JP2020511951A - 老化細胞の処置のためのタンパク質療法 - Google Patents
老化細胞の処置のためのタンパク質療法 Download PDFInfo
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Abstract
Description
本開示は、老化細胞を処置もしくは浄化する分野、および/または老化細胞に関係する疾患もしくは障害を処置する分野に関する。詳細には本開示は、老化細胞を標的とする条件付き活性タンパク質に関し、そしてそのような条件付き活性タンパク質を作製する方法に関する。
老化細胞は、代謝活性があるが、細胞増殖周期のG1期に捕らえられ、寿命は複数の優性遺伝子により制御される(Stanulis−Praeger,Mech.Ageing Dev.,vol.38,pp.1−48,1987)。老化細胞は、複数の重要な様相が静止細胞および最終分化細胞と異なり、拡張、平坦化および顆粒性増大(increased granularity)などの特徴的な形態変化を有する(Dimri et al., Proc. Nat. Acad. Sci. USA, vol. 92, pp.9363−9367, 1995)。老化細胞は、有糸分裂促進因子により刺激されたとしても、分裂しない(Campisi, Trends Cell Biol., vol. 11, pp. S27−S31, 2001)。老化は、p53および/またはRb、ならびにそれらの調節因子、例えばp16INK4a、p21、およびARFの活性化を含む。p53またはRbが不活性化された場合を除き、老化は、一般に不可逆性である。
一実施形態において、該開示は、老化細胞に関連する標的に結合する条件付き活性タンパク質を、該老化細胞に関連する該標的に結合する親タンパク質から生成する方法であって、
(i)1つまたは複数の進化的技術(evolutionaly techniques)を利用して該親タンパク質をコードするDNAを進化させて、突然変異体DNAを作出するステップと;
(ii)該突然変異体DNAを発現させて突然変異体タンパク質を得るステップと;
(iii)該突然変異体タンパク質を、該老化細胞の細胞外条件下でのアッセイおよび正常な生理学的条件下でのアッセイに供するステップと;
(iv)(a)アッセイにおける該親タンパク質の活性に比較した、該正常な生理学的条件下での同アッセイにおける同活性の低下、および該正常な生理学的条件下でのアッセイにおける該条件付き活性タンパク質の活性に比較した、該老化細胞の細胞外条件下での該アッセイにおける同活性の上昇;ならびに
(b)アッセイにおける該親タンパク質の活性に比較した、該正常な生理学的条件下での同アッセイにおける同活性の低下、および該老化細胞の細胞外条件下でのアッセイにおける該親タンパク質の活性に比較した、該老化細胞の細胞外条件下での該アッセイにおける同活性の上昇、
のうちの少なくとも1つを示す該突然変異体タンパク質から該条件付き活性タンパク質を選択するステップと;
を含む、方法を提供する。
本明細書で提供された実施例の理解を容易にするために、特定の頻出する方法および/用語を本明細書内で定義する。
本明細書および添付の特許請求の範囲で用いられる通り、単数形態の「a」、「an」、および「the」が他に明確に示されない限り複数の対象を含むことが、留意されなければならない。さらに、用語「a」(または「an」)、「1つまたは複数の」および「少なくとも1つの」は、本明細書では互換的に用いられ得る。用語「含むこと」、「包含すること」、「有すること」、および「から構築された」もまた、互換的に用いられ得る。
(i)1つまたは複数の進化的技術を利用して該親タンパク質をコードするDNAを進化させて、突然変異体DNAを作出するステップと;
(ii)該突然変異体DNAを発現させて突然変異体タンパク質を得るステップと;
(iii)該突然変異体タンパク質を、該老化細胞の細胞外条件下でのアッセイおよび正常な生理学的条件下でのアッセイに供するステップと;
(iv)(a)アッセイにおける該親タンパク質の活性に比較した、該正常な生理学的条件下での同アッセイにおける同活性の低下、および該正常な生理学的条件下でのアッセイにおける該条件付き活性タンパク質の活性に比較した、該老化細胞の細胞外条件下での該アッセイにおける同活性の上昇;ならびに
(b)アッセイにおける該親タンパク質の活性に比較した、該正常な生理学的条件下での同アッセイにおける同活性の低下、および該老化細胞の細胞外条件下でのアッセイにおける該親タンパク質の活性に比較した、該老化細胞の細胞外条件下での該アッセイにおける同活性の上昇、
のうちの少なくとも1つを示す該突然変異体タンパク質から該条件付き活性タンパク質を選択するステップと;
を含む。
(a)アッセイにおける該親タンパク質の活性に比較した、該正常な生理学的条件下での同アッセイにおける同活性の低下、および該正常な生理学的条件下でのアッセイにおける該条件付き活性タンパク質の活性に比較した、該老化細胞の細胞外条件下での該アッセイにおける同活性の上昇;ならびに
(b)アッセイにおける該親タンパク質の活性に比較した、該正常な生理学的条件下での同アッセイにおける同活性の低下、および該老化細胞の細胞外条件下でのアッセイにおける該親タンパク質の活性に比較した、該老化細胞の細胞外条件下での該アッセイにおける同活性の上昇、
のうちの少なくとも1つを示す。
(a)アッセイにおける該親タンパク質の活性に比較した、該正常な生理学的条件下での同アッセイにおける同活性の低下、および正常な生理学的条件下でのアッセイにおける該条件付き活性タンパク質の活性に比較した、該老化細胞の細胞外条件下での該アッセイにおける同活性の上昇;ならびに
(b)アッセイにおける該親タンパク質の活性に比較した、該正常な生理学的条件下での同アッセイにおける同活性の低下、および該老化細胞の細胞外条件下でのアッセイにおける該親タンパク質の活性に比較した、該老化細胞の細胞外条件下での該アッセイにおける同活性の上昇、
のうちの少なくとも1つを示す、第一の条件付き活性タンパク質が選択される。
(a)アッセイにおける該親タンパク質の活性に比較した、該正常な生理学的条件下での同アッセイにおける同活性の低下、および正常な生理学的条件下でのアッセイにおける該条件付き活性タンパク質の活性に比較した、該老化細胞の細胞外条件下での該アッセイにおける同活性の上昇;ならびに
(b)アッセイにおける該親タンパク質の活性に比較した、該正常な生理学的条件下での同アッセイにおける同活性の低下、および該老化細胞の細胞外条件下でのアッセイにおける該親タンパク質の活性に比較した、該老化細胞の細胞外条件下での該アッセイにおける同活性の上昇、
のうちの少なくとも1つを示す少なくとも1つの第二の条件付き活性タンパク質を選択してもよい。第二の活性は、第一の活性と同様であってもよく、その場合、第二の条件付き活性タンパク質が、第一の条件付き活性タンパク質に比較して、細胞外条件での活性と正常な生理学的条件での活性の間でより大きな比を有することが望ましい。幾つかの実施形態において、該第二の活性は、第一の活性と異なる活性であってもよく、その場合、内在化効率または特異的エピトープへの結合などの活性が、第二の活性であってもよい。
アルカロイド類:ドセタキセル、エトポシド、イリノテカン、パクリタキセル、テニポシド、テポテカン、ビンブラスチン、ビンクリスチン、ビンデシン、
アルキル化剤:ブスルファン、インプロスルファン、ピポスルファン、ベンゾデパ、カルボクオン、メツレデパ、ウレデパ、アルトレタミン、トリエチレンメラミン、トリエチレンホスホラミド、トリエチレンチオホスホラミド、クロラムブシル、クロラナファジン(Chloranaphazine)、シクロホスファミド、エストラムスチン、イフォスファミド、メクロレタミン、メクロレタミンオキシド塩酸塩、メルファラン、ノベメビキン(novemebichin)、ペルホスファミド、フェネステリン、プレドニムスチン、トロホスファミド、ウラシルマスタード、カルムスチン、クロロゾトシン、フォテムスチン、ロムスチン、ニムスチン、セムスチン、ラニムスチン、ダカルバジン、マノムスチン、ミトブロニトール、ミトラクトール、ピポブロマン、テモゾロミド、
抗生物質およびその類似体:アクラシノマイシン、アクチノマイシン、アントラマイシン、アザセリン、ブレオマイシン、カクチノマイシン、カルビシン、カルジノフィリン、クロモマイシン、ダクチノマイシン、ダウノルビシン、6−ジアゾ−5−オキソ−L−ノルロイシン、ドキソルビシン、エピルビシン、イダルビシン、メノガリル、マイトマイシン、ミコフェノール酸、ノガラマイシン、オリボマイシン、ペプロマイシン、ピラルビシン、プリカマイシン、ポルフィロマイシン、ピューロマイシン、ストレプトニグリン、ストレプトゾシン、ツベルシジン、ジノスタチン、ゾルビシン、
代謝拮抗薬:デノプテリン、エダトレキサート、メトトレキサート、ピリトレキシム、プテロプテリン、トムデックス、トリメトレキサート、クラドリジン(cladridine)、フルダラビン、6−メルカプトプリン、ペントスタチン、チアミプリン、チオグアニン、アンシタビン、アザシチジン、6−アザウリジン、カルモフチル(carmoftir)、シタラビン、ドキシフルリジン、エミテフール、フロクスウリジン、フルオロウラシル、ゲムシタビン、テガフール、
白金錯体:カロプラチン、シスプラチン、ミボプラチン、オキサリプラチン、
その他:アセグラトン、アムサクリン、ビサントレン、デフォスファミド、デメコルシン、ジアジクオン、エフロルニチン、エリプチニウム酢酸塩、エトグルシド、エトプシド(Etopside)、フェンレチニド、硝酸ガリウム、ヒドロキシ尿素、ロニダミン、ミルテフォシン、ミトグアゾン、ミトキサントロン、モピダモル、ニトラクリン、ペントスタチン、フェナメット、ポドフィリン酸、2−エチルヒドラジド、プロカルバジン、ラゾキサン、ソブゾキサン、スピロゲルマニウム、テニポシド、テヌアゾン酸、トリアジクオン、2,2’,2’’−トリクロロトリエチルアミン、ウレタン、
により具体化される。
アルキル化剤の例としては、シクロホスファミド、クロラムブシル、ブスルファン、メルファラン、チオテパ、イフォスファミド、ナイトロジェンマスタードが挙げられる。
代謝拮抗薬の例としては、メトトレキサート、5−フルオロウラシル、シトシンアラビノシド、6−チオグアニン、6−メルカプトプリンが挙げられる。
抗腫瘍抗生物質の例としては、ドキソルビシン、ダウノルビシン、イドルビシン、ニミトキサントロン(nimitoxantron)、ダクチノマイシン、ブレオマイシン、マイトマイシン、プリカマイシンが挙げられる。
ビンカアルカロイド類およびエピポドフィロトキシン類の例としては、ビンクリスチン、ビンブラスチン、ビンデスチン(vindestin)、エトポシド、テニポシドが挙げられる。
ニトロソ尿素類の例としては、カルムスチン、ロムスチン、セムスチン、ストレプトゾシンが挙げられる。
ホルモン剤および抗ホルモン剤の例としては、アドレノコルチコルチコイド類(adrenocorticorticoids)、エストロゲン類、抗エストロゲン剤、プロゲスチン類、アロマターゼ阻害剤、アンドロゲン類、抗アンドロゲン剤が挙げられる。
無作為な合成薬としては、ダカルバジン、ヘキサメチルメラミン、ヒドロキシ尿素、ミトタン、プロカルバジド(procarbazide)、シスプラチン、カルボプラチンが挙げられる。
(a)アッセイにおける該親タンパク質の活性に比較した、該正常な生理学的条件下での同アッセイにおける同活性の低下、および正常な生理学的条件下でのアッセイにおける該条件付き活性タンパク質の活性に比較した、異常な条件下での該アッセイにおける同活性の上昇;ならびに
(b)アッセイにおける該親タンパク質の活性に比較した、該正常な生理学的条件下での同アッセイにおける同活性の低下、および異常な条件下でのアッセイにおける該親タンパク質の活性に比較した、異常な条件下での該アッセイにおける同活性の上昇、
のうちの少なくとも1つを示す、修飾された有機化合物から選択されてもよい。異常な条件下でのアッセイおよび正常な生理学的条件下でのアッセイで用いられるアッセイ溶液は、先に議論された小分子および/または分子種を含有していてもよい。
該条件付き活性タンパク質または医薬組成物により処置される老化細胞関連疾患または障害は、心臓血管疾患であってもよい。該心臓血管疾患は、狭心症、不整脈、アテローム性硬化症、心筋症、うっ血性心不全、冠動脈疾患、頸動脈疾患、心内膜炎、心臓発作(冠動脈血栓症、心筋梗塞)高血圧/高血圧症、大動脈瘤、脳動脈瘤、心線維症、心臓拡張機能障害、高コレステロール血症/高脂質血症、僧帽弁逸脱、末梢血管疾患(例えば、末梢動脈疾患)、心臓ストレス抵抗性、および脳卒中のうちの任意の1つまたは複数であってもよい。
特定の実施形態において、老化細胞関連疾患または障害は、該条件付き活性タンパク質または医薬組成物の投与を含む、本明細書に記載された方法に従って処置または予防され得る(即ち、発生の見込みを低減する)、非限定的例として骨関節炎などの炎症性疾患または障害である。他の炎症性または自己免疫疾患または障害としては、骨粗しょう症、乾癬、口腔粘膜炎、関節リウマチ、炎症性腸疾患、湿疹、後弯症、椎間板ヘルニア、および肺疾患、COPDおよび特発性肺線維症が挙げられる。
一実施形態において、該条件付き活性タンパク質または医薬組成物を投与することにより肺疾患または障害を有する対象における該疾患または障害に関連する老化細胞(即ち、確定された老化細胞)を殺傷または除去することにより該疾患または障害である老化細胞関連疾患または障害を処置または予防する(即ち、発生の見込みを低減する)ための方法が、提供される。老化関連の肺疾患および障害としては、例えば特発性肺線維症(IPF)、慢性閉塞性肺疾患(COPD)、喘息、嚢胞性線維症、気管支拡張症および肺気腫が挙げられる。IPFにおける細胞老化の関与は、該疾患の発生率が年齢に応じて増加すること、およびIPF患者における肺組織がSA−P−Gal陽性細胞を豊富に含み、高レベルの老化マーカーp21を含む、という観察により示唆される(例えば、Minagawa et al, Am. J. Physiol. Lung Cell. Mol. Physiol., vol. 300, pp. L391−L401, 2011参照)。短いテロメアは、IPFおよび細胞老化の両方に共通する危険因子である(例えば、Alder et al, Proc. Natl. Acad. Sci. USA, vol. 105, pp. 13051−56, 2008参照)。理論に結び付けるのを望むものではないが、IPFへの細胞老化の寄与は、IL−6、IL−8およびIL−Iβなどの老化細胞のSASP成分が線維芽細胞から筋線維芽細胞への分化および上皮から間葉系への移行を促進して、肺胞および間質空間の細胞外マトリックスの大規模なリモデリングをもたらすことが、報告により示唆される(例えば、上掲のMinagawa et al参照)。
該条件付き活性タンパク質または医薬組成物を投与することにより処置可能な老化細胞関連疾患または障害は、神経疾患または障害を包含する。そのような老化細胞関連疾患および障害としては、パーキンソン病、アルツハイマー病(および他の認知症)、運動ニューロン機能不全(MND)、軽度認知障害(MCI)、ハンチントン病、ならびに加齢黄斑変性などの目の疾患および障害が挙げられる。年齢の増加に関連する目の他の疾患は、緑内障、視覚損失、老視、および白内障である。
MCIは、個体の年齢および教養を基に予測されたものを超えているが、個体の日常活動を妨害するほど充分に有意でない認知障害の発病および発展を含む脳機能症候群である。該条件付き活性タンパク質の投与は、老化細胞を殺傷または除去することによりMCIを低減または阻害してもよい。星状細胞の形態学的分析、アセチルコリンの放出、神経変性を評定するための銀染色、およびベータアミロイド沈着を検出するためのPiB PET画像など、MCIに関連する神経病理学的欠損を検出、モニタリング、定量または評定するための方法は、当該技術分野で公知である(例えば、US2012/0071468参照)。8方向放射状迷路パラダイム、非見本合わせ課題、水迷路中の他人中心性場所決定課題、モーリス迷路試験、視空間課題、および遅延反応空間記憶課題、嗅覚新規検査(olfactory novelty test)(同著書参照)など、MCIに関連する行動異常を検出、モニタリング、定量または評定するための方法もまた、当該技術分野で公知である。
MNDは、発話、歩行、呼吸、および嚥下などの不可欠な随意筋活動を制御する細胞である運動ニューロンを破壊する進行性の神経障害の群である。MNDの例としては、ルー・ゲーリッグ病としても知られる筋萎縮性側索硬化症(ALS)、進行性球麻痺、偽球麻痺、原発性側索硬化、進行性筋萎縮症、下位運動ニューロン疾患、および脊髄筋萎縮症(SMA)(例えば、ウェルドニッヒ−ホフマン病とも呼ばれるSMA1、クーゲルバーグ−ヴェランダー病、およびケネディ病とも呼ばれるSMA2、SMA3)、ポリオ後症候群、および遺伝性痙性対麻痺が挙げられるが、これらに限定されない。該条件付き活性タンパク質の投与は、老化細胞を殺傷または除去することによりMNDを低減または阻害し得る。MNDなどの、パーキンソン病に関連する自発運動不足および/または他の欠乏を検出、モニタリング、または定量するための方法は、当該技術分野で公知である(例えば、US20120005765参照)。病理組織学的、生化学的、および電気生理学的な検査および運動活性分析を含む、MNDに関係する運動不足および組織病理学的欠乏を検出、モニタリング、定量する、または評定するための方法は、当該技術分野で公知である(例えば、Rich et al., J Neurophysiol, vol. 88, pp. 3293−3304, 2002; Appel et al, Proc. Natl. Acad. Sci. USA, vol. 88, pp. 647−51, 1991参照)。
特定の実施形態において、老化細胞関連疾患または障害は、眼の疾患、障害、または疾病、例えば、老視、黄斑変性、または白内障である。他の特定の実施形態において、老化細胞関連疾患または障害は、緑内障である。黄斑変性は、斑と呼ばれる網膜の中央部分の光受容細胞の損失を引き起こす神経変性疾患である。加齢黄斑変性の厳密な原因は、まだ知られていないが、老化網膜色素上皮(RPE)細胞の数は、年齢と共に増加する。年齢および特定の遺伝的因子および環境因子は、ARMDを発症する危険因子である(例えば、Lyengar et al, Am. J. Hum. Genet., vol. 74, pp. 20−39, 2004; Kenealy et al, Mol. Vis., vol. 10, pp. 57−61, 2004; Gorin et al, Mol. Vis., vol. 5, p. 29, 1999参照)。マイクロRNAの減少は、老化細胞プロファイルに寄与し;DICER1切除は、早期老化を誘導する。黄斑変性の対象の診断およびモニタリングは、当該技術分野で容認された定期眼科検診の手順および対象による症状の報告に従って、眼科の技術分野の当業者により達成され得る。
該条件付き活性タンパク質または医薬組成物を投与することにより処置可能な老化関連疾患または障害は、代謝性の疾患または障害を包含する。そのような老化細胞関連疾患および障害としては、糖尿病、メタボリック症候群、糖尿病性潰瘍、および肥満が挙げられる。本明細書に記載された条件付き活性タンパク質は、2型糖尿病、特に年齢、食事、および肥満に関連する2型糖尿病を処置するのに用いられてもよい。
本明細書に記載された条件付き活性タンパク質または医薬組成物を投与することにより処置可能な老化細胞関連疾患または障害は、皮膚疾患または障害を包含する。そのような老化細胞関連疾患および障害としては、乾癬および湿疹が挙げられ、これらも炎症性疾患であり、先により詳細に議論されている。老化に関連する他の皮膚疾患および障害としては、細かいしわ(老化によるしわ);心因掻痒(糖尿病および老化に関連する);知覚不全(糖尿病および多発性硬化症に関連する化学療法の副作用);乾癬(述べられた通り)および他の丘疹鱗屑性障害、例えば、紅皮症、扁平苔癬、および苔癬様皮膚病症;アトピー性皮膚炎(湿疹の形態および炎症に関係する);湿疹性発疹(高齢患者に多く観察され、特定の薬物の副作用に関連する)が挙げられる。老化に関係する他の皮膚疾患および障害としては、好酸球性皮膚病(特定種類の血液癌に関連する);反応性の好中球性皮膚症(炎症性腸症候群などの基礎疾患に関係する);天疱瘡(自己抗体がデスモグレインに対して形成する自己免疫性疾患);天疱瘡様および他の免疫水疱性皮膚病(皮膚の自己免疫性水疱形成);加齢に関連する皮膚の線維性組織球性増殖;ならびに高齢の個体群でより一般的な皮膚リンパ腫が挙げられる。本明細書に記載された方法に従って処置可能であり得る別の皮膚疾患としては、紅斑性狼瘡の症状である皮膚の狼瘡が挙げられる。遅発性の狼瘡は、T細胞およびB細胞の機能低下(即ち、減退)、ならびに加齢に関連するサイトカイン(免疫老化)に関連付けられ得る。
特定の実施形態において、該条件付き活性タンパク質または医薬組成物は、体内の1つの臓器または組織から別の臓器または組織への転移(即ち、癌または腫瘍細胞の拡大および拡散)の処置または予防に用いられ得る。癌を有する対象は、転移を阻害するために該条件付き活性タンパク質または医薬組成物の投与から利益を受け得る。そのような条件付き活性タンパク質または医薬組成物は、腫瘍増殖を阻害し得る。癌の転移は、癌細胞(即ち、腫瘍細胞)が、発生および最初のコロニー形成の解剖学的部位を越えて対象の全身の他の領域に広がる時に生じる。腫瘍増殖は、腫瘍サイズにより計測され得、これは、例えば、PETスキャン、MRI、CATスキャン、生検などにより、当業者に熟知された様々な方法で測定され得る。腫瘍増殖に対する治療剤の効果も、腫瘍細胞の分化を検査することにより評価され得る。
別の実施形態において、該老化細胞関連の障害または疾病は、化学療法の副作用または放射線療法の副作用である。非癌細胞を老化へ誘導する化学療法剤の例としては、アントラサイクリン(ドキソルビシン、ダウノルビシンなど);タキソール(例えば、パクリタキセル);ゲムシタビン;ポマリドマイド;およびレナリドマイドが挙げられる。本明細書に記載された通り投与される老化細胞除去薬の1種または複数は、化学療法の副作用または放射線療法の副作用を処置および/または予防する(即ち、その発生の見込みを低減する)ために使用され得る。老化細胞の除去または破壊は、化学療法または放射線療法のエネルギー不均衡を含む急性毒性をなどの急性毒性を改善し得る。急性毒性の副作用としては、胃腸毒性(例えば、吐気、嘔吐、便秘、食欲不振、下痢)、末梢神経障害、疲労、倦怠感、低身体活動、血液毒性(例えば、貧血症)、肝毒性、脱毛症(脱毛)、疼痛、感染、粘膜炎、体液鬱滞、皮膚毒性(例えば、発疹、皮膚炎、色素過剰症、蕁麻疹、光過敏症、爪の変化)、口腔の問題(例えば、口腔粘膜炎)、歯肉もしくは咽喉の問題、または化学療法もしくは放射線療法により引き起こされた任意の毒性副作用が挙げられるが、これらに限定されない。例えば、放射線療法または化学療法により引き起こされた毒性副作用(例えば、National Cancer Instituteのウェブサイトを参照)は、本明細書に記載された方法により改善され得る。したがって特定の実施形態において、治療を受ける対象において化学療法もしくは放射線療法またはその両方の急性毒性を改善する(発生を低減、阻害または予防するため(即ち、発生の見込みを低減するため))、あるいはその毒性副作用(即ち、有害な副作用)の重症度を低減するための方法が、本明細書で提供され、ここで該方法は、老化細胞を選択的に殺傷、除去もしくは破壊する、またその選択的な破壊を容易にする薬剤を該対象に投与することを含む。
該条件付き活性タンパク質または医薬組成物は、自然な加齢のプロセスの一部として生じる、または対象が老化誘導剤もしくは誘導因子(例えば、放射線、化学療法、喫煙、高脂肪/高糖食、他の環境因子)に暴露された時に生じる年齢関係の疾患または障害を処置または予防する(即ち、発生の見込みを低減する)のに有用であり得る。年齢関係の障害もしくは疾患、または年齢の影響を受けやすい特性は、老化誘導性の刺激に関連し得る。本明細書に記載された処置の方法の効能は、老化誘導性の刺激に関連する年齢関連の障害もしくは年齢の影響を受けやすい特性の症状の数を減少させることにより、1つもしくは複数の症状の重症度を低下させることにより、または老化誘導性の刺激に関連する年齢関連の障害もしくは年齢の影響を受けやすい特性の進行を遅延させることにより、発現され得る。他の特定の実施形態において、老化誘導性の刺激に関係する年齢関連の障害または年齢の影響を受けやすい特性を予防することは、老化誘導性の刺激に関連する年齢関連の障害または年齢の影響を受けやすい特性の発病、あるいは老化誘導性の刺激に関連する1つもしくは複数の年齢関連の障害または年齢の影響を受けやすい特性の再発を予防する(即ち、発生の見込みを低減する)または遅延させることを指す。
条件付き活性タンパク質を作製するための実施例1〜9は、WO2016/138071に記載される。
・ MCF−7は、ERa+細胞株である。パルボシクリブは、この細胞株において抗増殖活性を有し、細胞増殖を停止させて、老化細胞を誘導する。
・ MDA−MB231は、ERa−細胞株である。パルボシクリブは、この細胞株において抗増殖活性を有し、細胞増殖を停止させて、老化細胞を誘導する。
・ MDA−MB468は、別のERa−細胞株である。パルボシクリブは、この細胞株において抗増殖効果を有さず、したがって製造成長を停止させず、老化細胞を誘導することができない。
1. 細胞をPBSで2回洗浄し、細胞をDetachin(商標)細胞剥離溶液で剥離させる。
2. Detachin(商標)とDMEMとの反応を停止させて、細胞をカウントする。
3. PBS中の2mM C12FDG(最終33μM)、抗体(5μL、1×106細胞まで)、およびZombie NIR色素(1:1000)により氷上で1時間、染色する。
4. 細胞をPBSで2回洗浄し、4%PFAにより室温で10分間固定する。
5. PBSで洗浄して、FACを100μL PBS中で回収する。
6. FITC−PE−APC/Cy7を適用する。
7. 細胞を以下の抗体と同時染色して、対応する抗原の発現を検出する:
a) PE抗ヒトCD54クローンHCD54、200μg/mL、アイソタイプ:Ms IgG1。Biolegend、カタログ番号322707、ロット番号B232865、5μl/106細胞
b) PE抗ヒトCD73クローンAD2、アイソタイプ:Ms IgG1。Biolegend、カタログ番号344004、ロット番号B216193、5μl/106細胞
c) PE抗ヒトCD261(DR4、TRAIL−R1)クローンDJR1、200 μg/mL、アイソタイプ:Ms IgG1。Biolegend、カタログ番号307205、ロット番号B189821、5μl/106細胞
d) PE抗ヒトCD95 (Fas) クローンDX2、100 μg/mL、アイソタイプ:Ms IgG1。Biolegend、カタログ番号305607、ロット番号B203942、5μl/106細胞
e) PE抗ヒトCD39クローンA1、50μg/mL、アイソタイプ:Ms IgG1。Biolegend、カタログ番号328208、ロット番号B199643、5μl/106細胞
f) PE抗ヒトNectin4、アイソタイプ:Ms IgG1。R&D systems、カタログ番号FAB2659P、ロット番号AAAO0217031、5μl/106細胞
g) PE−アイソタイプマウス抗IgG1、k:クローンMOPC−21、0.2 mg/mL。 Biolegend、カタログ番号400112、ロット番号B220359、5μl/106細胞。
Claims (92)
- 老化細胞に関連する標的に結合する条件付き活性タンパク質を、前記老化細胞に関連する前記標的に結合する親タンパク質から生成する方法であって、
(i)1つまたは複数の進化的技術(evolutionaly techniques)を利用して前記親タンパク質をコードするDNAを進化させて、突然変異体DNAを作出するステップと;
(ii)前記突然変異体DNAを発現させて突然変異体タンパク質を得るステップと;
(iii)前記突然変異体タンパク質を、前記老化細胞の細胞外条件下でのアッセイおよび正常な生理学的条件下でのアッセイに供するステップと;
(iv)(a)前記アッセイにおける前記親タンパク質の活性に比較した、前記正常な生理学的条件下での同アッセイにおける同活性の低下、および前記正常な生理学的条件下でのアッセイにおける前記条件付き活性タンパク質の活性に比較した、前記老化細胞の細胞外条件下での前記アッセイにおける同活性の上昇;ならびに
(b)前記アッセイにおける前記親タンパク質の活性に比較した、前記正常な生理学的条件下での同アッセイにおける同活性の低下、および前記老化細胞の細胞外条件下での前記アッセイにおける前記親タンパク質の活性に比較した、前記老化細胞の細胞外条件下での前記アッセイにおける同活性の上昇、
のうちの少なくとも1つを示す前記突然変異体タンパク質から前記条件付き活性タンパク質を選択するステップと;
を含む、方法。 - 前記親タンパク質が、酵素、抗体、受容体、リガンド、酵素断片、抗体断片、受容体断片、およびリガンド断片から選択される、請求項1に記載の方法。
- 前記活性が、前記標的への結合活性である、請求項1〜2のいずれか1項に記載の方法。
- 前記親タンパク質が、酵素であり、前記活性が、前記老化細胞の少なくとも一部を基質として用いる酵素活性である、請求項1〜2のいずれか1項に記載の方法。
- 前記標的が、老化細胞の外面に配置された表面分子である、請求項1〜4のいずれか1項に記載の方法。
- 前記表面分子が、老化細胞の細胞膜タンパク質である、請求項5に記載の方法。
- 前記標的が、APC、ARHGAP1、ARMCX−3、AXL、B2MG、BCL2L1、CAPNS2、CD261、CD39、CD54、CD73、CD95、CDC42、CDKN2C、CLYBL、COPG1、CRKL、DCR1、DCR2、DCR3、DEP1、DGKA、EBP、EBP50、FASL、FGF1、GBA3、GIT2、ICAM1、ICAM3、IGF1、ISG20、ITGAV、KITLG、ラミンB1、LANCL1、LCMT2、LPHN1、MADCAM1、MAG、MAP3K14、MAPK、MEF2C、miR22、MMP3、MTHFD2、NAIP、NAPG、NCKAP1、ネクチン4、NNMT、NOTCH3、NTAL、OPG、OSBPL3、p16、p16INK4a、p19、p21、p53、PAI1、PARK2、PFN1、PGM、PLD3、PMS2、POU5F1、PPP1A、PPP1CB、PRKRA、PRPF19、PRTG、RAC1、RAPGEF1、RET、Smurf2、STX4、VAMP3、VIT、VPS26A、WEE1、YAP1、YH2AX、およびYWHAEのうちの少なくとも1つから選択される、請求項1〜4のいずれか1項に記載の方法。
- 前記条件付き活性タンパク質が、環状ペプチドである、請求項1〜7のいずれか1項に記載の方法。
- 前記環状ペプチドが、約5〜約500アミノ酸、または約8〜約300アミノ酸、または約8〜約200アミノ酸、または約10〜約100アミノ酸、または約10〜約50アミノ酸の範囲内の長さを有する、請求項8に記載の方法。
- 前記正常な生理学的条件下での前記アッセイにおける前記条件付き活性タンパク質の前記活性に対する、前記老化細胞の細胞外条件下での前記アッセイにおける前記条件付き活性タンパク質の前記活性の比が、少なくとも約1.3:1、または少なくとも約2:1、または少なくとも約3:1、または少なくとも約4:1、または少なくとも約5:1、または少なくとも約6:1、または少なくとも約7:1、または少なくとも約8:1、または少なくとも約9:1、または少なくとも約10:1、または少なくとも約11:1、または少なくとも約12:1、または少なくとも約13:1、または少なくとも約14:1、または少なくとも約15:1、または少なくとも約16:1、または少なくとも約17:1、または少なくとも約18:1、または少なくとも約19:1、または少なくとも約20:1、または少なくとも約30:1、または少なくとも約40:1、または少なくとも約50:1、または少なくとも約60:1、または少なくとも約70:1、または少なくとも約80:1、または少なくとも約90:1、または少なくとも約100:1である、請求項1〜9のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、約5.5〜約7.0、または約6.0〜約7.0、または約6.2〜約6.8の範囲内のpHである、請求項1〜10のいずれか1項に記載の方法。
- 前記正常な生理学的条件が、約7.2〜約7.8、または約7.2〜約7.6、または約7.4〜約7.6の範囲内のpHである、請求項1〜11のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、デオキシヌクレオチドの正常な生理学的濃度よりも低濃度の同デオキシヌクレオチドである、請求項1〜10のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、酸素の正常な生理学的濃度よりも低濃度の酸素である、請求項1〜10のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、NAD+/NADHの正常な生理学的比よりも低い比のNAD+/NADHである、請求項1〜10のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、ヒポタウリン、システインスルフィン酸、システイン−グルタチオンジスルフィド、ガンマ−グルタミルアラニン、ガンマ−グルタミルメチオニン、ピリドキサート、ガンマ−グルタミルグルタミン、およびアラニンから選択される少なくとも1種のレドックスホメオスタシス代謝産物の正常な生理学的濃度に比較して高濃度の同レドックスホメオスタシス代謝産物である、請求項1〜10のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、3−ウレイドプロピオナート、ウラート、7−メチルグアニン、およびヒポキサンチンから選択される少なくとも1種のヌクレオチド代謝産物の正常な生理学的濃度に比較して高濃度の同ヌクレオチド代謝産物である、請求項1〜10のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、チミジンの正常な生理学的濃度に比較して低濃度のチミジンである、請求項1〜10のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、グリシルイソロイシン、グリシルバリン、グリシルロイシン、イソロイシルグリシン、およびバリルグリシンから選択される少なくとも1種のジペプチドの正常な生理学的濃度に比較して低濃度の同ジペプチドである、請求項1〜10のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、リノレアート、ジホモリノレアート、および10−ヘプタデカノアートから選択される少なくとも1種の脂肪酸の正常な生理学的濃度に比較して低濃度の前記脂肪酸である、請求項1〜10のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、2−ヒドロキシパルミタート、2−ヒドロキシステアラート、3−ヒドロキシデカノアート、3−ヒドロキシオクタノアート、およびグリセロホスホリルコリンから選択される少なくとも1種のリン脂質代謝産物の正常な生理学的濃度に比較して高濃度の前記リン脂質代謝産物である、請求項1〜10のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、アラニン、C−グリコシルトリプトファン、キヌレニン、ジメチルアルギニン、およびオルチチン(orthithine)から選択される少なくとも1種のアミノ酸代謝産物の正常な生理学的濃度に比較して高濃度の前記アミノ酸代謝産物である、請求項1〜10のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、フェニルピルバートの正常な生理学的濃度に比較して低濃度の前記フェニルピルバートである、請求項1〜10のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、フマラート、マロナート、エイコサペンタエノアート、およびシトラートから選択される少なくとも1種の代謝産物の正常な生理学的濃度に比較して高濃度の前記代謝産物である、請求項1〜10のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、ホスホコリンに対するグリセロホスホコリンの正常な生理学的比に比較して高い比の、ホスホコリンに対するグリセロホスホコリンである、請求項1〜10のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、前記老化細胞により分泌されるタンパク質の正常な生理学的濃度に比較して高濃度の前記タンパク質であり、前記老化細胞により分泌される前記タンパク質が、GM−CSF、GROa、GRC−α、β、γ、IGFBP−7、IL−lα、IL−6、IL−7、IL−8、MCP−1、MCP−2、MIP−la、MMP−1、MMP−10、MMP−3、アンフィレグリン、ENA−78、エオタキシン−3、GCP−2、GITR、HGF、ICAM−1、IGFBP−2、IGFBP−3、IGFBP−4、IGFBP−5、IGFBP−6、IL−13、IL−Iβ、MCP−4、MIF、MIP−3a、MMP−12、MMP−13、MMP−14、NAP2、オンコスタチンM、オステオプロテゲリン、PIGF、RANTES、sgpl30、TIMP−2、TRAIL−R3、Acrp30、アンギオゲニン、Axl、bFGF、BLC、BTC、CTACK、EGF−R、Fas、FGF−7、G−CSF、GDNF、HCC−4、I−309、IFN−γ、IGFBP−1、IL−1Rl、IL−11、IL−15、IL−2R−a、IL−6R、I−TAC、レプチン、LIF、MMP−2、MSP−a、PAI−1、PAI−2、PDGF−BB、SCF、SDF−1、sTNF RI、sTNF RII、トロンボポエチン、TIMP−1、tPA、uPA、uPAR、VEGF、MCP−3、IGF−1、TGF−β3 、MIP−1−デルタ、IL−4、IL−16、BMP−4、MDC、IL−10、Fit−3リガンド、ICAM−1、CNTF、EGF、およびBMP−6のうちの少なくとも1つから選択される、請求項1〜10のいずれか1項に記載の方法。
- 前記正常な生理学的条件下での前記アッセイおよび前記老化細胞の前記細胞外条件下での前記アッセイが、無機化合物、イオンおよび有機分子から選択される少なくとも1種の成分を含有するアッセイ溶液中で実施される、請求項1〜26のいずれか1項に記載の方法。
- 前記少なくとも1種の成分が、前記正常な生理学的条件下での前記アッセイおよび前記老化細胞の前記細胞外条件下での前記アッセイの両方で、前記アッセイ溶液中で実質的に同じ濃度を有する、請求項27に記載の方法。
- 前記少なくとも1種の成分が、前記無機化合物であり、ホウ酸、塩化カルシウム、硝酸カルシウム、リン酸二アンモニウム、硫酸マグネシウム、リン酸一アンモニウム、リン酸一カリウム、塩化カリウム、硫酸カリウム、硫酸銅、硫酸鉄、硫酸マンガン、硫酸亜鉛、硫酸マグネシウム、硝酸カルシウム、カルシウムキレート、銅キレート、鉄キレート、鉄キレート、マンガンキレート、亜鉛キレート、モリブデン酸アンモニウム、硫酸アンモニウム、炭酸カルシウム、リン酸マグネシウム、重炭酸カリウム、硝酸カリウム、塩酸、二酸化炭素、硫酸、リン酸、炭酸、尿酸、塩化水素、および尿素から選択される、請求項27〜28のいずれか1項に記載の方法。
- 前記少なくとも1種の成分が、前記イオンであり、リンイオン、硫黄イオン、塩化物イオン、マグネシウムイオン、ナトリウムイオン、カリウムイオン、アンモニウムイオン、鉄イオン、亜鉛イオン、および銅イオンから選択される、請求項27〜28のいずれか1項に記載の方法。
- 前記少なくとも1種の成分が、2〜7.0mg/dLの濃度範囲内の尿酸、8.2〜11.6mg/dLの濃度範囲内のカルシウムイオン、355〜381mg/dLの濃度範囲内の塩化物イオン、0.028〜0.210mg/dLの濃度範囲内の鉄イオン、12.1〜25.4mg/dLの濃度範囲内のカリウムイオン、300〜330mg/dLの濃度範囲内のナトリウムイオン、および15〜30mMの濃度範囲内の炭酸のうちの1つまたは複数から選択される、請求項27〜28のいずれか1項に記載の方法。
- 前記少なくとも1種の成分が、前記有機分子であり、ヒスチジン、アラニン、イソロイシン、アルギニン、ロイシン、アスパラギン、リシン、アスパラギン酸、メチオニン、システイン、フェニルアラニン、グルタミン酸、トレオニン、グルタミン、トリプトファン、グリシン、バリン、ピロリシン、プロリン、セレノシステイン、セリン、およびチロシンから選択されるアミノ酸である、請求項27〜28のいずれか1項に記載の方法。
- 前記少なくとも1種の成分が、前記有機分子であり、クエン酸、α−ケトグルタル酸、コハク酸、リンゴ酸、フマル酸、アセト酢酸、β−ヒドロキシ酪酸、乳酸、ピルビン酸、α−ケトン酸、酢酸、および揮発性脂肪酸から選択される有機酸である、請求項27〜28のいずれか1項に記載の方法。
- 前記少なくとも1種の成分が、前記有機分子であり、グルコース、ペントース、ヘキソース、キシロース、リボース、マンノース、ガラクトース、ラクトース、GlcNAcβ1−3Gal、Galα1−4Gal、Manα1−2Man、GalNAcβ1−3Gal、ならびにO−、N−、C−、およびS−グリコシドから選択される糖である、請求項27〜28のいずれか1項に記載の方法。
- 前記少なくとも1種の成分が、前記イオンであり、マグネシウムイオン、硫酸イオン、重硫酸イオン、炭酸イオン、重炭酸イオン、硝酸イオン、亜硝酸イオン、リン酸イオン、リン酸水素イオン、リン酸二水素イオン、過硫酸イオン、一過硫酸イオン、ホウ酸イオン、およびアンモニウムイオンから選択される、請求項27〜28のいずれか1項に記載の方法。
- 前記老化細胞の前記細胞外条件が、約5.5〜約7.0の範囲内の第一のpHであり、前記正常な生理学的条件が、約7.2〜約7.8の範囲内の第二のpHであり、
前記1つまたは複数のアッセイが、900a.m.u未満の分子量と、前記第一のpHから最大0.5、1、2、3、または4pH単位離れたpKaと、を有する少なくとも1種の分子種を含有するアッセイ溶液中で実施される、
請求項1に記載の方法。 - 前記老化細胞の前記細胞外条件が、約5.5〜約7.0の範囲内の第一のpHであり、前記正常な生理学的条件が、約7.2〜約7.8の範囲内の第二のpHであり、
前記1つまたは複数のアッセイが、900a.m.u未満の分子量を有する少なくとも1種の分子種を含有するアッセイ溶液中で実施され、
前記分子種が、前記第一のpHと前記第二のpHの間にpKaを有する、
請求項1に記載の方法。 - 前記老化細胞の細胞外条件が、約5.5〜約7.0の範囲内の第一のpHであり、前記正常な生理学的条件が、約7.2〜約7.8の範囲内の第二のpHであり、
前記1つまたは複数のアッセイが、ヒスチジン、ヒスタミン、水素化アデノシン二リン酸塩、水素化アデノシン三リン酸塩、クエン酸塩、重炭酸塩、酢酸塩、乳酸塩、二硫化物、硫化水素、アンモニウム、およびリン酸二水素塩から選択される少なくとも1種の分子種を含有するアッセイ溶液中で実施される、
請求項1に記載の方法。 - 前記選択のステップ(iv)が、(a)前記アッセイにおける前記親タンパク質の活性に比較した、正常な生理学的条件下での同アッセイにおける同活性の低下、および正常な生理学的条件下での前記アッセイにおける前記条件付き活性タンパク質の前記活性に比較した、前記老化細胞の前記細胞外条件下での前記アッセイにおける同活性の上昇、を示す条件付き活性タンパク質を選択することを含む、請求項1に記載の方法。
- 前記選択のステップ(iv)が、(b)前記アッセイにおける前記親タンパク質の活性に比較した、前記正常な生理学的条件下での同アッセイにおける同活性の低下、および前記老化細胞の前記細胞外条件下での前記アッセイにおける前記親タンパク質の活性に比較した、前記老化細胞の前記細胞外条件下での前記アッセイにおける同活性の上昇、を示す条件付き活性タンパク質を選択することを含む、請求項1に記載の方法。
- 前記条件付き活性タンパク質が条件付き活性抗体であり、前記条件付き活性抗体をリンカーによりマスキング部分にコンジュゲートするステップをさらに含む、請求項1〜26のいずれか1項に記載の方法。
- 前記マスキング部分が、前記標的への結合における前記条件付き活性抗体の活性を少なくとも50%、55%、60%、65%、70%、75%、80%、85%、90%、92%、93%、94%、95%、96%、97%、98%、99%または100%低減する、請求項41に記載の方法。
- 前記リンカーが、前記条件付き活性抗体の可変領域に共有結合される、請求項41〜42のいずれか1項に記載の方法。
- 前記マスキング部分が、前記条件付き活性抗体の可変領域に特異的に結合する、請求項41〜42のいずれか1項に記載の方法。
- 前記マスキング部分が、5%以下、7%以下、10%以下、15%以下、20%以下、25%以下、30%以下、35%以下、40%以下、45%以下、50%以下、55%以下、60%以下、65%以下、70%以下、75%以下、または80%以下の前記標的への配列同一性を有する、請求項44に記載の方法。
- 前記リンカーが、可撓性領域および切断部位を含む、請求項41〜45のいずれか1項に記載の方法。
- 前記可撓性領域が、グリシン、アラニンおよびセリンから選択される少なくとも1種のアミノ酸から本質的になる、請求項46に記載の方法。
- 前記可撓性領域が、1アミノ酸〜20アミノ酸、2アミノ酸〜15アミノ酸、3アミノ酸〜12アミノ酸、4アミノ酸〜10アミノ酸、5アミノ酸〜9アミノ酸、または6アミノ酸〜8アミノ酸の長さを有する、請求項46〜47のいずれか1項に記載の方法。
- 前記切断部位が、前記老化細胞の前記細胞外環境においてプロテアーゼにより切断され得る、請求項46〜48のいずれか1項に記載の方法。
- 前記プロテアーゼが、ADAM10、ADAM12、ADAM17、ADAMTS、ADAMTS5、BACE、カスパーゼ1〜14、カテプシンA,カテプシンB、カテプシンD、カテプシンE、カテプシンK、カテプシンS、FAP、MT1−MMP、グランザイムB、グアニジノベンゾアターゼ、へプシン、ヒト好中球エラスターゼ、レグマイン、マトリプターゼ2、メプリン、MMP1〜17、MT−SP1、ネプリライシン、NS3/4A、プラスミン、PSA、PSMA、TRACE、TMPRSS 3、TMPRSS 4、およびuPAのうちの少なくとも1種から選択される、請求項49に記載の方法。
- 前記条件付き活性タンパク質をリンカーにより細胞傷害剤、細胞増殖抑制剤、または抗増殖剤にコンジュゲートするステップをさらに含む、請求項1〜26のいずれか1項に記載の方法。
- 前記リンカーが、前記老化細胞の前記細胞外環境においてプロテアーゼにより切断され得る切断部位を含む、請求項51に記載の方法。
- 前記プロテアーゼが、ADAM10、ADAM12、ADAM17、ADAMTS、ADAMTS5、BACE、カスパーゼ1〜14、カテプシンA,カテプシンB、カテプシンD、カテプシンE、カテプシンK、カテプシンS、FAP、MT1−MMP、グランザイムB、グアニジノベンゾアターゼ、へプシン、ヒト好中球エラスターゼ、レグマイン、マトリプターゼ2、メプリン、MMP1〜17、MT−SP1、ネプリライシン、NS3/4A、プラスミン、PSA、PSMA、TRACE、TMPRSS 3、TMPRSS 4、およびuPAのうちの少なくとも1種から選択される、請求項52に記載の方法。
- 前記抗増殖剤が、化学療法剤である、請求項51に記載の方法。
- 前記条件付き活性タンパク質を、毒性薬剤、放射性薬剤、またはDレトロインベルソ型ペプチドから選択される薬剤にコンジュゲートするステップをさらに含む、請求項1〜26のいずれか1項に記載の方法。
- 前記条件付き活性タンパク質が、条件付き活性抗体である、請求項55に記載の方法。
- 前記Dレトロインベルソ型ペプチドが、天然タンパク質の断片または全長の逆配列との少なくとも70%、または少なくとも80%、または少なくとも90%、または少なくとも95%、または少なくとも98%、または100%のアミノ酸配列同一性を有するアミノ酸配列を有する、請求項55〜56のいずれか1項に記載の方法。
- 前記天然タンパク質が、FOXO4、AMPK、JNK、MST1、CK1、STAT3、p38、PRMT1、およびASK1のうちの少なくとも1種から選択される、請求項57に記載の方法。
- 前記Dレトロインベルソ型ペプチドが、5を含むそれ以下の、10を含むそれ以下の、15を含むそれ以下の、20を含むそれ以下の、25を含むそれ以下の、30を含むそれ以下の、35を含むそれ以下の、40を含むそれ以下の、45を含むそれ以下の、50を含むそれ以下の、60を含むそれ以下の、70を含むそれ以下の、80を含むそれ以下の、90を含むそれ以下の、または100を含むそれ以下のアミノ酸残基の長さを有する、請求項55〜58のいずれか1項に記載の方法。
- 前記Dレトロインベルソ型ペプチドが、最大で0、5、10、15、20、25、30、35、40、45、50、55または60%の、Lアミノ酸残基であるアミノ酸残基を有する、請求項55〜59のいずれか1項に記載の方法。
- 前記Dレトロインベルソ型ペプチドが、100%のDアミノ酸残基を有する、請求項55〜59のいずれか1項に記載の方法。
- 前記Dレトロインベルソ型ペプチドが、PPRRRQRRKKRG(SEQ ID NO:10)、GALFLGFLGA AGSTMGAWSQ PKKKRKV(SEQ ID NO:11)、KETWWETWWT EWSQPKKKRKV(SEQ ID NO:12)、Ac−GLWRALWRLLRSLWRLLWRA−Cya(SEQ ID NO:13)、およびオクタアルギニンから選択される1つまたは複数の機能的ドメインを含む、請求項55〜61のいずれか1項に記載の方法。
- 前記Dレトロインベルソ型ペプチドが、LTLRKEPASE IAQSILEAYS QNGWANRRSG GKRP(SEQ ID NO:5)、LTLRKEPASE IAQSILEAYS QNGWANRRSG GKRPPPRRRQ RRKKRG(SEQ ID NO:6)、またはSEIAQSILEAYSQNGW(SEQ ID NO:7)を含む、請求項56〜62のいずれか1項に記載の方法。
- 請求項1〜63のいずれか1項に記載の方法により生成される条件付き活性タンパク質。
- 抗体である、請求項64に記載の条件付き活性タンパク質。
- 前記抗体が、一本鎖抗体または抗体断片である、請求項65に記載の条件付き活性タンパク質。
- 前記抗体が、ヒト化抗体である、請求項65に記載の条件付き活性タンパク質。
- 前記抗体が、二重特異性抗体である、請求項65に記載の条件付き活性タンパク質。
- 前記抗体が、T細胞のキメラ抗原受容体の一部として操作されるのに適する、請求項64〜68のいずれか1項に記載の条件付き活性タンパク質。
- 受容体、調節タンパク質、可溶性タンパク質、サイトカイン、受容体断片、調節タンパク質断片、可溶性タンパク質断片、およびサイトカイン断片から選択される、請求項64に記載の条件付き活性タンパク質。
- 環状ペプチドである、請求項64に記載の条件付き活性タンパク質。
- 前記環状ペプチドが、約5〜約500アミノ酸、約8〜約300アミノ酸、約8〜約200アミノ酸、約10〜約100アミノ酸、または約10〜約50アミノ酸の長さを有する、請求項71に記載の条件付き活性タンパク質。
- 前記環状ペプチドが、少なくとも1種の非天然由来アミノ酸を含む、請求項71に記載の条件付き活性タンパク質。
- リンカーによりマスキング部分にコンジュゲートされた条件付き活性抗体である、請求項64に記載の条件付き活性タンパク質。
- 前記マスキング部分が、前記標的への結合における前記条件付き活性抗体の活性を少なくとも50%、少なくとも55%、少なくとも60%、少なくとも65%、少なくとも70%、少なくとも75%、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも92%、少なくとも93%、少なくとも94%、少なくとも95%、少なくとも96%、少なくとも97%、少なくとも98%、少なくとも99%または100%低減する、請求項74に記載の条件付き活性タンパク質。
- 前記リンカーが、前記条件付き活性抗体の可変領域に共有結合される、請求項74〜75のいずれか1項に記載の条件付き活性タンパク質。
- 前記リンカーが、可撓性領域および切断部位を含む、請求項74〜76のいずれか1項に記載の条件付き活性タンパク質。
- 前記切断部位が、老化細胞の細胞外環境においてプロテアーゼにより切断され得る、請求項74〜77のいずれか1項に記載の条件付き活性タンパク質。
- 前記プロテアーゼが、ADAM10、ADAM12、ADAM17、ADAMTS、ADAMTS5、BACE、カスパーゼ1〜14、カテプシンA,カテプシンB、カテプシンD、カテプシンE、カテプシンK、カテプシンS、FAP、MT1−MMP、グランザイムB、グアニジノベンゾアターゼ、へプシン、ヒト好中球エラスターゼ、レグマイン、マトリプターゼ2、メプリン、MMP1〜17、MT−SP1、ネプリライシン、NS3/4A、プラスミン、PSA、PSMA、TRACE、TMPRSS 3、TMPRSS 4、およびuPAのうちの少なくとも1種から選択される、請求項78に記載の条件付き活性タンパク質。
- リンカーにより細胞傷害剤、細胞増殖抑制剤、または抗増殖剤にコンジュゲートされる、請求項64〜73のいずれか1項に記載の条件付き活性タンパク質。
- 前記リンカーが、老化細胞の細胞外環境においてプロテアーゼの切断部位を含む、請求項80に記載の条件付き活性タンパク質。
- 前記プロテアーゼが、ADAM10、ADAM12、ADAM17、ADAMTS、ADAMTS5、BACE、カスパーゼ1〜14、カテプシンA,カテプシンB、カテプシンD、カテプシンE、カテプシンK、カテプシンS、FAP、MT1−MMP、グランザイムB、グアニジノベンゾアターゼ、へプシン、ヒト好中球エラスターゼ、レグマイン、マトリプターゼ2、メプリン、MMP1〜17、MT−SP1、ネプリライシン、NS3/4A、プラスミン、PSA、PSMA、TRACE、TMPRSS 3、TMPRSS 4、およびuPAのうちの少なくとも1種から選択される、請求項81に記載の条件付き活性タンパク質。
- 前記抗増殖剤が、化学療法剤である、請求項80に記載の条件付き活性タンパク質。
- 請求項64〜83のいずれか1項に記載の条件付き活性タンパク質の有効量と、医薬的に許容できる担体と、を含む、医薬組成物。
- 請求項64〜83のいずれか1項に記載の条件付き活性タンパク質または請求項84に記載の医薬組成物を、対象に投与するステップを含む、加齢および老化細胞関連疾患または障害のうちの1つの処置の方法。
- 前記老化細胞関連疾患または障害が、認知疾患、心臓血管疾患、代謝疾患および障害、運動機能疾患および障害、脳血管疾患、気腫、骨関節炎、肺疾患、炎症/自己免疫疾患および障害、眼科疾患または障害、転移、化学療法または放射線療法の副作用、加齢関連疾患および障害、線維性疾患および障害のうちの少なくとも1つから選択される、請求項85に記載の方法。
- 親有機化合物から約3000a.m.u未満の分子量を有する条件付き活性分子を作製するための方法であって、
1種または複数の部分的荷電または荷電基を前記親有機化合物に導入することにより前記親有機化合物を修飾して、1種または複数の修飾された有機化合物を生成するステップと;
前記正常な生理学的条件下でのアッセイにおける活性と比較して、異常な条件下での前記アッセイにおいてより高い同活性を示す前記修飾された有機化合物を選択するステップと、
を含む、方法。 - 親有機化合物から約3000a.m.u未満の分子量を有する条件付き活性分子を作製するための方法であって、
前記親有機化合物から1種または複数の部分的荷電または荷電基を除去することにより前記親有機化合物を修飾して、1種または複数の修飾された有機化合物を生成するステップと;
前記正常な生理学的条件下でのアッセイにおける活性と比較して、異常な条件下での前記アッセイにおいてより高い同活性を示す前記修飾された有機化合物を選択するステップと、
を含む、方法。 - 親有機化合物から約3000a.m.u未満の分子量を有する条件付き活性分子を作製するための方法であって、
前記親有機化合物の1つまたは複数の基を1種または複数の部分的荷電または荷電基で置換えることにより前記親有機化合物を修飾して、1種または複数の修飾された有機化合物を生成するステップと;
前記正常な生理学的条件下でのアッセイにおける活性と比較して、異常な条件下での前記アッセイにおいてより高い同活性を示す前記修飾された有機化合物を選択するステップと、
を含む、方法。 - 前記親有機化合物が、約100a.m.u〜約3000a.m.u、または約100a.m.u〜約1500a.m.u、または約150a.m.u〜約1250a.m.u、または約300a.m.u〜約1100a.m.u、または約400a.m.u〜約1000a.m.uの範囲内の分子量を有する、請求項87〜89のいずれか1項に記載の方法。
- 前記異常な条件が、老化細胞の細胞外条件の値であり、前記正常な生理学的条件が、正常細胞の同細胞外条件の異なる値である、請求項87〜90のいずれか1項に記載の方法。
- 前記異常な条件が、約5.0〜約7.0、または約5.5〜約7.0、または約6.0〜約7.0、または約6.2〜約6.8の範囲内のpHであり、前記正常な生理学的条件が、約7.0〜約7.8、または約7.2〜約7.8、または約7.2〜約7.6の範囲内のpHである、請求項87〜91のいずれか1項に記載の方法。
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