JP2022502408A - 妊娠中のfgfr3関連骨疾患の処置ためのインフィグラチニブ - Google Patents
妊娠中のfgfr3関連骨疾患の処置ためのインフィグラチニブ Download PDFInfo
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- achondroplasia
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- A—HUMAN NECESSITIES
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Abstract
Description
本発明は、妊娠中のFGFR3関連骨疾患の処置法に関する。
線維芽細胞増殖因子受容体(FGFR)は、5つのチロシンキナーゼ受容体(RTK)の中の1ファミリーであり、胚発生及び生後発達の全期間におよぶ、軟骨性骨化中及び膜性骨化中の骨格発達の重要な調節因子である。FGFR3は、骨及び軟骨の両方において発現され、FGFR3のシグナル伝達は、骨格の発達中の様々な生物学的事象を調節する。FGFR3の機能獲得型突然変異は、軟骨異形成症の1ファミリー、すなわち、最も一般的な形態の低身長症である軟骨無形成症(ACH)、致命的な形態の低身長症であるタナトフォリック骨異形成症(TD)、並びに、軟骨低形成症(HCH)に関与している。病原性優性FGFR3突然変異は、頭蓋骨縫合早期癒合症も引き起こす。ムンケ症候群は、最も一般的な頭蓋骨縫合早期癒合症症候群であり、黒色表皮腫(CAN)を伴うクルーゾン症候群は、稀な症候群である。FGFR3は、成長軟骨板において重要な役割を果たし、軟骨細胞の増殖速度及び軟骨細胞肥大の惹起の両方を抑制するように作用する。近年のデータは、インフィグラチニブ(NVP−BGJ398)が、軟骨無形成症の病理学的特徴を修正し、インフィグラチニブをFGFR3関連骨疾患の治療アプローチ候補として支持する(Komla-Ebri, D., Dambroise, E., Kramer, I., Benoist-Lasselin, C., Kaci, N., Le Gall, C. & Kneissel, M. (2016). Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. The Journal of clinical investigation, 126(5), 1871-1884 and Biosse Duplan, M., Komla-Ebri, D., Heuze, Y., Estibals, V., Gaudas, E., Kaci, N. & Porta, D. G. (2016). Meckel’s and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible. Human molecular genetics, 25(14), 2997-3010)。
本発明は、妊娠中のFGFR3関連骨疾患の処置法に関する。特に、本発明は、請求項によって定義される。
本発明は、妊娠被験者に有効量のインフィグラチニブを投与する工程を含む、胎児のFGFR3(線維芽細胞増殖因子受容体3)関連骨疾患を処置する方法に関する。
序論:
FGFRに関連した軟骨異形成症は、最も頻繁に起こる軟骨異形成症(軟骨無形成症及び軟骨低形成症)及び頭蓋骨縫合早期癒合症(ムンケ症候群)を包含する。これら全ての骨軟骨異形成症は、Fgfr3の胚の突然変異に起因し、これらのFgfr3の機能獲得型突然変異は、骨格形成中の軟骨形成及び骨形成を損なう。
BGJ398を用いて妊娠中の骨格の不完全な成長を処置することが可能であることを実証すること。
骨格発達に対するBGJ398の処置の有効性が以前に、低身長症を示すFgfr3Y367C/+の仔に対して実証された(Komla-Ebri et al 2016, Biosse-Duplan et al 2016)。
5匹の雌は49匹の仔を出産し、ビヒクルを受けた5匹の仔のFgfr3Y367C/+は、生誕時に典型的な疾患表現型を示し、BGJ398の投与を受けたその他の4匹のFgfr3Y367C/+は、骨格表現型の改善を示した。
データは、妊娠マウスにおける5日間のBGJ398による処置が、胚段階中に起こった骨格異常を成功裡に抑制したことを示した。妊娠マウスの処置は、骨格病態をより早期に治癒することを可能とした。結果は、BGJ398が、治療レベルで胎盤を通過することを示唆する。
本出願全体を通して、様々な参考文献が、本発明が属する技術分野の最先端技術を記載している。これらの参考文献の開示はここに、本開示への参照により組み込まれる。
Claims (6)
- 妊娠被験者に有効量のインフィグラチニブを投与する工程を含む、胎児のFGFR3(線維芽細胞増殖因子受容体3)関連骨疾患を処置する方法。
- FGFR3関連骨疾患が、FGFR3に関連した軟骨異形成症である、請求項1の方法。
- FGFR3に関連した軟骨異形成症が、I型タナトフォリック骨異形成症、II型タナトフォリック骨異形成症、軟骨低形成症、軟骨無形成症、発達遅滞と黒色表皮腫を伴う重症軟骨無形成症、及び軟骨低形成症からなる群より選択される、請求項2の方法。
- FGFR3関連骨疾患が、FGFR3に関連した頭蓋骨縫合早期癒合症である、請求項1の方法。
- FGFR3に関連した頭蓋骨縫合早期癒合症が、ムンケ症候群である、請求項4の方法。
- インフィグラチニブが、妊娠被験者に経口投与又は皮下投与される、請求項1の方法。
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PCT/EP2019/076241 WO2020065034A1 (en) | 2018-09-28 | 2019-09-27 | Infigratinib for treatment of fgfr3-related skeletal diseases during pregnancy |
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WO2023117879A1 (en) * | 2021-12-20 | 2023-06-29 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of a fgfr3 tyrosine kinase inhibitor for the treatment of fgfr-related bone repair and bone formation impairments |
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US20150011560A1 (en) * | 2011-12-12 | 2015-01-08 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Antagonist of the fibroblast growth factor receptor 3 (fgfr3) for use in the treatment or the prevention of skeletal disorders linked with abnormal activation of fgfr3 |
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"Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodys", EBIOMEDICINE, vol. 40, JPN6023021906, 23 January 2019 (2019-01-23), pages 695 - 709, ISSN: 0005077405 * |
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