JP7025781B2 - CCケモカイン受容体9(CCR9)の阻害剤と抗α4β7インテグリン遮断抗体の併用療法 - Google Patents
CCケモカイン受容体9(CCR9)の阻害剤と抗α4β7インテグリン遮断抗体の併用療法 Download PDFInfo
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Description
本願は2014年10月6日出願の米国特許仮出願第62/060,454号に対する優先権を主張し、同出願の開示の全内容をあらゆる目的で参照により援用する。
他の態様では、前記ケモカイン受容体CCR9阻害剤は分子量が750未満の小分子受容体阻害剤である。このCCR9に対する小分子受容体阻害剤の分子量は、約745、700、650、600、550、500、450、400、350、300、またはそれ以下であってよい。
本開示は、CCR9阻害剤(たとえばCCR9の小分子阻害剤)とα4β7インテグリンに対する抗体による併用療法が炎症性腸疾患(クローン病、潰瘍性大腸炎、不確定大腸炎など)の治療で相乗的に作用する可能性があるという予想外の知見に部分的に基づいている。本明細書では治療が必要な対象(たとえばヒトまたは対象動物)のIBDを治療するための方法、組成物、およびキットについて記載する。態様によっては、この方法はIBD患者に治療に有効な量のCCX507(バーサーノン)とベドリズマブを投与して、患者の臨床反応を誘発するか臨床的寛解を維持することを含む。
本発明の化合物、組成物、方法、および工程を記載する場合、以下の用語は、他に指示がない限り、以下の意味を有する。
(A.併用療法による炎症性腸疾患の治療)
本開示は、CCR9阻害剤と抗α4β7インテグリン抗体を含む併用療法に基づく方法、組成物、およびキットを提供する。この療法は、対象においてクローン病(CD)や潰瘍性大腸炎(UC)などのIBDを治療するのに有用である。本発明は、CCR9阻害剤と抗α4β7インテグリン抗体を相乗的に組み合わせることがIBDの治療に有効であるという予想外の知見に部分的に基づいている。
(1.クローン病)
本発明の組成物、方法、およびキットは、UC(すべての型のUCを含む)の患者に使用できる。CCR9阻害剤と抗α4β7インテグリン抗体の併用療法を有効な量で投与し、UCの患者の臨床反応を誘発するか臨床的寛解を維持することができる。態様によっては、併用療法によってUCの1つ以上の症状を緩和、軽減、またはその重症度を最低限にする。
(B.CCR9阻害剤と抗α4β7インテグリン抗体の併用療法)
本発明はCCR9活性を調節する化合物を提供する。具体的には、本発明は抗炎症活性または免疫調節活性を有する化合物を提供する。本発明の化合物は、ケモカイン受容体機能を特異的に調節または阻害することによって不適切なT細胞輸送を妨害すると考えられる。ケモカイン受容体は、ケモカインなどの細胞外リガンドと相互作用し、そのリガンドに対する細胞応答(たとえば走化性、細胞内カルシウムイオン濃度の増加など)を媒介する内在性膜タンパク質である。したがって、ケモカイン受容体機能の調節(たとえばケモカイン受容体とリガンドの相互作用の妨害)によってケモカイン受容体が関与する反応を阻害または低減でき、さらにはケモカイン受容体が関与する状態や疾患を治療または予防できる。
別の側面では、本開示はCCR9活性を調節する組成物または製剤を提供する。一般に、ヒトまたは動物などの対象でケモカイン受容体活性を調節するための組成物または製剤は、本明細書に記載の化合物と医薬的に許容される賦形剤または希釈剤を含む。
炎症性腸疾患(たとえばクローン病や潰瘍性大腸炎)の治療に用いるのに適した抗α4β7インテグリン抗体としては、α4β7インテグリンとそのリガンド(粘膜アドレシン細胞接着分子(MadCAM-1)、フィブロネクチン、血管細胞接着分子(VCAM)など)のうちいずれか1つとの結合を阻害する、任意の所望の供給源に由来する抗体が挙げられる。抗α4β7インテグリン抗体は、ヒト抗体、マウス抗体、ウサギ抗体、改変抗体(キメラ抗体、ヒト化抗体など)、および抗体の抗原結合性断片(Fab断片、Fv断片、scFv断片、Fab’断片、およびF(ab’)2断片など)であってよい。
本明細書では、抗体を安定化し、抗体凝集物の形成を低減し、抗体の分解を遅らせ、かつ/または抗体の免疫原性を最小限にすることができる抗α4β7インテグリン抗体の製剤を提供する。この製剤は、酸化防止剤またはキレート剤、少なくとも1種の遊離アミノ酸、界面活性剤、非還元糖、および/または緩衝剤を含むことができる。
別の側面では、本開示は、IBD(たとえばCDおよびUC)の治療のための併用療法を提供する。この併用療法は治療に有効な量のCCR9阻害剤と治療に有効な量の抗α4β7インテグリン遮断抗体を含む。治療剤を併用すると様々な障害の治療または予防に相乗的に作用することができる。この方法を用いることにより、各薬剤の用量をより少なくして治療の有効性を得ることができるため、有害な副作用の可能性を低減できる。
側面によっては、本明細書では、本明細書に開示のCCR9阻害剤と抗α4β7インテグリン抗体を含む、胃腸管の炎症を特徴とする疾患または障害(たとえば、CD、UC、不確定性大腸炎などのIBD)の治療に有用なキットを提供する。キットは、CCR9阻害剤化合物(たとえば小分子CCR9阻害剤)を含有する医薬組成物と抗α4β7インテグリン抗体を含有する医薬組成物とを含んでよい。態様によっては、CCR9阻害剤化合物はバーサーノン(Traficet-EN(商標))またはCCX507である。態様によっては、抗α4β7インテグリン抗体はベドリズマブである。場合によっては、キットは、書面による資料(たとえば、化合物、抗体、またはその医薬組成物の使用説明書)を含む。限定するものではないが、このキットは、緩衝剤、希釈剤、フィルター、針、シリンジ、および本明細書に開示のいずれかの方法を実施するための説明を含む同封の添付文書を含んでもよい。
以下の実施例は本願の発明を例示するために記載するものであり、発明を限定するものではない。
(A.序論)
循環細胞の様々な組織へのホーミングは、特定のケモカイン受容体および細胞接着分子を含む高度に協調した処理である。腸へ細胞が輸送されるには、ケモカイン受容体CCR9が関与する、CCL25として知られるケモカインへの走化性が必要である。また、CCL25によるCCR9の活性化は細胞表面のα4β7インテグリンのMAdCAMを発現する腸毛細血管内皮との高親和性結合を引き起こし、それにより強い拘束と腸組織への血管外遊出を起こす。
以下のように接着試験を実施した。ヒトのリンパ球を全PBMCから単離し、1μMのレチノイン酸(Sigma)と1ng/mLのヒトIL12(R&D Systems)の存在下でα-CD3εおよびα-CD28(1μg/mL;R&D Systems)により活性化した。さらに、生体外で活性化したT細胞を1μMのレチノイン酸(RA)と1ng/mLのヒトIL12の存在下で5日間かけて増殖させた。増殖した細胞を、APC結合抗CCR9抗体(カタログ番号248621;R&D Systems)および結合抗α4β7インテグリン抗体(Act-1)で染色した。染色した細胞を流動細胞計測法で分析した。増殖したT細胞でのCCR9およびα4β7インテグリンの発現を、図1Aの2つのパラメータの散布図として示した。
Claims (11)
- 前記炎症性腸疾患はクローン病(CD)または潰瘍性大腸炎(UC)である、請求項1に記載の組成物。
- 前記組成物と前記抗TNFα遮断抗体を複合製剤で投与する、請求項1に記載の組成物。
- 前記組成物と前記抗TNFα遮断抗体を逐次投与する、請求項1に記載の組成物。
- 前記組成物を前記抗TNFα遮断抗体より先に投与する、請求項4に記載の組成物。
- 前記組成物を前記抗TNFα遮断抗体の投与後に投与する、請求項4に記載の組成物。
- 治療に有効な量のケモカイン受容体CCR9阻害剤と治療に有効な量の抗TNFα遮断抗体と医薬的に許容される担体または賦形剤とを含む、哺乳動物の炎症性腸疾患の治療または発症低減のための組成物であって、
前記ケモカイン受容体CCR9阻害剤と前記抗TNFα遮断抗体は、請求項1に記載されたものと同一である、
組成物。 - 治療に有効な量のケモカイン受容体CCR9阻害剤と治療に有効な量の抗TNFα遮断抗体と有効な投与のための説明書とを含む、哺乳動物の炎症性腸疾患の治療または発症低減のためのキットであって、
前記ケモカイン受容体CCR9阻害剤と前記抗TNFα遮断抗体は、請求項1に記載されたものと同一である、
キット。 - 前記ケモカイン受容体CCR9阻害剤と前記抗TNFα遮断抗体は逐次投与用に製剤化されている、請求項8に記載のキット。
- 前記ケモカイン受容体CCR9阻害剤と前記抗TNFα遮断抗体は同時投与用に製剤化されている、請求項8に記載のキット。
- 抗TNFα遮断抗体を含む、哺乳動物の炎症性腸疾患の治療または発症低減用組成物であって、
前記組成物は、ケモカイン受容体CCR9阻害剤と併用投与され、
前記ケモカイン受容体CCR9阻害剤と前記抗TNFα遮断抗体は、請求項1に記載されたものと同一である、
組成物。
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