JP2019518479A - 細胞標的化された薬学的に活性な物質または標識送達系 - Google Patents
細胞標的化された薬学的に活性な物質または標識送達系 Download PDFInfo
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Abstract
Description
a) 精製された鉄結合タンパク質を提供すること、
b) 薬学的に活性な物質、標識または薬学的に活性な物質と標識を共有結合的または非共有結合的に連結し、および/または、薬学的に活性な物質、標識または薬学的に活性な物質と標識を鉄結合タンパク質中に封入すること、
c) CD45+白血球細胞を提供すること、および
d1) 鉄結合タンパク質と、工程b)で産生された薬学的に活性な物質、標識または薬学的に活性な物質と標識の複合体がCD45+白血球細胞に少なくとも部分的に負荷されるまで、工程b)で産生した鉄結合タンパク質の存在下でCD45+白血球細胞をインキュベートすること、および/または
d2) CD45+白血球細胞が少なくとも部分的に標識で標識されるまで、標識の存在下でCD45+白血球細胞をインキュベートすること
を含む、請求項1〜25の単離された標的化送達系の作製方法に関する。
好ましくは、相対濃度は、身体の疾患領域と、血液循環に同様のアクセスを有する身体の他の領域との間で比較される。好ましい態様において、所与の細胞数または疾患領域由来の所与の生検体積における標識、特に造影剤の濃度は、本発明の標的化送達系の投与後、好ましくは1〜24時間後の非疾患領域からの同一の細胞数または生検体積と比較した場合、少なくとも10%高い。より好ましくは、標識の濃度、特に患者の体の疾患領域における造影剤の濃度は、本発明の標的化送達系の投与後、好ましくは2〜24時間後の身体の非罹患領域よりも、少なくとも20%、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70 少なくとも80%、少なくとも90%、少なくとも100%、少なくとも150%、少なくとも200%、少なくとも250%、少なくとも300%、少なくとも350%、少なくとも400%、少なくとも450%、少なくとも500%、より好ましくは少なくとも1000%高い。全身体分布に基づいて評価する場合、標識、特に患者または診断される人に投与される造影剤の少なくとも5%、好ましくは少なくとも10 %、より好ましくは少なくとも15%は、身体の疾患領域に送達されることが好ましい。標識、特に造影剤の標的化送達は、標識、特に造影剤の身体の疾患領域への潜在的に有害な影響を制限する。
http://www.ebi.ac.uk/Tools/clustalw/ またはhttp://www.ebi.ac.uk/Tools/clustalw2/index.html またはonhttp://npsa-pbil.ibcp.fr/cgi-bin/npsa_automat.pl?page=/NPSA/npsa_clustalw.html.好ましいパラメーターはhttp://www.ebi.ac.uk/Tools/clustalw/ またはhttp://www.ebi.ac.uk/Tools/clustalw2/index.htmlに設定されているデフォルトのパラメーターが使用される。配列同一性(配列一致)の程度は例えばBLAST、BLATまたはBlastZ(または BlastX)を使用して計算してよい。BLASTタンパク検索は、BLASTPプログラム、スコア= 50、語長= 3で実施する。比較目的のためのギャップのあるアライメントを得るために、Altschulら (1997) Nucleic Acids Res. 25: 3389-3402に記載されているGapped BLASTを利用する。BLASTおよびGapped BLASTプログラムを利用する場合、それぞれのプログラムのデフォルトパラメーターが使用される。配列一致分析は、Shuffle-LAGAN (Brudno M., Bioinformatics 2003b, 19 Suppl 1:I54-I62)やマルコフ確率場のような確立された相同性マッピング技術によって補完してよい。配列データベース検索からの情報、3D構造およびユーザ定義の制約を有する利用可能な相同配列を使用して(Pei J、Grishin NV:PROMALS:towards accurate multiple sequence alignments of distantly related proteins.Bioinformatics 2007、23:802-808;3DCoffee@ igs:配列と構造を複数の配列アライメントに結合するためのWebサーバー;Poirot O, Suhre K, Abergel C, O'Toole E, Notredame C. NucleicAcidsRes. 2004 Jul 1;32:W37-40)、複数のタンパク質配列および/または構造のための構造ベースアライメントを使用してもよい。本願において配列同一性のパーセンテージが参照される場合、特に示さない限り、これらのパーセンテージは、より長い配列の全長に関して計算される。
(i) 単球は、CD11b+単球であり、好ましくは、CD11b+CD14+単球、CD11b+CD16+単球、CD11b+ CD14+CD16+単球、CD11b+ CD14+MHCII+単球、CD11b+ CD14+CD115+単球、CD11b+ CD114+単球、CD11b+CD116+単球、CD11b+CCR1+単球、CD11b+ CCR2+単球、CD11b+CX3CR+単球、CD11b+CXR4+単球、CD11b+ CXR6+単球およびCD11b+CD14+ CD33+単球からなる群から選択され、
好ましくは単球はIRF8、NFIL3、BATF3、RELB、PU/1、RBPJ、IIRF4、および/またはTCF4のうちの1つ以上の転写因子によって分化が制御される樹状細胞ではなく、および、より好ましくは単球は樹状細胞ではない、
(ii) M-CSF分化した単球または単球マクロファージは、M-CSFによって分化し、 マクロファージ、活性化マクロファージ、好ましくはCD11 b+マクロファージ、より好ましくはCD11b+ CD16+マクロファージ、CD11b+CD32+マクロファージ、CD11b+ CD64+マクロファージ、CD11b+CD68+マクロファージ、好ましくは、CD11b+ CD86+M1マクロファージ、好ましくは誘導性酸化窒素合成酵素(inducible nitric oxidesynthetase:iNOS)を産生するマクロファージ、および/または分泌性インターロイキン12(IL-12)を産生するマクロファージまたは好ましくはCD11b+ CCR2+ M2マクロファージ、CD11b+ CD204+ M2マクロファージ、CD11b+ CD206+ M2マクロファージ、CD11b+ CD204+ CD206+ M2マクロファージ、CD11b+主要組織適合性複合体II+(MHC II+)(低発現または高発現)M2マクロファージ、CD11b+ CD200R+ M2マクロファージ、CD11b+ CD163+ M2マクロファージ、またはアルギナーゼ-1および/またはインターロイキン10(IL-10)を産生および/または分泌する活性化マクロファージからなる群から選択され、好ましくは、分化した単球は、レクチン様酸化低密度リポタンパク質受容体-1 (Lox1+)、C-X-Cケモカインレセプタータイプ7(CXCR7+)および核因子(赤血球由来2)様2(NRF2+)を発現する泡沫細胞ではない。泡沫細胞は、低密度リポタンパク質を摂取し、脂質を負荷して泡沫の外観を与える血管壁の脂肪性沈着物に局在する一種のマクロファージである。これらの細胞は、プラーク増殖に関与する種々の物質を分泌し、その死により炎症が促進され、それにより心血管疾患に寄与する、
(iii) 単球マクロファージまたは活性化単球マクロファージはM-CSFによって分化され、好ましくは少なくとも1つのケモカイン受容体であって、好ましくはCCR1、CCR2、CXCR4、およびCXCR6からなる群から選択されるケモカイン受容体、または少なくとも1つの増殖因子受容体であって、好ましくはマクロファージコロニー刺激因子受容体(CD115)、顆粒球コロニー刺激因子受容体(CD114)、および顆粒球マクロファージコロニー刺激因子受容体(CD116およびCD131からなる)からなる群から選択される増殖因子受容体を発現する。これらの特徴の単球は、炎症状態および癌を治療するのに特に適している、
(iv) リンパ球は、CD3+およびCD4+ またはCD8+ Tリンパ球、またはCD19+、CD20+、CD21+、CD19+ CD20+、CD19+ CD21+、CD20+CD21+、もしくはCD19+ CD20+CD21+ Bリンパ球、またはナチュラルキラー(NK)細胞であって、好ましくはNK細胞はCD56+でありCD3を発現しない細胞、または、CD16+CD56+、CD56+CD94+、CD56+CD158a+、CD56+CD158f+、CD56+CD314+、CD56+CD335+細胞からなる群から選択される、または
(v) 顆粒球は、好中球、好ましくはCD66 b+好中球、好酸球および好塩基球、好ましくはCD193+好酸球からなる群より選択される。
活性化マクロファージは:
(i) 単球またはマクロファージまたはそれらの前駆体を、マクロファージ上の発現マーカーを変更することができる因子でインビトロでインキュベートすることによって産生され得るものであり、好ましくは
(a) 少なくとも1つのM1誘導因子で
(b) 少なくとも1つのM2誘導因子で
(c) またはサイトカイン、好ましくはIL-10およびIL-12、ケモカインを分泌する能力、および/またはiNOS、アルギナーゼまたは他の免疫調節酵素を産生する能力を変化させることができる因子で;そのような因子の例としては:活性化血小板、IL-4、IL-10、IL-13、抗原と抗体の免疫複合体、IgG、熱活性化ガンマグロブリン、グルココルチコステロイド、腫瘍成長因子-β(TGF-β)、IL-1R、CC- ケモカインリガンド2(CCL-2)、IL-6、マクロファージコロニー刺激因子(M-CSF)、ペルオキシソーム増殖因子活性化受容体γ(PPARγ)アゴニスト、白血球阻害因子(LIF)、アデノシン、蠕虫および真菌感染症、リポ多糖類(LPS)、インターフェロンγ(INF-γ)、ウイルスおよび細菌感染症が挙げられる;この点に関し、M1誘導因子、特にLPSによる単球の活性化は、細胞にiNOSを発現させ、M1誘導因子、特にLPSによる単球の活性化はアルギナーゼ-1を発現しない細胞を誘導し、M2誘導因子、特にIL-4による単球の活性化は細胞にアルギナーゼ-1を発現させ、およびM2誘導因子、特にIL-4での単球の活性化は細胞にiNOSを発現しないようすることが観察された、
(ii) 以下の抗原:CD64、CD86、CD16、CD32、MHCIIの高発現、および/またはiNOSおよび/またはIL-12の産生の少なくとも1つの発現を特徴とする、
(iii) マクロファージの貪食能を誘導することができる因子、例えば、IL-18、オプソニン(例えば、iC3b、免疫グロブリンGなどの補体由来タンパク質)、カルシトニン遺伝子関連ペプチド(CGRP)、リポ多糖(LPS)、インターフェロンγ(INF-γ)、ウイルス感染および/または細菌感染との単球またはマクロファージのインビトロインキュベーションによって産生される、
(iv) 以下の抗原の少なくとも1つの発現によって特徴づけられる:CD204、CD206、CD200R;CCR2、トランスフェリン受容体 (TfR)、CXC-モチーフケモカイン受容体4 (CXCR4)、CD163、および/またはT細胞免疫グロブリンドメインおよびムチンドメイン2(TIM-2)、および/またはMHCIIの低発現を示す;これらの特性を有する活性化マクロファージは、鉄結合タンパク質としてフェリチンを含む複合体に特に適している、
(v) 貪食する能力を有する;および/または
(vi) サイトカイン分泌、好ましくはIL-12もしくはIL-10、または誘導型一酸化窒素合成酵素(iNOS)(もしくは他の前炎症性化合物)、アルギナーゼまたは他の免疫抑制性/抗炎症性化合物の産生が可能である。
単球マクロファージは、
(i) CD34+造血前駆細胞から産生される、
(ii) 少なくとも1つの誘導因子、好ましくはM1またはM2誘導因子、より好ましくは少なくとも1つのM2誘導因子と単球をインビトロでインキュベートすることによって産生できる、
(iii) 以下の抗原のうち少なくとも1つの発現によって特徴付けられる:TfR、CD163、TIM-2、CD14、CD16、CD33、および/またはCD115、
(iv) 以下の抗原のうち少なくとも1つの発現によって特徴付けられる:TfR、CD163、TIM-2、CXCR4、CD14、および/またはCD16、および/または
(v) 貪食作用する能力を有する、および/または
(vi) 分化が以下の転写因子のうちの1つ以上によって制御される樹状細胞ではない:IRF8、NFIL3、BATF3またはRELB、PU/1、RBPJ、IRF4またはTCF4。
リンパ球は:
(i) 血液、脾臓、または骨髄から入手可能であるか、または当業者に知られているように、および、例えば、LefortおよびKim, 2010, J Vis Exp 40: 2017;Tassone andFidler, 2012, Methods in Molecular Biology 882: 351-357;Kouroら2005, Current Protocols in Immunology,66:F22F.1:22F.1.1-22F.1.9.にも記載されているように、CD34+前駆細胞から生産可能である、
(ii) 免疫学的に能力のあるリンパ球である、
(iii) 抗原特異的T細胞受容体を発現する、および/または
(iv) 以下の抗原のうち少なくとも1つの発現によって特徴付けられる: (a) CD3 および CD4 またはCD8、または (b): CD19、CD20、CD21、CD19 CD20、CD19CD21、CD20CD21、またはCD19 CD20CD21 抗原、および好ましくは免疫グロブリンを産生可能である。
(i) 血液、脾臓または骨髄から得ることが可能であるか、またはCD34+前駆細胞から産生可能であるか、および/または
(ii) CD3発現の欠失および以下のCD56+および/またはCD94+、CD158a+ CD158f+CD314+CD335+の少なくとも1つの発現によって特徴づけられる。
顆粒球は:
(i) 血液、脾臓または骨髄から得ることが可能であるか、または、例えば、Kuhsら 2015, Curr Protoc Immunol111:7.23-1-7.23.16; Coqueryら 2012, Cytometry A 81(9):806-814; Swemydas および Lionakis 2013, J Vis Exp 77:50586.に記載されているとおりCD34+前駆細胞から生産可能である、
(ii) 以下のCD66bおよび/またはCD193少なくとも1つの発現によって特徴づけられる、
(iii) その細胞質中に顆粒が存在することを特徴とする多形核白血球である、および/または
(iv) 以下のTfR、CD163、TIM-2、および/またはCXCR4の少なくとも1つの発現によって特徴づけられる。
a) 精製された鉄結合タンパク質を提供すること、
b) 薬学的に活性な物質、標識または薬学的に活性な物質と標識を共有結合的または非共有結合的に連結し、および/または、薬学的に活性な物質、標識または薬学的に活性な物質と標識を鉄結合タンパク質中に封入すること、
c) CD45+白血球細胞を提供すること、および
d1) 鉄結合タンパク質と、工程b)で産生された薬学的に活性な物質、標識または薬学的に活性な物質と標識の複合体がCD45+白血球細胞に少なくとも部分的に負荷されるまで、工程b)で産生した鉄結合タンパク質の存在下でCD45 +白血球細胞をインキュベートすること、および/または
d2) CD45+白血球細胞が少なくとも部分的に標識で標識されるまで、標識の存在下でCD45+白血球細胞をインキュベートすること
を含む。
本発明で使用されるマクロファージは、以下のとおり、得られ、分化され、活性化された。マクロファージを活性化するために、それらは第一に骨髄前駆体(例えば以下の文献参照: Weischenfeld and Porse,2008,CSH Protoc, doi. 10.1101/pdb.prot.5080)または血液単球から得られる。あるいは、それらは腹膜から得られる。マクロファージの単離、培養、分化および極性化/活性化の方法は当業者によく知られている。例えば、それらは詳細にMurrayら (Immunity, 2014, 41(1):14-20)に記載されている。
本発明のこの実用的な実現において単球を得るために、骨髄由来または脾臓由来の単球は、BALB/cまたはC57Bl/6マウスから得たが、イヌ血液単球または市販の単球細胞株が使用された(単球−マクロファージ系譜マウス細胞:RAW 264.7、J744、ヒト細胞:THP-1、U937、またはイヌ細胞DH82)。
血液から顆粒球細胞を得るために、9部の血液を1部のACD緩衝液(0.17 Mのd−グルコース、0.10 Mのクエン酸、0.11Mのクエン酸三ナトリウムを含有する)で希釈した。この工程からの血液をPBSで1:1の比率でさらに希釈し、そして遠心分離した。血漿およびバフィーコートを除去した後、残りの細胞をPBSと最初の工程(ACD−血液)からの元の容量の80%まで混合し、次いで4:12の比率で冷蒸留水で希釈した。次に、6部の2.7%NaCl溶液を添加しそして遠心分離した。上清を除去した後、細胞をRPMI-1640培地に再懸濁した。これらの細胞は顆粒球と見なされた。
脾臓由来リンパ球を得るために、本発明のこの実用的な実現において、脾臓は、単細胞懸濁液を得るために機械的に解離され、そして70μm細胞ストレーナーを通過させた。細胞を遠心分離し、そして上清を除去した。赤血球溶解後、製造元の指示に従ったEasySep(商標)CD4+富化キット(CD4+ Enrichment Kit) (Stemcell)を用いてネガティブ細胞単離戦略を用いてリンパ球を単離した。
血液単球からマクロファージを得るために、新鮮な血液(12時間以内)をHistopaqueシステム1.077 g/mlまたは同等物を使用する遠心分離によって精製し、そして白血球(または、血液バンクから採取された白血球のみ)を手順のさらなる工程のために使用する。あるいは、白血球は、本発明のこの実用的な実現において行われたように、全血の赤血球溶解後に得られる。
フェリチンを抗癌剤(例えば、シクロホスファミド、クロラムブシル、メルファラン、ベンダムスチン、バノキサントロン、低酸素活性化プロドラッグ(TH-302)など)または「造影剤」(例えば、フェリヒドリドまたは同位体)と組み合わせるために、マクロファージ治療の前にフェリチンを調製する必要がある。簡潔にいえば、配列番号4(図1)による組換えマウスタンパク質は以下のようにして得られる。配列番号4のフェリチンタンパク質をコードする合成遺伝子を含む発現ベクターpET-22bを大腸菌BL21 (DE3)に形質転換した。大腸菌培養液は、アンピシリン(100 mg/L)を添加した1LのLuria-Bertaniブロス(LB)中、37℃でOD600 0.6まで増殖させた。1mMイソプロピルチオ−b−D−ガラクトシド(IPTG)を添加することによってタンパク質発現を誘導し、そして培養物を一晩インキュベートした。細胞を遠心分離(15000gで15分間)により回収し、そして20mMのHepes(pH7.5)、150mMのNaCl、0.1mg/mLのDNase、10mMのMgCl2中に懸濁し、そして超音波処理により破壊した。溶解物を15000gで30分間遠心分離し、上清を50℃で10分間処理し、遠心分離して変性タンパク質を除去し、次いで70℃で10分間処理し、そして再び遠心分離した。上清を4℃で1時間撹拌しながら30%(NH)4SO4を加え、15000gで30分間遠心分離した。上清を4℃で1時間撹拌しながら70%(NH)4SO4を加え、15000gで30分間遠心分離した。ペレットを20mMのHepes(pH7.5)、150mMのNaClに再懸濁し、そして同じ緩衝液に対して4℃で一晩透析した。タンパク質をHILOAD 26/600 SUPERDEX 200ゲル濾過カラム(GE-Healthcare)にロードし、次いで滅菌濾過して4℃で保存した (図9)。タンパク質濃度は、モル吸光係数21000M−1m−1を使用し、595nmでの吸光度を測定するブラッドフォードアッセイによって、280nmの分光光度的に決定した。
ヒトヘモグロビンはRossi-Fanelliら(Archivesofbiochemistry and biophysics 77:478-492, 1958)に記載のとおり、新鮮な赤血球から調製する。簡潔に言えば、健康なドナーから得たヘパリン処理した血液を、1600rpmで30分間(4℃)遠心分離してRBCを沈殿させた。バフィーコートはペレットの表面上の針吸引によって正確に除去された。血漿上清を捨て、そしてRBCを等張の0.9%食塩水中に再懸濁し、そして4℃で30分間1600rpmで遠心分離することによりRBCペレットを3回洗浄した。最終食塩水洗浄および遠心分離工程の後、RBCペレットを5mMリン酸カリウム緩衝液(PB、pH=7.2)でpH7.2に緩衝化した蒸留水に再懸濁し、そして穏やかに撹拌しながら4℃で一晩溶解させた。続いて透析したRBC溶解物を4℃で30分間13.000rpmで遠心分離し、上清を室温でQ−セファロースXL樹脂(GEHealthcare)を充填したXK 26/40カラムを備えたAKTA Explorerシステムに直接ロードした。カラムを緩衝液A(20mMTris−HCl、pH=8.2)で流速12mL/分で平衡化し、同じ緩衝液で3回洗浄した。100%緩衝液Aから75%緩衝液B(20mMTris−Cl、および0.2MNaCl pH8.20)に変更し、続いて100%緩衝液Bの段階的勾配変化によって線形勾配溶出を行った。溶出時に、フラクションコレクターを使用してタンパク質画分を収集した。このようにして得られたタンパク質をSDS pageで分析し、-80℃で凍結保存した。
血清を健康なドナーから入手し、過剰の鉄をキレート剤および重炭酸塩としてクエン酸イオンの存在下で添加し、トランスフェリンへの鉄の結合を促進させた。反応混合物は、100mLの血清当たり1時間、pH=8、4℃で6.5mgの重炭酸ナトリウムおよび153.16クエン酸第二鉄を含有していた。続いて、アルコール溶液を血清試料に4℃で3.5V/Vの比で、pH=9.4で2時間添加することによって、アルブミンをリバノール(4%)によって沈殿させた。次に、該溶液を3000rpmで20分間遠心分離し、最後に0.8mmシリンジフィルターで濾過した。続いて、硫酸アンモニウム0.025M中、SephadexG−25カラムでゲル濾過することにより、過剰のリバノールを除去した。続いて、pH=6.5で50%飽和硫酸アンモニウムによる沈殿を行い、続いて3000rpmで10分間遠心分離した(免疫グロブリン除去)。次いで、80%飽和硫酸アンモニウムで2回目の沈殿を行い、沈殿物中のトランスフェリンを回収した。次いで、固体沈殿物を、1MのNaClを含有する0.06MのTrisHCl緩衝液、pH=8の緩衝液に溶解した。溶液を同じ緩衝液中で透析して硫酸アンモニウムを完全に除去した。次にタンパク質溶液をセントリコンPM50遠心濃縮機で10〜15 mg/ml(ブラッドフォード法で推定)まで濃縮し、1M NaClで平衡化したSephadex G-100ゲル濾過カラム(2.4 x 80 cm)にロードし、流速15ml/hで実施した。このようにして得られたトランスフェリンは、SDSpageにより純度88〜90%であると推定された。次いで陰イオン交換DEAE Sephadex A-50によるイオン交換クロマトグラフィーを最終研磨工程として使用した。トランスフェリン試料を、pH=8の0.06MTrisHClで平衡化したカラムにロードし、溶出緩衝液、0.3MTrisHCl、pH=8を用いて直線濃度勾配により溶出した。タンパク質純度は98%より高く、血清100mL当たり約150mgの収量であった。
得られた細胞は、それらの全負荷に対するフェリチン/細胞の適切な比率を確実にし、また適切な画像化のための治療効果またはコントラストを得るのに適切な薬物含量を確実にするために十分な時間および濃度のフェリチン溶液中でインキュベートする。時間および濃度は、フェリチンケージ中に封入/吸着された分子の数、細胞活性化の状態、それらの意図される投与の状態および数に応じて変わってよい。
得られた細胞は、それらの全負荷に対するヘモグロビン/細胞の適切な比率を確実にし、また適切な画像化のための治療効果またはコントラストを得るのに適切な薬物含量を確実にするために十分な時間および濃度のヘモグロビン溶液中でインキュベートする。時間および濃度は、ヘモグロビン分子内に結合した分子の数、細胞活性化の状態、それらの意図される投与の状態および数に応じて変わってよい。
それにもかかわらず、当業者は、上記の条件を再調整し、そして自身の実験室においてそれ自身の目的のためにプロトコールを最適化することができる。
得られた細胞は、それらの全負荷に対するトランスフェリン/細胞の適切な比率を確実にし、また適切な画像化のための治療効果またはコントラストを得るのに適切な薬物含量を確実にするために十分な時間および濃度のトランスフェリン溶液中でインキュベートする。時間および濃度は、トランスフェリン分子内に結合した分子の数、細胞活性化の状態、それらの意図される投与の状態および数に応じて変わってよい。
実施例8、9および10に記載のように調製した実施例2からの単球は、非常に容易にフェリチン、ヘモグロビン、トランスフェリンを癌細胞に送達する(図14)。しかしながら、両者の細胞型の比率が非常に重要である。単球が多いほど、送達はより良くより速くなる。癌細胞への最も効率的な送達は、癌細胞に対する単球の比が1:1以上のときに観察された。
実施例8、9および10に記載のように調製した実施例3からの顆粒球は、非常に容易にフェリチン、ヘモグロビン、トランスフェリンを癌細胞に送達する(図15)。しかしながら、両者の細胞型の比率が非常に重要である。顆粒球が多いほど、送達はより良くより速くなる。癌細胞への最も効率的な送達は、癌細胞に対する顆粒球の比が1:1以上のときに観察された。
実施例8、9および10に記載のように調製した実施例4からのリンパ球は、非常に容易にフェリチン、ヘモグロビン、トランスフェリンを癌細胞に送達する(図16)。しかしながら、両者の細胞型の比率が非常に重要である。リンパ球が多いほど、送達はより良くより速くなる。癌細胞への最も効率的な送達は、癌細胞に対するリンパ球の比が1:1以上のときに観察された。
本発明において、細胞はPET上で画像化されるようにするために、18F−FDGまたは89Zr−オキシネートで標識した。細胞をプレートから分離し、そして細胞による最も最適な18F−FDGまたは89Zr−オキシネート取り込みを確実にするために、適切な濃度の18F−FDGまたは89Zr−オキシネート溶液と共にインキュベートし、それらの蓄積部位でのそれらの放射線検出を可能にした。本発明のこの実施において細胞を、5百万の細胞あたり3〜9MBqを含有する89Zr−オキシネート溶液中、室温で少なくとも90分間インキュベートした。しかしながら、放射性同位体と細胞の比率は反応効率に有意に影響する(図26)。標識後、細胞を遠心分離し、そして上清を除去した。この工程は上清中に放射能が検出されなくなるまで繰り返すべきである。
実施例9、10、11および11に記載のように調製した実施例1からのマクロファージ;実施例9、10、11および12に記載のように調製した実施例2からの単球;実施例9、10、11および12に記載のように調製した実施例3からの顆粒球;ならびに、実施例9、10、11および12に記載のように調製した実施例4からのリンパ球は、非常に効率的に腫瘍(図22、23)、関節炎の関節(図24)、(特定の実施例において単球マクロファージ細胞株を使用)および炎症を起こしたリンパ節(図25)、(特定の実施例においてM−CSFおよびCCL−2を用いて活性化した単球/若いマクロファージを使用)に移動する。それらが腫瘍または他の組織に移動すると、それらは、画像化システムを用いて検出されるのに十分な量で腫瘍にフェリチン、ヘモグロビン、トランスフェリンおよび標識を非常に容易に送達する(図2、3、7、17、および18)。
上記のように調製したマクロファージを腫瘍のある動物の尾静脈に注射する(適切な数のマクロファージは、腫瘍の大きさ、発生段階、および転移の有無に合わせて調整する必要がある)。図2および17に示されるように、それらは特異的に腫瘍に到達し(数時間後)、そして動物全体の他の器官にも分散する(図18)。さらに、図19に示されるように、低酸素モデルにおいて、それらは無血管および低酸素部位に移動し、そして担体タンパク質を癌細胞に送達することもできる(図3および20)。
本発明に記載の標的化送達系の標的化に続いて、フェリチンを造影剤に結合することができる。図21に示されるとおり、実施例8に記載のように造影剤(この場合、フェリハイドライト、しかしながら、同位体、例えば123Iを用いて同じ結果が得られる)でカップリングした、または同位体(この場合、89Zr−オキシネートまたは18F−FDG)で標識したフェリチンを負荷した1〜50mlのマクロファージの注射後、それらはMRI、PETまたはSPECTにより容易に検出することができる。この実施例(図7)において、乳房腫瘍担持マウスを、フェリチンFhを負荷したマクロファージの静脈内投与後3、22および24時間にMRIを用いて画像化した。マウスをマクロファージで処置した(時点0h)。次いで、注射されたマクロファージで満たされた血管(矢印)の直径の増大が観察され(有意なT2シグナルの減少をもたらす)、その後マクロファージが組織に広がった(スポット様のパターン;矢印)。これらの(同じ時点での)変化は試験したすべてのマウスで観察された。
Mammalian ferritin H chain (SEQ ID NO: 1 to7) 哺乳動物フェリチンH鎖(配列番号1〜7)
Mammalian ferritin L chain (SEQ ID NO: 8 to14) 哺乳動物フェリチンL鎖(配列番号8〜14)
Mammalian haemoglobin alpha chains (SEQ IDNO: 15 to 18) 哺乳動物ヘモグロビンアルファ鎖(配列番号15〜18)
Mammalian haemoglobin beta chains (SEQ IDNO: 19 to 22) 哺乳動物ヘモグロビンベータ鎖(配列番号19〜22)
Mammalian transferrins (SEQ ID NO: 23 to28) 哺乳動物トランスフェリン(配列番号23〜28)
Survival 生存
Percent survival 生存率
Time(d) 時間(日)
Ft-Melphalan フェリチン−メルファラン
Ft-Chlorambucil フェリチン−クロラムブシル
Cancer cell apoptosis がん細胞アポトーシス
due to cyclophosphamide treatment シクロホスファミド治療による
Number of apoptotic cells (%) アポトーシス細胞数(%)
ctrl 対照
drug 薬物
Mq+Feritin+drug マクロファージ+フェリチン+薬物
condition 条件
uptake 取り込み
MFI of FITC FITCの平均蛍光強度
min 分
Time of incubation インキュベーション時間
Monocyte Ft and Hb uptake 単球のフェリチンおよびヘモグロビン取り込み
Mean Fluorescence Intensity 平均蛍光強度
untreated 未処理
treatment 処理
MFI of Granulocyte-Ft 顆粒球−フェリチンの平均蛍光強度
MFI of Lymphocyte-Ft リンパ球−フェリチンの平均蛍光強度
Time of treatment 処理時間
Ft-Banoxantrone leakage from cells to themedium 細胞から培地へのフェリチン−バノキサントロン漏出
FACS analysis FACS解析
Percentage of cancer cells がん細胞の割合
Relative Mean Fluorescence Intensity 相対平均蛍光強度
No. of cancer cells loaded with Ft-FITCafter 2 hrs of co-culture withmacrophages pre-loaded with Ft-FITC フェリチン−FITC事前負荷マクロファージと2時間共培養後のフェリチン−FITC負荷がん細胞の数
No. of loaded cells (%) 負荷された細胞の数(%)
cell line 細胞株
human bladder cancer ヒト膀胱がん
human breast cancer ヒト乳がん
human pancreatic cancer ヒト膵臓癌
canine mammary carcinoma イヌ乳癌
Transfer between species 種間の移動
Transfer from mouse RAW264.7 to humancancer cell line MDA-MB361 マウスRAW264.7からヒトがん細胞株MDA-MB361への移動
% of loaded cells 負荷細胞の%
protein タンパク質
Percentage of acceptor cells with Ft-FITC フェリチン−FITCを有する受容細胞の割合
time of co-culture 共培養の時間
EMT6 load of Ft-Banoxantrone (0.2 mg/mlFt-0.65 mg Banox) after 2 hrs co-culturewith RAW264.7 pre-loaded with Ft-Banox フェリチン−バノキサントロン事前負荷RAW264.7と2時間共培養後フェリチン−バノキサントロン(0.2 mg/mlフェリチン、0.65 mgバノキサントロン)負荷EMT6
Number of apoptotic cells (%) アポトーシス細胞の数(%)
% of cells receiving iron-bindinprotein-FITC from human monocyte due toco-culture 共培養によるヒト単球から鉄結合タンパク質−FITCを受け取る細胞の%
Transporter 輸送体
MFI of CMT-U27 cells cultured with loadedgranulocytes 負荷された顆粒球で培養されたCMT-U27細胞の平均蛍光強度
MFI of CMT-U309 cells cultured with loadedgranulocytes 負荷された顆粒球で培養されたCMT-U309細胞の平均蛍光強度
transferred compound 移動した化合物
No. of cells [%] 細胞の数[%]
MFI of EMT6 cells cultured with loaded CD4+cells 負荷されたCD4+細胞で培養されたEMT6細胞の平均蛍光強度
MFI of 4T1 cells cultured with loaded CD4+cells 負荷されたCD4+細胞で培養された4T1細胞の平均蛍光強度
MFI of CT26 cells cultured with loaded CD4+cells 負荷されたCD4+細胞で培養されたCT26細胞の平均蛍光強度
Number of EMT6 cells cultured with loadedCD4+ 負荷されたCD4+で培養されたEMT6細胞の数
Number of 4T1 cells cultured with loadedCD4+ 負荷されたCD4+で培養された4T1細胞の数
Number of CT26 cells cultured with loadedCD4+ 負荷されたCD4+で培養されたCT26細胞の数
macrophage マクロファージ
plain ferritin-FITC 明白なフェリチン−FITC
control 対照
tumor 腫瘍
injection site 注射部位
Lung Radioactivity 肺放射能
native mice ネイティブマウス
Tumour 腫瘍
Avg Radiant Efficiency 平均放射効率
Leukocytes 白血球
CD4+Tcells CD4+T細胞
macrophage + monocyte cells マクロファージ+単球細胞
Therapy 治療
Days 8-12 8〜12日
Cisplatin 5mg/kg i.p. シスプラチン5mg/kg腹腔内投与
Ft-Cisplatin 0.1 mg/kg i.v. フェリチン−シスプラチン0.1 mg/kg静脈内投与
MQ-Ft-Cisplatin マクロファージ−フェリチン−シスプラチン
Fluorescence 蛍光
positive cells 陽性細胞
healthy feet 健常な足
inflamed knees 炎症した膝
+ labeled macrophages intravenously 標識されたマクロファージを静脈内に
5 mln of cells 細胞5百万
10 mln of cells 細胞10百万
20 mln of cells 細胞20百万
Number of ferritin-loaded EMT6 cells (%) フェリチン負荷されたEMT6細胞の数(%)
MFI of ferritin-loaded EMT6 cells フェリチン負荷されたEMT6細胞の平均蛍光強度
Claims (31)
- 細胞内に1以上の鉄結合タンパク質と薬学的に活性な物質、標識または薬学的に活性な物質と標識との複合体を含む、CD45+単球、CD45+単球-マクロファージ、CD45+リンパ球、および/またはCD45+顆粒球(以下、「CD45+白血球細胞」という)を含む単離された標的化送達系。
- 1以上の標識、特に放射性標識またはそれらの結合体および組み合わせを含むCD45+白血球細胞を含む単離された標的化送達系。
- CD45+白血球細胞がCD34+造血前駆細胞から産生され得る、請求項1または2に記載の単離された標的化送達系。
- (i) 単球は、CD11b+単球であり、好ましくは、CD11b+ CD14+単球、CD11b+CD16+単球、CD11b+ CD14+CD16+単球、CD11b+ CD14+MHCII+単球、CD11b+ CD14+CD115+単球、CD11b+ CD114+単球、CD11b+CD116+単球、CD11b+CCR1+単球、CD11b+ CCR2+単球、CD11b+CX3CR+単球、CD11b+CXR4+単球、CD11b+ CXR6+単球およびCD11b+CD14+ CD33+単球からなる群から選択されるが、
単球はIFN調節因子8(IRF8)、核因子インターロイキン(IL)-3調節タンパク質(NFIL3)、塩基性ロイシンジッパー転写因子ATF様3(BATF3)または転写因子RelB(NF-KBサブユニット)-RELB、Spi-1プロトオンコジーン(PU/1)、組換え結合タンパク質サプレッサーオブヘアレス(RBPJ)、IFN調節因子4(IRF4)または転写因子E2-2(TCF4としても知られる)の転写因子によって分化が制御される樹状細胞ではなく、
(ii) 分化した単球は、マクロファージ、活性化マクロファージ、好ましくはCD11 b+マクロファージ、より好ましくはCD11b+ CD16+マクロファージ、CD11b+CD32+マクロファージ、CD11b+ CD64+マクロファージ、CD11b+CD68+マクロファージ、好ましくは、CD11b+ CD86+M1マクロファージ、好ましくはiNOSを産生するマクロファージ、 および/または分泌性インターロイキン12(IL-12)を産生するマクロファージまたは好ましくはCD11b+CCR2+ M2マクロファージ、CD11b+CD204+M2マクロファージ、CD11b+ CD206+M2マクロファージ、CD11b+ CD204+ CD206+M2マクロファージ、CD11b+主要組織適合性複合体II+(MHC II+)(低発現または高発現)M2マクロファージ、CD11b+ CD200R+M2マクロファージ、CD11b+ CD163+ M2マクロファージ、またはアルギナーゼおよび/またはインターロイキン10(IL-10)を産生および/または分泌する活性化マクロファージからなる群から選択され、好ましくは、分化した単球-マクロファージは、Lox1+、CXCR7+およびNRF2+を発現する泡沫細胞ではなく、
(iii) 単球マクロファージまたは活性化単球マクロファージは、少なくとも1つのケモカイン受容体、好ましくはCCR1、CCR2+、CXCR4+、およびCXCR6+からなる群から選択されるケモカイン受容体、または少なくとも1つの増殖因子受容体、好ましくはマクロファージコロニー刺激因子受容体(CD115)、顆粒球コロニー刺激因子受容体(CD114)、および顆粒球マクロファージコロニー刺激因子受容体(CD116およびCD131からなる)からなる群から選択される増殖因子受容体を発現し、これらの特徴の単球は、炎症状態および癌を治療するのに特に適しており、
(iv) リンパ球は、CD3+およびCD4+またはCD8+ Tリンパ球、またはCD19+、CD20+、CD21+、CD19+ CD20+、CD19+CD21+、CD20+CD21+、もしくはCD19+ CD20+CD21+ Bリンパ球、またはナチュラルキラー(NK)細胞からなる群から選択され、または
(v) 顆粒球は、好中球、好ましくはCD66 b+好中球、好酸球および好塩基球、好ましくはCD193+好酸球からなる群より選択される、
ものである、請求項3に記載の単離された標的化送達系。 - 活性化マクロファージは、
(i) 単球またはマクロファージを、マクロファージ上の発現マーカーを変更することができる因子でインビトロでインキュベートすることによって産生され得るものであり、好ましくは
(a) 少なくとも1つのM1誘導因子で
(b) 少なくとも1つのM2誘導因子で
(c) またはサイトカイン、好ましくはIL-10およびIL-12、ケモカインを分泌するマクロファージの能力、および/またはiNOS、アルギナーゼまたは他の免疫調節酵素を産生するマクロファージの能力を変化させることができる因子で、
(ii) 以下の抗原:CD64、CD86、CD16、CD32、MHCIIの高発現、および/またはiNOSおよび/またはIL-12の産生の少なくとも1つの発現を特徴とする、
(iii) マクロファージの貪食能を誘導することができる因子との単球またはマクロファージのインビトロインキュベーションによって産生される、
(iv) 以下の抗原の少なくとも1つの発現によって特徴づけられる:CD204、CD206、CD200R;CCR2、トランスフェリン受容体 (TfR)、CXC-モチーフケモカイン受容体4 (CXCR4)、CD163、および/またはT細胞免疫グロブリンドメインおよびムチンドメイン2(TIM-2)、および/またはMHCIIの低発現を示す、
(v) 貪食する能力を有する;および/または
(vi) サイトカイン分泌、好ましくはIL-12もしくはIL-10の分泌、または誘導型一酸化窒素合成酵素(iNOS)(もしくは他の前炎症性化合物)、アルギナーゼまたは他の免疫抑制性/抗炎症性化合物の産生が可能である、
請求項4に記載の単離された標的化送達系。 - (i) M1誘導因子は、LPS、INF-γならびにウイルス感染および細菌感染からなる群から選択され、
(ii) M2誘導因子は、IL-4、IL-10、IL-13、抗原と抗体の免疫複合体、IgG、熱活性化ガンマ−グロブリン、糖質コルチコイド、TGF-β、IL-1R、CCL-2、IL-6、M-CSF、PPARγアゴニスト、白血球抑制因子、アデノシンおよび蠕虫感染および真菌感染からなる群から選択される、
請求項5に記載の単離された標的化送達系。 - 単球−マクロファージは、
(i) CD34+造血前駆細胞から産生される、
(ii) 少なくとも1つの誘導因子、好ましくはM1またはM2誘導因子、より好ましくは少なくとも1つのM2誘導因子、と単球/単球−マクロファージをインビトロでインキュベートすることによって産生できる、
(iii) 以下の抗原のうち少なくとも1つの発現によって特徴付けられる:TfR+、CD163+、TIM-2+、CD14+、CD16+、CD33+、および/またはCD115+、
(iv) 以下の抗原のうち少なくとも1つの発現によって特徴付けられる:TfR+、CD163+、TIM-2+、CXCR4+、CD14+、および/またはCD16+、および/または
(v) 貪食作用する能力を有する、
請求項4に記載の単離された標的化送達系。 - (i) M1誘導因子は、LPS、INF-γならびにウイルス感染および細菌感染からなる群から選択され、
(ii) M2誘導因子は、IL-4、IL-10、IL-13、抗原と抗体の免疫複合体、IgG、熱活性化ガンマ−グロブリン、糖質コルチコイド、TGF-β、IL-1R、CCL-2、IL-6、M-CSF、PPARγアゴニスト、白血球抑制因子、癌馴化培地、癌細胞、アデノシンおよび蠕虫感染および真菌感染からなる群から選択される、
請求項7に記載の単離された標的化送達系。 - リンパ球は、
(i) 血液、脾臓、または骨髄から入手可能であるか、またはCD34+前駆細胞から生産可能である、
(ii) 免疫学的に能力のあるリンパ球である、
(iii) 抗原特異的T細胞受容体を発現する、および/または
(iv) 以下の抗原のうち少なくとも1つの発現によって特徴付けられる: (a) CD3+ および CD4+ または CD8+、または (b): CD19+、CD20+、CD21+、CD19+ CD20+、CD19+CD21+、CD20+ CD21+、またはCD19+ CD20+ CD21+ 抗原、および好ましくは免疫グロブリンを産生可能である、
請求項4に記載の単離された標的化送達系。 - 顆粒球は、
(i) 血液、脾臓または骨髄から得ることが可能であるか、または、CD34+前駆細胞から生産可能である、
(ii) 以下のCD66b+および/またはCD193+の少なくとも1つの発現によって特徴づけられる、
(iii) その細胞質中に顆粒が存在することを特徴とする多形核白血球である、および/または
(iv) 以下のTfR+、CD163+、TIM-2+、および/またはCXCR4+の少なくとも1つの発現によって特徴づけられる、
請求項4に記載の単離された標的化送達系。 - NK細胞は、
(i) 血液、脾臓または骨髄から得ることが可能であるか、またはCD34+前駆細胞から産生可能であるか、および/または
(ii) CD3発現の欠失および以下のCD56+および/またはCD94+、CD158a+ CD158f+CD314+CD335+の少なくとも1つの発現によって特徴づけられる、
請求項4に記載の単離された標的化送達系。 - 鉄結合タンパク質は、フェリチン、好ましくは重(H)型フェリチン、軽(L)フェリチンおよび/またはミトコンドリアフェリチン;ヘモグロビン、好ましくはヘモグロビンA、ヘモグロビンAS、ヘモグロビンSC、ヘモグロビンC、ヘモグロビンD、ヘモグロビンE、ヘモグロビンF、ヘモグロビンH;ヘモグロビン−ハプトグロビン複合体、ヘモペキシン、トランスフェリン;およびラクトフェリンからなる群から選択される、請求項1〜11のいずれか1項に記載の単離された標的化送達系。
- 薬学的に活性な物質は、タンパク質、核酸、1.5kD未満の分子量を有する非タンパク質非核酸化合物、好ましくは抗癌剤、特に細胞分裂阻害薬、細胞毒性剤およびそれらのプロドラッグ;抗動脈硬化薬;および抗炎症薬;光感作化合物;ウイルス、特に腫瘍溶解性ウイルス;および細胞に損傷を与える量のγ線を放射もするα線またはβ線を放射する放射性同位体、好ましくは、ルテチウム−177、イッテルビウム−90、ヨウ素−131、サマリウム−153、リン−32、セシウム−131、パラジウム−103、ラジウム−233、ヨウ素−125、およびホウ素−10からなる群から選択される、または細胞に損傷を与える量のα線を放射する放射性同位体、好ましくはアクチニウム225、ビスマス213、鉛212、およびポロニウム212からなる群から選択される、またはナノ粒子に結合した上記化合物または同位体の複合体である、請求項1〜12のいずれか1項に記載の単離された標的化送達系。
- 抗癌薬は、アポトーシス誘導薬、アルキル化物質、代謝拮抗剤、抗生物質、エポチロン、核内受容体アゴニストおよびアンタゴニスト、抗アンドロゲン、抗エストロゲン、白金化合物、ホルモン、抗ホルモン、インターフェロン、細胞周期依存性プロテインキナーゼ(CDK)の阻害剤、シクロオキシゲナーゼおよび/またはリポキシゲナーゼの阻害剤、生体脂肪酸、プロスタノイドおよびロイコトリエンを含む生体脂肪酸誘導体、プロテインキナーゼ阻害剤、プロテインホスファターゼ阻害剤、脂質キナーゼ阻害剤、白金配位錯体、エチレンイミン、メチルメラミン、トリアジン、ビンカアルカロイド、ピリミジン類似体、プリン類似体、アルキルスルホン酸塩、葉酸類似体、アントラセンジオン、置換尿素、およびメチルヒドラジン誘導体、エン-ジイン抗生物質、メイタンシノイド、オーリスタチン誘導体、免疫チェックポイント阻害剤、および腫瘍特異的タンパク質またはマーカーの阻害剤、好ましくはRho−GDP解離阻害剤、より好ましくはGrp94、またはAXL阻害剤からなる群から選択される、請求項13に記載の単離された標的化送達系。
- 抗癌薬は、アセジアスルホン、アクラルルビシン、アンバゾン、アミノグルテチミド、L−アスパラギナーゼ、アザチオプリン、バノキサントロン、ベンダムスチン、ブレオマイシン、ブスルファン、フォリン酸カルシウム、カルボプラチン、カルペシタビン、カルムスチン、セレコキシブ、クロラムブシル、シスプラチン、クラドリビン、シクロホスファミド、シタラビン、ダカルバジン、ダクチノマイシン、ダプソン、ダウノルビシン、ジブロムプロパミジン、ジエチルスチルベストロール、ドセタキセル、ドキソルビシン、エンジイン、エピルビシン、エポチロンB、エポチロンD、エストラムシンホスフェート、エストロゲン、エチニルエストラジオール、エトポシド、フラボピリドール、フロキスウリジン、フルダラビン、フルオロウラシル、フルオキシメステロン、フルタミドホスフェストロール、フラゾリドン、ゲムシタビン、ゴナドトロピン放出ホルモン類似体、ヘキサメチルメラミン、ヒドロキシカルバミド、ヒドロキシメチルニトロフラントイン、ヒドロキシプロゲステロンカプロート、ヒドロキシウレア、イダルビシン、イドクスウリジン、イホスファミド、インターフェロンα、イリノテカン、ロイプロリド、ロムスチン、ルルトテカン、硫酸マフェニドオラミド、メクロレタミン、酢酸メドロキシプロゲステロン、メガストロアセテート、メルファラン、メパクリン、メルカプトプリン、メトトレキサート、メトロニダゾール、マイトマイシンC、ミトポドジド、ミトタン、ミトキサントロン、ミトラマイシン、ナリジクス酸、ニフラテル、ニフロキサジド、ニフララジン、ニフルチモックス、ニムスチン、ニノラゾール、ニトロフラントイン、ニトロジェンマスタード、オレオムチン、オキソリン酸、ペンタミジン、ペントスタチン、フェナゾピリジン、フタルスルファチアゾール、ピポブロマン、プレドニムスチン、プレドニゾン、プレシン、プロカルバジン、ピリメタミン、ラルチトレックスド(raltitrexed)、ラパマイシン、ロフェコキシブ、ロシグリタゾン、サラゾスルファピリジン、スクリフラビニウムクロライド(scriflavinium chloride)、セムスチン、ストレプトゾシン、スルファカルバミド、スルファセタミド、スルファクロピリダジン、スルファジアジン、スルファジクラミド、スルファジメトキシン、スルファエチドール、スルファフラゾール、スルファグアニジン、スルファグアノール、スルファメチゾール、スルファメトキサゾール、コ-トリモキサゾール、スルファメトキシジアジン、スルファメトキシピリダジン、スルファモキソール、スルファニルアミド、スルファペリン、スルファフェナゾール、スルファチアゾール、スルフイソミジン、スタウロスポリン、タモキシフェン、タキソール、テニポシド、ターチポシド、テストラクトン、テストステロンプロピオネート、チオグアニン、チオテパ、チニダゾール、トポテカン、トリアジコン、トレオスルファン、トリメトプリム、トロホスファミド、UCN-01、ビンブラスチン、ビンクリスチン、ビンデシン、ビンブラスチン、ビノレルビン、およびゾルビシンからなる群から選択され、好ましくは、アウリスタチン、バノキサントロン、ベンダムスチン、クロラムブシル、チャリセアマイシン(chaliceamycin)、ダイナマイシンA、メイタンシン、メルファラン、メルタンシン、およびネオカジノスタチンからなる群から選択される、請求項13に記載の単離された標的化送達系。
- 免疫調節薬は、免疫細胞の活性を活性化または阻害し、好ましくは、免疫調節薬は、リガンドまたはパターン認識受容体、特にToll様受容体、NOD様受容体(NLR)、RIG−1様受容体(RLR)のアンタゴニストである、請求項13に記載の単離された標的化送達系。
- 抗癌薬は、増殖阻害タンパク質、好ましくは細胞周期阻害剤、または増殖促進タンパク質に特異的に結合する抗体もしくは抗体様結合タンパク質または、増殖促進タンパク質またはsiRNAもしくはDNAザイムに特異的に結合する抗体または抗体様結合タンパク質を好ましくはコードする核酸である、請求項13に記載の単離された標的化送達系。
- 薬学的に活性な物質は、低酸素活性化プロドラッグであり、好ましくはベンゾトリアジンN−オキシド、アパジコン(EO9)、チラパザミン(TPN)、SN30000、PR-104A、TH-302、TH-4000、AQ4Nからなる群から選択される、請求項1〜13のいずれか1項に記載の単離された標的化送達系。
- 薬学的に活性な物質は、抗原または抗原をコードする核酸である、請求項1〜13のいずれか1項に記載の単離された標的化送達系。
- 標識は、蛍光染料、蛍光発光同位体、放射性同位体、検出可能なポリペプチド、または検出可能なポリペプチドをコードする核酸および造影剤からなる群から選択される、請求項1〜19のいずれか1項に記載の単離された標的化送達系。
- 標識は、二価または三価の金属カチオンと錯体を形成するキレート剤を含む、請求項1〜19のいずれか1項に記載の単離された標的化送達系。
- キレート剤は、1,4,7,10−テトラアザシクロドデカン−N,N’,N,N’−四酢酸(DOTA)、エチレンジアミン四酢酸(EDTA)、1,4,7−トリアザシクロノナン-1,4,7−三酢酸(NOTA)、トリエチレンテトラミン(TETA)、イミノ二酢酸、ジエチレントリアミン−N,N,N’,N’,N’’−ペンタ酢酸(DTPA)および6−ヒドラジノピリジン−3−カルボン酸(HYNIC)からなる群から選択される、請求項21に記載の単離された標的化送達系。
- 造影剤は、Gd、Eu、WおよびMnから好ましくは選択される常磁性剤、またはフェリハイドライドを含む、請求項14に記載の単離された標的化送達系。
- 放射性同位体/蛍光放出同位体は、アルファ線放出同位体、ガンマ線放出同位体、オージェ電子放出同位体、X線放出同位体、蛍光同位体、例えば 65Tb、蛍光放出同位体、例えば18F、51Cr、67Ga、68Ga、89Zr、111In、99mTc、140La、175Yb、153Sm、166Ho、88Y、90Y、149Pm、177Lu、47Sc、142Pr、159Gd、212Bi、72As、72Se、97Ru、109Pd、105Rh、101m15Rh、119Sb、128Ba、123I、124I、131I、197Hg、211At、169Eu、203Pb、212Pb、64Cu、67Cu、188Re、186Re、198Auおよび199Agならびに、タンパク質、ペプチド、小分子阻害剤、抗体または他の化合物と上記との結合体および組み合わせからなる群から選択される、請求項20に記載の単離された標的化送達系。
- 蛍光染料は、以下のクラスの蛍光染料からなる群から選択される:キサンテン、アクリジン、オキサジン、シニン、スチリル染料、クマリン、ポルフィン、金属−配位子−錯体、蛍光タンパク質、ナノクリスタル、ペリレンおよびフタロシアニンならびにこれらの種類の染料の結合体および組合せ、請求項20に記載の単離された標的化送達系。
- 検出可能なポリペプチドは、自己蛍光タンパク質、好ましくは緑色蛍光タンパク質、または改変された吸着および/または発光スペクトルを有するその任意の構造的変異体である、請求項20に記載の単離された標的化送達系。
- (i) 複合体中に含まれる鉄結合タンパク質と薬学的に活性な物質、標識または薬学的に活性な物質と標識との間の結合は共有結合および/または非共有結合である、および/または
(ii) 複合体中に含まれる薬学的に活性な物質、標識または薬学的に活性な物質と標識は鉄結合タンパク質またはその多量体によって捕捉/封入されている、
請求項1〜26のいずれか1項に記載の単離された標的化送達系。 - a) 精製された鉄結合タンパク質を提供すること、
b) 薬学的に活性な物質、標識または薬学的に活性な物質と標識を共有結合的または非共有結合的に連結し、および/または、薬学的に活性な物質、標識または薬学的に活性な物質と標識を鉄結合タンパク質中に封入すること、
c) CD45+白血球細胞を提供すること、および
d1) 鉄結合タンパク質と、工程b)で産生された薬学的に活性な物質、標識または薬学的に活性な物質と標識の複合体がCD45+白血球細胞に少なくとも部分的に負荷されるまで、工程b)で産生した鉄結合タンパク質の存在下でCD45+白血球細胞をインキュベートすること、および/または
d2) CD45+白血球細胞が少なくとも部分的に標識で標識されるまで、標識の存在下でCD45+白血球細胞をインキュベートすること、
の工程を含む、請求項1〜27のいずれか1項に記載の単離された標的化送達系の製造方法。 - 医薬または診断に使用するための、請求項1〜27のいずれか1項に記載の単離された標的化送達系または請求項28に記載の方法。
- 請求項1〜27のいずれか1項に記載の単離された標的化送達系または請求項28に記載の方法によって産生可能な単離された標的化送達系と薬学的に許容される担体および/または適切な賦形剤を含む医薬組成物。
- 腫瘍、好ましくは固形腫瘍および/またはその転移、好ましくは乳がん、膵臓がん、膀胱がん、肺がん、大腸がん、または、低酸素領域を有する腫瘍、炎症性疾患または虚血領域、特に皮膚創傷または臓器梗塞(心臓)または虚血性網膜の後の虚血領域の予防、治療もしくは診断に使用するための、または予防的または治療的ワクチン接種のための、特に感染性疾患もしくは癌を予防または治療するための、請求項1〜27のいずれか1項に記載の単離された標的化送達系または請求項28に記載の方法によって産生可能な単離された標的化送達系。
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