JP2023537798A - 顔面肩甲上腕型筋ジストロフィーを処置するための組成物および方法 - Google Patents
顔面肩甲上腕型筋ジストロフィーを処置するための組成物および方法 Download PDFInfo
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Abstract
Description
本出願は、2020年3月19日に出願された米国仮特許出願第62/992,071号および2020年8月17日に出願された米国仮特許出願第63/066,655号の利益を主張するものであり、これらは各々、その全体において引用により本明細書に組み込まれる。
RNAによって誘導される遺伝子サイレンシングによる遺伝子抑制は複数のレベルの制御、すなわち、転写不活性化、低分子干渉RNA(siRNA)によって誘導されるmRNA低下、およびsiRNA誘導転写減衰を提供する。いくつかの例において、RNA干渉(RNAi)は、複数の細胞分裂にわたって長い永続的な効果を与える。したがって、RNAiは、薬物標的の検証、遺伝子機能分析、経路分析、および疾患治療に役立つ実行可能な方法を表す。
本明細書で言及されるすべての刊行物、特許、および特許出願は、個々の刊行物、特許、または特許出願が、参照により組み込まれることが具体的かつ個別に示されている場合と同程度に、参照により本明細書に組み込まれる。
特定の実施形態において、ポリ核酸分子は、ダブルホメオボックス4(DUX4)遺伝子の標的配列にハイブリダイズする。場合によっては、本明細書に記載のポリ核酸分子は、ヒトDUX4遺伝子(DUX4)の標的配列にハイブリダイズし、筋細胞においてDUX4 mRNAを減少させる。
いくつかの実施形態において、本明細書に記載されるポリ核酸分子は、当該技術分野で知られている手順を用いて、化学合成および/または酵素ライゲーション反応を用いて構築される。例えば、ポリ核酸分子は、自然発生のヌクレオチドを使用して、あるいは、分子の生体安定性を増大させるために、または、ポリ核酸分子と標的核酸との間で形成された二重鎖の物理安定度を増大させるために設計されたさまざまな修飾ヌクレオチドを用いて、化学合成される。例示的な方法は、以下に記載されるものを含む:米国特許第5,142,047号;第5,185,444号;第5,889,136号;第6,008,400号;および、第6,111,086号;PCT国際公開第WO2009099942号;あるいは、欧州特許公開第1579015号。追加の例示的な方法は、以下に記載されるものを含む:Griffey et al.,“2’-O-aminopropyl ribonucleotides:a zwitterionic modification that enhances the exonuclease resistance and biological activity of antisense oligonucleotides,” J.Med.Chem.39(26):5100-5109(1997));Obika,et al.“Synthesis of 2’-O,4’-C-methyleneuridine and -cytidine.Novel bicyclic nucleosides having a fixed C3,-endo sugar puckering”.Tetrahedron Letters 38(50):8735 1997;Koizumi,M.“ENA oligonucleotides as therapeutics”.Current opinion in molecular therapeutics 8(2):144-149(2006);and Abramova et al.,“Novel oligonucleotide analogues based on morpholino nucleoside subunits-antisense technologies:new chemical possibilities,” Indian Journal of Chemistry 48B:1721-1726(2009)。代替的に、ポリ核酸分子は、ポリ核酸分子がアンチセンス配向にサブクローン化された発現ベクターを用いて生物学的に生成される(つまり、挿入されたポリ核酸分子の転写されたRNAは所望の標的ポリ核酸分子に対してアンチセンス配向になる)。
いくつかの実施形態において、ポリ核酸分子(B)はさらに、所望の部位へ送達されるポリペプチドAに結合する。場合によっては、ポリ核酸分子はポリペプチドAと随意にポリマー部分に結合する。いくつかの例において、少なくとも1つのポリペプチドAは少なくとも1つのBに結合する。いくつかの例において、少なくとも1つのポリペプチドAは、A-Bコンジュゲートを形成するために少なくとも1つのBに結合する。いくつかの実施形態において、少なくとも1つのAは、Bの5’末端、Bの3’末端、Bの内部部位、あるいはその任意の組み合わせに結合する。いくつかの例において、少なくとも1つのポリペプチドAは少なくとも2つのBに結合する。いくつかの例において、少なくとも1つのポリペプチドAは、少なくとも2、3、4、5、6、7、8、あるいはそれ以上のBに結合する。
いくつかの実施形態において、結合部分Aはポリペプチドである。いくつかの例において、ポリペプチドは、抗体またはそのそのフラグメントである。場合によっては、フラグメントは結合フラグメントである。いくつかの例において、抗体またはその抗原結合フラグメントは、ヒト化抗体またはその抗原結合フラグメント、マウス抗体またはその抗原結合フラグメント、キメラ抗体またはその抗原結合フラグメント、モノクローnal 抗体またはその抗原結合フラグメント、軽鎖ドメインおよび重鎖ドメインを有する結合フラグメント、2つの軽鎖ドメインおよび2つの重鎖ドメインを有する結合フラグメント、2つ以上の軽鎖ドメインおよび重鎖ドメインを有する結合フラグメント、一価Fab’、二価Fab2、F(ab)’3フラグメント、単鎖可変フラグメント(scFv)、ビス-scFv、(scFv)2、ダイアボディ、ミニボディ、ナノボディ、三重特異性抗体、四重特異性抗体、ジスルフィド安定化Fvタンパク質(dsFv)、単一ドメイン抗体(sdAb)、Ig NAR、ラクダ科抗体またはその抗原結合フラグメント、二重特異性抗体またはその結合フラグメント、あるいはその化学修飾された誘導体を含む。
いくつかの実施形態において、結合部分は血漿タンパク質である。いくつかの例において、血漿タンパク質はアルブミンを含む。いくつかの例において、結合部分Aはアルブミンである。いくつかの例において、アルブミンは、本明細書に記載される結合化学の1つ以上によって、ポリ核酸分子に結合する。いくつかの例において、アルブミンは、天然のライゲーション化学によってポリ核酸分子に結合する。いくつかの例において、アルブミンは、リジン結合によってポリ核酸分子に結合する。
いくつかの実施形態において、本明細書に記載されるポリペプチド(例えば、抗体とその抗原結合フラグメント)は、とりわけ、化学合成によって、あるいは組換え発現によって、ポリペプチド(例えば、抗体)の合成に役立つように、当該技術分野で知られている任意の方法を使用して生成され、および、好ましくは組換え発現技術によって生成される。
いくつかの実施形態において、ポリ核酸分子Bは結合部分にコンジュゲートする。いくつかの実施形態において、ポリ核酸分子Bは、式A-X-B(XはAおよびBをコンジュゲートするリンカーである)の中の結合部分にコンジュゲートされる。いくつかの例において、結合部分は、アミノ酸、ペプチド、ポリペプチド、タンパク質、抗体、抗原、毒素、ホルモン、脂質、ヌクレオチド、ヌクレオシド、糖類、炭水化物、ポリエチレングリコールとポリプロピレングリコールなどのポリマー、ならびに、これらのクラスの物質のすべてのアナログあるいは誘導体を含む。結合部分の追加の例はさらに、コレステロール、リン脂質、ジアシルグリセロールおよびトリアシルグリセロール、脂肪酸、炭化水素(例えば、飽和、不飽和、または、置換を含む)、酵素基質、ビオチン、ジゴキシゲニン、および多糖類などのステロイドを含む。いくつかの例において、結合部分は、抗体またはその抗原結合フラグメントである。いくつかの例において、ポリ核酸分子はさらにポリマーに結合され、随意にエンドソーム溶解性部分に結合する。
いくつかの実施形態において、ポリマー部分Cはさらに、本明細書に記載されるポリ核酸分子、本明細書に記載される結合部分、あるいはこれらの組み合わせに結合する。いくつかの例において、ポリマー部分Cは、式A-X1-B-X2-C(X1、X2は、AおよびB、BおよびCをそれぞれコンジュゲートする2つのリンカーである)の中のコンジュゲートされたポリ核酸分子である。ポリ核酸分子に結合する。場合によっては、ポリマー部分Cは結合部分に結合する。他の場合には、ポリマー部分Cはポリ核酸分子結合部分分子に結合する。さらなる場合には、ポリマー部分Cは上で例証されるように結合する。
いくつかの実施形態において、式(I):A-X1-B-X2-Cの分子はさらに、追加の結合部分を含む。いくつかの例において、追加の結合部分は、エンドソーム溶解性部分および/または細胞膜透過部分である。場合によっては、エンドソーム溶解性部分は、細胞区画放出成分、例えば、エンドソーム、リソソーム、小胞体(ER)、ゴルジ体、微小管、ペルオキシソーム、あるいは細胞を有する他の小胞体などの、当該技術分野で知られている細胞の区分のいずれかから放出することができる化合物である。場合によっては、エンドソーム溶解性部分は、エンドソーム溶解性ポリペプチド、エンドソーム溶解性ポリマー、エンドソーム溶解性脂質、あるいはエンドソーム溶解性小分子を含む。場合によっては、エンドソーム溶解性部分はエンドソーム溶解性ポリペプチドを含む。他の場合では、エンドソーム溶解性部分はエンドソーム溶解性ポリマーを含む。場合によっては、細胞膜透過部分は細胞透過ペプチド(CPP)を含む。他の場合では、細胞膜透過部分は細胞透過脂質を含む。他の場合では、細胞膜透過部分は細胞透過小分子を含む。
いくつかの実施形態において、式(I):A-X1-B-X2-Cの分子は、エンドソーム溶解性ポリペプチドとさらに結合する。場合によっては、エンドソーム溶解性ポリペプチドはpH依存性膜活性ペプチドである。場合によっては、エンドソーム溶解性ポリペプチドは両親媒性ポリペプチドである。追加の場合には、エンドソーム溶解性ポリペプチドはペプチド模倣薬である。いくつかの例において、エンドソーム溶解性ポリペプチドは、INF、メリチン、ムチン(meucin)、あるいはそのそれぞれの誘導体を含む。いくつかの例において、エンドソーム溶解性ポリペプチドは、INFまたはその誘導体を含む。他の場合には、エンドソーム溶解性ポリペプチドは、メリチンまたはその誘導体を含む。さらなる場合には、エンドソーム溶解性ポリペプチドは、ムチンまたはその誘導体を含む。
いくつかの実施形態において、エンドソーム溶解性部分は脂質(例えば、融合性脂質)である。いくつかの実施形態において、式(I):A-X1-B-X2-Cの分子は、エンドソーム溶解性脂質(例えば、融合性脂質)とさらに結合する。例示的な融合性脂質は、1,2-ジレオイル(dileoyl)-sn-3-ホスホエタノールアミン(DOPE)、ホスファチジルエタノールアミン(POPE)、パルミトイルオレオイルホスファチジルコリン(POPC)、(6Z、9Z、28Z、31Z)-ヘプタトリアコンタ-6、9、28、31-テトラエン-19-オール(Di-Lin)、およびN-メチル(2,2-ジ(9Z、12Z)-オクタデカ-9,12-ジエニル)-1,3-ジオキソラン-4-イル)メタンアミン(DLin-k-DMA)ならびにN-メチル-2-(2,2-ジ(9Z、12Z)-オクタデカ-9,12-ジエニル)-1,3-ジオキソラン-4-イル)エタンアミン(XTC)を含む。
いくつかの実施形態では、エンドソーム溶解性部分は小分子である。いくつかの実施形態において、式(I):A-X1-B-X2-Cの分子は、エンドソーム溶解性小分子とさらに結合する。エンドソーム溶解性部分として適切な例示的な小分子としては、限定されないが、キニーネ、クロロキン、水酸化クロロキン、アモジアキン(carnoquines)、アモピロキン、プリマキン、メフロキン、nivaquines、ハロファントリン、キノンイミン、あるいはそれらの組み合わせを含む。いくつかの例において、キノリンエンドソーム溶解性部分としては、限定されないが、7-クロロ-4-(4-ジエチルアミノ-1-メチルブチル-アミノ)キノリン(クロロキン);7-クロロ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチル-アミノ)キノリン(ヒドロキシクロロキン);7-フルオロ-4-(4-ジエチルアミノ-1-メチルブチル-アミノ)キノリン;4-(4-ジエチルアミノ-1-メチルブチルアミノ)キノリン;7-ヒドロキシ-4-(4-ジエチル-アミノ-1-メチルブチルアミノ)キノリン;7-クロロ-4-(4-ジエチルアミノ-1-ブチルアミノ)キノリン(デスメチルクロロキン);7-フルオロ-4-(4-ジエチルアミノ-1-ブチルアミノ)キノリン;4-(4-ジエチル-アミノ-1-ブチルアミノ)キノリン;7-ヒドロキシ-4-(4-ジエチルアミノ-1-ブチルアミノ)キノリン;7-クロロ-4-(1-カルボキシ-4-ジエチルアミノ-1-ブチルアミノ)キノリン;7-フルオロ-4-(1-カルボキシ-4-ジエチル-アミノ-1-ブチルアミノ)キノリン;4-(1-カルボキシ-4-ジエチルアミノ-1-ブチルアミノ)キノリン;7-ヒドロキシ-4-(1-カルボキシ-4-ジエチルアミノ-1-ブチルアミノ)キノリン;7-クロロ-4-(1-カルボキシ-4-ジエチルアミノ-1-メチルブチルアミノ)キノリン;7-フルオロ-4-(1-カルボキシ-4-ジエチル-アミノ-1-メチルブチルアミノ)キノリン;4-(1-カルボキシ-4-ジエチルアミノ-1-メチルブチルアミノ)キノリン;7-ヒドロキシ-4-(1-カルボキシ-4-ジエチルアミノ-1-メチルブチルアミノ)キノリン;7-フルオロ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン;4-(4-エチル-(2-ヒドロキシ-エチル)-アミノ-1-メチルブチルアミノ-)キノリン;7-ヒドロキシ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン;ヒドロキシクロロキンホスフェート;7-クロロ-4-(4-エチル-(2-ヒドロキシエチル-1)-アミノ-1-ブチルアミノ)キノリン(デスメチルヒドロキシクロロキン);7-フルオロ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン;4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン;7-ヒドロキシ-4-(4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ(キノリン;7-クロロ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン;7-フルオロ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン;4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン;7-ヒドロキシ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-ブチルアミノ)キノリン;7-クロロ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン;7-フルオロ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン;4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン;7-ヒドロキシ-4-(1-カルボキシ-4-エチル-(2-ヒドロキシエチル)-アミノ-1-メチルブチルアミノ)キノリン;8-[(4-アミノペンチル)アミノ-6-メトキシジヒドロクロリドキノリン;1-アセチル-1,2,3,4-テトラヒドロキノリン;8-[(4-アミノペンチル)アミノ]-6-メトキシキノリンジヒドロクロリド;1-ブチリル-1,2,3,4-テトラヒドロキノリン;3-クロロ-4-(4-ヒドロキシ-α,α’-ビス(2-メチル-1-ピロリジニル)-2,5-キシリジノキノリン)(4-[(4-ジエチル-アミノ)-1-メチルブチル-アミノ]-6-メトキシキノリン;3-フルオロ-4-(4-ヒドロキシ-α,α’-ビス(2-メチル-1-ピロリジニル)-2,5-キシリジノキノリン(4-[(4-ジエチルアミノ)-1-メチルブチル-アミノ]-6-メトキシキノリン;4-(4-ヒドロキシ-α、α’-ビス(2-メチル-1-ピロリジニル)-2,5-キシリジノキノリン;4-[(4-ジエチルアミノ)-1-メチルブチル-アミノ]-6-メトキシキノリン;3,4-ジヒドロ-1-(2H)-キノリンカルボキシアルデヒド;1、1’-ペンタメチレンキノリニウムヨージド;8-硫酸キノリノールおよびアミノ、アルデヒド、カルボン酸、ヒドロキシル、ハロゲン、ケト、スルフヒドリル、ならびにビニル誘導体またはそのアナログ。いくつかの例において、エンドソーム溶解性部分は、Naisbitt et al(1997,J Pharmacol Exp Therapy 280:884-893)および米国特許第5,736,557号に記載される小分子である。
いくつかの実施形態では、細胞透過性ポリペプチドは、5~30個のアミノ酸を有する正に荷電した短いペプチドを含む。いくつかの実施形態では、細胞透過性ポリペプチドは、アルギニンまたはリジンに富むアミノ酸配列を含む。いくつかの実施形態では、細胞透過性ポリペプチドは、表9に列挙された任意のポリペプチドまたはその組み合わせを含む
いくつかの実施形態において、本明細書に記載されるリンカーは、切断可能なリンカーまたは切断不可能なリンカーである。いくつかの例において、リンカーは切断可能なリンカーである。他の例では、リンカーは切断不可能なリンカーである。
筋萎縮症は、筋肉量の喪失および/または筋肉の進行性の低下と変性を指す。場合によっては、筋肉量の喪失あるいは筋肉の進行性の低下と変性は、高いタンパク質分解率、低いタンパク質合成率、あるいは両方の組み合わせによって生じる。場合によっては、高い筋タンパク質分解率は、筋タンパク質異化作用(つまり、糖新生のために基質としてアミノ酸を使用するための筋タンパク質の分解)による。
いくつかの実施形態において、本明細書に記載される医薬製剤は、限定されないが、非経口(例えば、静脈内、皮下、筋肉内)、経口、鼻腔内、頬側、直腸、または経皮の投与経路を含む複数の投与経路によって、被験体に投与される。いくつかの例において、本明細書に記載される医薬組成物は、非経口(例えば、静脈内、皮下、筋肉内、動脈内、腹腔内、髄腔内、大脳内、脳室内、あるいは頭蓋内)投与のために製剤化される。他の例において、本明細書に記載される医薬組成物は、経口投与のために製剤化される。また他の例において、本明細書に記載される医薬組成物は、経鼻投与のために製剤化される。
いくつかの実施形態において、本明細書に記載される医薬組成物は治療用途のために投与される。いくつかの実施形態において、医薬組成物は、1日に一回、1日に2回、1日に3回、またはそれ以上投与される。医薬組成物は、毎日、1日おき、週5日、週1日、1週おき、月2週間、月3週間、月1回、月2回、月3回、2か月に1回、3か月に1回、4か月に1回、5か月に1回、6か月に1回、またはそれ以上投与される。医薬組成物は、少なくとも1か月、2か月、3か月、4か月、5か月、6か月、7か月、8か月、9か月、10か月、11か月、12か月、18か月、2年、3年、またはそれ以上の間投与される。
ある実施形態において、本明細書に記載される1つ以上の組成物と方法とともに使用されるキットおよび製品が本明細書で開示される。このようなキットは、バイアル、チューブなどの1つ以上の容器を収容するために仕切られた運搬装置、包装または容器を含み、各容器は、本明細書中に記載されている方法を使用するための別個の要素の1つを備える。適切な容器は、例えば、ボトル、バイアル、シリンジ、および試験管を含む。一実施形態において、容器は、ガラスまたはプラスチックなどの様々な材料から形成される。
別段の定めのない限り、本明細書で使用される技術用語と科学用語はすべて、主題が属する当該技術分野の当業者によって一般に理解されるものと同じ意味を有する。前述の一般的な記載および以下の詳細な記載は例示的かつ説明的なものに過ぎず、任意の主題に限定されるものではないことが理解されよう。本出願では、単数の使用は、特別に別記しない限り複数を含む。明細書および添付の請求項内で用いられる場合、単数形「a」、「an」、および「the」は、その文脈が明確に他のことを定めていない限り、複数の指示対象を含む。本出願において、「または」の使用は特に明記しない限り、「および/または」を意味する。さらに、用語「含む(including)」の使用は、「含む(include)」、「含む(includes)」、および「含まれる(included)」といった他の形態と同じく、限定的なものではない。
標準的なホスホロアミダイト化学を使用して固相上ですべてのsiRNA一本鎖を完全に組み立てて、HPLC上で精製した。精製された一本鎖を二重にし、二本鎖siRNAを得た。すべてのsiRNAパッセンジャー鎖は、鎖の各末端にひとつある、C6-NH2および/またはC6-SHといった様々なフォーマットのコンジュゲーションハンドルを含む。コンジュゲーションハンドルまたは複数のコンジュゲーションハンドルは、逆脱塩基ホスホジエステルまたはホスホロチオエートを介してsiRNAパッセンジャー鎖またはsiRNAガイド鎖に接続される。以下は、インビボ実験で使用されるフォーマットの代表的な構造である。
以下の構造は、本明細書に記載される例示的なA-X1-B-X2-Y(式I)構造を例証する。
抗体を、ホウ砂緩衝液(pH8)で緩衝液交換し、最大10mg/mlの濃度とした。この溶液に、水中の2当量のTCEPを加え、RTで2時間回転させた。結果として生じる反応混合物を、5mMのEDTAを含むpH7.4のPBSで緩衝液交換し、RTで5mMのEDTAを含むpH7.4のPBSにおいてSMCC-C6-siRNAまたはSMCC-C6-siRNA-C6-NHCO-PEG-XkDa(2当量)の溶液に加え(X=0.5kDa~10kDa)、一晩回転させた。分析的SAXカラムクロマトグラフィーによる反応混合物の分析は、未反応の抗体およびsiRNAと共に抗体siRNAコンジュゲートを示した。
粗製反応混合物を、実施例3.4に記載されるような陰イオン交換クロマトグラフィー方法-1を使用するAKTA explorer FPLCによって精製した。DAR1およびDAR>2の抗体-siRNA-PEGのコンジュゲートを含む分画を分離し、濃縮し、pH7.4のPBSで緩衝液交換した。
分離されたコンジュゲートを、SEC、SAXクロマトグラフィー、およびSDS-PAGEにより特徴化した。コンジュゲートの純度を、陰イオン交換クロマトグラフィー方法-2または陰イオン交換クロマトグラフィー方法-3のいずれかを使用する分析的HPLCによって評価した。両方の方法は実施例3.4に記載されている。単離されたDAR1コンジュゲートは典型的には、分析的SAX方法上で9.0±0.3分で溶出され、90%を超える純度である。典型的なDAR>2のシステインコンジュゲートは、85%を超えるDAR2および15%未満のDAR3を含んでいる。
抗体を、ホウ砂緩衝液(pH8)で緩衝液交換し、最大5mg/mlの濃度とした。この溶液に、水中の2当量のTCEPを加え、RTで2時間回転させた。結果として生じる反応混合物を、5mMのEDTAを含むpH7.4のPBSで交換し、RTで5mMのEDTAを含むpH7.4のPBSにおいてBisMal-C6-siRNA-C6-S-NEM(2当量)の溶液に加え、40℃で一晩維持した。分析的SAXカラムクロマトグラフィーによる反応混合物の分析は、未反応の抗体およびsiRNAと共に抗体siRNAコンジュゲートを示した。
粗製反応混合物を、陰イオン交換クロマトグラフィー方法-1を使用するAKTA explorer FPLCによって精製した。DAR1およびDAR2抗体-siRNAのコンジュゲートを含む分画を分離し、濃縮し、pH7.4のPBSで緩衝液交換した。
分離されたコンジュゲートを、質量スペクトルまたはSDS-PAGEのいずれかにより特徴化した。コンジュゲートの純度を、陰イオン交換クロマトグラフィー方法-2とサイズ排除クロマトグラフィー方法-1のいずれかを使用する分析的HPLCによって評価した。
抗体を、pH4.0、20mMの酢酸ナトリウム/酢酸緩衝液で緩衝液交換し、最大5mg/mlの濃度とした。固定されたペプシン(Thermo Scientific,Prod#20343)を加え、37℃で3時間インキュベートした。反応混合物を、30kDaのMWCO AmiconスピンフィルターおよびpH7.4のPBSを使用して濾過した。残余分を集めて、サイズ排除クロマトグラフィーを使用して精製し、F(ab’)2を単離した。その後、集めたF(ab’)2を、10当量のTCEPによって還元し、pH7.4のPBSにおいて室温でSMCC-C6-siRNA-PEG5とコンジュゲートさせた。SAXクロマトグラフィー上での反応混合物の分析は、未反応のFabおよびsiRNA-PEGと共にFab-siRNAのコンジュゲートを示した。
粗製反応混合物を、陰イオン交換クロマトグラフィー方法-1を使用するAKTA explorer FPLCによって精製した。DAR1およびDAR2 Fab-siRNAのコンジュゲートを含む分画を分離し、濃縮し、pH7.4のPBSで緩衝液交換した。
単離されたコンジュゲートの特徴付けと純度は、SEC方法-1と同様に、陰イオン交換クロマトグラフィー方法-2あるいは3を使用する分析的なHPLCによって評価された。
陰イオン交換クロマトグラフィー方法(SAX)-1.
1.カラム:Tosoh Bioscience、TSKGel SuperQ-5PW、21.5mm ID X 15cm、13um
2.溶媒A:20mMのTRIS緩衝液、pH8.0;溶媒B:20mMのTRIS、1.5MのNaCl、pH8.0;流速:6.0mL/分
3.勾配:
a.%A %B カラム体積
b.100 0 1.00
c.60 40 18.00
d.40 60 2.00
e.40 60 5.00
f.0 100 2.00
g.100 0 2.00
1.カラム:Thermo Scientific、ProPacTM SAX-10、Bio LCTM、4×250mm
2.溶媒A:80%、10mMのTRIS、pH8、20%のエタノール;溶媒B:80%、10mMのTRIS、ph8、20%のエタノール、1.5MのNaCl;流速:0.75mL/分
3.勾配:
a.時間 %A %B
b.0.0 90 10
c.3.00 90 10
d.11.00 40 60
e.13.00 40 60
f.15.00 90 10
g.20.00 90 10
1.カラム:Thermo Scientific、ProPacTM SAX-10、Bio LCTM、4×250mm
2.溶媒A:80%、10mMのTRIS、pH8、20%のエタノール;溶媒B:80%、10mMのTRIS、pH8、20%のエタノール、1.5MのNaCl;
3.流速:0.75mL/分
4.勾配:
a.時間 %A %B
b.0.0 90 10
c.3.00 90 10
d.11.00 40 60
e.23.00 40 60
f.25.00 90 10
g.30.00 90 10
1.カラム:TOSOH Biosciences、TSKgelG3000SW XL、7.8×300mm、5μM
2.移動相:150mMのリン酸塩緩衝液
3.流速:15分間で1.0ml/分
工程1:TCEPによる抗体の還元
抗体を、1mMのDTPAを有する25mMのホウ酸塩緩衝液(pH8)と緩衝液交換し、最大で10mg/mlの濃度とした。この溶液に、同じホウ酸塩緩衝液中の4当量のTCEPを加え、37℃で2時間インキュベートした。結果として生じた反応混合物をRTでpH6.0、10mMの緩衝酢酸溶液中でBisMal-siRNA(1.25の当量)の溶液と組み合わせて、4℃で夜通し維持した。分析的SAXカラムクロマトグラフィーによる反応混合物の分析は、未反応の抗体およびsiRNAと共に抗体siRNAコンジュゲートを示した。任意の残っている遊離システイン残基をキャップするために、反応混合物を、(10mg/mLのDMSO中の)N-エチルマレイミドの10EQで処置した。
粗製反応混合物を、陰イオン交換クロマトグラフィー(SAX)方法-1を使用するAKTA Pure FPLCによって精製した。DAR1およびDAR2抗体-siRNAのコンジュゲートを含む分画を単離し、濃縮し、および、pH7.4のPBSで緩衝液交換した。
カラム:Tosoh Bioscience、TSKGel SuperQ-5PW、21.5mm ID X 15cm、13um
溶媒A:20mMのTRIS緩衝液、pH8.0;溶媒B:20mMのTRIS、1.5MのNaCl、pH8.0;流速:6.0ml/分
勾配:
a.%A %B カラム体積
b.100 0 1
c.81 19 0.5
d.50 50 13
e.40 60 0.5
f.0 100 0.5
g.100 0 2
カラム:Thermo Scientific、ProPacTM SAX-10、Bio LCTM、4×250mm
溶媒A:80%、10mMのTRIS、pH8、20%のエタノール;溶媒B:80%、10mMのTRIS、ph8、20%のエタノール、1.5MのNaCl;流速:0.75ml/分
勾配:
a.時間 %A %B
b.0.0 90 10
c.3.00 90 10
d.11.00 40 60
e.14.00 40 60
f.15.00 20 80
g.16.00 90 10
h.20.00 90 10
健康な個体およびFSHD患者に由来する筋管を、DUX4発現について評価した。図4に示すように、DUX4発現を検出するために筋管を免疫染色した。筋細胞の核および細胞質を、DAPI (4’,6-ジアミジノ-2-フェニルインドール)およびトロポニンTを標識することによって免疫染色した。示されるように、DUX4の発現は、筋核の1%未満で、低くかつ散発的に検出され-このことは、細胞からの直接的なDUX4発現の検出は、DUX4 siRNA 活性の効果を決定する上で困難である可能性があることを示す。
2つのDUX4 siRNA(siDUX4-1およびsiDUX4-4は、Geng LNら、Dev.Cell,2012に開示されている)を使用して、疾患筋細胞(FSHDドナー筋細胞)を処置し、5つのDUX4のRNA発現レベル依存性バイオマーカー遺伝子は、図5の棒グラフに示されるように定量化された。示されるように、siDUX4-1とsiDUX4-4の両方が、ベースライン(100%)と比較して、MBD3L2、TRIM43、PRAMEF1、ZSCAN4、およびLEUTXの発現を大幅に減少させた。より具体的には、siDUX4-4は、MBD3L2、TRIM43、PRAMEF1、ZSCAN4、およびLEUTXの発現を、ベースライン(100%)と比較して少なくとも~75%減少させた。バイオマーカーとしてのDUX4標的遺伝子は、siRNAを媒介するDUX4のダウンレギュレーションを測定するのに敏感であった。
FSHD1患者由来の初代筋芽細胞(MB06)を使用して、公開された2つのDUX4 siRNA、siDUX4-およびsiDUX4-4(Geng LNら、Dev.Cell,2012)を用いて、用量依存濃度において、DUX4 siRNA活性を評価した。FSHD初代筋芽細胞(MB06(FSHD1))は、推奨される培地で培養した。播種する前に、96ウェル組織培養プレート(Costar)を、ウェルあたり50μLの1%Matrigelで37℃にて少なくとも2時間コーティングし、PBSで2回洗浄した。コーティング後、筋芽細胞を抗生物質なしで4000細胞/ウェルにて4連で播種し、トランスフェクションの24時間前に維持した。トランスフェクション当日、DUX4-4siRNAは、市販のトランスフェクション試薬Lipofectamine RNAiMAX(Life Technologies)およびOptiMEM(Life Technologies)を使用して、メーカーの「フォワードトランスフェクション」の説明書に従って製剤化した。DUX4-4 siRNAはIntegrated DNA Technologies(IDT)によって合成された。筋芽細胞に、25nMの高濃度のDUX4-4 siRNAを用いて9倍連続希釈でトランスフェクトした。トランスフェクションの24時間後、15%KOSR含有分化培地で筋原性分化を誘導した。筋管は、分化を誘導してから4日後にTrizolで収集し、処理するまで-80℃で保存した。製造元の指示に従って、Direct-zol-96RNA分離キット(Zymo)を使用してRNA分離を実施した。SimpliAmp Thermal Cycler(AppliedBiosystems)を使用するHigh-Capacity cDNA Reverse Transcription Kit(Applied Biosystems)を使用して、100~500ngの精製RNAをcDNAに変換した。QuantStudio 6または7 Flex Real-Time PCR機器(Applied Biosystems)を使用して、TaqMan Fast Universal Master Mix II(Thermo Fisher)およびTaqManプローブ(Thermo Fisher)を2連で使用して、qPCRによりcDNAを分析した。データは QuantStudio(商標)Real-Time PCR Software v1.3(Applied Biosystems)によって分析した。5つのDUX4標的遺伝子、MBD3L2、ZSCAN4、LEUTX、KHDC1L、およびTRIM43の発現レベルを評価した。DUX4標的遺伝子の発現は、2つの参照遺伝子、AHSA1とRPL27の複合体に対して正規化した。標的mRNA発現のパーセンテージは、2-ΔΔCt法(LivakおよびSchmittgen,Methods2001)を使用することにより、モック処理細胞と比較して決定された。図6A-Bは、培養FSHD初代筋管における5つのDUX4標的バイオマーカー遺伝子発現のDUX4 siRNA媒介減少を示す。DUX4 siRNAは、5つの個々のDUX4標的バイオマーカー遺伝子(MBD3L2、ZSCAN4、LEUTX、KHDC1L、およびTRIM43)の発現(図6A)、またはFSHD初代筋管における5つのDUX4標的バイオマーカー遺伝子のFSHD複合体として(図6B)の発現を減少させた。
この実施例では、70個のDUX4 siRNAを、2つのFSHD初代筋芽細胞株(MB02(FSHD1)およびMB06(FSHD1))におけるそれらの活性についてスクリーニングして、より望ましいsiRNA候補を同定した。細胞を4,000細胞/ウェル(MW96)の密度で播種し、次いでDUX4 siRNA、および対照としてツールsiRNAを4連でトランスフェクトした。トランスフェクションは、10nM濃度でプレーティングしてから24時間後に実施した。筋原性分化は、15%KOSR(DMEM/F-12中)培地でプレーティングしてから2日後(トランスフェクションから24時間後)に誘導された。細胞株に応じて、分化を誘導してから3日または4日後にサンプルを採取した。DUX4下流の標的遺伝子発現は、RT-qPCRによって評価さした(複合AHSA1およびRPL27ハウスキーピング遺伝子発現値に正規化)。この実施例に示されているデータは、平均FSHD複合体-/+SEMとして表される。N=4。
この実施例では、全部で9つの高品質FSHD患者由来初代筋芽細胞株(6つのFSHD1、3つのFSHD2)を使用した。社内でFSHD筋管におけるDUX4標的遺伝子発現の信頼できる検出を可能にする条件は、細胞を分化培地(DMEM/F-12中15%KOSR)で培養することによって確立されました。時点は、各細胞株に対して具体的に選択された。9つのFSHD細胞株すべてが、ツールDUX 4siRNAに対して濃度依存的な応答を示した。
この実施例における実験の目的は、オフターゲット分析のために最良のEmaxおよび効力を有する8つのsiRNAを選択することである。3つのFSHD初代筋芽細胞株(MB02、MB05、MB06)を使用した。細胞を4,000細胞/ウェル(MW96)の密度で播種し、選択した14個のDUX4 siRNAで4連でトランスフェクトした。トランスフェクションは、プレーティングの24時間後に行った。筋原性分化は、15%KOSR(DMEM/F-12中)培地でプレーティングしてから2日後(トランスフェクションから24時間後)に誘導した。細胞株に応じて、分化を誘導してから3日または4日後にサンプルを採取した。DUX4下流の標的遺伝子発現は、RT-qPCRによって評価した(複合AHSA1およびRPL27ハウスキーピング遺伝子発現値に正規化)。データは平均-/+SEMとして表される。N=4。
16個のDUX4-AOC(8個のvpUq AOCまたは8個の非VP AOC)のインビトロ濃度応答効力および最大有効性を、FSHD1患者由来の初代筋管(MB06)において評価した。AOCのDUX4 siRNAのガイド鎖は、鎖の5’末端にビニルホスホネートを含む(vpUq)か、鎖の5’末端にビニルホスホネートを含まない(非VP)のいずれかであった。
野生型雌性CD-1マウス(約6~8週齢)に、Malat1またはScranble AOCのいずれかを5mL/kg体重で尾静脈に単回IVボーラス注射することにより1回投与し、ここで、siRNAは、0.3、1、3、6mg/kg体重(siRNA量)の用量でマウス抗トランスフェリン受容体(mTfR1)抗体にコンジュゲートされていた。処置の2週間後にセラミックビーズを含むチューブに筋肉組織サンプルを採取し、液体窒素で瞬間凍結し、次いでFastPrep-24(MP Biomedicals)を使用して1mLの冷却Trizol中でホモジナイズした。製造元の指示に従って、Direct-zol-96 RNA単離キット(Zymo)を使用して、ホモジネート上清をRNA分離に使用した。SimpliAmp Thermal Cycler(Applied Biosystems)を使用するHigh-Capacity cDNA Reverse Transcription Kit(Applied Biosystems)を使用して、100~500ngの精製RNAをcDNAに変換した。QuantStudio 6または7 Flex Real-TimePCR機器(Applied Biosystems)を使用して、TaqMan Fast Universal Master MixII(Thermo Fisher)およびTaqManプローブ(Thermo Fisher)を2連で使用して、qPCRによりcDNAを分析した。データはQuantStudio(商標)Real-TimePCR Softwarev1.3(Applied Biosystems)によって分析された。標的遺伝子の発現は、参照遺伝子Ppibに対して正規化された。2-ΔΔCt法を使用して、対照処置と比較して、処置サンプルにおける標的mRNA発現のパーセンテージを決定した。データは、PBS対照の%として表される(平均±SEM;siMalat1およびsiScramble AOCについてN=4、PBSグループについてN=5)。
野生型雄性C57BL/6マウス(約12~16週齢)に、ビニルホスホネートを含まないか(非VP)またはビニルホスホネートを含むか(vpUq)のいずれかである、3mg/kg体重(siRNA量)の用量でマウス抗TfR1(mTfR1)抗体に結合したSsbsiRNAの、5mL/kg体重の単回IVボーラス注射を尾静脈に1回投与した。投与後、以下の時点で腓腹筋を収集しました:1、7、14、28、43、および57日目。セラミックビーズを含むチューブに筋肉を入れ、液体窒素で瞬間凍結し、次いでFastPrep-24(MP Biomedicals)を使用して1mLの冷Trizolでホモジナイズした。製造元の指示に従って、Direct-zol-96 RNA分離キット(Zymo)を使用して、ホモジネート上清をRNA分離に使用した。SimpliAmp Thermal Cycler(Applied Biosystems)を使用するHigh-Capacityc DNA Reverse Transcription Kit(Applied Biosystems)を使用して、100~500ngの精製RNAをcDNAに変換した。QuantStudio 6または7 Flex Real-Time PCR機器(Applied Biosystems)を使用して、TaqMan Fast Universal Master Mix II(Thermo Fisher)およびTaqManプローブ(Thermo Fisher)を2連で使用して、qPCRによりcDNAを分析した。データはQuantStudio(商標)Real-Time PCR Softwarev1.3(Applied Biosystems)によって分析された。Ssb遺伝子発現は、参照遺伝子Ppibに対して正規化された。2-ΔΔCt法を使用して、対照処置(PBS)と比較して、処置サンプルにおける標的mRNA発現のパーセンテージを決定した。データは、PBS対照の%として表される(平均±SEM;siSsb-AOCsについてN=4、PBSグループについてN=3-5)。
Claims (37)
- DUX4の標的配列にハイブリダイズするポリ核酸分子にコンジュゲートされた抗体またはその抗原結合フラグメントを含み、DUX4に対するRNA干渉を媒介する、ポリ核酸分子コンジュゲート。
- 前記抗体またはその抗原結合フラグメントが、非ヒト抗体またはその抗原結合フラグメント、ヒト抗体またはその抗原結合フラグメント、ヒト化抗体またはその抗原結合フラグメント、キメラ抗体またはその抗原結合フラグメント、モノクローナル抗体またはその抗原結合フラグメント、一価Fab’、二価Fab2、単鎖可変フラグメント(scFv)、ダイアボディ、ミニボディ、ナノボディ、単一ドメイン抗体(sdAb)、またはラクダ抗体または抗原結合そのフラグメントを含む、請求項1に記載のポリ核酸分子コンジュゲート。
- 抗体またはその抗原結合フラグメントが、抗トランスフェリン受容体抗体またはその抗原結合フラグメントである、請求項1-2のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 前記ポリ核酸分子がセンス鎖および/またはアンチセンス鎖を含み、前記センス鎖および/または前記アンチセンス鎖がそれぞれ独立して、少なくとも1つの2’修飾ヌクレオチド、少なくとも1つの修飾ヌクレオチド間結合、または少なくとも1つの反転脱塩基(inverted abasic)部分を含む、請求項1-3のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 前記ポリヌクレオチドが、DUX4の標的配列の少なくとも8個の連続する塩基にハイブリダイズする、請求項1-4のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 前記ポリヌクレオチドが長さ約8-約50ヌクレオチド長、または約10-約30ヌクレオチド長である、請求項1-5のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 前記ポリ核酸分子がセンス鎖および/またはアンチセンス鎖を含み、前記センス鎖が、配列番号1-70または配列番号141-210から選択される配列と、少なくとも80%、少なくとも85%、少なくとも90%、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%同一である配列を含む、請求項1-6のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 前記ポリ核酸分子がセンス鎖および/またはアンチセンス鎖を含み、前記アンチセンス鎖が、配列番号71-140または配列番号211-280から選択される配列と、少なくとも80%、少なくとも85%、少なくとも90%、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%同一である配列を含む、請求項1-7のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 前記ポリヌクレオチドが少なくとも1つの2’修飾ヌクレオチドを含み、さらに2’修飾ヌクレオチドが、
2’-O-メチル、2’-O-メトキシエチル(2’-O-MOE)、2’-O-アミノプロピル、2’-デオキシ、2’-デオキシ-2’-フルオロ、2’-O-アミノプロピル(2’-O-AP)、2’-O-ジメチルアミノエチル(2’-O-DMAOE)、2’-O-ジメチルアミノプロピル(2’-O-DMAP)、2’-O-ジメチルアミノエチルオキシエチル(2’-O-DMAEOE)、または2’-O-N-メチルアセトアミド(2’-O-NMA)修飾ヌクレオチドを含み、
ロックド核酸(LNA)またはエチレン核酸(ENA)を含み、または
これらの組み合わせを含む、
請求項1-8のいずれか一項に記載のポリ核酸分子コンジュゲート。 - 少なくとも1つの修飾ヌクレオチド間結合が、ホスホロチオエート結合またはホスホロジチオエート結合を含む、請求項1-9のいずれか一項に記載のポリ核酸分子コンジュゲート。
- ポリ核酸分子が、2’-O-メチルおよび2’-デオキシ-2’-フルオロから選択される3つ以上の2’修飾ヌクレオチドを含む、請求項1-10のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 前記ポリ核酸分子が5’末端ビニルホスホネート修飾ヌクレオチドを含む、請求項1-11のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 前記2’修飾ヌクレオチドが2’-O-メチル修飾ヌクレオチドであり、2’-O-メチル修飾ヌクレオチドが、センス鎖および/またはアンチセンス鎖の5’末端にある、請求項1-12のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 前記2’-O-メチル修飾ヌクレオチドがプリンヌクレオチドである、請求項13に記載のポリ核酸分子コンジュゲート。
- 前記2’-O-メチル修飾ヌクレオチドがピリジンヌクレオチドである、請求項13に記載のポリ核酸分子コンジュゲート。
- 前記センス鎖および/または前記アンチセンス鎖が、5’末端に少なくとも2つ、3つ、または4つの連続する前記2’-O-メチル修飾ヌクレオチドを含む、請求項13-15のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 前記抗体またはその抗原結合フラグメントを前記ポリ核酸分子に接続するリンカーを含む、請求項1-16のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 前記リンカーがC1-C6アルキルリンカーである、請求項17に記載のポリ核酸分子コンジュゲート。
- 前記リンカーがホモ二官能性リンカーまたはヘテロ二官能性リンカーであり、マレイミド基、ジペプチド部分、安息香酸基、またはその誘導体を含む、請求項17記載のポリ核酸分子コンジュゲート。
- 前記リンカーが、切断可能なまたは切断不可能なリンカーである、請求項17記載のポリ核酸分子コンジュゲート。
- 前記ポリ核酸分子と前記抗体またはその抗原結合フラグメントとの間の比率が約1:1、2:1、3:1、または4:1である、請求項1-20のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 前記ポリ核酸分子が、ヒトDUX4に対するRNA干渉を媒介し、対象における筋萎縮を調節する、請求項1-21のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 前記RNA干渉が、未処理細胞におけるDUX4遺伝子のmRNA転写物の量と比較して、DUX4遺伝子のmRNA転写物の発現を少なくとも50%、少なくとも60%、または少なくとも70%以上低下させることを含む、請求項22に記載のポリ核酸分子コンジュゲート。
- 前記RNA干渉が、細胞におけるMBD3L2、TRIM43、PRAMEF1、ZSCAN4、KHDC1L、およびLEUTXからなる群より選択されるマーカー遺伝子の発現に影響を及ぼすことを含む、請求項22-23のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 前記マーカー遺伝子の発現に影響を及ぼすことが、マーカー遺伝子の発現を少なくとも20%、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、またはそれ以上減少させることである、請求項24に記載のポリ核酸分子コンジュゲート。
- 筋ジストロフィーが顔面肩甲上腕型筋ジストロフィー(FSHD)である、請求項22-25のいずれか一項に記載のポリ核酸分子コンジュゲート。
- 式(I)
A-X-B
(式I)
の分子を含み、式中、
Aは前記抗体またはその抗原結合フラグメントであり、
BはDUX4の標的配列にハイブリダイズするポリ核酸分子であり、
Xは結合または非ポリマーリンカーであり、
ここで、XはAのシステイン残基に結合している、
請求項1-26のいずれか一項に記載のポリ核酸分子コンジュゲート。 - 請求項1-27に記載のポリ核酸分子コンジュゲート、および
薬学的に許容される賦形剤
を含む、医薬組成物。 - ナノ粒子製剤として処方される、請求項28に記載の医薬組成物。
- 非経口、経口、鼻腔内、口腔、直腸、経皮、静脈内、皮下、または髄腔内投与用に製剤化される、請求項28-29のいずれか一項に記載の医薬組成物。
- 必要とする対象において筋ジストロフィーを治療するための方法であって、
請求項1-30のいずれか一項に記載のポリ核酸コンジュゲートを供給する工程、および
筋ジストロフィーを治療するために必要とする対象にポリ核酸コンジュゲートを投与する工程であって、ここで、前記ポリ核酸コンジュゲートがヒトDUX4のmRNA転写物の量を減少させる、工程、
を含む、方法。 - 前記ポリ核酸部分が、ヒトDUX4に対するRNA干渉を媒介し、対象における筋萎縮を調節する、請求項31に記載の方法。
- 前記RNA干渉が、筋ジストロフィーに冒された細胞において、MBD3L2、TRIM43、PRAMEF1、ZSCAN4、KHDC1L、およびLEUTXからなる群より選択されるマーカー遺伝子の発現に影響を及ぼすことを含む、請求項32に記載の方法。
- 前記筋ジストロフィーが顔面肩甲上腕型筋ジストロフィー(FSHD)である、請求項31-33のいずれか一項に記載の方法。
- 顔面肩甲上腕型筋ジストロフィー(FSHD)と診断されたかまたはその疑いのある対象を治療するための、請求項1-27のいずれか一項に記載のポリ核酸分子コンジュゲートまたは請求項28-30のいずれか一項に記載の医薬組成物の使用。
- 顔面肩甲上腕型筋ジストロフィー(FSHD)と診断されたかまたはその疑いのある対象を治療するための医薬を製造するための、請求項1-27のいずれか一項に記載のポリ核酸分子コンジュゲートまたは請求項28-30のいずれか一項に記載の医薬組成物の使用。
- 請求項1-27に記載のポリ核酸分子コンジュゲートまたは請求項28-30のいずれか一項に記載の医薬組成物を含むキット。
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