JP2017525706A - 血液脳関門の透過性を高める方法およびその使用 - Google Patents
血液脳関門の透過性を高める方法およびその使用 Download PDFInfo
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Abstract
Description
本願は、合衆国法典第35巻第119条(e)の下、2014年8月20日に出願された米国特許仮出願第62/039,899号に対して優先権を主張するものであり、その内容全体を参照によって本明細書中に援用する。
従って、脳疾患を治療または診断するためにBBBを横断して治療薬および診断薬の送達を容易にするための新しいアプローチを開発する必要性が存在している。
従って、本開示の1つの態様は:(i)血管内皮増殖因子(VEGF)を脳腫瘍を有している対象に全身投与し;そして、(ii)VEGF投与の5時間後以内に、有効量の抗癌剤を該対象に全身投与すること、を含む脳腫瘍の処置方法を特徴とする。
診断薬が使用されているとき、方法は、対象の脳領域の診断薬の存在またはそのレベルを検出することをさらに含んでもよい。診断薬は、コンピューター断層撮影法(CT)または磁気共鳴映像法(MRI)によって検出され得る。
本発明の1もしくは複数の実施形態の詳細は、以下での説明に規定される。本発明の他の特徴または利点は、以下の図面およびいくつかの実施形態の詳細な説明から、ならびに添付の請求項からも明らかになる。
BBBの破壊、BBBの迂回、BBBの透過、またはそれらの組み合わせを含めた数多くのアプローチが、BBBを横断する薬物送達に関連した課題を克服するために試みられた。浸透圧処理は関門を混乱させることができるので、薬物の取り込みと送達のための内在担体タンパク質を利用した、多くの試みがなされてきた。BBBは、脳脊髄液中または直接脳内への薬剤の直接注入を完全に回避し得る。しかしながら、これらの方法は、例えばイオン平衡障害、神経伝達物質の漏出および循環中へのケモカイン遊離などのそれ自体の課題を示す。Obermeier et al., Nat Med 19(12): 1584-1596; 2013。
便宜上、本開示に関連して用いられる特定の用語をここにまとめる。別段の規定がない限り、本明細書中に使用される学術用語は、本願発明が属する当該技術分野の当業者に一般的に理解されるのと同じ意味を有する。
単数形の「a」、「and」、および「the」は、文脈が別段明確に指示しない限り、複数の指示物を含むように本明細書中に使用される。
本開示の一態様は、VEGFと治療薬または診断薬の同時使用を伴う脳疾患を治療するかまたは診断する方法を特徴とし、ここで、VEGFは、治療薬または診断薬の投与前の好適な時間域中に低用量で全身投与される。VEGFと同時に、例えばIGF−IやIGF−IIなどの他の増殖因子もまた、は本明細書中に記載した方法で使用されてもよい。
本明細書中で特に言及した5つのファミリーのいずれのVEGFも、本明細書中に開示した方法に使用できる。VEGFは、好適な起源、例えばヒト、サル、マウス、ラット、ブタ、イヌ、およびネコに由来し得る。いくつかの実施形態において、本明細書中に記載した方法で使用されるVEGF分子は、例えばVEGF−A165アイソフォームなどのVEGF−A分子である。ヒトVEGF−A165のアミノ酸配列は、以下のとおりである:
APMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQEYPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNKCECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR(配列番号1)。
本明細書中に記載した方法に使用するための活性物質(例えば、VEGF、治療薬、および診断薬)はいずれも、バッファーを含めた医薬的に許容し得る担体(賦形剤)と混合されて、スクレロスチン発現を阻害する、骨芽細胞分化を促進する、および/または骨折治癒を促進するのに使用するための医薬組成物を形成し得る。「許容される」は、担体が組成物の有効成分に適合できる必要がある(そして好ましくは、有効成分を安定させることができる)および処置されるべき対象にとって有害でないことを意味する。バッファーを含めた医薬的に許容される賦形剤(担体)は、当該技術分野で周知である。例えば、Remington: The Science and Practice of Pharmacy 20th Ed. (2000) Lippincott Williams and Wilkins, Ed. K. E. Hooverを参照のこと。
好ましくは、無菌の医薬的に許容される溶媒中の組成物は、ガスの使用によって噴霧されてもよい。
VEGF(ならびに他の増殖因子)は、脳腫瘍、脳卒中、神経精神疾患、または神経変性疾病、例えば本明細書中に記載した疾患を含めた脳疾患を治療するかまたは診断するための治療薬または診断薬と同時に使用できる。本明細書中に記載した方法はまた、脳の造影にも適用できる。
増殖因子、ならびに治療薬/診断薬は、例えば経口、経鼻、肺、例えば受動またはイオン泳動送達などの経皮、あるいは非経口、例えば直腸、デポー剤、皮下、静脈内、筋肉内、鼻腔内、腹腔内、動脈内、頭蓋内、小脳内、皮下、点眼液または軟膏剤などで適切なまたは所望の作用部位に増殖因子および/または治療薬を効率的に輸送し得る任意の経路によって、哺乳動物、好ましくはヒトに投与され得る。さらに、治療薬と本願発明の増殖因子の投与は、同時であっても、または連続していてもよい。
本開示はまた、脳疾患を治療するかまたは診断するための本明細書中に記載した方法に使用するためのキットを提供する。斯かるキットは、VEGFを含む第一の製剤が入った一方と、本明細書中に記載した治療薬(例えば、抗癌剤)または本明細書中に記載した診断薬(例えば、イメージング剤)を含む第二の製剤の入ったもう片方の、少なくとも2個のコンテナを包含し得る。
コンテナおよびコンテナ上のまたは付随したラベルまたは(単数若しくは複数の)添付文書を含む。いくつかの実施形態において、本発明は、製造物品を含んでいる、先に記載したキットの内容物を提供する。
本発明の実施では、別段の指示がない限り、(遺伝子組み換え技術を含む)分子生物学、微生物学、細胞生理学、生化学、および免疫学の従来技術を利用し、そしてそれは、当該技術分野の技能の範囲内にある。分子クローニング:A Laboratory Manual, second edition (Sambrook, et al., 1989) Cold Spring Harbor Press;Oligonucleotide Synthesis (M. J. Gait, ed., 1984);Methods in Molecular Biology, Humana Press;細胞生理学:A Laboratory Notebook (J. E. Cellis, ed., 1998) Academic Press;Animal Cell Culture (R. I. Freshney, ed., 1987);Introduction to Cell and Tissue Culture (J. P. Mather and P. E. Roberts, 1998) Plenum Press;細胞及び組織培養:Laboratory Procedures (A. Doyle, J. B. Griffiths, and D. G. Newell, eds., 1993-8) J. Wiley and Sons;Methods in Enzymology (Academic Press, Inc.);Handbook of Experimental Immunology (D. M. Weir and C. C. Blackwell, eds.);Gene Transfer Vectors for Mammalian Cells (J. M. Miller and M. P. Calos, eds., 1987);Current Protocols in Molecular Biology (F. M. Ausubel, et al., eds., 1987);PCR:The Polymerase Chain Reaction, (Mullis, et al., eds., 1994);Current Protocols in Immunology (J. E. Coligan et al., eds., 1991);Short Protocols in Molecular Biology (Wiley and Sons, 1999);Immunobiology (C. A. Janeway and P. Travers, 1997);Antibodies (P. Finch, 1997);抗体:a practical approach (D. Catty., ed., IRL Press, 1988-1989);モノクローナル抗体:a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000);抗体の使用:a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999);The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995)。
材料と方法
(i)エバンスブルー(EB)浸出によるBBB透過性の測定
BBB透過性を、エバンスブルー(Fluka)によって量的に評価した。エバンスブルー(生理的食塩水中に2%または4%v/v、4ml/kg)を静脈内に注射した。浸出分析のために、動物を、動脈、腎臓、および肝臓から無色の液体が出てくるまで50mlの0.9% 生理的食塩水(10i.u./mlのヘパリンを含む)で灌流して、脈管内の色素を取り除いた。次に、動物を屠殺し、そして、脳を計量し、N,N−ジメチルホルムアミド(Sigma-Aldrich)(1ml/150mg組織重量)中で均質化し、18時間55℃にてインキュベートし、遠心分離した(14000rpm/20分)。色素上清を620nmにて分光測光によって分析した。MCAOモデルラットに関しては、脳を梗塞側と非梗塞側に分割し、両側からの上清を計測した。
VEGF投薬量;対照(生理的食塩水のみ)、0.1μg/kg、0.3μg/kg、0.5μg/kg、1.0μg/kg、および2.0μg/kgのVEGF、に応じて、マウスを6つの群に割り付けた。BBB透過性を、先に記載したように、VEGF注射の1時間後のEBアッセイによって測定した。最大のBBB透過性に達する最も低用量のVEGFを更なる実験のために選択した。VEGFおよび薬物送達の最適なタイミングを、最適なVEGF用量注射後のさまざまな時点(0、15、30、45、60、120分)でのEB浸出を調べることによって確立した。
COOH−修飾ナノ粒子(20〜500nm)を、以前に刊行されたプロトコール(Nance et al., Sci Transl Med 4(149): 149ra119; 2012)に従ってメトキシ(MeO)−PEG−アミン(NH2)を用いて共有結合修飾した。20nm、100nm、および500nmのペグ化蛍光ナノ粒子を、FVBマウスへの静脈内注射および潅流後の生体分布および浸出を調査するのに使用した。これらのナノ粒子を、IVISと免疫組織化学によって定量化した。
すべてのIVIS画像を、Xenogen IVIS Spectrumデバイス(PerkinElmer, Waltham, MA)を使用して取得した。
GraphPad Prism5ソフトウェアをデータ分析に使用した。結果を、図面の説明に示したように、標準誤差(SEM)または標準偏差(SD)を伴った平均値として提示する。One−way ANOVAを多重比較に使用した。2つの群を比較する場合、片側スチューデントt−検定が使用して統計的有意性を決定した。結果はP<0.05で有意であると見なした。
(i)時間域内の低用量でのVEGF前処置はBBB透過性を増強した
この実施例において、BBB透過性を増強するVEGF前処置の時間域および投薬量を調査した。マウスを、最初に生理的食塩水(対照)または様々な用量のVEGF165A(0.1μg/kg、0.3μg/kg、0.5μg/kg、1.0μg/kg、および2.0μg/kg)で処置し、次に、VEGF処置後のさまざまな時点(0、15、30、45、60、および120分)でEvan Blue(EB)を投与した。BBB透過性を、「材料と方法」の項に記載の手順に従ってマウス脳組織内のEBレベルを計測することによって評価した。結果を図1に示す。
よって、この試験から得られた結果は、低用量でのVEGFの前処置が作用物質のBBB透過性を促進できることを示し、低用量のVEGFがBBBを横断する薬物送達を容易にするために使用できることを示唆した。
マウスにおけるBBBを横断するペグ化蛍光ナノ粒子の浸透を促進するための低用量のVEGF前処置の効果を調査した。最初に、マウスに低用量のVEGF(0.3μg/kg)を静脈内に注射した。VEGF注射の45分後、様々なサイズ(直径20nm、100nmまたは200nm)を有するペグ化ナノ粒子をマウスに注射した。ナノ粒子の注射の30分後に、マウスを所定の手順に従った潅流にかけ、そして、脳組織をIVIS造影および免疫組織化学によって分析した。図2、パネルA。(すなわち、BBBを通過して)脳組織に蓄積したナノ粒子の量を、蛍光シグナルの強さを計測することによって決定した。結果を、図2、パネルB〜Dに示す。
8週齢の雄FVBマウスに、抗nrCAM抗体の注射の45分前に、0.3μg/kgのVEGF165Aまたは標準生理的食塩溶液対照のいずれか静脈内注射し、そしてそれを、組織切片を染色するための標識二次抗体を使用して検出した。脳が取り出し、そして、組織学切片を調製する前に1時間、抗体を循環させた。正の対照として、標識抗nrCAM抗体を直接脳組織に注射した。二次抗体を陰性対照として使用した。実験対照として、標準生理的食塩水を注射し、その後、標識した抗nrCAM抗体を注射した。
この試験は、低用量のVEGF前処置がBBBを横断した抗体などの巨大分子の送達を容易にしたことを示した。
脳血管障害(CVA)としても知られている脳卒中は、脳への血液供給の障害による脳機能の急速な損失である。脳卒中には:脳出血性脳卒中および虚血性脳卒中の2つの型がある。脳出血性脳卒中は、頭蓋内動脈の破損から生じ、その結果、急性頭蓋内血腫を引き起こす。脳梗塞としても知られている虚血性脳卒中は、例えば血栓または遠位塞栓症によるなどして血流量が妨げられた脳の領域における脳の細胞死である。現在、虚血性脳卒中のための2つの標準的治療法は、血栓溶解剤の注射と血管内手順であり、その両方が、局所的な血流量を再確立し、そして、できるだけ早く脳組織に対する低酸素性障害を低減することを目指す。
梗塞サイズを計測するために、虚血再灌流傷害および処置の3日後に、ラットを屠殺した。脳を摘出し、そして、冠状切片を厚さ2mmにスライスし、そして、2%の2,3,5−トリフェニルテトラゾリウムクロライド(TTC)で20分間染色した。次に、脳切片をスキャンし、そして、梗塞サイズを、ImageJソフトウェアを用いて血の気のない領域を計測することによって計算した。図3、パネルC〜E。
グレードIVの神経膠腫としても知られている多形性神経膠芽腫(GBM)は、最も一般的で、かつ、最も浸潤性が高いタイプの脳組織の悪性腫瘍である。現行の標準的な処置は、外科的切除、放射線治療法、および化学療法の組み合わせである。GBMは、健全な組織への侵襲性および浸透性が高いので、ほとんどの患者が、外科的に切除するには腫瘍が大きくなり過ぎ、かつ、広く分散し過ぎてから診断される。そのため、現代の治療を受けたときでさえ、GBM患者の生存率の中央値は処置を開始して12〜15カ月であり、すべてのヒト癌のうちの最も低い5年生存率の1つである。外科切除がめったにうまくいかないので、薬物療法が改善のための最も有望な領域である。好適な抗癌剤は既に存在している;しかし、BBBが脳腫瘍への薬物送達を妨げている。Patel et al., J Neurooncol. 61(3): 203-207; 2003。
ルシフェラーゼを発現するヒト神経膠芽腫細胞株U−87MGをすべてのGBM実験に使用した。細胞を、5%のCO2、37℃にて10%のFBSを含むEMEM中で規定通りに培養した。
DNAメチル化剤テモゾロミド(TMZ)を、GBMモデルマウスの治療法として使用した。6〜8週齢のBALB/c−ν/νマウスを4つの群;偽手術、ビヒクル対照(生理的食塩水)、TMZ(生理的食塩水中に5mg/kg)、およびVEGF前処置(0.3μg/kg)を伴ったTMZ、に割り付けた。腫瘍増殖を、インビボにおける生物発光造影によって観察した。マウスを60日間にわたって観察し、そして、それらの生存率をカプラン−マイヤー生存率曲線に記録した。
試験動物の生存率を、表1にまとめる。
さらに、6つの重要臓器、脳、肺、肝臓、腎臓、脾臓、および心臓への抗癌剤ドキソルビシンの送達に対する低用量のVEGF前処置の効果を調査した。
脳造影はCVAの診断における主要因の1つである。造影は、梗塞部の位置およびサイズを確認するため、および例えば脳腫瘍または脳間出血などの同様の症状が存在し得る他の発作を除外するために使用される。米国では、脳卒中の疑いに向けた現在の最前線の画像分析法は、無造影コンピューター断層撮影法(CT)であるが、注射した造影剤を利用するコンピューター断層撮影血管造影法(CTA)がより一般的に使用されるようになりつつある。Birenbaum et al., Western Journal of Emergency Medicine 12(1); 2011。
造影剤は、血管の視覚化を改善するために使用される。低用量は、例えば大動脈などの大血管を視覚化するために好適であるが、より小さい動脈には、より高用量が必要である。
しかし、これらの作用物質は、高価であり、また、何らかの毒性を有し、一部の患者で腎臓障害につながり、そして、禁忌とされている。
簡単に言えば、3匹のマウス(FVBマウス、25g、8週齢)に、0.3μg/kgのVEGFを静脈(尾静脈)内に注射した。45分後に、そのマウスに0.2mmol/kgのガドリニウム造影剤を注射した。脳画像を、VEGF注射後であるが、造影剤注射前に撮影し、次に、T1およびT2強調画像を造影剤注射の5分後に撮影した。標準生理的食塩水を注射したマウスを対照として使用した(図8)。
SE−T1WIパラメーター:TR=400ms;TE=10.8ms;FOV=2×2cm;NEX=8;スライス厚=0.8mm、16スライス;時間=6分49秒;マトリクス=256*128を256*256に再構成。
FSE−T2WIパラメーター:TR=4000ms;TEeff=70ms;FOV=2×2cm;NEX=4;スライス厚=0.8mm、16スライス;時間=4分16秒;マトリクス=256*128を256*256に再構成。
対象の血液脳関門(BBB)を横断した作用物質の送達を容易にする方法であって、(i)血管内皮増殖因子(VEGF)、I型インシュリン様増殖因子(IGF−1)、IGF−II、その一部、およびそれらの組み合わせから成る群から選択される増殖因子の有効量;および(ii)任意の治療薬またはイメージング剤である作用物質、を連続してまたは同時に該対象に投与することを含み、ここで、増殖因子の投与量は、該対象のBBB透過性を一時的に増強することが可能であり、その結果、作用物質がBBBを横断して送達されるようにする。
代謝拮抗物質は、フルオロピミジン、デオキシヌクレオシド類似体、チオプリン、メトトレキサート、またはペメトレキセドであってもよい。
抗凝血物質は、アスピリン、クロピドグレル(clopidoqrel)、ジピリダモール、ワルファリンまたはヘパリンであってもよい。
タンパク質は、組織プラスミノーゲンアクチベータ(TPA)であってもよい。
抗認知症薬は、メマンチンまたはアセチルコリンエステラーゼ阻害剤(AChEI)であり、そしてそれは、ガランタミン、タクリン、ドネペジル、リバスチグミン、ヒューペルジンA、ザナペジル、ガンスチグミン、フェンセリン、フェネチルノルシムセリン、シムセリン、チアシムセリン、SPH1371、ER127528、RS1259またはその混合物であってもよい。
本明細書に開示された全ての特徴は、任意の組み合わせで組み合わせることができる。本明細書に開示された個々の特徴は、同様の、等価な、あるいは類似の目的を果たす代替の特徴に置き換えることができる。よって、特段の記述がない限り、開示された個々の特徴は等価または同様な一連の一般的な特徴の単なる例示である。上述の説明によって、当業者は本発明の本質的な特徴を簡単に確認することができ、その思想および範囲から逸脱することなく、本発明にさまざまな変化や修正を加えさまざまな用途や条件に適用することができる。したがって、他の実施形態もまた特許請求の範囲に含まれる。
Claims (27)
- 脳腫瘍を処置する方法に使用するための血管内皮増殖因子(VEGF)であって:
(i)前記VEGFを脳腫瘍を有している対象に全身投与し;そして
(ii)VEGF投与の5時間後以内に、有効量の抗癌剤を対象に全身投与すること、
を含む前記方法に使用するための血管内皮増殖因子。 - 前記VEGFの量が5〜200ng/kgである、請求項1に記載の使用のためのVEGF。
- 前記VEGFの量が25ng/kgである、請求項2に記載の使用のためのVEGF。
- 前記抗癌剤が、VEGF投与の15〜180分後に投与される、請求項1〜3のいずれか1項に記載の使用のためのVEGF。
- 前記抗癌剤が、VEGF投与の45分〜3時間後に投与される、請求項4に記載の使用のためのVEGF。
- 前記抗癌剤が、アルキル化剤、トポイソメラーゼ阻害剤、代謝拮抗物質、細胞毒性抗生物質、または生物学的製剤である、請求項1〜5のいずれか1項に記載の使用のためのVEGF。
- 前記アルキル化剤が、シスプラチン、カルボプラチン、オキサリプラチン、メクロールエサミン、シクロホスファミド、メルファラン、クロラムブシル、イホスファミド、ブスルファン、N−ニトロソ−N−メチル尿素(MNU)、カルムスチン、ロムスチン、セムスチン、フォテムスチン、ストレプトゾトシン、ダカルバジン、ミトゾロミド、テモゾロミド、チオテパ、マイトマイシン、およびジアジクオンから成る群から選択される、請求項6に記載の使用のためのVEGF。
- 前記トポイソメラーゼ阻害剤が、カンプトテシン、イリノテカン、トポテカン、エトポシド、ドキソルビシン、テニポシド、ノボビオシン、メルバロン、およびアクラルビシンから成る群から選択される、請求項6に記載の使用のためのVEGF。
- 前記代謝拮抗物質が、フルオロピミジン、デオキシヌクレオシド類似体、チオプリン、メトトレキサート、およびペメトレキセドから成る群から選択される、請求項6に記載の使用のためのVEGF。
- 前記細胞毒性抗生物質が、アクチノマイシン、ブレオマイシン、プリカマイシン、マイトマイシン、ドキソルビシン、ダウノルビシン、エピルビシン、イダルビシン、ピラルビシン、アルカルビシン、およびミトキサントロンから成る群から選択される、請求項6に記載の使用のためのVEGF。
- 前記生物学的製剤が、ベバシズマブ、セツキシマブ、ペムツモマブ、オレゴボマブ、ミンレツモバブ、エタラシズマブ、ボロシキシマブ、セツキシマブ、パニツムマブ、ニモツズマブ、トラスツズマブ、ペルツズマブ、AVE1642、IMC−A12、MK−0646、R1507、CP751871、マパツムマブ、KB004またはIIIA4から成る群から選択される、請求項6に記載の使用のためのVEGF。
- (i)血管内皮増殖因子(VEGF)を含む第一の製剤が入った第一のコンテナ、および
(ii)抗癌剤を含む第二の製剤が入った第二のコンテナ、
を具備するキット。 - 脳腫瘍を処置する方法に使用するためのキットであって、VEGFを含む第一の製剤および抗癌剤を含む第二の製剤を含み、ここで、第一の製剤と第二の製剤の両方が、脳腫瘍を有している対象への全身投与のための製剤であり、かつ、ここで、第一の製剤が、第二の製剤投与の5時間前以内に投与されるキット。
- 前記第一の製剤のVEGFが、5〜200ng/kgの量で対象に投与される、請求項13に記載の使用のためのキット。
- 対象の血液脳関門を横断する作用物質の送達を容易にする方法に使用するための血管内皮増殖因子(VEGF)であって、作用物質投与の5時間前以内に、有効量のVEGFを、それを必要としている対象に全身投与することを含み、ここで、有効量のVEGFが5〜200ng/kgであり、かつ、ここで、作用物質が治療薬または診断薬である方法に使用するための血管内皮増殖因子。
- 前記VEGFの有効量が25ng/kgである、請求項15に記載の使用のためのVEGF。
- 前記VEGFが、作用物質投与の15分〜3時間前に投与される、請求項15または16に記載の使用のためのVEGF。
- 前記VEGFが、作用物質投与の45分〜3時間前に投与される、請求項17に記載の使用のためのVEGF。
- 前記対象が脳疾患を有しているか、有していることが疑われるか、または脳疾患の危険があるヒト患者である、請求項15〜18のいずれか1項に記載の使用のためのVEGF。
- 前記脳疾患が、虚血性脳卒中、神経変性疾病、および神経精神疾患から成る群から選択される、請求項19に記載の使用のためのVEGF。
- 前記作用物質が治療薬である、請求項19または20に記載の使用のためのVEGF。
- 前記作用物質が診断薬である、請求項19または20に記載の使用のためのVEGF。
- 前記診断薬が造影剤である、請求項22に記載の使用のためのVEGF。
- 前記方法が、対象の脳領域内の診断薬の存在またはレベルを検出することをさらに含む、請求項22または23に記載の使用のためのVEGF。
- 前記診断薬が、コンピューター断層撮影法(CT)または磁気共鳴映像法(MRI)によって検出される、請求項24に記載の使用のためのVEGF。
- 脳疾患を処置するかまたは診断する方法に使用する治療薬または診断薬と同時に使用するための医薬組成物であって、VEGFを含み、ここで、医薬組成物が、治療薬または診断薬投与の5時間前以内に、それを必要としている対象に投与され、かつ、ここで、対象に投与されるVEGFの量が5〜200ng/kgである医薬組成物。
- 脳疾患を治療するかまたは診断する方法に使用するためのキットであって、VEGFを含む第一の製剤および治療薬または診断薬を含む第二の製剤を含み、ここで、第一の製剤と第二の製剤の両方が、脳疾患を有している対象への全身投与のための製剤であり、かつ、ここで、第一の製剤が、第二の製剤投与の5時間前以内に投与されるキット。
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