JP2020007346A - 標的免疫療法のための化合物 - Google Patents
標的免疫療法のための化合物 Download PDFInfo
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- JP2020007346A JP2020007346A JP2019165174A JP2019165174A JP2020007346A JP 2020007346 A JP2020007346 A JP 2020007346A JP 2019165174 A JP2019165174 A JP 2019165174A JP 2019165174 A JP2019165174 A JP 2019165174A JP 2020007346 A JP2020007346 A JP 2020007346A
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Abstract
Description
本出願は、2012年7月18日出願の中国特許出願第201210248481.9号の利益および同出願に対する優先権を主張し、この出願の全開示は、その全体が参照として本明細書に組み込まれる。
治療抗体は、20年以上にわたって臨床用途に使用されてきた。現在、Rituxan(1997年)、Herceptin(1998年)、Mylotarg(2000年)、Campath(2001年)、Zevalin(2002年)、Bexxer(2003年)、Avastin(2004年)、Erbitux(2004年)、Vectibix(2006年)、Arzerra(2009年)、Benlysta(2011年)、Yervoy(2011年)、Adcetris(2011年)、Perjeta(2012年)、およびKadcyla(2013年)を含む15種の抗腫瘍抗体薬が臨床において存在する。これらの抗体は、主に、EGFR、Her2、CD20、およびVEGFの4つの分子を標的にする。
式中、TMは、標的部分であり、AMは、樹状細胞、マクロファージ、単球、骨髄由来抑制細胞、NK細胞、B細胞、T細胞、もしくは腫瘍細胞、またはこれらの組み合わせが含まれるが、これらに限定されないヒト免疫細胞を活性化することができる活性化部分であり、Lnは、リンカーであり、nは、0および1から選択される整数である、化合物を提供する。
式中、TMは、標的部分であり、AMは、ヒトTLR7および/もしくはTLR8に特異的に結合すること、またはTLR7および/もしくはTLR8を介してヒト免疫細胞を活性化することができる活性化部分であり、Lnは、リンカーであり、nは、0および1から選択される整数である、化合物を提供する。
式中、TMは、標的部分であり、AMは、活性化部分であり、Lnは、リンカーであり、nは、0および1から選択される整数であり、
但し、TMが抗体を含む場合、AMは、CpGオリゴヌクレオチドまたは治療剤を含まない、化合物を提供する。
(i)(a)加熱死菌生成物、好ましくはHKAL、HKEB、HKHP、HKLM、HKLP、HKLR、HKMF、HKPA、HKPG、またはHKSA、HKSP、および(b)細胞壁成分生成物、好ましくはLAM、LM、LPS、LTA、LTA、PGN、FSL、Pam2CSK4、Pam3CSK4、またはザイモサンからなる群から選択されるTLR2のリガンド、
(ii)ポリ(I:C)およびポリ(A:U)からなる群から選択されるTLR3のリガンド、
(iii)LPSおよびMPLAからなる群から選択されるTLR4のリガンド、
(iv)FLAおよびフラゲリンからなる群から選択されるTLR5のリガンド、
(v)ORN02、ORN06、ssポリ(U)、ssRNA40、ssRNA41、ssRNA−DR、ポリ(dT)、CL075、CL097、CL264、CL307、ガーディキモド、ロキソリビン、イミキモド、およびレシキモド(resiquimod)からなる群から選択されるTLR7/8のリガンド、
(vi)ODN1585、ODN1668、ODN1826、ODN2006、ODN2007、ODN2216、ODN2336、ODN2395、およびODN M362からなる群から選択されるTLR9のリガンド、
(vii)TLR10のリガンド、
(viii)NOD1作動薬(C12−iE−DAP、iE−DAP、Tri−DAP)、NOD2作動薬(L18−MDP、MDP、M−TriLYS、M−TriLYS−D−ASN、ムラブチド(Murabutide)、N−グリコリル−MDP)、およびNOD1/NOD2作動薬(M−TriDAP、PGN)からなる群から選択されるヌクレオチドオリゴマー化ドメイン(NOD)様のリガンド、
(ix)5′ppp−dsRNA、ポリ(dA:dT)、ポリ(dG:dC)、およびポリ(I:C)からなる群から選択される1つ以上のRIG−I−様受容体(RLR)のリガンド、
(x)カードランAL、HKCA、HKSC、WGP、ザイモサン、およびトレハロース−6,6−ジベヘン酸塩からなる群から選択される1つ以上のC型レクチン受容体(CLR)のリガンド、
(xi)c−GMP、c−G−AMP、c−G−GMP、c−A−AMP、c−di−AMP、c−di−IMP、c−di−GMP、c−di−UMP、HSV−60、ISD、pCpG、ポリ(dA:dT)、ポリ(dG:dC)、ポリ(dA)、およびVACV−70からなる群から選択される1つ以上の細胞質DNAセンサー(CDS)のリガンド、あるいは
(xii)(a)NLRP3インフラマソームタンパク質複合体、好ましくはミョウバン結晶、ATP、CPPD結晶、ヘルモゾイン(Hermozoin)、MSU結晶、ナノSiO2、ナイジェリシン、および(b)AIM2インフラマソームタンパク質複合体、好ましくはポリ(dA:dT)からなる群から選択されるインフラマソーム誘発剤、
を含む。
本明細書に記述された全ての刊行物、特許、および特許出願は、まるでそれぞれ個別の刊行物、特許、および特許出願が特定的および個別に参照により組み込まれるように示されているかのように、同じ程度で、参照により組み込まれる。
特に定義のない限り、本明細書において使用される全ての技術および科学用語は、一般に、本発明が属する当業者により一般的に理解されるものと同じ意味を有する。一般に、本明細書、ならびに細胞培養、分子遺伝子技術、有機化学、および核酸化学とハイブリッド形成における実験室手順に使用される命名法は、当該技術において周知であり、一般的に用いられているものである。標準的な技術が、核酸およびペプチド合成に使用される。技術および手順は、当該技術における従来の方法、およびこの文書の全体にわたって提供されている多様な一般的な参照に従って一般に実施される。本明細書、ならびに分析化学および下記に記載されている有機合成における実験室手順に使用される命名法は、当該技術において周知であり、一般的に用いられているものである。標準的な技術またはそれらの変更が、化学合成および化学分析に使用される。
一態様において、本発明は、式(I)、TM−Ln−AM (I)の構造を有する化合物であって、
式中、TMは、標的部分であり、AMは、ヒト樹状細胞、NK細胞、もしくは腫瘍細胞、またはこれらの組み合わせを活性化することができる活性化部分であり、Lnは、リンカーであり、nは、0および1から選択される整数である、化合物を提供する。
式中、TMは、標的部分であり、AMは、ヒトTLR7および/またはTLR8に特異的に結合することができる活性化部分であり、Lnは、リンカーであり、nは、0および1から選択される整数である、化合物を提供する。
式中、TMは、標的部分であり、AMは、活性化部分であり、Lnは、リンカーであり、nは、0および1から選択される整数であり、但し、TMが抗体を含む場合、AMは、CpGオリゴヌクレオチドまたは治療剤を含まない、化合物を提供する。
一般に、本発明の化合物は、標的部分を含む。
本明細書において「標的」または「マーカー」とは、特定の標的部分に特異的に結合することができる任意の実体を意味する。幾つかの実施形態において、標的は、1つ以上の特定の細胞または組織型と特異的に関連する。幾つかの実施形態において、標的は、1つ以上の特定の疾患状態と特異的に関連する。幾つかの実施形態において、標的は、1つ以上の特定の発達段階と特異的に関連する。例えば、細胞型特異的マーカーは、典型的には、その細胞型において基準細胞個体群より少なくとも2倍大きなレベルで発現する。幾つかの実施形態において、細胞型特異的マーカーは、基準個体群における平均発現より少なくとも3倍、少なくとも4倍、少なくとも5倍、少なくとも6倍、少なくとも7倍、少なくとも8倍、少なくとも9倍、少なくとも10倍、少なくとも50倍、少なくとも100倍、または少なくとも1,000倍大きなレベルで存在する。細胞型特異的マーカーの検出または測定は、多くの、大部分の、または全ての他の細胞型から、目的の細胞型(単数)または細胞型(複数)を識別することを可能にし得る。幾つかの実施形態において、標的は、本明細書に記載されているように、タンパク質、炭水化物、脂質、および/または核酸を含むことができる。
幾つかの実施形態において、標的部分は、非腫瘍細胞と比較して、腫瘍細胞に特異的または優先的に結合することができる。
幾つかの実施形態において、標的部分は、抗体またはその機能性フラグメントを含む。
幾つかの実施形態において、標的部分は、葉酸またはその誘導体を含む。
幾つかの実施形態において、標的部分は、PD−1、CTLA4、CD47、BTLA、KIR、TIM3、4−1BB、LAG3、表面リガンドアンフィレギュリンの一部の完全長、ベータセルリン、EGF、エフリン、エピジェン、エピレギュリン、IGF、ニューレグリン、TGF、TRAIL、またはVEGFの細胞外ドメイン(ECD)または可溶形態を含む。
幾つかの実施形態において、標的部分は、粒子(標的粒子)、好ましくはナノ粒子、場合により、標的に特異的または優先的に結合することができる標的分子に結合する標的化ナノ粒子を含む。幾つかの実施形態において、標的粒子は、それ自体本発明の化合物を(例えば、腫瘍細胞または組織中の濃縮によって)導き、その中には追加の標的化合物は何も結合していない。
幾つかの実施形態において、標的部分は核酸標的部分を含む。
一般に、本発明の化合物は、活性化部分を含む。
樹状細胞は、最も強力な抗原提示細胞である。樹状細胞は、先天および適応免疫応答の両方の開始に必須の役割を果たす。樹状細胞は、免疫寛容性の誘発および維持において主要な役割も果たす。
幾つかの実施形態において、活性化部分は、ナチュラルキラー細胞(NK細胞)、好ましくはヒトNK細胞を活性化することができる。
幾つかの実施形態において、活性化部分は、腫瘍細胞を活性化することができる。幾つかの報告が、マウスまたはヒトの癌または癌細胞系におけるTLRの発現を記載している。例えば、TLR1〜TLR6は、結腸、肺、前立腺、および黒色腫のマウス腫瘍細胞系により発現され(Huang B,et al.Toll−like receptors on tumor cells facilitate evasion of immune surveillance.Cancer Res.2005;65(12):5009-5014)、TLR3は、ヒト乳癌細胞により発現され(Salaun B,Coste I,Rissoan MC,Lebecque SJ,Renno T.TLR3 can directly trigger apoptosis in human cancer cells.J Immunol.2006;176(8):4894-4901)、肝細胞癌および胃癌細胞は、TLR2およびTLR4(Huang B,et al.Listeria monocytogenes promotes tumor growth via tumor cell toll−like receptor 2 signaling.Cancer Res.2007;67(9):4346-4352)を発現し、TLR9(Droemann D,et al.Human lung cancer cells express functionally active Toll−like receptor 9.Respir Res.2005;6:1)およびTLR4(He W,Liu Q,Wang L,Chen W,Li N,Cao X.TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance.Mol Immunol.2007;44(11):2850-2859)は、ヒト肺癌細胞により発現される。TLR7およびTLR8は、ヒト肺癌の腫瘍細胞において見出される(Cherfils−Vicini J,Platonova S,Gillard M,Laurans L,Validire P Caliandro R,Magdeleinat P,Mami−Chouaib F,Dieu−Nosjean MC,Fridman WH,Damotte D,Sautes−Fridman C,Cremer I.J.Clin Invest.2010;120(4):1285-1297)。
一般に、本発明の活性化部分は、タンパク質、抗体、核酸、小分子、またはリガンドを含む。
(i)(a)加熱死菌生成物、好ましくはHKAL、HKEB、HKHP、HKLM、HKLP、HKLR、HKMF、HKPA、HKPG、またはHKSA、HKSP、および(b)細胞壁成分生成物、好ましくはLAM、LM、LPS、LTA、LTA、PGN、FSL、Pam2CSK4、Pam3CSK4、またはザイモサンからなる群から選択されるTLR2のリガンド、
(ii)ポリ(I:C)およびポリ(A:U)からなる群から選択されるTLR3のリガンド、
(iii)LPSおよびMPLAからなる群から選択されるTLR4のリガンド、
(iv)FLAおよびフラゲリンからなる群から選択されるTLR5のリガンド、
(v)ORN02(TLR8)、ORN06(TLR8)、ssポリ(U)(TLR8)、ssRNA40(TLR8)、ssRNA41(TLR8)、ssRNA−DR(TLR8)ポリ(dT)(TLR7/8)、CL075(TLR7/8)、CL097(TLR7/8)、CL264(TLR7)、CL307(TLR7)、ガーディキモド(TLR7)、ロキソリビン(TLR7)、イミキモド(TLR7/8)、およびレシキモド(resiquimod)(TLR7/8)からなる群から選択されるるTLR7、TLR8またはTLR7およびTLRのリガンド、
(vi)ODN1585、ODN1668、ODN1826、ODN2006、ODN2007、ODN2216、ODN2336、ODN2395、およびODN M362からなる群から選択されるTLR9のリガンド、
(vii)TLR10のリガンド、
(viii)NOD1作動薬(C12−iE−DAP、iE−DAP、Tri−DAP)、NOD2作動薬(L18−MDP、MDP、M−TriLYS、M−TriLYS−D−ASN、ムラブチド(Murabutide)、N−グリコリル−MDP)、およびNOD1/NOD2作動薬(M−TriDAP、PGN)からなる群から選択されるヌクレオチドオリゴマー化ドメイン(NOD)様のリガンド、
(ix)5′ppp−dsRNA、ポリ(dA:dT)、ポリ(dG:dC)、およびポリ(I:C)からなる群から選択される1つ以上のRIG−I−様受容体(RLR)のリガンド、
(x)カードランAL、HKCA、HKSC、WGP、ザイモサン、およびトレハロース−6,6−ジベヘン酸塩からなる群から選択される1つ以上のC型レクチン受容体(CLR)のリガンド、
(xi)c−GMP、c−G−AMP、c−G−GMP、c−A−AMP、c−di−AMP、c−di−IMP、c−di−GMP、c−di−UMP、HSV−60、ISD、pCpG、ポリ(dA:dT)、ポリ(dG:dC)、ポリ(dA)、およびVACV−70からなる群から選択される1つ以上の細胞質DNAセンサー(CDS)のリガンド、ならびに
(xii)(a)NLRP3インフラマソームタンパク質複合体、好ましくはミョウバン結晶、ATP、CPPD結晶、ヘルモゾイン(Hermozoin)、MSU結晶、ナノSiO2、ナイジェリシン、および(b)AIM2インフラマソームタンパク質複合体、好ましくはポリ(dA:dT)からなる群から選択されるインフラマソーム誘発剤、
を含む。
一般に、本発明の化合物は、標的部分および活性化部分を結合するリンカーを含む。しかし、幾つかの化合物において、リンカーが存在せず、活性化部分および標的部分は直接結合している。
式中、−T−は、ストレッチャー単位であり、aは、0または1であり、各−W−は、独立してアミノ酸単位であり、wは、独立して2〜12の範囲の整数であり、−Y−は、スペーサー単位であり、yは、0、1、または2である。
ストレッチャー単位(−T−)は、存在する場合、標的部分をアミノ酸単位(−W−)に結合させる。天然または化学操作された抗体のような標的部分に存在し得る有用な官能基には、スルフヒドリル、アミノ、ヒドロキシル、炭水化物のアノマーヒドロキシル基、およびカルボキシルが含まれるが、これらに限定されない。適切な官能基は、スルフヒドリルおよびアミノである。スルフヒドリル基は、抗体の分子内ジスルフィド結合の還元により生成され得る。あるいは、スルフヒドリル基は、抗体のリシン部分のアミノ基と、2−イミノチオラン(Traut試薬)または他のスルフヒドリル生成試薬との反応により、生成され得る。幾つかの実施形態において、抗体は、組み換え抗体であり、1つ以上のリシンを担持するために操作される。他の実施形態において、組み換え抗体は、追加のスルフヒドリル基、例えば追加のシステインを担持するために操作される。
アミノ酸単位(−W−)は、ストレッチャー単位(−T−)を、スペーサー単位が存在する場合にはスペーサー単位(−Y−)に結合させ、ストレッチャー単位を、スペーサー単位が不在の場合には細胞障害剤または細胞増殖抑制剤(活性化部分、D)に結合させる。−Ww−は、ジペプチド、トリペプチド、テトラペプチド、ペンタペプチド、ヘキサペプチド、ヘプタペプチド、オクタペプチド、ノナペプチド、デカペプチド、ウンデカペプチド、またはドデカペプチド単位である。各−W−単位は、独立して、下記に示されている角括弧内に式を有し、wは、2〜12の範囲の整数であり、
スペーサー単位(−Y−)は、存在する場合、アミノ酸単位を薬剤単位に結合させる。スペーサー単位には、自己犠牲的および非自己犠牲的の2つの一般的な種類がある。非自己犠牲的スペーサー単位は、スペーサー単位の一部または全てが、TM−リンカー−AM複合体または薬剤−リンカー化合物からのアミノ酸単位の酵素切断の後、活性化部分単位に結合したままであるものである。非自己犠牲的スペーサー単位の例には、(グリシン−グリシン)スペーサー単位およびグリシンスペーサー単位が挙げられるが、これらに限定されない。グリシン−グリシンスペーサー単位またはグリシンスペーサー単位を含有するTM−リンカー−AM複合体が、腫瘍細胞関連プロテアーゼ、癌細胞関連プロテアーゼ、またはリンパ球関連プロテアーゼを介して酵素切断を受ける場合、グリシン−グリシン−薬剤部分またはグリシン−薬剤部分は、A−T−Ww−から切断される。AMを遊離するため、独立している加水分解反応が、標的細胞内で生じて、グリシン−薬剤単位結合を切断するべきである。
本発明は、更に、本明細書の化合物またはその薬学的に許容される塩と、1つ以上の薬学的に許容される担体とを含む、薬学的製剤に関する。
別の態様において、本発明は、1つ以上の本発明の化合物または組成物と、化合物または組成物の使用指示書とを含むキットを提供する。例示的な実施形態において、本発明は、本発明のリンカーアームを別の分子と複合させるキットを提供する。キットは、リンカーと、リンカーを特定の官能基に結合するための指示書とを含む。キットは、1つ以上の細胞障害薬、標的剤、検出可能標識、薬学的塩、または緩衝液も含むことができる。キットは、容器、および場合により1つ以上のバイアル、試験管、フラスコ、ボトル、またはシリンジも含むことができる。キットの他のフォーマットは、当業者に理解され、本発明の範囲内である。
別の態様において、本発明は、疾患状態の治療の必要な対象において疾患状態を治療する方法であって、治療有効量の本発明の化合物またはその薬学的に許容される塩と、薬学的に許容される担体とを含む薬学的組成物を、対象に投与することを含む方法を提供する。
本発明における使用に適した薬学的組成物には、活性成分が治療有効量、すなわち、その意図される目的を達成する有効量で含有される組成物が含まれる。特定の用途のための実際の有効量は、とりわけ、治療される状態によって決まる。有効量の決定は、とりわけ本明細書の詳細な開示を考慮すると、十分に当業者の能力の範囲内である。
her2またはegfr形質移入L細胞系
試薬:L細胞は、ATCC(Manassas,VA;Cat No CRL2648)由来のものであり、Her2/pEZ−Lv105またはegfr/pCMV cDNAは、Sino Biological Inc.,(カタログ番号H10004)またはGeneCopoeia(カタログ番号Z2866)から購入し、グルコースDMEM、L−グルタミン、リポフェクタミン2000は(Invitrogen;Carlsbad,CA)のものである。
複合トラスツズマブの結合能を決定するため、ヒトher2を発現するL細胞のFACS分析を実施した。簡潔には、her2を一過的に導入した100μl中およそ106細胞のL細胞を、様々な量のトラスツズマブ複合抗体、PBS、もしくは二次抗体のみと共にインキュベートするか、または無関係のhuIgGを陰性対照として使用した。洗浄した後、細胞をFACS緩衝液に再懸濁し、100μLの反応量中の20μLの、フィコエリトリン(Mu抗ヒトPE)二次抗体に結合したマウス抗ヒトIgGと共に室温で30分間インキュベートした。洗浄した後、細胞を200μLの2%パラホルムアルデヒド/PBSで固定し、フローサイトメトリーを実施した。同じ手順をアイソタイプ対照として無関係のヒトIgG抗体に対して使用して、細胞系毎にベースラインPMTを設定した。フローサイトメトリーを、BD FACSCalibur(登録商標)により実施し、幾何平均蛍光強度をそれぞれの試料に対して記録した。記録したデータを、FlowJoソフトウエアを使用して分析した。結果を図1に示す。
試薬:トラスツズマブ(Roche/Genentech Corporation,South San Francisco,CA)、セツキシマブ(Merck,)、レシキモド(resiquimod)と結合したMC−val−cit−PAB(MC−vc−PAB−TLRL)またはレシキモド(resiquimod)と結合したMC(MC−TLRL)(Contract Research Organization,Chinaにおいて合成)、ホウ酸ナトリウム、塩化ナトリウム、ジチオスレイトール(DTT)、Sephadex G25、DTPA、DTNB、およびマレイミドカプロイル−モノメチル(Sigma−Aldrich,Milwaukee,Wisconsin)。
トラスツズマブを、20mg/mLでの緩衝液交換によりHERCEPTIN(登録商標)から精製し、500mMのホウ酸ナトリウムおよび500mMの塩化ナトリウムにpH8.0で溶解した抗体を、100mMの過剰量ジチオスレイトール(DTT)で処理する。37℃で約30分間インキュベートした後、緩衝液をSephadex G25樹脂による溶出で交換し、1mMのDTPAを有するPBSで溶出する。チオール/Ab値は、DTNB(Sigma−Aldrich,Milwaukee,Wisconsin)との反応および412nmでの吸光度の決定により、溶液の280nmでの吸光度およびチオール濃度から還元抗体濃度を決定することによって調べる。PBSに溶解した還元抗体を氷上で冷やす。DMSOに溶解した、レシキモド(resiquimod)と結合したMcである薬剤リンカー試薬を、既知の濃度でアセトニトリルおよび水において希釈し、PBS中の冷却還元抗体に加える。約1時間後、過剰量のマレイミドを加えて、反応を停止させ、あらゆる未反応抗体のチオール基をキャップする。幾つかの場合において、標準的な手順により免疫グロブリンのリシンへの結合を実施した。反応混合物を遠心分離限外濾過により濃縮し、複合抗体を精製し、PBS中のG25樹脂を介する溶出により脱塩し、0.2μmフィルターにより滅菌条件下で濾過し、凍結保存した。セツキシマブMC−TLRLの調製は、同じ手順を使用した。
抗体を、マレイミドカプロイル−バリン−シトルリン(vc)−p−アミノベンジルオキシカルボニル(MC−vc−PAB)によりシステインを介してTLRLに結合した。MC−vc−PABリンカーは、カテプシンBのような細胞間プロテアーゼにより切断可能であり、切断されると、遊離薬剤を放出し(Doronina et al.,Nat.Biotechnol.,21:778−784(2003))、一方、MCリンカーは、細胞内プロテアーゼによる切断に対して抵抗性がある。精製されたトラスツズマブを、500mMのホウ酸ナトリウムおよび500mMの塩化ナトリウムにpH8.0で溶解し、100MMの過剰量ジチオスレイトール(DTT)で更に処理した。37℃で約30分間インキュベートした後、緩衝液をSephadex G25樹脂による溶出で交換し、1mMのDTPAを有するPBSで溶出する。チオール/Ab値は、DTNB(Sigma−Aldrich,Milwaukee,Wisconsin)との反応および412nm(吸光係数=13600cm−1M−1)での吸光度の決定により、溶液の280nmでの吸光度およびチオール濃度から還元抗体濃度を決定することによって調べた。PBSに溶解した還元抗体を氷上で冷やした。DMSO中のレシキモド(resiquimod)と結合したMC−val−cit−PAB−PNPを、アセトニトリルおよび水に溶解し、PBS中の冷却還元抗体に加えた。1時間のインキュベーションの後、過剰量のマレイミドを加えて、反応を停止させ、あらゆる未反応抗体のチオール基をキャップした。幾つかの場合において、標準的な手順により免疫グロブリンのリシンへの結合を実施した。反応混合物を遠心分離限外濾過により濃縮し、抗体薬剤複合体を精製し、PBS中のG25樹脂を介する溶出により脱塩し、0.2μmフィルターにより滅菌条件下で濾過し、凍結保存した。セツキシマブMC−vc−TLRLの調製は、同じ手順を使用した。
試薬:SKBR3細胞(ATCC、カタログ番号HTB−30)、McCoy’s 5A(Invitrogen、カタログ番号22400、ロット番号747809)、RPMI−1640(Invitrogen、カタログ番号11835、ロット番号764956)、FCS(Hyclone、カタログ番号SH30084.03、ロット番号GRH0054)、Ficoll−Hypaque(Amersham Biosciences,Piscataway,NJ、カタログ番号17−1440−02)、96ウエルプレート(Costar、カタログ番号3599、カタログ番号3916)、トリパンブルー(Invitrogen、カタログ番号15250−061)、LDHキット(Promega、カタログ番号G7891)、ELISA読み取り機MD5(Molecule device)、ヒト化抗体Herceptin(登録商標)(Genentech Corporation,South San Francisco,CA;商標名トラスツズマブ(Trastuzumab))を、使用前に、水で再構成して10mg/mlの貯蔵液を作製した。
細胞障害%=100%×[A490nm(試料)−A490(標的細胞)−A490(効果細胞]/[A490nm(溶解標的細胞)−A490nm(標的細胞)]に従って計算した。
ヒトPBMCは、Ficoll遠心分離により、健康な志願提供者から得た軟膜から調製した。樹状細胞は、ヒトPBMCからの抗CD3、CD19、CD20、CD14、およびCD16抗体の混合物により、磁気ビーズ(Miltenyi Biotec)を用いる負の枯渇(negative depletion with magnetic beads)を使用して濃縮した。DCの濃縮を、ヤギ抗マウスFITC(系列)、HLA−DR−APCCy7、CD123−BV421、およびCD11C−APCで染色した。染色された細胞をBD LSR Fortessaにより分析した。抗CD3、CD4、CD11C、CD19、CD14、CD16、CD123モノクローナル抗体は、BD BiosciencesまたはBiolgendから購入した。
1〜2×105濃縮DCを、96ウエルプレートにおいて100μLの培地にプレーティングし、100μLの希釈刺激薬をプレートに加え、37℃のインキュベーター中で20〜22時間培養した。上澄みを収集し、ヒトIFN−α、IL−6、IL−12(p70)、およびTNA−αをELISA(Mattech AB)により分析した。
全ての比較の有意性は、偽(mock)と試料群との間の不等分散を推定し、スチューデント両側t検定を使用して計算され、結果は、p<0.05の場合に有意であるとした。パラメーター間の相関関係は、スピアマンの順位相関検定を使用して評価し、P値<0.05を統計的に有意であるとした。
患者由来胃癌異種移植片(PDX)マウスモデルの作製のため、6〜8週齢の雌Balb/cヌードマウス(SLAC,Shanghai,China)を、腫瘍フラグメント埋め込みに使用した。動物には、通常のヌードマウス食餌を与え、実験動物の飼育および使用のガイド(Guide for Care and Use of Laboratory Animals)、ならびに研究機関の動物管理および使用委員会(Institutional Animal Care and Use Committee)の規制に従って、SPF動物施設に収容した。大きさが約15〜30mm3の特許STO番号69胃癌フラグメントをBalb/cヌードマウスの腹部右側(皮下)に埋め込んだ。
式(I)、TM−Ln−AM (I)の構造を有し、
式中、TMは、標的部分であり、AMは、ヒト樹状細胞、NK細胞、もしくは腫瘍細胞、またはこれらの組み合わせを活性化することができる活性化部分であり、Lnは、リンカーであり、nは、0および1から選択される整数である、化合物。
前記ヒト樹状細胞は、形質細胞様樹状細胞である、
ことを特徴とする付記1に記載の化合物。
前記ヒト樹状細胞は、骨髄樹状細胞である、
ことを特徴とする付記1に記載の化合物。
前記AMは、ヒトTLR7またはTLR8に特異的に結合することができる、
ことを特徴とする付記1に記載の化合物。
前記AMは、ヒトTLR7およびTLR8に特異的に結合することができる、
ことを特徴とする付記1に記載の化合物。
式(I)、TM−Ln−AM (I)の構造を有し、
式中、TMは、標的部分であり、AMは、ヒトTLR7および/またはTLR8に特異的に結合することができる活性化部分であり、Lnは、リンカーであり、nは、0および1から選択される整数である、化合物。
前記AMは、ヒトTLR7およびTLR8の両方に特異的に結合することができる、
ことを特徴とする付記6に記載の化合物。
TMが抗体を含む場合、AMはCpGオリゴヌクレオチドを含まない、
ことを特徴とする付記1乃至7のいずれか1つに記載の化合物。
前記標的部分は、非腫瘍細胞と比較して、腫瘍細胞に特異的または優先的に結合することができる、
ことを特徴とする付記1乃至8のいずれか1つに記載の化合物。
前記腫瘍細胞は、癌腫、肉腫、リンパ腫、骨髄腫、または中枢神経系癌のものである、
ことを特徴とする付記9に記載の化合物。
前記標的部分は、非腫瘍抗原と比較して、腫瘍抗原に特異的または優先的に結合することができる、
ことを特徴とする付記1乃至8のいずれか1つに記載の化合物。
前記腫瘍抗原は、CD2、CD19、CD20、CD22、CD27、CD33、CD37、CD38、CD40、CD44、CD47、CD52、CD56、CD70、CD79、およびCD137からなる群から選択される、
ことを特徴とする付記11に記載の化合物。
前記腫瘍抗原は、4−1BB、5T4、AGS−5、AGS−16、アンジオポエチン2、B7.1、B7.2、B7DC、B7H1、B7H2、B7H3、BT−062、BTLA、CAIX、癌胎児性抗原、CTLA4、クリプト(Cripto)、ED−B、ErbB1、ErbB2、ErbB3、ErbB4、EGFL7、EpCAM、EphA2、EphA3、EphB2、FAP、フィブロネクチン、葉酸受容体、ガングリオシドGM3、GD2、グルココルチコイド誘発性腫瘍壊死因子受容体(GITR)、gp100、gpA33、GPNMB、ICOS、IGF1R、インテグリンαν、インテグリンανβ、KIR、LAG−3、ルイスY、メソテリン、c−MET、MN炭酸脱水酵素IX、MUC1、MUC16、ネクチン−4、NKGD2、NOTCH、OX40、OX40L、PD−1、PDL1、PSCA、PSMA、RANKL、ROR1、ROR2、SLC44A4、シンデカン−1、TACI、TAG−72、テネイシン、TIM3、TRAILR1、TRAILR2、VEGFR−1、VEGFR−2、VEGFR−3、およびこれらの変異体からなる群から選択される、
ことを特徴とする付記11に記載の化合物。
前記標的部分は、免疫グロブリン、タンパク質、ペプチド、小分子、ナノ粒子、または核酸を含む、
ことを特徴とする付記1乃至13のいずれか1つに記載の化合物。
前記標的部分は、抗体またはその機能性フラグメントを含む、
ことを特徴とする付記14に記載の化合物。
前記抗体は、Rituxan(リツキシマブ)、Herceptin(トラスツズマブ)、Erbitux(セツキシマブ)、Vectibix(パニツムマブ)、Arzerra(オファツムマブ)、Benlysta(ベリムマブ)、Yervoy(イピリムマブ)、Perjeta(ペルツズマブ)、トレメリムマブ、ニボルマブ、ダセツズマブ、ウレルマブ(Urelumab)、MPDL3280A、ランブロリズマブ(Lambrolizumab)、およびブリナツモマブ(Blinatumomab)からなる群から選択される、
ことを特徴とする付記15に記載の化合物。
前記標的部分は、Fab、Fab′、F(ab′)2、単一ドメイン抗体、TおよびAbs二量体、Fv、scFv、dsFv、ds−scFv、Fd、線状抗体、ミニボディ、二特異性抗体(diabody)、二重特異的抗体フラグメント、バイボディ(bibody)、トリボディ(tribody)、sc−二特異性抗体、カッパ(ラムダ)体、BiTE、DVD−Ig、SIP、SMIP、DART、または1つ以上のCDRを含む抗体類縁体を含む、
ことを特徴とする付記15に記載の化合物。
前記標的部分は、VEGFRのATWLPPRポリペプチド、トロンボスポンジン−1模倣体、CDCRGDCFCG(環状)ポリペプチド、SCH221153フラグメント、NCNGRC(環状)ポリペプチド、CTTHWGFTLCポリペプチド、CGNKRTRGCポリペプチド(LyP−1)、オクトレオチド、バプレオチド、ランレオチド、C−3940ポリペプチド、デカペプチル、ルプロン、ゾラデックス、またはセトロレリクスを含む、
ことを特徴とする付記14に記載の化合物。
前記標的部分は、葉酸またはその誘導体を含む、
ことを特徴とする付記14に記載の化合物。
前記標的部分は、PD−1、CTLA4、BTLA、KIR、TIM3、4−1BB、LAG3、表面リガンドアンフィレギュリンの一部の完全長、ベータセルリン、EGF、エフリン、エピジェン(epigen)、エピレギュリン、IGF、ニューレグリン、TGF、TRAIL、またはVEGFの細胞外ドメイン(ECD)または可溶形態を含む、
ことを特徴とする付記14に記載の化合物。
前記標的部分は、ナノ粒子を含む、
ことを特徴とする付記14に記載の化合物。
前記標的部分は、アプタマーを含む、
ことを特徴とする付記14に記載の化合物。
前記活性化部は、(a)一本鎖RNA(ssRNA)、好ましくはORN02、ORN06、ssポリ(U)、ssRNA40、ssRNA41、ssRNA−DR、もしくはポリ(dT)、または(b)受容体リガンド類縁体、好ましくはCL075、CL097、CL264、CL307、ガーディキモド、ロキソリビン、イミキモド、もしくはレシキモド(Resiquimod)を含む、
ことを特徴とする付記1乃至22のいずれか1つに記載の化合物。
前記AMは、レシキモド(Resiquimod)(R848)を含む、
ことを特徴とする付記23に記載の化合物。
前記リンカーは、ヒドラジン基、ポリペプチド、ジスルフィド基、およびチオエーテル基からなる群から選択される、
ことを特徴とする付記1乃至24のいずれか1つに記載の化合物。
前記リンカーは、酵素切断性である、
ことを特徴とする付記1乃至24のいずれか1つに記載の化合物。
前記リンカーは、酵素切断性ではない、
ことを特徴とする付記1乃至24のいずれか1つに記載の化合物。
付記1乃至27のいずれか1つに記載の化合物またはその薬学的に許容される塩と、1つ以上の薬学的に許容される担体と、を含む、薬学的組成物。
第2の化学療法剤を更に含む、付記28に記載の薬学的組成物。
前記化学療法剤は、タモキシフェン、ラロキシフェン、アナストロゾール、エキセメスタン、レトロゾール、イマタニブ(imatanib)、パクリタキセル、シクロホスファミド、ロバスタチン、ミノシン(minosine)、ゲムシタビン、シタラビン、5−フルオロウラシル、メトトレキセート、ドセタキセル、ゴセレリン、ビンクリスチン、ビンブラスチン、ノコダゾール、テニポシド、エトポシド、ゲムシタビン、エポチロン、ビノレルビン、カンプトテシン、ダウノルビシン、アクチノマイシンD、ミトキサントロン、アクリジン、ドキソルビシン、エピルビシン、またはイダルビシンからなる群から選択される、
ことを特徴とする付記29に記載の薬学的組成物。
疾患状態の治療の必要な対象において疾患状態を治療する方法であって、治療有効量の付記1乃至27のいずれか1つに記載の化合物またはその薬学的に許容される塩と、薬学的に許容される担体と、を含む薬学的組成物を、前記対象に投与することを含む、方法。
前記疾患状態は、腫瘍である、
ことを特徴とする付記31に記載の方法。
前記疾患状態は、異常細胞増殖を含む、
ことを特徴とする付記31に記載の方法。
前記異常細胞増殖は、前癌性病変を含む、
ことを特徴とする付記33に記載の方法。
前記異常増殖は、癌細胞のものである、
ことを特徴とする付記33に記載の方法。
前記癌は、乳癌、結腸直腸癌、びまん性大細胞型B細胞リンパ腫、子宮内膜癌、濾胞性リンパ腫、胃癌、神経膠芽腫、頭頸部癌、肝細胞癌、肺癌、黒色腫、多発性骨髄腫、卵巣癌、膵癌、前立腺癌、および腎細胞癌からなる群から選択される、
ことを特徴とする付記35に記載の方法。
式(I)、TM−Ln−AM (I)の構造を有し、
式中、TMは、標的部分であり、AMは、活性化部分であり、Lnは、リンカーであり、nは、0および1から選択される整数であり、
但し、TMが抗体を含む場合、AMは、CpGオリゴヌクレオチドまたは治療剤を含まない、化合物。
前記活性化部分は、TLRリガンド(TLRL)、Nod様受容体リガンド、RIG様受容体リガンド、CLRリガンド、CDSリガンド、またはインフラマソーム誘発剤を含む、
ことを特徴とする付記37に記載の化合物。
前記活性化部分は、TLR2、TLR3、TLR4、TLR5、TLR7、TLR8、TLR7/TLR8、TLR9、およびTLR10からなる群から選択される1つ以上のTLRのリガンドを含む、
ことを特徴とする付記38に記載の化合物。
前活性化部分は、
(i)(a)加熱死菌生成物、好ましくはHKAL、HKEB、HKHP、HKLM、HKLP、HKLR、HKMF、HKPA、HKPG、またはHKSA、HKSP、および(b)細胞壁成分生成物、好ましくはLAM、LM、LPS、LTA、LTA、PGN、FSL、Pam2CSK4、Pam3CSK4、またはザイモサンからなる群から選択されるTLR2のリガンド、
(ii)ポリ(I:C)およびポリ(A:U)からなる群から選択されるTLR3のリガンド、
(iii)LPSおよびMPLAからなる群から選択されるTLR4のリガンド、
(iv)FLAおよびフラゲリンからなる群から選択されるTLR5のリガンド、
(v)ORN02、ORN06、ssポリ(U)、ssRNA40、ssRNA41、ssRNA−DR、ポリ(dT)、CL075、CL097、CL264、CL307、ガーディキモド、ロキソリビン、イミキモド、およびレシキモド(Resiquimod)からなる群から選択されるTLR7/8のリガンド、
(vi)ODN1585、ODN1668、ODN1826、ODN2006、ODN2007、ODN2216、ODN2336、ODN2395、およびODN M362からなる群から選択されるTLR9のリガンド、
(vii)TLR10のリガンド、
(viii)NOD1作動薬(C12−iE−DAP、iE−DAP、Tri−DAP)、NOD2作動薬(L18−MDP、MDP、M−TriLYS、M−TriLYS−D−ASN、ムラブチド(Murabutide)、N−グリコリル−MDP)、およびNOD1/NOD2作動薬(M−TriDAP、PGN)からなる群から選択されるヌクレオチドオリゴマー化ドメイン(NOD)様のリガンド、
(ix)5′ppp−dsRNA、ポリ(dA:dT)、ポリ(dG:dC)、およびポリ(I:C)からなる群から選択される1つ以上のRIG−I−様受容体(RLR)のリガンド、
(x)カードランAL、HKCA、HKSC、WGP、ザイモサン、およびトレハロース−6,6−ジベヘン酸塩からなる群から選択される1つ以上のC型レクチン受容体(CLR)のリガンド、
(xi)c−GMP、c−G−AMP、c−G−GMP、c−A−AMP、c−di−AMP、c−di−IMP、c−di−GMP、c−di−UMP、HSV−60、ISD、pCpG、ポリ(dA:dT)、ポリ(dG:dC)、ポリ(dA)、およびVACV−70からなる群から選択される1つ以上の細胞質DNAセンサー(CDS)のリガンド、あるいは
(xii)(a)NLRP3インフラマソームタンパク質複合体、好ましくはミョウバン結晶、ATP、CPPD結晶、ヘルモゾイン(Hermozoin)、MSU結晶、ナノSiO2、ナイジェリシン、および(b)AIM2インフラマソームタンパク質複合体、好ましくはポリ(dA:dT)からなる群から選択されるインフラマソーム誘発剤、
を含む、
ことを特徴とする付記39に記載の化合物。
前記活性化部分は、IMO2134、IMO205、MGN−1703、MGN−1704、アガトリモド(Agatolimod)、SD−101、QAX−935、DIMS0150、ポリネクスクアットロ(Pollinex Quattro)、OM−174、エリトラン、TAK−242、NI−0101、I型インターフェロン、II型インターフェロン、III型インターフェロン、IL−12、IL−23、IL−18、IL−7、またはIL−15を含む、
ことを特徴とする付記37に記載の化合物。
Claims (15)
- 式(I)、TM−Ln−AM (I)の構造を有し、
式中、TMは、腫瘍細胞上に発現する抗原に特異的に結合し、且つ、直接的に又は間接的に、細胞増殖を抑制すること又はアポトーシスを誘導することができる免疫グロブリン又はその機能性フラグメントを含む標的部分であり、
AMは、ヒトのTLR7およびTLR8に特異的に結合し、且つ、ヒトの、樹状細胞、NK細胞、又はこれらの両方を活性化する活性化部分であり、
Lは、リンカーであり、nは、0および1から選択される整数である、
ことを特徴とする化合物。 - 前記TMは、治療モノクローナル抗体を含む、
ことを特徴とする請求項1に記載の化合物。 - 前記治療モノクローナル抗体は、抗体依存性細胞仲介細胞障害(ADCC)又は補体依存性細胞傷害(CDC)を媒介する、
ことを特徴とする請求項2に記載の化合物。 - 前記AMは、レシキモドである、
ことを特徴とする請求項1に記載の化合物。 - 前記抗原は、CD19、CD20、CD22、CD37、CD38、CD47、CD52、アンジオポエチン2、ErbB3、ErbB4、EGFL7、EGFR、EphA2、EphA3、EphB2、Her2、IGF1R、ルイスY、メソテリン、c−MET、MUC1、NKGD2リガンド、NOTCH、PD−L1、PSCA、PSMA、RANKL、ROR1、およびROR2からなる群より選択される、
ことを特徴とする請求項1に記載の化合物。 - 前記抗原は、CD19、CD20、CD38、EGFR、Her2、およびPD−L1からなる群より選択される、
ことを特徴とする請求項1に記載の化合物。 - 前記腫瘍細胞は、癌腫、肉腫、リンパ腫、骨髄腫、または中枢神経系癌のものである、
ことを特徴とする請求項1に記載の化合物。 - 請求項1から7のいずれか1項に記載の化合物又はその薬学的に許容される塩と、1つ以上の薬学的に許容される担体とを含む、
ことを特徴とする医薬組成物。 - 第2の化学療法剤を更に含む、
ことを特徴とする請求項8に記載の医薬組成物。 - 前記化学療法剤は、タモキシフェン、ラロキシフェン、アナストロゾール、エキセメスタン、レトロゾール、イマタニブ(imatanib)、パクリタキセル、シクロホスファミド、ロバスタチン、ミノシン(minosine)、ゲムシタビン、シタラビン、5−フルオロウラシル、メトトレキセート、ドセタキセル、ゴセレリン、ビンクリスチン、ビンブラスチン、ノコダゾール、テニポシド、エトポシド、エポチロン、ビノレルビン、カンプトテシン、ダウノルビシン、アクチノマイシンD、ミトキサントロン、アクリジン、ドキソルビシン、エピルビシン、およびイダルビシンからなる群から選択される、
ことを特徴とする請求項9に記載の医薬組成物。 - 請求項1から7のいずれか1項に記載の化合物又はその薬学的に許容される塩と、1つ以上の薬学的に許容される担体とを含む、
ことを特徴とする、異常細胞増殖を特徴とする疾患状態を治療するための医薬組成物。 - 前記疾患状態は、腫瘍である、
ことを特徴とする請求項11に記載の医薬組成物。 - 前記異常細胞増殖は、前癌性病変を含む、
ことを特徴とする請求項11に記載の医薬組成物。 - 前記異常細胞増殖は、癌細胞のものである、
ことを特徴とする請求項11に記載の医薬組成物。 - 前記癌は、乳癌、結腸直腸癌、びまん性大細胞型B細胞リンパ腫、子宮内膜癌、濾胞性リンパ腫、胃癌、神経膠芽腫、頭頸部癌、肝細胞癌、肺癌、黒色腫、多発性骨髄腫、卵巣癌、膵癌、前立腺癌、および腎細胞癌からなる群から選択される、
ことを特徴とする請求項14に記載の医薬組成物。
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