JP2023521545A - 修飾マクロファージ、組成物およびその使用 - Google Patents
修飾マクロファージ、組成物およびその使用 Download PDFInfo
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Abstract
Description
本願発明の修飾単球は、約1時間~12時間、細胞培養培地とマクロファージコロニー刺激因子(M-CSF)、顆粒球マクロファージコロニー刺激因子(GM-CSF)、顆粒球コロニー刺激因子(G-CSF)、IL-4またはそれらの組み合わせを含む分極化混合物との存在下でPBMNCsから得られ、修飾単球の分極化を導く。一実施形態において、修飾単球は表面マーカーCD14を発現している。別の実施形態では、本願発明の培養方法の結果として、修飾単球はCD14の表現型(すなわち、CD14+)を呈し、かつ、タンパク質またはRNAレベルでII型コラーゲン(Col II)を発現している。別の実施形態において、PBMNCsと細胞培養培地と分極化混合物との接触時間は、約1時間~4時間である。
一実施形態において、修飾マクロファージを作製するインビトロ培養方法は以下の手順を含む。
(a)被験体からサンプルを採取する。サンプルには、末梢血、臍帯血および骨髄サンプルなど、一個以上の単核細胞を含有する体液が含まれるが、これらに限定されない。
(b)密度勾配遠心分離法(例:Ficoll-PaqueTM PREMIUM、GE Healthcare USA)を用いて、工程(a)のサンプル中の修飾マクロファージを他の種類の血液細胞から分離する。その他の単核細胞を分離する方法は、公知であるか、当業者にとって明らかであろう。
(c)CD14に対する抗体(例:BioLegend(米国)が市販する抗CD14 FITCコンジュゲート)を用いて工程(b)の単核細胞を標識し、フローサイトメトリーを用いることにより、単球の%を判定する方法は、本技術分野において公知である。
(d)精製した修飾マクロファージを、細胞培養培地と、M-CSF、GM-CSF、G-CSF、IL-4またはそれらの組み合わせを含む分極化混合物とに接触させる方法。
Claims (21)
- CD14+CD206+により特徴付けられたマクロファージの表現型;および
II型コラーゲン
を含む修飾マクロファージ。 - 前記II型コラーゲンが前記修飾マクロファージ内で発現している請求項1に記載の修飾マクロファージ。
- 前記II型コラーゲンが前記修飾マクロファージの表面に発現している請求項1に記載の修飾マクロファージ。
- CD14+により特徴付けられた単球の表現型;および
II型コラーゲン
を含む修飾単球。 - 前記II型コラーゲンが前記修飾単球内で発現している請求項4に記載の修飾単球。
- (a)請求項1に記載の修飾マクロファージまたは請求項4に記載の修飾単球;および
(b)薬学的に許容される担体または添加剤
を含む医薬組成物。 - 約0.01%~99.9%の前記修飾マクロファージまたは前記修飾単球を含む、請求項6に記載の医薬組成物。
- 筋骨格系疾患を治療するために、有効量の請求項1に記載の修飾マクロファージまたは有効量の請求項4に記載の修飾単球を、それを必要とする被験体に投与することを含む筋骨格系疾患の治療法。
- 前記筋骨格系疾患が関節炎である請求項8に記載の方法。
- 前記関節炎が、変形性関節症、自己免疫性関節炎または外傷性関節炎である請求項9に記載の方法。
- 前記筋骨格系疾患が、変形性椎間板疾患または椎間板変性症である請求項8に記載の方法。
- 前記椎間板が、関節軟骨の軟骨組織部位、半月板の軟骨組織部位および椎間板の軟骨組織部位からなる群より選ばれるものである請求項11に記載の方法。
- 前記筋骨格系疾患が腱炎である請求項8に記載の方法。
- 前記修飾単球または前記修飾マクロファージを関節内注射により投与する請求項8に記載の方法。
- さらにヒアルロン酸またはその誘導体若しくは塩、成長因子、軟骨形成剤、ビタミンD3(コレカルシフェロール)、加水分解コラーゲン、ルサラチドアセタート、アボカド大豆不ケン化物(ASU)、ステロイド、および非ステロイド性抗炎症薬(NSAID)から選択される薬剤を、前記被験体に投与することを含む請求項8に記載の方法。
- 請求項1に記載の修飾マクロファージまたは請求項4に記載の修飾単球を、それを必要とする被験体の身体部位に投与する工程を含む、被験体の体内の一部で軟骨形成を誘導する方法。
- (a)細胞培養培地;および
(b)IL-4、GM-CSF、G-CSFまたはM-CSFのうち少なくとも一つを含む分極化混合物
を含む有効量の組成物に、末梢血単球が接触することを含む、
単球を請求項1に記載の修飾マクロファージに分化誘導するインビトロ方法。 - 前記細胞培養培地が、RPMI-1640またはイスコフ改変ダルベッコ培地(IMDM)である請求項17に記載の方法。
- 前記修飾マクロファージと前記組成物の接触時間を約2時間~約7日間とする請求項17に記載の方法。
- 前記分極化混合物が、IL-4およびM-CSFである請求項17に記載の方法。
- 前記分極化混合物が、実質的にIL-10、IL-13およびTGF-βを含有しない請求項17に記載の方法。
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PCT/JP2021/015925 WO2021215410A1 (en) | 2020-04-20 | 2021-04-19 | Modified macrophages, compositions and uses thereof |
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US11738046B2 (en) * | 2017-11-03 | 2023-08-29 | Wisconsin Alumni Research Foundation | Macrophage cell therapy to treat orthopedic injury |
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