JP2019529539A - 白金を用いた化合物による免疫記憶の誘導 - Google Patents
白金を用いた化合物による免疫記憶の誘導 Download PDFInfo
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Abstract
Description
がん免疫空間(immuno−oncology space)は適応および先天性免疫で注目されているが、我々の所見は、式Iおよび式IIの化合物が体液性応答を開始するそのクラスの初の化合物として浮上し、臨床に多大な価値を創造した。式Iおよび式IIの化合物は、標準治療と同様のT細胞性免疫応答を示す。しかし、この作用は、再発を予防する可能性がある体液性免疫細胞の腫瘍への動員ほど顕著ではなかった。実際、IGKCが高いTNBC患者は生存期間が長いことと関連していた。さらに、すでに腫瘍が退行した治療群に癌細胞を再移植した際に腫瘍増殖が認められなかったことから、式Iの化合物は免疫記憶を誘発できることを示している。
[実施例]
腫瘍を作成するため、4T1細胞がBalb/cマウスに皮下移植された。腫瘍が平均容積100mm3に達した時点で化合物1またはオキサリプラチンを投与した。1サイクルの治療とその後の退行後、腫瘍を採取し、各群の腫瘍の一部を全RNAの単離に使用した。腫瘍浸潤免疫細胞の免疫活性化および免疫抑制遺伝子の相対的mRNA発現レベルを評価した(Denkert et al.,Clin Oncol.2015;33(9):983−91)。
癌免疫療法に関する多くの臨床試験は、腫瘍の縮小と生存の延長を示した。前記理論的枠組みは、T細胞受容体(TCR)刺激がないために記憶T細胞は不活性なままであるが、制御性T(Treg)細胞は記憶T細胞の静止状態を調整することが多いというものである(Kalia et al.,Immunity 42,1116−1129,June 16,2015)。エフェクターT細胞と記憶CD8+ T細胞の活性化に加え、Treg細胞の消失は予防効果を生むだろう。
長期的に癌が増殖しないようにしておくには、今後癌が再発した場合に、前記免疫系が癌細胞を認識し、攻撃する方法を覚えておく必要がある。したがって、「免疫記憶」は、がんの再発に対して身体が戦うことができるようにする。
白金薬物の作用機序は、主にDNA形成付加体への配位により、DNA複製および転写を崩壊させ、その後、アポトーシスにより細胞死に導くものである(Fink et al.,Cancer Res,1997,57:1841−1845;Takahara et al.,J.Am.Chem.Soc.1996,118,12309;Silverman et al.,J.Biol.Chem.2002,277,49743)。白金薬物のDNAおよびオリゴヌクレオチドへの結合は、詳細に特徴付けられている(Reedijk,Proc.Natl.Acad.Sci.U.S.A.2003,100,3611;Reedijk,Curr.Opin.Chem.Biol.1999,3,236;Guo and Sadler,J.AdV.Inorg.Chem.2000,49,183)。白金薬物の付加体形成は、これがDNAに特異的であるのか、またはRNA付加体も形成できるのかという問題を提示することが多い。この疑問は、蛍光標識されたシスプラチンは、細胞のリソソーム、ゴルジタイ、および分泌コンパートメントに加えて核でも検出されたという所見で補足された(Safaei et al.,Clin Cancer Res.2005 Jan 15;11(2 Pt 1):756−67)。その後の研究では、シスプラチン投与が、複雑な構造を持つRNAsの内部ループおよび他の異常架橋に白金付加体を形成する可能性があり、長期間安定で、DNA依存性の生物プロセスに変化を誘導すると結論付けた。(Hostetter et al.,J.Am.Chem.Soc.,2009,131(26),pp 9250−9257)。酵母の研究では、白金がポリ(A)−mRNA、rRNAを含むRNAに蓄積し、付加体を形成することが確立された(Hostetter et al.,ACS Chem.Biol.,2012,7(1),pp 218−225)。細胞RNAの白金蓄積はDNAよりも多い。RNAと小分子RNAとの相互作用崩壊がRNAで制御されるプロセスを崩壊する可能性があるため、これらの所見は、白金薬物の細胞効果に新たなレパートリーをはっきりと加える(Chapman et al.,J.Am.Chem.Soc.,2010,132(6),pp 1946−1952)。Small dsRNAsも、哺乳類細胞における免疫経路を活性化することが示された(Gantier and Williams,Cytokine Growth Factor Rev.2007;18(5−6):363−371;Chiappinelli et al.,Cell.2015 Aug 27;162(5):974−86)。
マウス脾臓B細胞は、実施例3に説明した1群および3群から単離した。実験詳細の略図は図6Aに詳細に示す。マウス(n=3)から脾臓を採取し、RPMI−1640基本培地で細かく刻んだ。断片を40メッシュの膜上に置き、シリンジの背でつぶし、50ml試験管1本に細胞懸濁液を収集した。前記細胞懸濁液1本をPBSで2回洗い、2000rpmで遠心分離することで細片を取り除いた。脾細胞は血球計算器により計数し、1億個の非細胞を1mlの単離用緩衝液(DPBS中、2% FBS、100mM EDTA)に再懸濁し、5mlポリスチレンチューブに移した。前記B細胞は、EasySep Stem Cell B細胞単離キットを用い、製造業者のプロトコールに従って脾細胞から単離した。1000万個のB細胞をRNAの単離に用い、続いてB細胞分化に関与する遺伝子の相対的mRNA発現レベルおよびTLRの活性化を評価した。
Claims (18)
- 請求項1記載の方法において、前記被験者がヒトを含む哺乳類である方法。
- 請求項1記載の方法において、前記癌は乳癌、卵巣癌、神経膠腫、消化管癌、前立腺癌、癌腫、肺癌、肝臓癌、精巣癌、子宮頚癌、子宮内膜癌、膀胱癌、頭頚部癌、肺癌、胃食道癌、および婦人科癌、またはそれらの任意の組み合わせから成る群から選択される方法。
- 請求項1記載の方法において、式Iまたは式IIの化合物はその誘導体、塩型、互変異性型、異性体、多形体、溶媒和物、およびそれらの中間体である方法。
- 請求項1記載の方法において、式Iの化合物の脂質構造は、脂肪、ワックス、ステロール、ステロイド、胆汁酸、脂溶性ビタミン、モノグリセリド、ジグリセリド、リン脂質、糖脂質、硫脂質、アミノリピド、色素脂質、グリセロリン脂質、スフィンゴ脂質、プレノール脂質、サッカロリピド(saccharolipids)、ポリケチド、α−トコフェロールおよび脂肪酸、またはそれらの任意の組み合わせ、好ましくはルミステロール、コレステロール、クロロギ酸コレステロール、およびその誘導体から選択されるステロール、またはそれらの任意の組み合わせから成る群から選択される方法。
- 請求項1記載の方法において、式Iの化合物のリンカーは、−CH2CH2−、−CH2CH2NHC(O)−、−CH2C(O)NHCH2CH2−、−CH2CH2OCH2CH2−、−C(O)CH2−、−CH2CH2NHC(O)CH2−、またはそれらの任意の組み合わせである方法。
- 前述の請求項いずれか記載の方法において、式Iまたは式IIの化合物は、白金濃度が約50mg/m2〜約500mg/m2の範囲の用量で投与される方法。
- 請求項1記載の方法において、式Iまたは式IIの化合物は、静脈内投与、関節内投与、膵十二指腸動脈投与、腹腔内投与、肝門投与、経口投与、または筋肉内投与により、選択的に薬学的に許容される賦形剤とともに投与される方法。
- 請求項9記載の方法において、前記賦形剤が造粒剤、結合剤、潤滑剤、崩壊剤、甘味剤、流動促進剤、抗接着剤、帯電防止剤、界面活性物質、抗酸化剤、増粘剤、コーティング剤、着色剤、香料、コーティング剤、可塑剤、防腐剤、懸濁剤、乳化剤、植物セルロース系材料、および球形化剤、またはそれらの任意の組み合わせから成る群から選択される方法。
- 前述の請求項いずれか記載の方法において、式Iまたは式IIの化合物は、注射液、錠剤、凍結乾燥粉末、およびリポソーム懸濁液、またはそれらの任意の組み合わせから成る群から選択される投与形態に製剤化される方法。
- 請求項1記載の方法において、式Iまたは式IIの化合物は、前記癌被験者の腫瘍微小環境において、免疫グロブリンκCの発現を亢進する方法。
- 請求項1記載の方法において、式Iまたは式IIの化合物は、免疫増強分子による免疫反応の誘導によって前記転移または前記再発を予防し、それによってサイトカイン、B細胞、T細胞、単球、マクロファージ、ナチュラルキラー細胞、樹状細胞、またはそれらの任意の組み合わせを活性化する方法。
- 前述の請求項いずれかに記載の方法において、式Iまたは式IIの化合物は、B細胞による体液性免疫反応を誘発することで転移または前記再発を予防し、前記B細胞は形質芽細胞、形質細胞、リンパ形質細胞様細胞、記憶B細胞、濾胞性B細胞、辺縁帯B細胞、B−1細胞、B−2細胞、制御性B細胞、またはそれらの任意の組み合わせから成る群から選択される方法。
- 請求項13記載の方法において、前記T細胞はTヘルパー細胞、細胞障害性T細胞、記憶T細胞、サプレッサーT細胞、ナチュラルキラーT細胞、粘膜関連インバリアントT細胞、およびγδT細胞、またはそれらの任意の組み合わせから成る群から選択される方法。
- 請求項13記載の方法において、前記免疫反応は、好ましくは二本鎖DNA付加体、一本鎖DNA付加体、二本鎖RNA付加体、または一本鎖RNA付加体を介した核酸付加体形成により活性化される方法。
- 被験者の癌を治療または管理し、前記癌の転移または再発を予防するための式Iまたは式IIの化合物の使用であって、前記被験者に治療有効量の式Iまたは式IIの化合物を投与する工程を有する使用。
- 癌に罹患した被験者の免疫反応を亢進する方法であって、前記方法は治療有効量の式Iまたは式IIの化合物で前記癌を治療する工程を有する方法。
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