JP2017524732A - 肺の炎症を治療する方法 - Google Patents
肺の炎症を治療する方法 Download PDFInfo
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- JP2017524732A JP2017524732A JP2017519463A JP2017519463A JP2017524732A JP 2017524732 A JP2017524732 A JP 2017524732A JP 2017519463 A JP2017519463 A JP 2017519463A JP 2017519463 A JP2017519463 A JP 2017519463A JP 2017524732 A JP2017524732 A JP 2017524732A
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Abstract
Description
本出願は、2014年6月20日に出願された米国特許仮出願第62/014,967号の優先権を主張する。この出願の内容は、参照により全体に組み込まれる。
本明細書に開示された発明は、少なくとも一部分において、国立衛生研究所からの助成金番号R21CA167238を受けて政府の支援によりなされた。したがって、米国政府は、本発明において一定の権利を有する。
本発明は、医薬組成物、および肺の炎症を治療するための方法に関する。
LtxAは、グラム陰性バクテリア、アグリゲイティバクター・アクチノミセテムコミタンス(Aggregatibacter actinomycetemcomitans)により産生された、〜115kDaタンパク質である。LtxAは、LFA−1に特異的に結合するので、LFA−1を欠く細胞は、その毒性に耐性がある。例えば、LtxAは、ヒト赤血球細胞、ヒト上皮細胞、ラット細胞、またはマウス細胞に対して活性を有さない。LtxAはまた、ヒト末梢血の存在下で活性を維持する。
a.シングルコロニーのアグリゲイティバクター・アクチノミセテムコミタンス(Aggregatibacter actinomycetemcomitans)を植菌し、培養物を増殖させる;
b.増殖した培養物を新鮮な培養液へ添加し、ガラスビーズを添加し、インキュベートする;
c.インキュベートした培養物を遠心分離し、ペレットおよび上清を生成する;
d.膜を通して上清をろ過し、ろ過した上清を得る;
e.(NH4)2SO4およびろ過した上清を共に混合し、混合物を生成する;
f.混合物を遠心分離し、混合物のペレットを生成する;
g.混合物のペレットをバッファーに再懸濁し、タンパク質の再懸濁液を生成する;
h.タンパク質の再懸濁液をカラムに通す;ならびに、
i.カラムから流出したタンパク質を収集する。
本発明はまた、肺への投与に適したLtxAおよび薬学的に許容される担体を含む医薬組成物を提供する。薬学的に許容される担体の例は、制限されないが、微粒子、乾燥分散可能(dry dispersible)な粉末、無水エタノール、噴霧乾燥によって形成された粒子など、ならびに肺内投与に適したものであると当技術分野で公知なその他の調製物を含む。したがって、LtxAを含む本発明の医薬組成物は、肺の細気管支の領域へ粉末または液体エアロゾル粒子の形態において医薬組成物のデリバリのために構成された一般的に公知なデバイスを用いて投与することができる。このようなデバイスは、特に制限されないが、吸入器、噴霧器、鼻スプレー、乾燥粉末吸入システム;超音波吸入システム;定量吸入器;溶液計量装置を含む。本発明の医薬組成物の薬学的に許容される担体は、製剤の目的に有用であり、物質的にLtxAの新規で有用な性質に影響を与えない様々な不活性成分を含むことができる。
本発明は、ロイコトキシンおよび薬学的に許容される担体を含む医薬組成物を肺の炎症を抑制するのに有効な量において患者に投与することで、活性化した白血球の増加したレベルを特徴とする、肺の炎症の抑制を必要とする患者における肺の炎症を抑制する方法を提供する。他の実施形態において、本発明は、疾患を特徴づける肺の炎症を抑制するのに有効な量でロイコトキシンおよび薬学的に許容される担体を含む医薬組成物を必要とする患者に投与することを含む、肺の炎症を特徴とする疾病を治療する方法を提供する。
以下の非限定的な実施例は、本発明をさらに説明する目的を果たす。
LtxA精製。LtxAは、A.アクチノミセテムコミタンス(actinomycetemcomitans)株4500(Diaz et al.,(2006)Microb Pathog 40,48−55.)の培養上清から精製された。
アレルギー性喘息患者および健康な対照からのWBCに対するLFA−1の発現。我々は、8人のアレルギー性喘息患者および11人の健康な対照からの末梢血単核細胞(PBMC)を分析した。喘息と診断された患者は、イエダニに対するアレルギー反応が陽性であった。全体のPBMCの集団から、患者からのCD11a(LFA−1)陽性細胞の割合は、健康な対照からのものよりも有意に高かった。患者は、95.1±3.14%のCD11a陽性細胞を有し、一方健康な対照は、90.3±4.11%であった。また、アレルギー性喘息患者からのCD11a+ WBCの表面におけるLFA−1分子の数(8605±2519)は、平均蛍光強度が示すように、健康な対照のWBCの表面における数(5089±2107)よりも有意に多かった。
Claims (21)
- 活性化した白血球の増加したレベルを特徴とする、肺の炎症の抑制を必要とする患者における肺の炎症を抑制する方法であって、前記肺の炎症を抑制するのに有効な医薬組成物の量を前記患者に投与することを含み、前記医薬組成物がロイコトキシンおよび薬学的に許容される担体を含む、方法。
- 前記活性化した白血球が正常で健常な患者からの白血球と比較して、より多いレベルのLFA−1を発現する、請求項1に記載の方法。
- 前記活性化した白血球がCD11ahi細胞である、請求項2に記載の方法。
- 前記ロイコトキシンがアグリゲイティバクター・アクチノミセテムコミタンス(Aggregatibacter actinomycetemcomitans)から調製される、請求項1に記載の方法。
- 前記ロイコトキシンが配列番号1に記載のペプチドと少なくとも90%の相同性を有する、請求項1に記載の方法。
- 前記医薬組成物が経口的に、非経口的に、静脈内に、腹腔内に、または吸入により投与される、請求項1に記載の方法。
- 前記炎症が疾病または慢性疾患により生じる、請求項1に記載の方法。
- 前記疾病または慢性疾患が喘息、嚢胞性線維症、慢性閉塞性肺疾患、アレルゲン、または感染症である、請求項7に記載の方法。
- 前記感染症が細菌性、真菌性、またはウイルス性の感染症である、請求項8に記載の方法。
- 前記患者に投与される量が気管支肺胞洗浄液または肺組織における局所のサイトカインレベルを下げるのに有効である、請求項1に記載の方法。
- 1以上のサイトカインがIL−4、IL−5、IL−9、IL17FおよびIL−23αからなる群から選択される、請求項10に記載の方法。
- 前記投与される量が少なくとも1つのサイトカインのレベルを少なくとも約5倍低下させるのに有効である、請求項11に記載の方法。
- 前記医薬組成物がネブライザー、定量吸入器、および乾燥粉末吸入器からなる群から選択される吸入器を用いるために処方され、ならびに前記吸入器を用いて投与される、請求項1に記載の方法。
- 肺の炎症を特徴とする疾病を治療する方法であって、前記炎症を抑制するのに有効な量で前記治療を必要とする患者に医薬組成物を投与することを含み、前記医薬組成物がロイコトキシンおよび薬学的に許容される担体を含み、ならびに前記疾病が喘息、嚢胞性線維症、慢性閉塞性肺疾患、アレルギー、および感染症からなる群から選択される、方法。
- 前記ロイコトキシンが配列番号1に記載のペプチドと少なくとも90%の相同性を有する、請求項14に記載の方法。
- 前記医薬組成物がネブライザー、定量吸入器、および乾燥粉末吸入器からなる群から選択される吸入器を用いるために処方され、および前記吸入器を用いて投与される、請求項14に記載の方法。
- 患者に投与される前記量が気管支肺胞洗浄液または肺組織における局所のサイトカインレベルを下げるのに有効である、請求項14に記載の方法。
- 1以上のサイトカインがIL−4、IL−5、IL−9、IL17FおよびIL−23αからなる群から選択される、請求項17に記載の方法。
- 前記投与される量が少なくとも1つのサイトカインのレベルを少なくとも約5倍低下させるのに有効である、請求項18に記載の方法。
- ロイコトキシンおよび薬学的に許容される担体を含み、吸入に適した形態である医薬組成物。
- 前記薬学的に許容される担体がエアロゾルまたは乾燥粉末の形態である、請求項20に記載の医薬組成物。
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