JP2019523295A - ミオスタチン阻害剤の使用および併用療法 - Google Patents
ミオスタチン阻害剤の使用および併用療法 Download PDFInfo
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Abstract
Description
i)肥大を促進するために治療しようとする筋肉が、十分な同化能力を保持または回復していること、
ii)肥大を促進するためにおよび/または萎縮を予防するために治療しようとする筋肉が、運動ニューロンの少なくとも部分的な機能的神経支配を保持するかまたは取り戻していること、およびさらに一部の場合では、
iii)治療しようとする筋肉が、速筋(例えば、II型)線維に依存する運動機能に必要であること。
定義
脊髄性筋萎縮症(SMA)
SMAの治療手法−SMN修正因子
ミオスタチンを標的とした筋肉機能の改善−ミオスタチン阻害剤
脊髄性筋萎縮症を治療するための併用療法
患者集団
投薬量および投与
ミオスタチン阻害剤およびSMN修正因子の生物学的効果
拡大ハマースミス運動機能評価スケール
運動機能尺度(MFM)
上肢モジュール(ULM)
改訂版上肢モジュール
CHOP INTENDスコア
CMAP試験
MUNE試験
ヒト対象における筋肉の質量および/または機能に対する効果
筋肉内脂肪沈着のレベルに対する効果
ヒト対象の生活の質に対する効果
筋肉喪失または萎縮の予防に対する効果
骨恒常性に対する効果
代謝制御に対する効果
i)ヒト対象のインスリン感受性に対する効果
ii)ヒト対象の脂肪組織のレベルに対する効果
iii)ヒト対象の脂肪対筋組織の比に対する効果
iv)ヒト対象のグルコース取込みに対する効果
v)ヒト対象の筋肉内脂肪浸潤に対する効果
α−運動ニューロン喪失遅延の効果
バイオマーカーの発現
筋肥大を促進するための療法
筋萎縮を予防するための療法
本発明を実施するための非限定的な実施形態としては、以下のものが挙げられる。
上記に記載される本発明のさらなる実施形態では、抗体またはその抗原結合性部分は、プロ型/潜在型ミオスタチンには結合するが、成熟ミオスタチンまたはGDF11とは結合しない。上記に記載される本発明の異なる実施形態では、抗体またはその抗原結合性部分は、成熟ミオスタチンには結合するが、成熟GDF11とは結合しない。上記に記載される本発明の別の実施形態では、抗体またはその抗原結合性部分は、1mg/kg〜30mg/kgの間の範囲の投薬量で対象に投与される。上記に記載される本発明の異なる実施形態では、抗体またはその抗原結合性部分は、週2回、週1回、2週に1回、または月1回で対象に投与される。ミオスタチン阻害剤が記載されている上記の実施形態のいずれかでは、抗体またはその抗原結合性部分は、対象に静脈内投与(つまり、静脈に注射される)または皮下投与される(つまり、皮膚に注射される)。
SRK−015:ミオスタチン活性化の特異的阻害
他のTGFβファミリーメンバーと同様に、ミオスタチンは、プロドメインが存在することにより、その受容体への増殖因子の接近が遮断されている、プロミオスタチンと称される不活性前駆体として分泌される。ミオスタチン活性化は、2つの別個のタンパク質分解的切断ステップに起因する(図1)。プロミオスタチンは、まず、プロドメインと成熟増殖因子との間のRXXR部位を認識する、フューリンなどのプロタンパク質転換酵素により切断される(30、62)。切断後、増殖因子およびプロドメインは、依然として一緒のままであり、その受容体に結合することができない潜在型複合体(潜在型ミオスタチン)を形成する。活性増殖因子は、BMP/トロイドファミリー(TLL−2、トロイド様タンパク質2など)のメンバーによる第2の切断後に放出される(63)。活性化後、ミオスタチンは、I型受容体(Alk4/5)およびII型受容体(ActRIIA/B)からなる受容体複合体に結合し、Smad2/3のリン酸化および活性化をもたらす。最終的に、このシグナル伝達経路の活性化は、タンパク質合成の低減およびタンパク質分解の増強を引き起こす(64)。ミオスタチンは、in vivoでは2つの区画:循環中および筋肉中で検出されている。循環中では潜在型が多く、筋肉中ではプロミオスタチンが多く、これは、パールカンなどの細胞外マトリックスタンパク質と結合している(65〜68)。
(実施例2)
ミオスタチンプロ型のin situ局在化
(実施例3)
SRK−015はデキサメタゾン誘導性筋萎縮を予防する
(実施例4)
SRK−015Pは、健常動物の筋肉重量および機能を増強する
(実施例5)
ミオスタチン阻害は、スプライス修正因子で治療したSMAマウスの筋肉機能を改善する
(実施例6)
ミオスタチン阻害の利益は、十分な筋神経支配を必要とする
(実施例7)
SMNΔ7マウスでの標的結合
(実施例8)
scidマウスにおけるSRK−015の薬物動態および薬力学
(実施例9)
カニクイザルにおけるSRK−015の薬物動態および薬力学
(実施例10)
出生時から十分な治療用量のSMN−C1で治療したSMNΔ7マウスの筋肉性能
参考文献
Claims (26)
- 対象の脊髄性筋萎縮症(SMA)を治療するための方法であって、
前記対象に、SMAの治療に有効な量のミオスタチン阻害剤を投与するステップであって、前記対象が、SMN修正因子療法を受けているか、またはSMN修正因子療法を受けることが予想される、ステップ、
それにより前記対象の脊髄性筋萎縮症を治療するステップ
を含む、方法。 - 前記対象が、前記ミオスタチン阻害剤の投与の6カ月以内に前記SMN修正因子療法を受けることが予想される、請求項1に記載の方法。
- 前記ミオスタチン阻害剤が、
プロ型のミオスタチンと結合することによってミオスタチンの活性化を阻害する抗体またはその抗原結合性部分、
成熟ミオスタチンと結合することによってミオスタチン活性を中和する抗体またはその抗原結合性部分、
ミオスタチン受容体と結合する抗体またはその抗原結合性部分、
成熟ミオスタチンと結合するプロドメインまたはその断片、
成熟ミオスタチンと結合する可溶性ミオスタチン受容体断片、および
ミオスタチンの低分子アンタゴニスト
からなる群から選択される、請求項1〜2のいずれか一項に記載の方法。 - 前記抗体またはその抗原結合性部分が、前記プロ型のミオスタチンのプロドメインと結合する、請求項3に記載の方法。
- 前記抗体またはその抗原結合性部分が、プロ型/潜在型ミオスタチンと結合する、請求項3または4に記載の方法。
- 前記抗体またはその抗原結合性部分が、前記プロ型のミオスタチンに関連していない成熟ミオスタチンには結合しない、請求項5に記載の方法。
- 前記対象が、SMN修正因子の応答個体である、前記請求項のいずれか一項に記載の方法。
- 前記対象が、SMN修正因子の非応答個体または低応答個体である、請求項1〜7のいずれか一項に記載の方法。
- 前記SMN修正因子が、
a)スプライス修飾因子、
b)SMN遺伝子置換もしくは遺伝子療法剤、
c)SMN転写エンハンサー、
d)SMNタンパク質翻訳エンハンサー、または
e)SMNタンパク質安定化剤
を含む、前記請求項のいずれか一項に記載の方法。 - 前記SMN修正因子が、アンチセンスRNAまたは低分子である、前記請求項のいずれか一項に記載の方法。
- 前記対象が、歩行不可能なSMAまたは歩行可能なSMAを有する、前記請求項のいずれか一項に記載の方法。
- 前記対象が、I型SMA、II型SMA、またはIII型SMAと診断されている、前記請求項のいずれか一項に記載の方法。
- 対象の歩行可能なSMAを治療するための方法であって、歩行可能なSMAを有する対象に、有効量のミオスタチン阻害剤を投与するステップを含み、前記対象がSMN修正因子療法を受けていない、方法。
- 対象のSMAを治療するための方法であって、Smn突然変異のキャリアであると遺伝学的に同定されている対象に、筋肉萎縮の予防に有効な量のミオスタチン阻害剤を投与するステップを含み、前記対象がSMN修正因子療法を受けていない、方法。
- 前記対象が、前記ミオスタチン阻害剤の投与前に、≦65のベースラインの拡大ハマースミス運動機能評価スケールスコアを有する、前記請求項のいずれか一項に記載の方法。
- SMAの治療に有効な量が、
a)筋萎縮を遅延または緩和すること、
b)α−運動ニューロンの喪失を遅延させること、
c)未熟筋肉マーカーの発現を予防または遅延させること、
d)筋組織の脂肪置換を特徴とする筋肉内脂肪沈着を予防、緩和、または遅延させること、
e)拡大ハマースミス運動機能評価スケールスコアを、未治療対照群と比較して≧1ポイント、または治療前に測定されたベースラインから≧1ポイント増加させること、
f)12カ月、24カ月、または36カ月間にわたって拡大ハマースミス運動機能評価スケールの漸進的減少を遅延させること、
g)CHOP INTENDスコアを、未治療対照と比較して≧1ポイント増加させること、および/または
h)MFM−32スコアを、未治療対照と比較して少なくとも1ポイント増加させること
に有効な量である、前記請求項のいずれか一項に記載の方法。 - 前記抗体またはその抗原結合性断片が、静脈内注射または注入により投与される、請求項1〜16のいずれか一項に記載の方法。
- 前記抗体またはその抗原結合性断片が、皮下注射により投与される、請求項1〜16のいずれか一項に記載の方法。
- 筋肥大を促進するための方法であって、
筋肉成長から利益を得る可能性があり、ミオスタチン阻害剤の低応答個体である対象に、前記ミオスタチン阻害剤の効果がブーストされるように有効量の同化刺激因子を投与するステップ
を含む方法。 - 前記同化刺激因子および前記ミオスタチン阻害剤が、併用療法として投与される、請求項19に記載の方法。
- 前記対象が、筋肉減少症、悪液質、慢性SCI、慢性または頻発感染症、骨粗鬆症、および高頻度の転倒/骨折からなる群から選択される状態を罹患している、請求項19または20に記載の方法。
- 前記対象が、65歳またはそれよりも年長である、請求項19〜21のいずれか一項に記載の方法。
- 前記対象が、ニューロン療法でさらに治療される、請求項19〜22のいずれか一項に記載の方法。
- 前記対象が、筋萎縮性側索硬化症(ALS)またはSMAを有する、請求項23に記載の方法。
- 前記ミオスタチン阻害剤が、ミオスタチンの低分子アンタゴニストまたはミオスタチンの生物学的アンタゴニストである、請求項19〜24のいずれか一項に記載の方法。
- 前記ミオスタチンの生物学的アンタゴニストが、抗体またはその抗原結合性部分である、請求項25に記載の方法。
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