JP2021091695A - 脳腫瘍の治療方法 - Google Patents
脳腫瘍の治療方法 Download PDFInfo
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- JP2021091695A JP2021091695A JP2021026411A JP2021026411A JP2021091695A JP 2021091695 A JP2021091695 A JP 2021091695A JP 2021026411 A JP2021026411 A JP 2021026411A JP 2021026411 A JP2021026411 A JP 2021026411A JP 2021091695 A JP2021091695 A JP 2021091695A
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
Description
本願は、2015年3月6日に出願された米国特許仮出願第62/129,623号および2015年11月2日に出願された米国特許仮出願第62/249,807号(これらの開示は全文を参照することにより本明細書に組み入れられるものとする)の優先権を主張する。
本発明は、化学および医薬の分野に関する。より詳細には、本発明は、プリナブリンを用いた脳腫瘍の治療方法に関する。
特に定義されない限り、本明細書で使用する全技術および科学用語は、本開示に属する分野の当業者により共通に理解されるのと同じ意味を有する。全特許、出願、公開された出願、および他の出版物は、その全文を参照することにより組み入れられる。本明細書の用語の複数の定義がある場合、特に指定されない限り、本節中のものが適用される。
「予防的治療」という語は、疾病もしくは病状の徴候をまだ示していないが特定の疾病もしくは病状に罹患し易い、さもなければそのリスクがある対象を治療して、それにより、治療が、患者が該疾病もしくは病状にかかる可能性を減らすことを表す。「治療処置」という語は、既に疾病または病状に罹患している対象への投与治療を表す。
に組み入れられる)に記載のものなど、本明細書に記載の医薬組成物を製造するために使用できる。従って、いくつかの実施形態は:(a)プリナブリンまたはその薬剤的に許容可能な塩の安全かつ治療効果のある量;および(b)薬剤的に許容可能な担体、希釈剤、賦形剤またはその組合せを含む医薬組成物を含む。
全かつ治療効果のある量および(b)薬剤的に許容可能な担体、希釈剤、賦形剤またはその組合せを含む第二医薬組成物を含む。いくつかの実施形態は、(a)プリナブリンまたはその薬剤的に許容可能な塩の安全かつ治療効果のある量;(b)追加の治療薬の安全かつ治療効果のある量;および(c)薬剤的に許容可能な担体、希釈剤、賦形剤またはその組合せを含む医薬組成物を含む。
Therapeutics, 8th Ed., Pergamon Press(その全文を参照することにより本明細書に組み入れられる)に記載されている。
必要に応じて、化合物または組成物の活性と実質的に干渉しない医薬活性物質を含有してもよい。化合物または組成物と共に使用する担体の量は、化合物の単位用量当たり投与する物質の実用量を提供するのに充分なものである。本明細書に記載の方法で有用な剤形を製剤するための技術および組成物は、以下の参考文献(全て参照により本明細書に組み入れられる)に記載されている:Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms:Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004)。
鼻腔用剤形が挙げられる。このような組成物は、典型的には、ショ糖、ソルビトールおよびマンニトールなどの可溶充填物質;およびアカシア、結晶セルロース、カルボキシメチルセルロースおよびヒドロキシプロピルメチルセルロースなどの結合剤の1つ以上を含む。上記開示の流動促進剤、潤滑剤、甘味料、着色料、酸化防止剤および香料も含んでもよい。
ン酸が挙げられるが、これに限定されない。様々な実施形態では、最終組成物のpHは、2〜8、または好ましくは4〜7の範囲である。酸化防止賦形剤としては、亜硫酸水素ナトリウム、アセトン−重亜硫酸ナトリウム、ホルムアルデヒドスルホキシル酸ナトリウム、チオ尿素、およびEDTAが挙げられ得る。最終静脈内組成物中に見られる適切な賦形剤の他の非限定的な例としては、リン酸ナトリウムまたはカリウム、クエン酸、酒石酸、ゼラチン、およびブドウ糖、マンニトール、およびデキストランなどの炭水化物が挙げられ得る。さらに許容可能な賦形剤は、Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311および Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332(これら両方ともその全文を参照することにより本明細書に組み入れられる)に記載されている。抗菌剤を含有して、静菌性または静真菌性溶液を達成してもよく、硝酸フェニル水銀、チメロサール、塩化ベンゼトニウム、塩化ベンザルコニウム、フェノール、クレゾール、およびクロロブタノールが挙げられるが、これに限定されない。
ブリンまたは他の治療薬の単回用量は、約20mg〜約60mg、約27mg〜約60mg、約20mg〜約45mg、約27mg〜約45mgであり得る。いくつかの実施形態では、プリナブリンまたは他の治療薬の単回用量は、約5mg、約10mg、約12.5mg、約13.5mg、約15mg、約17.5mg、約20mg、約22.5mg、約25mg、約27mg、約30mg、約40mg、約50mg、約60mg、約70mg、約80mg、約90mg、約100mg、約125mg、約150mg、または約200mgであり得る。
いくつかの実施形態は、脳腫瘍の治療方法に関し、該方法は、それを必要とする対象にプリナブリンの効果量を投与することを含む。
オマイシン、アクチノマイシン、シクロホスファミド、またはイホスファミドであり得る。いくつかの実施形態では、追加の治療薬はテモゾロミドであり得る。いくつかの実施形態では、追加の治療薬はロムスチンであり得る。
使用したグリオーマのマウスモデルは、グリオブラストーマ(GBM)の前神経分子サブグループを模倣するグリオーマのPDGF誘導GEMMであった。このモデルは、体細胞特異性遺伝子導入に基づき;複製可能なALVスプライスアクセプター(RCAS)レトロウイルスシステムは、細胞型特異的に分化の厳密に調節されたウインドウ内の特定の遺伝子変異の点滴を可能とした。RCAS/tv−aシステムは、RCASレトロウイルスベクターを使用して、特定の細胞集団においてRCAS受容体(tv−a)を発現する
ように遺伝子組換えしたマウスを感染させた。ここで、脳内のネスチン発現細胞にPDGFをRCAS媒介導入することにより、グリオーマを生成した。脳内の幹細胞/前駆細胞集団においてネスチンを発現し、ヒトおよびマウス脳腫瘍の両方において血管周辺部(PVN)にあるがん幹細胞のマーカーであることを示した。PDGF誘導グリオーマは、感染後4〜5週間までにInk4a−arf−/−欠失と組み合わせた場合、完全な浸透率を有して発生した。これらの腫瘍は、CDKN2A(p16INK4Aおよびp14ARFの両方をコードする)欠失が「前神経」ヒトグリオーマの56%で観察されたGBMの「前神経」サブタイプを密接に模倣した。シェーレル構造、微小血管増殖および偽柵状ネクローシスなどのヒトグリオーマを規定する腫瘍細胞構造を、図1a〜1dに示すようにこのGEMMにおいて再形成した。詳細には、図1aは、ヒトGBMのT2 MRI画像が腫瘍周囲の浮腫を示すことを示し;図1bは、マウスGBMのT2 MRI画像が腫瘍周囲の浮腫を示すことを示し;図1cは、特徴的な偽柵状ネクローシスおよび微小血管増殖を有するGBMのH&E染色のヒト顕微鏡写真画像を示し;図1dは、特徴的な偽柵状ネクローシスおよび微小血管増殖を有するGBMのH&E染色のマウス顕微鏡写真画像を示す。
し始め、数日内に症状の改善を示し、そのMRI画像の特徴は腫瘍サイズの安定化または縮小を示し、その後、再発および死亡した。
G12D変異KRASを発現するPDGF誘導グリオーマを有するマウスを、実施例1に記載の手順を用いて準備してこの実験で使用した。4〜6週齢ネスチン−tv−a/ink4a−arf−/−マウスをイソフルランで麻酔し、Df−1細胞にトランスフェクトしたRCAS−PDGF−B−HA、RCAS−KRASを注射した。ハミルトンシリンジに装着した26ゲージニードルにより定位フレームを用いて、2×105RCAS−PDGF−B−HA/RCAS−KRASの1:1混合物1マイクロリットルをマウスに注射した。細胞を右前頭葉内に注射したが、十字縫合1.75mm、側方−0.5mm、および深さ2mmに調整する。マウスを重量減少に対して注意深くモニターし、合計2連続日にわたって>0.3グラム減少した場合または腫瘍の外的徴候を示した場合試験を供した。
Claims (13)
- それを必要とする対象にプリナブリンの効果量を投与することを含む、脳腫瘍の治療方法。
- 前記脳腫瘍が、転移性脳腫瘍、未分化星状細胞腫、多形性グリオブラストーマ、乏突起膠腫、上衣腫、またはその組合せである、請求項1に記載の方法。
- 前記脳腫瘍が、多形性グリオブラストーマである、請求項2に記載の方法。
- 前記脳腫瘍が、転移性脳腫瘍である、請求項2に記載の方法。
- 追加の治療薬を投与することをさらに含む、請求項1〜4のいずれか一項に記載の方法。
- 前記追加の治療薬が、テモゾロミドである、請求項5に記載の方法。
- 前記対象に放射線療法を付すことをさらに含む、請求項1〜6のいずれか一項に記載の方法。
- 前記脳腫瘍が、KRASの変異型の発現を特徴とする、請求項1〜7のいずれか一項に記載の方法。
- 前記脳腫瘍細胞をプリナブリンと接触させることを含む、脳腫瘍細胞の増殖阻害方法。
- 前記接触が、前記脳腫瘍細胞を有する対象にプリナブリンの効果量を投与することを含む、請求項9に記載の方法。
- 前記脳腫瘍細胞をプリナブリンと接触させることを含む、脳腫瘍細胞のアポトーシス誘導方法。
- 前記接触が、前記脳腫瘍細胞を有する対象にプリナブリンの効果量を投与することを含む、請求項11に記載の方法。
- それを必要とする対象にプリナブリンの効果量を投与することを含む、脳腫瘍の進行阻害方法。
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CA2978679A1 (en) | 2016-09-15 |
US20190000841A1 (en) | 2019-01-03 |
CN107530340A (zh) | 2018-01-02 |
AU2016229295B2 (en) | 2021-11-04 |
RU2017131448A3 (ja) | 2019-08-20 |
AU2016229295A1 (en) | 2017-09-28 |
IL254262A0 (en) | 2017-10-31 |
EP3265091A1 (en) | 2018-01-10 |
CN107530340B (zh) | 2021-06-08 |
BR112017018964A2 (pt) | 2018-05-22 |
KR102623404B1 (ko) | 2024-01-11 |
JP7264331B2 (ja) | 2023-04-25 |
WO2016144636A1 (en) | 2016-09-15 |
MX2017011375A (es) | 2018-01-23 |
HK1250007A1 (zh) | 2018-11-23 |
CL2017002242A1 (es) | 2018-04-02 |
ZA201706035B (en) | 2019-12-18 |
AU2021254549A1 (en) | 2021-11-18 |
KR20170123642A (ko) | 2017-11-08 |
RU2017131448A (ru) | 2019-04-08 |
SG11201707128TA (en) | 2017-09-28 |
US10076518B2 (en) | 2018-09-18 |
HK1249051A1 (zh) | 2018-10-26 |
RU2728796C2 (ru) | 2020-07-31 |
US10357491B2 (en) | 2019-07-23 |
JP2018507245A (ja) | 2018-03-15 |
EP3265091A4 (en) | 2018-08-01 |
JP6904570B2 (ja) | 2021-07-21 |
MY194341A (en) | 2022-11-29 |
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