JP2016521973A - 免疫を強化する抗cd47因子の使用 - Google Patents
免疫を強化する抗cd47因子の使用 Download PDFInfo
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- JP2016521973A JP2016521973A JP2016511766A JP2016511766A JP2016521973A JP 2016521973 A JP2016521973 A JP 2016521973A JP 2016511766 A JP2016511766 A JP 2016511766A JP 2016511766 A JP2016511766 A JP 2016511766A JP 2016521973 A JP2016521973 A JP 2016521973A
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Abstract
Description
抗CD47因子。本明細書中において、「抗CD47因子」という用語は、CD47(例えば、標的細胞上の)のSIRPα(例えば、食細胞)の結合を減少させる任意の因子を指している。適当な抗CD47試薬の限定的でない例としては、限定的でなく高親和性のSIRPαポリペプチドを含むSIRPα試薬、抗SIRPα抗体、可溶性のCD47ポリペプチド及び抗CD47抗体、抗体断片、ペプチド、低分子、ペプチド模倣薬等がある。いくつかの実施形態においては、適当な抗CD47因子(例えば、抗CD47抗体、SIRPα試薬等)は、CD47のSIRPαへの結合を減少するようにCD47に特異的に結合する。いくつかの実施形態においては、適当な抗CD47因子(例えば、抗SIRPα抗体、可溶性のCD47ポリペプチド等)は、CD47のSIRPαに対する結合を減少するようにSIRPαに特異的に結合する。SIRPαに結合する適当な抗CD47因子は、(例えば、SIRPαを発現している食細胞中において)SIRPαを活性化しない。
末梢神経系(PNS)癌、乳癌、子宮頸癌、小児非ホジキンリンパ腫、結腸癌及び直腸癌、子宮内膜癌、食道癌、ユーイングファミリー腫瘍(例えば、ユーイング肉腫)、眼癌、胆嚢癌、消化管カルチノイド腫瘍、消化管間質腫瘍、妊娠性絨毛疾患、ホジキンリンパ腫、カポジ肉腫、腎臓癌、喉頭癌、下喉頭癌、肝癌、肺癌、肺カルチノイド腫瘍、非ホジキンリンパ腫、男性乳癌、悪性中皮腫、多発性骨髄腫、骨髄異形成症候群、骨髄増殖性疾患、鼻腔癌及び副鼻腔癌、鼻咽頭癌、神経芽細胞種、口腔癌及び口咽頭癌、骨肉腫、卵巣癌、膵臓癌、陰茎癌、下垂体腫瘍、前立腺癌、網膜芽細胞腫、横紋筋肉腫、唾液腺癌、肉腫、黒皮腫皮膚癌、非黒皮腫皮膚癌、胃癌、精巣癌、胸腺癌、甲状腺癌、子宮癌(例えば、子宮肉腫)、移行上皮癌、膣癌、外陰癌、中皮腫、扁平上皮癌、類表皮癌、気管支線種、絨毛癌、頭頚部癌、奇形癌腫、ワルデンシュトレームマクログロブリン血症が含まれる。癌細胞が非癌化細胞に比べてCD47の増加した発現を示す任意の癌が、対象の方法及び構成により処置されることに適した癌である。
T細胞が媒介する、抗原、特に微粒子抗原、更に特に標的細胞に対する免疫応答を強化する方法が提供される。本方法は、生物学的サンプルから分離され、又は前駆体細胞の源(限定的ではないが血液又は骨髄由来の単球を含む)からインビトロで導出され得る貪食抗原提示細胞を得るステップと、その後抗CD47因子の有効量の存在下で、phAPCを微粒子抗原と接触させるステップとを含む。接触は、任意の適当な培地において実行され得る。phAPCは、微粒子抗原を貪食し、一般的には、約1時間から約4時間が貪食に十分である。充填されたphAPCは、標的細胞由来のタンパク質を処理し、それらを細胞表面に提示する。充填されたphAPCは、インビボ又はインビトロでT細胞の群に接触する。
本方法において使用されるキットもまた提供される。本キットは、例えば、剤形(例えば、抗原刺激量剤形)中に、抗CD47因子を含む。いくつかの実施形態において、抗CD47因子は剤形(例えば、治療学上有効剤形)で、任意の適当なパッケージ(スティックパック、ドーズパック等)中の液体形態で又は固体形態で提供される。phAPCの選別又はインビトロでの導出のための試薬、例えば、M−CSF、IL−4、組織培養試薬、微粒子抗原等もまた提供され得る。
以下の例は、当業者に、本発明の実現及び使用の方法の完全な開示及び記述を提供するために挙げられており、発明者らが発明とみなした範囲を限定することを意図するものではなく、また、以下の実験が、実施された実験の全て又は唯一であると示すことを意図しているのではない。使用された数値(例えば、量、温度等)に関して正確さを確保するために尽力したが、多少の実験誤差及び偏差を考慮すべきである。特に示していない限り、比率は、重量比率であり、分子量は重量平均分子量であり、温度は摂氏温度であり、圧力は大気圧又はその近傍値である。
抗CD47抗体介在のマクロファージによる癌の貪食が効果的な抗腫瘍T細胞応答に抗原刺激を与える。
癌に対するT細胞応答の動員は、持続性の治癒を達成する可能性を有する。しかしながら、効果的な抗腫瘍T細胞応答を達成するためにどのように抗原提示細胞を最適に利用するかは知られていない。本研究では、抗CD47抗体を介したマクロファージによる癌の貪食が抗腫瘍T細胞免疫応答を起こしうることが示される。オボアルブミンモデルの抗原システムを使用して、抗CD47抗体を介したマクロファージによる癌細胞の貪食は、OT−IT細胞(CD8+ )の抗原刺激を増加し、OT−IIT細胞(CD4+ )を抗原刺激しないという結果となった。CD4+T細胞は、Foxp3+ 調節性T細胞における減少により特徴づけられた。抗CD47を介した貪食の後、マクロファージはインビボで細胞傷害性の機能を示すためにCD8+ T細胞を抗原刺激した。この応答は、腫瘍の挑戦から動物を保護する。我々は、抗CD47抗体処置は、マクロファージの癌の貪食を可能とするだけでなく、抗腫瘍細胞傷害性T細胞免疫応答を起こし得ると結論づけられる。
マウス。C57BL/Ka(CD45.2)、C57BL/Ka(CD45.1)、C57BL/KaRosa26−mRFP1マウスを含めて、マウスは、実験動物ケア管理委員会(APLAC)に従って、スタンフォード大学研究動物施設(Stanford University Research Animal Facility)で繁殖され、飼育された。動物の全ては、無菌のマイクロインシュレータに収容され、水及びげっ歯類のエサが不断で与えられた。OT−ITCRトランスジェニックマウス、OT−IITCRトランスジェニックマウス及びFoxp3−GFPマウスはジャクソン研究所(Jackson laboratory)から購入された。
ヒト抗原提示細胞の生産
ヒトマクロファージ。PBMC又はロイコフォレーシス単球(新鮮又は冷凍)(ポジティブ又はネガティブ選別、プラスチック接着、パーコール、流動選別、向流遠心エルトリエーションによるCD14+細胞由来)。Harding 他著「Choosing and Preparing Antigen-Presenting Cells 」(2010)「Current Protocols in Immunology 」16.1.1- 16.1.30 に記載されているように、単球由来のマクロファージを生産するための培地単独での分化又は組み換えヒトM−CSF。
本発明は、国立衛生研究所によって授与された認可番号CA86017、P01CA139490、及びF30CA168059に基づき米国政府の支援によりなされた。米国政府は、本発明について一定の権利を有している。
Claims (14)
- 微粒子抗原に対する免疫応答を誘導する方法であって、
(a)貪食抗原提示細胞(phAPC)を、充填されたphAPCを生産するために、インビトロで抗CD47因子の有効量の存在下で微粒子抗原と接触させるステップ、及び
(b)T細胞群を前記充填されたphAPCに接触させるステップ
を有し、
前記T細胞群は、前記微粒子抗原に特異的な応答を起こすこと
を特徴とする方法。 - 前記微粒子抗原は、哺乳類の標的細胞であることを特徴とする請求項1に記載の方法。
- 前記標的細胞は癌細胞であることを特徴とする請求項2に記載の方法。
- 前記標的細胞は、病原体感染細胞であることを特徴とする請求項2に記載の方法。
- 前記標的細胞は、病原体であることを特徴とする請求項2に記載の方法。
- T細胞群を接触させるステップは、インビボで実行されることを特徴とする請求項1に記載の方法。
- T細胞群を接触させるステップは、インビトロで実行されることを特徴とする請求項1に記載の方法。
- 前記抗CD47因子は、CD47に特異的に結合することを特徴とする請求項1に記載の方法。
- 前記抗CD47因子は、抗体であることを特徴とする請求項8に記載の方法。
- 前記抗CD47因子は、SIRPα試薬であることを特徴とする請求項8に記載の方法。
- 前記抗CD47因子は、SIRPαに特異的に結合し、結合においてCD47を活性化しないことを特徴とする請求項1に記載の方法。
- 前記抗CD47因子は、抗体であることを特徴とする請求項11に記載の方法。
- 前記抗CD47因子は、可溶性のCD47ポリペプチドであることを特徴とする請求項1に記載の方法。
- 請求項1から請求項13に記載されたいずれかの方法で使用されるキット。
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CN115561145A (zh) * | 2022-07-08 | 2023-01-03 | 苏州尔生生物医药有限公司 | 一种癌细胞特异性t细胞的检测方法及试剂盒 |
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PT2569013T (pt) | 2010-05-14 | 2017-02-08 | Univ Leland Stanford Junior | Anticorpos monoclonais humanizados e quiméricos para cd47 |
DK2804617T3 (da) | 2012-01-17 | 2020-08-10 | Univ Leland Stanford Junior | Højaffine sirp-alpha-reagenser |
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JP2011519345A (ja) * | 2008-01-15 | 2011-07-07 | ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティ | Cd47によって媒介される食作用を操作するための方法 |
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EP2992089A4 (en) | 2017-01-25 |
CA2910466A1 (en) | 2014-11-06 |
AU2020203355B2 (en) | 2022-05-26 |
AU2014260245B2 (en) | 2020-02-27 |
US10064925B2 (en) | 2018-09-04 |
HK1222676A1 (zh) | 2017-07-07 |
US20160144009A1 (en) | 2016-05-26 |
ES2898627T3 (es) | 2022-03-08 |
JP2019134724A (ja) | 2019-08-15 |
EP2992089A1 (en) | 2016-03-09 |
AU2020203355A1 (en) | 2020-06-11 |
JP6940551B2 (ja) | 2021-09-29 |
EP2992089B1 (en) | 2021-09-08 |
WO2014179132A1 (en) | 2014-11-06 |
AU2014260245A1 (en) | 2015-12-10 |
US11154600B2 (en) | 2021-10-26 |
JP6843611B2 (ja) | 2021-03-17 |
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