JP7463281B2 - コロニー刺激因子を標的とすることによる、緑内障および視神経症のための療法 - Google Patents
コロニー刺激因子を標的とすることによる、緑内障および視神経症のための療法 Download PDFInfo
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Description
本願は、2018年3月5日に提出された米国特許仮出願第62/638,884号の恩典を主張するものであり、その全文が参照により本明細書に組み入れられる。
本発明は、米国国立眼病研究所からR01 EY025259として授与された政府支援を得てなされた。米国政府は本発明に一定の権利を有する。
本発明は眼障害に関する。
緑内障は、眼圧(IOP)の上昇、および網膜神経節細胞(RGC)の死、および視神経変性を伴う一群の眼障害である。緑内障は、世界的に、不可逆的な失明の主な原因である。治療選択肢は眼圧(IOP)を下げることしかなく、それによって疾患の進行は緩やかになるが、疾患が止まることはない。
コロニー刺激因子-1(CSF1)もしくはその受容体の阻害物質を眼部に局所投与する工程を含むか、またはコロニー刺激因子-2(CSF2)のタンパク質もしくはポリペプチドを眼部に局所投与することによる、対象における視神経因性障害を治療するための方法。
[本発明1002]
前記対象が緑内障と診断されている、本発明1001の方法。
[本発明1003]
前記阻害物質またはCSF2ポリペプチドが硝子体内に投与される、本発明1001の方法。
[本発明1004]
前記阻害物質が、CSF1にまたはCSF1受容体(CSF1R)に特異的な抗体を含む、本発明1001の方法。
[本発明1005]
CSF1R阻害物質が、PLX3397、GW-2580、BLZ-945、RG-7155、FPA-008、M279、またはそれらの組み合わせを含む、本発明1001~1004のいずれかの方法。
[本発明1006]
前記阻害物質が小分子である、本発明1001の方法。
[本発明1007]
対象における視神経因性障害を予防または治療する方法であって、
コロニー刺激因子-1(CSF1)またはその受容体の阻害物質およびコロニー刺激因子-2(CSF2)ポリペプチドの治療有効量を含む薬学的組成物を、眼部に局所投与する工程を含み、それによって該視神経因性障害を予防または治療する、該方法。
[本発明1008]
CSF1またはその受容体の前記阻害物質、およびCSF2タンパク質またはポリペプチドの組み換えタンパク質が、ミクログリア活性化を抑制する、本発明1006の方法。
[本発明1009]
CSF1またはその受容体の前記阻害物質、およびCSF2タンパク質またはポリペプチドの組み換えタンパク質が、網膜神経節細胞(RGC)の喪失を防ぎかつ視覚機能を保護する、本発明1006の方法。
[本発明1010]
CSF1またはその受容体の前記阻害物質が、抗体、抗体断片、アプタマー、小分子、アンチセンスオリゴヌクレオチド、siRNA試薬、Fab、Fab’、F(ab’) 2 断片、Fv断片、単鎖抗体、抗体ミメティック、ペプトイド、サイトカイン、細胞因子、酵素、またはそれらの組み合わせを含む、本発明1006の方法。
[本発明1011]
前記薬学的組成物が、抗CSF1抗体および/またはCSF1受容体(CSF1R)の阻害物質、ならびにCSF2組み換えペプチドを含む、本発明1006の方法。
[本発明1012]
CSF1R阻害物質が、PLX3397、GW-2580、BLZ-945、RG-7155、FPA-008、M279、またはそれらの組み合わせを含む、本発明1006~1011のいずれかの方法。
[本発明1013]
コロニー刺激因子-1(CSF1)またはその受容体の阻害物質およびコロニー刺激因子-2(CSF2)のタンパク質またはポリペプチドの治療有効量を含む、薬学的組成物。
[本発明1014]
CSF1またはその受容体の前記阻害物質、およびCSF2タンパク質またはポリペプチドの組み換えタンパク質が、ミクログリア活性化を抑制する、本発明1013の薬学的組成物。
[本発明1015]
CSF1またはその受容体の前記阻害物質、およびCSF2タンパク質またはポリペプチドの組み換えタンパク質が、網膜神経節細胞(RGC)の喪失を防ぎかつ視覚機能を保護する、本発明1013または1014の薬学的組成物。
[本発明1016]
CSF1またはその受容体の前記阻害物質が、抗体、抗体断片、アプタマー、小分子、アンチセンスオリゴヌクレオチド、siRNA試薬、Fab、Fab'、F(ab')2断片、Fv断片、単鎖抗体、抗体ミメティック、ペプトイド、サイトカイン、細胞因子、酵素、またはそれらの組み合わせを含む、本発明1010の薬学的組成物。
[本発明1017]
CSF1R阻害物質が、PLX3397、GW-2580、BLZ-945、RG-7155、FPA-008、M279、またはそれらの組み合わせを含む、本発明1013~1016のいずれかの薬学的組成物。
[本発明1018]
対象におけるミクログリア活性化を抑制する方法であって、
該対象にコロニー刺激因子-1(CSF1)もしくはその受容体の阻害物質を投与する工程を含むか、またはコロニー刺激因子-2(CSF2)のタンパク質もしくはポリペプチドを眼部に局所投与することによる、該方法。
[本発明1019]
前記対象が緑内障と診断されている、本発明1018の方法。
[本発明1020]
CSF1の前記阻害物質および/もしくはCSF1受容体阻害物質、またはCSF2ポリペプチドが、硝子体内に投与される、本発明1018の方法。
[本発明1021]
CSF1またはその受容体の前記阻害物質が、抗体、抗体断片、アプタマー、小分子、アンチセンスオリゴヌクレオチド、siRNA試薬、Fab、Fab’、F(ab’) 2 断片、Fv断片、単鎖抗体、抗体ミメティック、ペプトイド、サイトカイン、細胞因子、酵素、またはそれらの組み合わせを含む、本発明1018~1020のいずれかの方法。
[本発明1022]
CSF1R阻害物質が、PLX3397、GW-2580、BLZ-945、RG-7155、FPA-008、M279、またはそれらの組み合わせを含む、本発明1018~1022のいずれかの方法。
[本発明1023]
眼内投与用に製剤化されているコロニー刺激因子-1(CSF1)阻害物質。
[本発明1024]
眼内投与用に製剤化されているコロニー刺激因子-1受容体(CSFR1)阻害物質。
[本発明1025]
眼内投与用に製剤化されている、コロニー刺激因子-2(CSF2)のポリペプチドまたはタンパク質。
[本発明1026]
コロニー刺激因子-1(CSF1)阻害物質、コロニー刺激因子-1受容体(CSFR1)阻害物質、コロニー刺激因子-2(CSF2)のポリペプチドもしくはタンパク質、またはそれらの組み合わせを含む、眼用製剤。
[本発明1027]
溶液、懸濁剤、ゲル、メッシュ、インプラント、または乳剤を含む、本発明1026の眼用製剤。
本発明の他の特徴および利点は、以下のその好ましい態様の説明から、および特許請求の範囲から明らかであろう。別途定義しない限り、本明細書で用いられる科学技術用語はすべて、本発明が属する技術分野の当業者が一般に理解するのと同じ意味をもつ。本明細書に記載されるものと類似のまたは同等の方法および材料を本発明の実施または試験に用いることができるが、好適な方法および材料を以下に記載する。本明細書で引用する、公開された外国特許および特許出願はすべて、参照により本明細書に組み入れられる。本明細書で引用する、アクセッション番号で示されるGenbankおよびNCBIへの提出物は、参照により本明細書に組み入れられる。本明細書で引用する、他のすべての発表された参考資料、書類、論文、および科学文献は、参照により本明細書に組み入れられる。不一致がある場合は、定義を含め、本明細書が優先される。また、材料、方法、および例は、あくまで説明のためであり、限定的な意図はない。
ミクログリアの活性化は、緑内障の神経変性の進行において重要な役割を果たす。コロニー刺激因子1(CSF1)およびコロニー刺激因子2(CSF2)が、ミクログリア機能の調節による緑内障性の神経細胞喪失に関与している。緑内障のマウスは、上方制御されたCSF1レベル、およびCSF2の下方制御を示した。さらに、緑内障マウスモデルにおけるCSF2組み換えタンパク質の追加、または抗CSF1もしくはCSF1受容体に対する抗体の硝子体内注射によるCSF1の中和によって、緑内障マウスモデルにおいて有意にミクログリア活性化が抑制され、網膜神経節細胞(RGC)の喪失が防御され、かつ視覚機能が保護された。このデータは、CSF経路をモジュレートすることが、緑内障および/または視神経症を有する対象に臨床的利益を与えるのに有用であることを示している。
CSF-1は、主としてプロテオグリカンの形態で、およそ10 ng/mLの生物学的活性濃度で循環血中に存在する。構成的には間葉系および上皮系の起源をもつ、非常に多様な細胞により産生される。循環血中のレベルは、病因にかかわらず炎症、がん、および慢性炎症性疾患などの多くの異なる病態で増大する。CSF1は、単核食細胞の生存、増殖、および分化を制御し、かつ女性の生殖器官の細胞を調節する。CSF1はまた、卵巣、子宮内膜、***、および骨髄系リンパ系組織のがんでは自己分泌および/または傍分泌の役割を果たすこともある。CSF1レベルはまた、妊娠中に循環血中で上昇し、胎盤形成に寄与する。マウスでもヒトでも、分娩前後に組織および循環血中のCSF1の急増がある。炎症において、CSF1は、動員されたマクロファージ自体によって産生されることもあるが、少なくともマウスでは大半のマクロファージはCSF1を産生せず、このタンパク質の非存在下で細胞死に至る。正常な定常状態の条件下では、CSF1の産生は、CSF1受容体(CSF1R)による受容体媒介性飲食作用と、その後の細胞内破壊を通じて、組織マクロファージによって消費されることでバランスがとれている。
本明細書に記載される諸研究により、細菌叢の非存在下で飼育したマウス(無菌マウス)は眼圧(IOP)が上昇しても網膜神経節細胞(RGC)の破損を生じないことが示された。さらに、データにより、無菌マウスでは、コロニー刺激因子1(CSF1)の発現が下方制御されたが、CSF2は上方制御されたことが示された。次いで研究を実施して、CSF1およびCSF2が、緑内障のRGC喪失を媒介する相対する役割を果たしたかどうかを判定した。本明細書では、緑内障の標準マウスモデルにおけるCSF1およびCSF2の発現および関与について報告する。
。
潜在的な免疫調節および抗悪性腫瘍活性を有する、サイトカインコロニー刺激因子1(CSF1;CSF-1;マクロファージコロニー刺激因子;M-CSF)に対するヒト化免疫グロブリン(Ig)G2モノクローナル抗体(mAb)、抗CSF1モノクローナル抗体PD-0360324は、CSF1を標的とし、結合し、そして中和する。これにより、CSF1は、さまざまな免疫細胞、たとえば単球およびマクロファージ上に発現しているその受容体CSF1R(CD115;M-CSFR)と結合できなくなる。これにより、これらの細胞におけるCSF1R活性化およびCSF1R媒介性シグナリングが妨げられ、したがって単球分化が阻害され、マクロファージ活性が妨害され、それらによる炎症性メディエーター産生が低下し、炎症が低減される。腫瘍微小環境におけるCSF1R依存性腫瘍関連マクロファージ(TAM)の活性および増殖を妨害することによって、PD-0360324は、TAM媒介性免疫抑制を低下させ、調節性T細胞(Treg)を減少させ、免疫系を再活性化させ、そして細胞毒性T細胞による浸潤の増大により媒介される抗腫瘍細胞応答を向上させる。TAMは、免疫抑制、ならびに腫瘍細胞の増殖および生存において主要な役割を果たす。CSF-1は、単球およびマクロファージの増殖、分化、および生存の調節において主要な役割を果たす。
上述したように、本発明の組成物は、当業者には公知の多様な方法で調製することができる。本発明の組成物は、そのもとの供給源または取得様式にかかわらず、それらの使用に応じて製剤化することができる。たとえば、上述した核酸およびベクターを、組織培養での細胞への適用のための、または患者もしくは対象への投与のための組成物中に製剤化することができる。本発明の薬学的組成物はすべて、医薬の調製に使用するように製剤化することができ、治療という状況における具体的な使用を以下に示す。これらの組成物は、製薬業界で周知のように調製することができ、局所的治療または全身的治療のどちらが望ましいかによって、また治療部位によって、多様な経路で投与することができる。投与は、局所的(眼および粘膜への、たとえば鼻腔内、膣内、および直腸内送達を含む)、肺内(たとえば、粉末またはエアロゾルの、たとえばネビュライザーによる、吸入または吹込による;気管内、鼻腔内、上皮的、および経皮的)、眼内、経口、または非経口であり得る。眼内送達の方法には、局所投与(点眼)、結膜下注射、眼周囲注射、もしくは硝子体内注射、またはバルーンカテーテルによるもしくは結膜嚢に外科的に配置される眼用インサートによる導入が含まれ得る。非経口投与には、静脈内、動脈内、皮下、腹腔内、または筋内注射または輸注;あるいは頭蓋内、たとえば髄腔内または脳室内投与が含まれる。非経口投与は単回急速投与の形態であり得、または、たとえば連続灌流ポンプによるものでもよい。局所投与用の薬学的組成物および製剤としては、経皮パッチ、軟膏、ローション、クリーム、ゲル、液滴、座薬、スプレー、液体、粉末等を挙げることができる。従来の薬学的担体、水性、粉末、または油性の基剤、増粘剤等が必要であるか望ましい場合がある。
別途定義しない限り、本明細書で用いられる科学技術用語はすべて、(たとえば細胞培養、分子遺伝学、および生化学の)当業者が一般に理解するのと同じ意味をもつものとする。
本発明をその詳細な説明と併せて記載してきたが、上記説明は、説明することを意図され、本発明の範囲を限定することを意図されるものではなく、本発明の範囲は添付の特許請求の範囲により定められる。他の局面、利点、および変更形態は、以下の特許請求の範囲内である。
Claims (10)
- コロニー刺激因子-1受容体(CSF1R)に特異的な抗体を含む、対象における緑内障を予防するまたは治療する方法において使用するための医薬であって、
該方法が、該抗体を眼部に硝子体内投与する工程を含む、
医薬。 - 前記抗体が、網膜神経節細胞(RGC)の生存および視覚機能を保護する、請求項1に記載の医薬。
- RGCの生存が、パターン網膜電図(PERG)により査定される、請求項2に記載の医薬。
- 前記抗体が、CSF1受容体のある部分に特異的に結合する、請求項1~3のいずれか一項に記載の医薬。
- 前記抗体が、SEQ ID NO:1または2のある部分に特異的に結合する、請求項1~4のいずれか一項に記載の医薬。
- 前記抗体が、抗体断片、Fab、Fab’、F(ab’)2断片、Fv断片、単鎖抗体、ヒト化抗体またはそれらの組み合わせを含む、請求項1~5のいずれか一項に記載の医薬。
- 少なくとも1日1回投与される、請求項1~6のいずれか一項に記載の医薬。
- 2日または3日おきに1回投与される、請求項1~6のいずれか一項に記載の医薬。
- 前記抗体が、網膜神経節細胞(RGC)の生存および視覚機能を保護する、請求項6に記載の医薬。
- RGCの生存が、パターン網膜電図(PERG)により査定される、請求項9に記載の医薬。
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US20200399361A1 (en) | 2020-12-24 |
KR20210010435A (ko) | 2021-01-27 |
AU2019232730A1 (en) | 2020-10-01 |
CN112423780A (zh) | 2021-02-26 |
WO2019173361A3 (en) | 2019-11-07 |
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