細胞抗原系療法、免疫サイトカイン、熱ショックタンパク質系ワクチン、腫瘍溶解物系ワクチン、腫瘍抗原を含有するウイルスベクター、ウイルスワクチン、細菌ワクチン、及び真菌ワクチン、またはこれらの組合せからなる群から選ばれる、請求項21に記載の方法。
- 前記追加薬剤が、免疫アジュバントである、請求項1に記載の方法。
- 前記免疫アジュバントが、アルミニウム塩、ビロソーム、及び油性アジュバント、またはこれらの組合せからなる群から選ばれる、請求項23に記載の方法。
- 前記追加薬剤が、免疫調節剤である、請求項1に記載の方法。
- 前記免疫調節剤が、mTOR阻害剤、STAT阻害剤、TGFβ受容体阻害剤、及びチロシンキナーゼ阻害剤、またはこれらの組合せからなる群から選ばれる、請求項25に記載の方法。
- 前記mTOR阻害剤が、小分子、ペプチド、抗体またはその断片、核酸分子、及びマクロライド化合物からなる群から選ばれる、請求項14に記載の方法。
- 前記mTOR阻害剤が、(i)テムシロリムス(CCI−779)またはその医薬的な等価物、アナログ、誘導体、もしくは塩、(ii)エベロリムス(evirolimus)(RAD−001)またはその医薬的な等価物、アナログ、誘導体、もしくは塩、及び(iii)シロリムス(ラパマイシン)またはその医薬的な等価物、アナログ、誘導体、もしくは塩からなる群から選ばれる、請求項27に記載の方法。
- CD4リンパ球除去剤を含む組成物。
- CD4リンパ球除去剤、並びに、免疫チェックポイント阻害薬、養子免疫治療剤、免疫アジュバント、及び免疫調節剤からなる群から選ばれた少なくとも1つの追加薬剤を含む組成物。
- 医薬的に許容される担体をさらに含む、請求項29または30に記載の組成物。
- 対象の疾患の治療、予防、その重篤度の軽減、及び/またはその進行の遅延用のキットであって、
CD4リンパ球除去剤を含む組成物;並びに
前記対象の前記疾患を治療し、予防し、その重篤度を軽減し、及び/またはその進行を遅延させるための前記組成物の使用説明書
を含む、前記キット。 - 対象の疾患の治療、予防、その重篤度の軽減、及び/またはその進行の遅延用のキットであって、
CD4リンパ球除去剤;
免疫チェックポイント阻害薬、養子免疫治療剤、免疫アジュバント、及び免疫調節剤からなる群から選ばれた少なくとも1つの追加薬剤;並びに、
前記対象の前記疾患を治療し、予防し、その重篤度を軽減し、及び/またはその進行を遅延させるための、前記組成物の使用説明書
を含む、前記キット。
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