JP2018502892A - ガイドとして自身のカルレティキュリンを使用して癌細胞を食べるマクロファージ - Google Patents
ガイドとして自身のカルレティキュリンを使用して癌細胞を食べるマクロファージ Download PDFInfo
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Abstract
Description
カルレティキュリン。カルレティキュリンは417アミノ酸の多機能タンパク質であり、分子量は48kDaで、Ca2+イオンと結合して活性が失われる。Ca2+は低親和性だが高容量で結合し、シグナルで放出されることができる。カルレティキュリンは、小胞体に関連した貯蔵区画に位置することができ、そこで誤って折り畳まれたタンパク質と結合して、それらがゴルジ体に排出されることを防止する。カルレティキュリンは核にも存在しており、それが転写調節の役割を有し得ることを示唆する。カルレティキュリンは合成ペプチドKLGFFKRと結合しており、それは核内受容体のスーパーファミリーのDNA結合領域のアミノ酸配列とほぼ同一である。カルレティキュリンの遺伝子名はCALRであり、ヒト配列は、タンパク質登録番号NP_004334、ヌクレオチド登録番号NM_004343としてPubmedでアクセスできる。
癌治療のための方法を提供する。TLRシグナル伝達の活性化剤またはBTKアゴニストは、CD47の遮断と組み合わせて提供され、癌細胞の除去は、単独療法としていずれかの薬剤の存在下で、細胞除去と比較して増加する。いくつかの実施形態では、マクロファージを含む細胞集団は、少なくとも約25%、少なくとも約50%、少なくとも約75%までマクロファージの細胞表面上のCRTを増加させるために効果的であり、及び刺激されていない細胞と比較して2倍、3倍、5倍以上に発現を増加する場合がある、TLRアゴニストもしくはBTKアゴニストの用量に、生体外または生体外で接触する。このように処置した細胞の食作用のレベルは少なくとも約25%、少なくとも約50%、少なくとも約75%であり得て、刺激されていない細胞と比較して2倍、3倍、5倍以上に食作用を増加させることができる。CD47とSIRPαの相互作用を阻止する薬剤がある場合、TLRアゴニストもしくはBTKアゴニストの有効量で処置した細胞の食作用の漸増は、少なくとも約25%、少なくとも約50%、少なくとも約75%であり得て、及びCD47の遮断がない状態でTLRアゴニストで処置した細胞と比較して、2倍、3倍、5倍以上に食作用を増加させる場合がある。
マクロファージは、ガイド、TLR及びBTKの役割としてそれ自身のカルレティキュリンを使用して、癌細胞を食べる。
マクロファージ媒介性のプログラムされた細胞除去(PrCR)は、プログラムされた細胞死に先立って、疾患及び損害細胞を除去する重要なメカニズムである。腫瘍細胞上の「eat me」シグナルによるPrCRの誘発は、CD47などの「don’t eat me」シグナルによって相殺されて、それは、食作用を阻害するために、マクロファージシグナル調節性タンパク質(SIRPα)を結合する。腫瘍細胞上のCD47の遮断は、マクロファージによる食作用を導く。ここで本発明者らは、マクロファージのtoll様受容体(TLR)シグナル伝達経路の活性化が、PrCRを強化するために、腫瘍細胞上のCD47の遮断と相乗作用することを実証した。ブルトン型チロシンキナーゼ(Btk)は、マクロファージのTLRシグナル伝達を媒介する。癌細胞上の「eat me」シグナルであると既に示したカルレティキュリンは、分泌、及びTLR及びBtkによる細胞表面露出のためにマクロファージで活性化されて、癌細胞がそれ自身カルレティキュリンを発現しない場合でも、食作用の癌細胞を標的とする。
マウス。BALB/c、RAG2−/−、γc−/−、BALB/c及びNOD.Cg−PrkdcscidII2rgtm1WjI/SzJ(NSG)マウスは、スタンフォード大学のInstitute for Stem Cell Biology and Regenerative Medicineの無菌施設で飼育した。すべての動物作業は、スタンフォード大学のAdministrative Panel on Laboratory Animal Careによって承認された。
本出願は、2015年1月21日出願の米国特許仮出願第62/106,050号の利益を主張するものであり、その全体が参照により本明細書に組み込まれる。
Claims (16)
- 癌細胞の食作用を増加させる方法であって、
食細胞の集団を、前記食細胞表面上のカルレティキュリンの発現を増加させるために効果的な用量のTLRアゴニストと、CD47遮断剤の有効量とに、接触させることを含み、
前記食細胞による癌細胞のプログラムされた細胞除去が増加することを特徴とする方法。 - 前記接触させることが生体内で実施されることを特徴とする請求項1に記載の方法。
- 前記接触させることが生体外で実施されることを特徴とする請求項1に記載の方法。
- 前記食細胞はマクロファージであることを特徴とする請求項1〜3のいずれか一項に記載の方法。
- 前記TLRアゴニストはイミキモドであることを特徴とする請求項1〜4のいずれか一項に記載の方法。
- 前記TLRアゴニストはポリI:Cであることを特徴とする請求項1〜4のいずれか一項に記載の方法。
- 前記CD47遮断剤は抗体であることを特徴とする請求項1〜6のいずれか一項に記載の方法。
- 前記抗体はCD47に特異的に結合することを特徴とする請求項7に記載の方法。
- 前記食細胞が、TLRアゴニスト及びCD47遮断剤に接触させた後、対象内へ導入されることを特徴とする請求項3に記載の方法。
- 前記食細胞表面上のカルレティキュリンの発現が、前記導入する工程の前に測定されることを特徴とする請求項9に記載の方法。
- 血液細胞を食作用から保護する方法であって、
前記血液細胞をBtk阻害剤に接触させることを含むことを特徴とする方法。 - 対象の血液細胞をBtk阻害剤に生体内で接触させることを特徴とする請求項11に記載の方法。
- 前記対象は骨髄異形成症候群を患っていることを特徴とする請求項12に記載の方法。
- 前記対象は自己免疫溶血性貧血(AIHA)を患っていることを特徴とする請求項12に記載の方法。
- 前記対象は免疫性血小板減少性紫斑病(ITP)を患っていることを特徴とする請求項12に記載の方法。
- 前記Btk阻害剤はイブルチニブであることを特徴とする請求項11〜15のいずれか一項に記載の方法。
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