JP7053269B2 - 細胞標的化標識送達系 - Google Patents
細胞標的化標識送達系 Download PDFInfo
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- JP7053269B2 JP7053269B2 JP2017567303A JP2017567303A JP7053269B2 JP 7053269 B2 JP7053269 B2 JP 7053269B2 JP 2017567303 A JP2017567303 A JP 2017567303A JP 2017567303 A JP2017567303 A JP 2017567303A JP 7053269 B2 JP7053269 B2 JP 7053269B2
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Description
a)好ましくは精製鉄結合タンパク質を準備する工程と、
b)標識を鉄結合タンパク質に共有結合的若しくは非共有結合的に連結する、及び/又は標識を鉄結合タンパク質に封入する工程と、
c)CD45+白血球細胞を準備する工程と、
d1)CD45+白血球細胞を、工程b)において作製される鉄結合タンパク質と標識との複合体の存在下で、該CD45+白血球細胞に工程b)において作製される該鉄結合タンパク質と標識との複合体が少なくとも部分的にロードされるまでインキュベートする工程、及び/又は、
d2)CD45+白血球細胞を、標識の存在下で該CD45+白血球細胞が該標識で少なくとも部分的に標識されるまでインキュベートする工程と、
を含む、方法に関する。
本発明の実施には、特に示されない限り、当該技術分野での文献(例えば、Molecular Cloning: A Laboratory Manual, 2nd Edition, J.Sambrook et al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989を参照)に説明される化学、生化学、及び組換えDNA技法の慣用の方法が使用される。
(i)単球が、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+単球及びCD11b+CD14+ CD33+単球からなる群から選択されるCD11b+単球である;
(ii)分化単球が、マクロファージ、活性化マクロファージ、好ましくはCD11b+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、好ましくは誘導性一酸化窒素合成酵素(iNOS)を産生する及び/又はインターロイキン12(IL-12)を分泌するもの、又は好ましくは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+主要組織適合遺伝子複合体II+(MHCII+)(低発現又は高発現)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、若しくはアルギナーゼ-1及び/又はインターロイキン10(IL-10)を産生及び/又は分泌する活性化マクロファージ、又は好ましくはCD11b CD11c、CD11b CD80、CD11c CD80、CD11c CD86、CD11c MHCII及びCD11c CD123の発現を有する樹状細胞からなる群から選択され、好ましくは、分化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ケモカイン受容体タイプ7(CXCR7+)及び核因子(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、血管壁の脂肪性沈着物に局在化し、そこで低密度リポタンパク質を捕食し、脂質がロードされ、泡沫状外観が与えられるマクロファージの一種である。これらの細胞はプラーク成長に関与する様々な物質を分泌し、それらの死により炎症が促進されるため、心血管疾患に寄与する;
(iii)単球又は活性化単球が、好ましくはCCR1、CCR2、CXR4及びCXR6からなる群から選択される少なくとも1つのケモカイン受容体、又は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)及び顆粒球-マクロファージコロニー刺激因子受容体(CD116及びCD131からなる)からなる群から選択される少なくとも1つの成長因子受容体を発現する。これらの特徴の単球は炎症状態及び癌の治療に特に好適である;
(iv)リンパ球が、CD3+及びCD4+若しくはCD8+ Tリンパ球、若しくはCD19+、CD20+、CD21+、CD19+ CD20+、CD19+ CD21+、CD20+CD21+若しくはCD19+ CD20+ CD21+Bリンパ球からなる群から選択される;又は、
(v)顆粒球が、好中球、好ましくはCD66b+好中球、好酸球及び好塩基球、好ましくはCD193+好酸球からなる群から選択される。
(i)マクロファージ上の発現マーカーを変化させることが可能な因子との、好ましくは、
(a)少なくとも1つのM1誘導因子との、
(b)少なくとも1つのM2誘導因子との、若しくは、
(c)サイトカイン、好ましくはIL-10及びIL-12、ケモカインを分泌する、及び/又はiNOS、アルギナーゼ若しく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可能な因子(かかる因子の例は活性化血小板、IL-4、IL-10、IL-13、抗原と抗体との免疫複合体、IgG、熱活性化γ-グロブリン、糖質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、白血球阻止因子(LIF)、アデノシン、蠕虫感染及び真菌感染、リポ多糖(LPS)、インターフェロンγ(INF-γ)、顆粒球マクロファージコロニー刺激因子(GM-CSF)、並びにウイルス感染及び細菌感染である;この点で、M1誘導因子、特にLPSによる単球の活性化が細胞にiNOSを発現させ、M1誘導因子、特にLPSによる単球の活性化が細胞にアルギナーゼ-1を発現させず、M2誘導因子、特にIL-4による単球の活性化が細胞にアルギナーゼ-1を発現させ、M2誘導因子、特にIL-4による単球の活性化が細胞にiNOSを発現させないことが観察された)との、
単球若しくはマクロファージ、若しくはそれらの前駆体のin vitroインキュベーションによって作製可能であり、
(ii)以下の抗原:CD64、CD86、CD16、CD32の少なくとも1つの発現、MHCIIの高発現、及び/又はiNOS及び/又はIL-12の産生を特徴とし、
(iii)マクロファージの貪食能力を誘導することが可能な因子、例えばIL-18、オプソニン(例えば、iC3b等の補体由来タンパク質、免疫グロブリンG)、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)、顆粒球マクロファージコロニー刺激因子(GM-CSF)、ウイルス感染及び/又は細菌感染との単球若しくはマクロファージのin vitroインキュベーションによって作製可能であり、
(iv)以下の抗原:CD204、CD206、CD200R;CCR2、トランスフェリン受容体(TfR)、CXC-モチーフ(motif)ケモカイン受容体4(CXCR4)、CD163、及び/又はT細胞免疫グロブリン-ドメイン及びムチン-ドメイン2(TIM-2)の少なくとも1つの発現を特徴とし、及び/又はMHCIIの低発現を示し(これらの特性を有する活性化マクロファージは、フェリチンを鉄結合タンパク質として含む複合体に特に好適である)、
(v)貪食能力を有し、及び/又は、
(vi)サイトカイン、好ましくはIL-12若しくはIL-10の分泌、若しくは誘導性一酸化窒素合成酵素(iNOS)(又は他の炎症誘発性化合物)、アルギナーゼ若しくは他の免疫抑制性/抗炎症性化合物の産生が可能である。
(i)CD34+造血前駆細胞から作製可能であり、
(ii)少なくとも1つの誘導因子、好ましくはM1又はM2誘導因子、より好ましくは少なくとも1つのM2誘導因子との単球のinvitroインキュベーションによって作製可能であり、
(iii)以下の抗原:TfR、CD163、TIM-2、CD14、CD16、CD33及び/又はCD115の少なくとも1つの発現を特徴とし、
(iv)以下の抗原:TfR、CD163、TIM-2、CXCR4、CD14及び/又はCD16の少なくとも1つの発現を特徴とし、及び/又は、
(v)貪食能力を有する。
(i)血液、脾臓若しくは骨髄から得られるか、又は当業者に既知であり、また例えばLefort and Kim, 2010, J Vis Exp 40: 2017、Tassone and Fidler, 2012, Methods in Molecular Biology882: 351-357、Kouro et al. 2005, Current Protocols inImmunology, 66:F22F.1:22F.1.1-22F.1.9.に記載されるようにCD34+前駆細胞から作製可能であり、
(ii)免疫適格リンパ球であり、
(iii)抗原特異的T細胞受容体を発現し、及び/又は、
(iv)以下の抗原:(a)CD3及びCD4若しくはCD8、又は(b)CD19、CD20、CD21、CD19 CD20、CD19 CD21、CD20CD21若しくはCD19 CD20 CD21抗原の少なくとも1つの発現を特徴とし、好ましくは免疫グロブリンを産生することが可能である。
(i)血液、脾臓若しくは骨髄から得られるか、又は例えばKuhs et al. 2015, Curr Protoc Immunol 111:7.23-1-7.23.16、Coquery et al. 2012, Cytometry A 81(9): 806-814、Swemydas and Lionakis 2013, J Vis Exp 77: 50586.に記載のようにCD34+前駆細胞から作製可能であり、
(ii)CD66b及び/又はCD193の少なくとも1つの発現を特徴とし、
(iii)その細胞質における顆粒の存在を特徴とする多形核白血球であり、及び/又は、
(iii)TfR、CD163、TIM-2及び/又はCXCR4の少なくとも1つの発現を特徴とする。
a)上に規定の精製鉄結合タンパク質を準備する工程と、
b)標識を鉄結合タンパク質に共有結合的若しくは非共有結合的に連結する、及び/又は標識を鉄結合タンパク質に封入する工程と、
c)上に規定のCD45+白血球細胞を準備する工程と、
d1)CD45+白血球細胞を、工程b)において作製される鉄結合タンパク質と標識との複合体の存在下で、該CD45+白血球細胞に工程b)において作製される該鉄結合タンパク質と標識との複合体が少なくとも部分的に、好ましくは完全にロードされるまでインキュベートする工程、及び/又は、
d2)CD45+白血球細胞を、標識の存在下で該CD45+白血球細胞が該標識で少なくとも部分的に標識されるまでインキュベートする工程と、
を含む、方法に関する。
腫瘍の標的化と、
を含む。
本発明に使用されるマクロファージを以下のように得て、分化させ、活性化させた。マクロファージを活性化するために、マクロファージを初めに骨髄前駆体(例えば、論文:Weischenfeld and Porse, 2008, CSHProtoc, doi. 10.1101/pdb.prot.5080を参照されたい)又は血液単球から得る。代替的には、マクロファージを腹膜から得ることができる。マクロファージの単離、培養、分化及び極性化/活性化の方法は当業者に既知である。例えば、これらはMurray et al. (Immunity, 2014,41(1):14-20)によって詳細に記載されている。
本発明のこの実用化において単球を得るために、骨髄由来又は脾臓由来単球をBALB/c又はC57Bl/6マウスから得た。また、イヌ血液単球又は市販の単球細胞株(単球-マクロファージ系統マウス細胞:RAW 264.7、J744、ヒト:THP-1、U937又はイヌDH82細胞株)を使用した。
顆粒球細胞を血液から得るために、9部の血液を1部のACD緩衝液(0.17 M d-グルコース、0.10 Mクエン酸、0.11 M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1:1比のPBSで更に希釈し、遠心分離した。血漿及びバフィーコートを除去した後、残りの細胞を第1の工程(ACD-血液)の元の容量の80%までPBSと混合し、続いて4:12の比率の冷蒸留水で希釈した。次いで、6部の2.7%NaCl溶液を添加し、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。これらの細胞を顆粒球とみなした。
本発明のこの実用化において脾臓由来リンパ球を得るために、脾臓を機械的に解離して単一細胞懸濁液を得て、70 μmセルストレーナーに通した。細胞を遠心分離し、上清を除去した。赤血球溶解の後、リンパ球を磁性ビーズ精製、例えばEasySep Mouse CD4+Enrichment Kitプロトコル及び適切な磁石を用いて単離した。
フェリチンに抗癌剤(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、バノキサントロンのような古典的薬物、又はTH-302のような低酸素活性化プロドラッグ)又は「イメージング造影剤」(例えばフェリハイドライト又はアイソトープ)を組み込むために、フェリチンをマクロファージ処理前に調製する必要がある。簡潔に述べると、配列番号4による組み換えマウスタンパク質(図1)を以下のように得る。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有する発現ベクターpET-22bを、大腸菌(E. coli)BL21(DE3)に形質転換した。大腸菌培養物を、アンピシリン(100 mg/L)を添加した1 LのLuria-Bertaniブロス(LB)中、37℃でOD600 0.6まで成長させた。タンパク質発現を1 mMイソプロピルチオ-b-D-ガラクトシド(IPTG)の添加によって誘導し、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)によって採取し、20 mM Hepes(pH 7.5)、150 mM NaCl、0.1mg/mL DNase、10 mM MgCl2中に懸濁し、超音波処理によって破壊した。溶解物を15000 g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た後、70℃で10分間再び遠心分離した。上清に30%(NH)4SO4を4℃で添加し、1時間撹拌し、15000 gで30分間遠心分離した。上清に70%(NH)4SO4を4℃で添加し、1時間撹拌し、15000 gで30分間遠心分離した。ペレットを20 mM Hepes(pH 7.5)、150 mM NaCl中に再懸濁し、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)にロードした後、滅菌濾過し、4℃で保管した(図9)。タンパク質濃度を、21000 M-1 m-1のモル吸光係数を用いた280 nmでの分光光度法及び595 nm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決定した。
ヒトヘモグロビンを、Rossi-Fanelli et al. (Archives of biochemistry and biophysics77:478-492, 1958)に記載のように新鮮赤血球から調製する。簡潔に述べると、健常ドナーから得られるヘパリン化血を、1600 rpmで30分間遠心分離し(4℃)、RBCを沈殿させた。バフィーコートをペレットの表面上の針吸引によって正確に除去した。血漿上清を捨て、等張0.9%生理食塩溶液中にRBCを再懸濁し、1600 rpm、4℃で30分間遠心分離することによってRBCペレットを3回洗浄した。最終生理食塩水洗浄及び遠心分離工程後に、RBCペレットを5 mMリン酸カリウム緩衝液(PB、pH=7.2)でpH 7.2に緩衝化した蒸留水中に再懸濁し、穏やかに撹拌しながら4℃で一晩溶解させた。透析RBC溶解物を続いて13.000(13000) rpm、4℃で30分間遠心分離し、Q-sepharose XL樹脂(GE Healthcare)を充填したXK 26/40カラムを備えるAKTA Explorerシステムに上清を室温で直接ロードした。カラムを緩衝液A(20 mMトリス-HCl、pH=8.2)により12 mL/分の流速で平衡化し、同じ緩衝液で3回洗浄した。線形勾配溶出を、100%緩衝液Aから75%緩衝液B(20 mMトリス-Cl+0.2 MNaCl(pH 8.20))、続いて100%緩衝液Bの段階勾配へと変化させることによって生成した。溶出時に、フラクションコレクターを用いてタンパク質画分を回収した。このようにして得られたタンパク質をSDS pageによって分析し、-80℃で凍結保管した。
血清を健常ドナーから得て、キレート剤としてのクエン酸イオン及びトランスフェリンへの鉄結合を促進する重炭酸塩の存在下で過剰な鉄を添加した。反応混合物は、血清100 mL当たり6.5 mgの重炭酸ナトリウム及び153.16のクエン酸酸化鉄(pH=8、4℃、1時間)を含有していた。アルブミンを続いて、アルコール溶液を血清サンプルに3.5V/V比で添加することにより、4℃及びpH=9.4で2時間Rivanol(4%)によって沈殿させた。次いで、溶液を3000 rpmで20分間遠心分離し、0.8mmシリンジフィルターで濾過することによって最後に濾過した。過剰なRivanolを続いて、0.025 M硫酸アンモニウム中のSephadex G-25カラムでのゲル濾過によって除去した。50%飽和硫酸アンモニウム(pH=6.5)による最初の沈殿を続いて行い、その後3000 rpmで10分間の遠心分離を行った(免疫グロブリン除去)。次いで、80%飽和硫酸アンモニウムでの2回目の沈殿を行い、トランスフェリン沈殿物を回収した。次いで、固体沈殿物を、1 M NaClを含有する0.06 MトリスHCl緩衝液(pH=8)中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。次いで、タンパク質溶液を、centricon PM50遠心濃縮器を用いて10 mg/ml~15 mg/ml(ブラッドフォード法によって推定される)まで濃縮し、1M NaClで平衡化したSephadex G-100ゲル濾過カラム(2.4×80 cm)に15 ml/時間の流速でロードした。このようにして得られたトランスフェリンは、SDS pageにより純度88%~90%であることが推定された。次いで、陰イオン交換体DEAE Sephadex A-50によるイオン交換クロマトグラフィーを最終精製(polishing)工程として使用した。トランスフェリンサンプルを0.06 MトリスHCl(pH=8)で平衡化したカラムにロードし、溶出緩衝液0.3 MトリスHCl(pH=8)を用いた線形濃度勾配により溶出した。タンパク質純度は98%超であり、収率は血清100 mL当たり約150 mgであった。
得られる細胞をフェリチン溶液中、それらの完全なロードに適当なフェリチン/細胞比を確実にし、また適当なイメージングを得るのに適当な造影剤含量を確実にするのに十分な時間及び濃度でインキュベートする)。時間及び濃度はフェリチンケージに封入/吸着される分子の数、細胞活性化の状態、条件及びそれらの意図される投与の回数に応じて変更することができる。
得られる細胞をヘモグロビン溶液中、それらの完全なロードに適当なヘモグロビン/細胞比を確実にし、また適当なイメージングを得るのに適当な造影剤含量を確実にするのに十分な時間及び濃度でインキュベートする)。時間及び濃度はヘモグロビン分子に連結する分子の数、細胞活性化の状態、条件及びそれらの意図される投与の回数に応じて変更することができる。
得られる細胞をトランスフェリン溶液中、それらの完全なロードに適当なトランスフェリン/細胞比を確実にし、また適当なイメージングを得るのに適当な造影剤含量を確実にするのに十分な時間及び濃度でインキュベートする)。時間及び濃度はトランスフェリン分子に連結する分子の数、細胞活性化の状態、条件及びそれらの意図される投与の回数に応じて変更することができる。
本発明では、細胞をPETでイメージングされるように18F-FDGで標識した。細胞をプレートから分離し、細胞による最適な18F-FDG取込みを確実にし、それらの蓄積部位でのそれらの放射検出を可能にする適切な濃度の18F-FDG溶液とともにインキュベートした。本実用的発明では、細胞を様々なサイトカインカクテル、成長因子及びそれらの活性化状態に影響を与え、それらの標識取込みを向上させる他の因子で前処理し、20 MBq~60 MBqを含有する温18F-FDG溶液中でインキュベートした。標識化後に、細胞を遠心分離する必要があり、上清を除去する必要がある。この工程を上清中で放射活性が検出されなくなるまで繰り返す必要がある。
実施例8、9、10及び11に記載のように調製した実施例1によるマクロファージ、実施例8、9、10及び11に記載のように調製した実施例2による単球、実施例8、9、10及び11に記載のように調製した実施例3による顆粒球、並びに実施例8、9、10及び11に記載のように調製した実施例4によるリンパ球は、フェリチン、ヘモグロビン、トランスフェリン及び標識を腫瘍へとイメージングシステムを用いた検出に十分な量で非常に容易に輸送する(図2、図3、図4、図7及び図8)。
上記のように調製したマクロファージを、腫瘍を有する動物の尾静脈へと注射する(適切な数のマクロファージを腫瘍サイズ、発生の段階及び転移の存在に対して調整する必要がある)。図2、図3、図4、図7、図8及び図10に示されるように、マクロファージは特異的に腫瘍に到達し(数時間後)、動物全体の他の器官にも分散する(。さらに、図9に示されるように、低酸素モデルでは、マクロファージは無血管の低酸素部位へと移動することが可能である。
本発明に記載される標的化送達系は、非常に有用なイメージングツールを構成する。図4及び図10に示されるように、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、しかしながらアイソトープ、例えば123Iによっても同じ結果が得られる)とカップリングした又はアイソトープ(この場合、18F-FDG)(図10)で標識したフェリチンをロードした1 ml~50 mlのマクロファージの注射後に、これらをMRI、PET又はSPECTによって容易に検出することができる。本実施例では(図4)、乳腺腫瘍担持マウスを、フェリチンFhをロードしたマクロファージの静脈内注射の3時間、22時間及び24時間後にMRIを用いてイメージングした。図4に示されるように、フェリチン/マクロファージ複合体は非常に有用なイメージングツールである。マウスをマクロファージで処理した(0時間の時点)。次いで、注射したマクロファージで満たされた血管の直径の増大(矢印)(顕著なT2-シグナルの低減をもたらす)、その後マクロファージの組織への広がり(スポット状パターン;矢印)が観察された。これらの変化(同じ時点)は検査した全てのマウスに観察された。
1. 造影剤を運搬するフェリチンがロードされた活性化マクロファージを含む標的化送達系。
2. 造影剤がフェリハイドライト又は同位体である、実施形態1による標的化送達系。
3. 造影剤を運搬するフェリチンがロードされた活性化マクロファージを含む標的化送達系を作製する方法であって、
a)フェリチンを精製する工程と、
b)フェリチンと上記造影剤とを連結することによって、造影剤を運搬するフェリチンを得る工程と、
c)単離マクロファージを活性化する工程と、
d)造影剤を運搬するフェリチンのマクロファージへの完全なロードを確実にするのに十分な時間及びフェリチン濃度で、工程b)において得られる造影剤を運搬するフェリチンの溶液中でマクロファージをインキュベートする工程と、
を含む、方法。
4. 活性化マクロファージが骨髄由来のマクロファージである、実施形態3の方法。
5. 活性化マクロファージが血液由来のマクロファージである、実施形態3の方法。
6. 活性化マクロファージがマクロファージ細胞株に由来する、実施形態3の方法。
7. 活性化マクロファージがM1又はM2へと偏向したマクロファージである、実施形態3~6のいずれか1つの方法。
8. 活性化マクロファージがM2へと偏向している、実施形態7の方法。
9. 活性化マクロファージが鉄代謝に関して操作されている、実施形態7の方法。
10. 造影剤がフェリハイドライト又は同位体である、実施形態3~9のいずれか1つの方法。
11. イメージングツールとして使用される、実施形態1又は2のいずれかに規定の標的化送達系。
図1
Mammalianferritin H chain (SEQ ID NO: 1 to 7) 哺乳動物フェリチンH鎖(配列番号1~7)
SEQ ID NO 配列番号
Mammalianferritin L chain (SEQ ID NO: 8 to 14) 哺乳動物フェリチンL鎖(配列番号8~14)
Mammalianhaemoglobin alpha chains (SEQ ID NO: 15 to 18) 哺乳動物ヘモグロビンα鎖(配列番号15~18)
Mammalianhaemoglobin beta chains (SEQ ID NO: 19 to 22) 哺乳動物ヘモグロビンβ鎖(配列番号19~22)
Mammaliantransferrins (SEQ ID NO: 23 to 28) 哺乳動物トランスフェリン(配列番号23~28)
Transferrin トランスフェリン
図5
uptake 取込み
MFI of FITC FITCのMFI
Time ofincubation インキュベーション時間
min 分
Monocyte Ftand Hb uptake 単球によるFt及びHbの取込み
MeanFluorescence Intensity 平均蛍光強度
treatment 処理
untreated 未処理
MFI ofGranulocyte-Ft 顆粒球-FtのMFI
Time oftreatment 処理時間
MFI ofLymphocyte-Ft リンパ球-FtのMFI
図6
Ft-Banoxantrone(0.8 mg/ml) leakage from cells to the medium 細胞から培地へのFt-バノキサントロン(0.8 mg/ml)の漏出
FACS analysis FACS分析
Percentage ofcancer cells 癌細胞のパーセンテージ
h 時間
hrs 時間
Ft-Banoxantrone(0.2 mg/ml) leakage from cells to the medium 細胞から培地へのFt-バノキサントロン(0.2 mg/ml)の漏出
Relative MeanFluorescence Intensity 相対平均蛍光強度
図7
macrophage マクロファージ
plainferritin-FITC 素フェリチン-FITC
図8
control 対照
tumor 腫瘍
injectionsite 注射部位
図10
LungRadioactivity 肺放射活性
naive miceMQ-FDG ナイーブマウスMQ-FDG
Graph legend グラフの説明
Mice withmetastatic 4T1 tumour + intravenous macrophages loaded with 18F-FDG 転移性4T1腫瘍を有するマウス+18F-FDGをロードした静脈内マクロファージ
Mice withmetastatic 4T1 tumour + intravenous free18F-FDG 転移性4T1腫瘍を有するマウス+遊離18F-FDG
Naive micewithout tumour + intravenous macrophages loaded with 18F-FDG 腫瘍を有しないナイーブマウス+18F-FDGをロードした静脈内マクロファージ
Claims (22)
- 腫瘍、炎症領域または低酸素マーカーであるpimonidazoloneで可視化可能な低酸素領域を診断するためのin vivo方法で使用するための単離標的化送達系であって、CD45+白血球細胞を含み、該細胞内に1つ以上の鉄結合タンパク質と標識との複合体を含む、単離標的化送達系。
- 前記白血球細胞がCD34+造血前駆細胞から作製される、請求項1に記載の単離標的化送達系。
- 前記白血球が単球、分化単球、リンパ球及び顆粒球からなる群から選択される、請求項1又は2に記載の単離標的化送達系。
- (i)前記単球が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+単球及びCD11b+CD14+CD33+単球からなる群から選択されるCD11b+単球であり、
(ii)前記分化単球がマクロファージ、活性化マクロファージ、若しくはCD11b+マクロファージ、若しくは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、若しくはCD11b+ CD86+ M1マクロファージ、若しくはiNOSを産生する及び/又はインターロイキン12(IL-12)を分泌するもの、若しくは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+主要組織適合遺伝子複合体II+(MHCII+)(低発現又は高発現)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、若しくはアルギナーゼを産生する及び/又はインターロイキン10(IL-10)を分泌する活性化マクロファージ;若しくはCD11b CD11c、CD11b CD80、CD11c CD80、CD11c CD86、CD11c MHCII及びCD11c CD123の発現を有する樹状細胞からなる群から選択され、若しくは前記分化単球がLox1+、CXCR7+及びNRF2+泡沫細胞ではなく、
(iii)単球若しくは活性化単球がCCR1、CCR2+、CXR4+及びCXR6+からなる群から選択される少なくとも1つのケモカイン受容体、若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)及び顆粒球-マクロファージコロニー刺激因子受容体(CD116及びCD131からなる)からなる群から選択される少なくとも1つの成長因子受容体を発現し、これらの特徴の単球が炎症状態及び癌の治療に好適であり、
(iv)前記リンパ球がCD3+及びCD4+若しくはCD8+ Tリンパ球、若しくはCD19+、CD20+、CD21+、CD19+ CD20+、CD19+ CD21+、CD20+CD21+若しくはCD19+ CD20+ CD21+Bリンパ球からなる群から選択され、又は、
(v)前記顆粒球が好中球、若しくはCD66b+好中球、好酸球及び好塩基球、若しくはCD193+好酸球からなる群から選択される、
請求項3に記載の単離標的化送達系。 - 前記活性化マクロファージが、
(i)マクロファージ上の発現マーカーを変化させることが可能な因子との、
(a)少なくとも1つのM1誘導因子との、
(b)少なくとも1つのM2誘導因子との、又は、
(c)サイトカイン、若しくはIL-10及びIL-12、ケモカインを分泌する、及び/又はiNOS、アルギナーゼ若しく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可能な因子との、
単球又はマクロファージのin vitroインキュベーションによって作製され、
(ii)以下の抗原:CD64、CD86、CD16、CD32の少なくとも1つの発現、MHCIIの高発現、及び/又はiNOS及び/又はIL-12の産生を特徴とし、
(iii)マクロファージの貪食能力を誘導することが可能な因子との単球又はマクロファージのinvitroインキュベーションによって作製され、
(iv)以下の抗原: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、及び/又はT細胞免疫グロブリン-ドメイン及びムチン-ドメイン2(TIM-2)の少なくとも1つの発現を特徴とし、及び/又はMHCIIの低発現を示し、
(v)貪食能力を有し、及び/又は、
(vi)サイトカイン、若しくはIL-12若しくはIL-10の分泌、又は誘導性一酸化窒素合成酵素(iNOS)(又は他の炎症誘発性化合物)、アルギナーゼ又は他の免疫抑制性/抗炎症性化合物の産生が可能である、
請求項4に記載の単離標的化送達系。 - (i)前記M1誘導因子がLPS、INF-γ、GM-CSF、並びにウイルス感染及び細菌感染からなる群から選択され、又は、
(ii)前記M2誘導因子がIL-4、IL-10、IL-13、抗原と抗体との免疫複合体、IgG、熱活性化γ-グロブリン、糖質コルチコステロイド、TGF-β、IL-1R、CCL-2、IL-6、M-CSF、PPARγアゴニスト、白血球阻止因子、アデノシン、蠕虫感染及び真菌感染からなる群から選択される、
請求項5に記載の標的化送達系。 - 前記単球が、
(i)CD34+造血前駆細胞から作製され、
(ii)少なくとも1つの誘導因子、若しくはM1又はM2誘導因子、若しくは少なくとも1つのM2誘導因子との単球のinvitroインキュベーションによって作製され、
(iii)以下の抗原:TfR+、CD163+、TIM-2+、CD14+、CD16+、CD33+及び/又はCD115+の少なくとも1つの発現を特徴とし、
(iv)以下の抗原:TfR+、CD163+、TIM-2+、CXCR4+、CD14+及び/又はCD16+の少なくとも1つの発現を特徴とし、及び/又は、
(v)貪食能力を有する、
請求項4に記載の単離標的化送達系。 - (i)前記M1誘導因子がLPS、INF-γ、GM-CSF、又はウイルス感染若しくは細菌感染からなる群から選択され、
(ii)前記M2誘導因子がIL-4、IL-10、IL-13、抗原と抗体との免疫複合体、IgG、熱活性化γ-グロブリン、糖質コルチコステロイド、TGF-β、IL-1R、CCL-2、IL-6、M-CSF、PPARγアゴニスト、白血球阻止因子、癌馴化培地、癌細胞、アデノシン、及び蠕虫感染又は真菌感染からなる群から選択される、
請求項7に記載の標的化送達系。 - 前記リンパ球が、
(i)血液、脾臓若しくは骨髄から得られるか、又はCD34+前駆細胞から作製され、
(ii)免疫適格リンパ球であり、
(iii)抗原特異的T細胞受容体を発現し、及び/又は、
(iv)以下の抗原:(a)CD3+及びCD4+若しくはCD8+、又は(b)CD19+、CD20+、CD21+、CD19+ CD20+、CD19+ CD21+、CD20+CD21+若しくはCD19+ CD20+ CD21+抗原の少なくとも1つの発現を特徴とし、若しくは免疫グロブリンを産生することが可能である、
請求項4に記載の単離標的化送達系。 - 前記顆粒球が、
(i)血液、脾臓若しくは骨髄から得られるか、又はCD34+前駆細胞から作製され、
(ii)CD66b+及び/又はCD193+の少なくとも1つの発現を特徴とし、
(iii)それらの細胞質中の顆粒の存在を特徴とする多形核白血球であり、及び/又は、
(iv)TfR+、CD163+、TIM-2+及び/又はCXCR4+の少なくとも1つの発現を特徴とする、
請求項4に記載の単離標的化送達系。 - 前記鉄結合タンパク質がフェリチン、若しくは重鎖(H)型フェリチン、軽鎖(L)フェリチン及び/又はミトコンドリアのフェリチン;ヘモグロビン、若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;並びにラクトフェリンからなる群から選択される、請求項1~10のいずれか一項に記載の単離標的化送達系。
- 前記標識が蛍光色素、蛍光発光同位体、放射性同位体、検出可能なポリペプチド又は検出可能なポリペプチドをコードする核酸、及び造影剤から選択される、請求項1~11のいずれか一項に記載の単離標的化送達系。
- 前記標識が二価又は三価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1~12のいずれか一項に記載の単離標的化送達系。
- 前記キレート剤が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アミン(TETA)、イミノ二酢酸、ジエチレントリアミン-N,N,N',N',N''-五酢酸(DTPA)及び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13に記載の単離標的化送達系。
- 前記造影剤がGd、Eu、W及びMn、又はフェリハイドライトから選択される常磁性剤を含む、請求項12に記載の単離標的化送達系。
- 前記放射性同位体/蛍光発光同位体がα線放出同位体、γ線放出同位体、オージェ電子放出同位体、X線放出同位体、65Tb等の蛍光同位体、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及び199Ag等の蛍光発光同位体、並びに上記のものとタンパク質、ペプチド、小分子阻害剤、抗体又は他の化合物とのコンジュゲート及び組合せからなる群から選択される、請求項12に記載の単離標的化送達系。
- 前記蛍光色素が以下の蛍光色素群:キサンテン、アクリジン、オキサジン、シアニン、スチリル色素、クマリン、ポルフィン、金属-配位子錯体、蛍光タンパク質、ナノ結晶、ペリレン及びフタロシアニン、並びにこれらの色素群のコンジュゲート及び組合せからなる群から選択される、請求項12に記載の単離標的化送達系。
- 前記検出可能なポリペプチドが自家蛍光タンパク質、若しくは緑色蛍光タンパク質、又は吸着及び/又は発光スペクトルが変更された任意のその構造変異体である、請求項12に記載の単離標的化送達系。
- (i)前記複合体に含まれる1以上の鉄結合タンパク質と前記標識が1以上の共有結合及び/又は非共有結合で連結され、及び/又は、
(ii)前記複合体に含まれる前記標識が前記鉄結合タンパク質又はその多量体によって捕捉/封入される、
請求項1~18のいずれか一項に記載の単離標的化送達系。 - 請求項1~19のいずれか一項に記載の単離標的化送達系を作製する方法であって、
a)精製鉄結合タンパク質を準備する工程と、
b)標識を鉄結合タンパク質に共有結合的若しくは非共有結合的に連結する、及び/又は標識を鉄結合タンパク質に封入する工程と、
c)CD45+白血球細胞を準備する工程と、
d1)前記CD45+白血球細胞を、工程b)において作製される前記鉄結合タンパク質と前記標識との複合体の存在下で、該CD45+白血球細胞に工程b)において作製される該鉄結合タンパク質と標識との複合体が少なくとも部分的にロードされるまでインキュベートする工程、及び/又は、
d2)CD45+白血球細胞を、前記標識の存在下で該CD45+白血球細胞が該標識で少なくとも部分的に標識されるまでインキュベートする工程と、
を含む、方法。 - 請求項1~19のいずれか一項に記載の単離標的化送達系と、薬学的に許容可能な担体及び/又は好適な賦形剤とを含む診断用組成物。
- 腫瘍、若しくは固形腫瘍、その転移、又は乳癌、膵癌、膀胱癌、肺癌、結腸癌若しくはその転移、又は低酸素マーカーであるpimonidazoloneで可視化可能な低酸素領域を有する腫瘍の診断するためのinvivo方法に使用される、請求項1~19のいずれか一項に記載の単離標的化送達系。
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