JP2022513482A - 抗トランスフェリン受容体抗体およびその使用 - Google Patents
抗トランスフェリン受容体抗体およびその使用 Download PDFInfo
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Abstract
Description
本出願は、2018年12月21日に出願された米国仮特許出願第62/784,181号の利益を主張し、その全体は引用によって本明細書に組み込まれる。
特定の実施形態では、抗トランスフェリン受容体抗体が本明細書に開示される。いくつかの例では、抗トランスフェリン受容体抗体は、トランスフェリン受容体(TfR)に特異的に結合する。いくつかの例では、抗トランスフェリン受容体抗体は、ヒトトランスフェリン受容体(TfR)に特異的に結合する。場合によっては、抗トランスフェリン受容体抗体は、トランスフェリン受容体1(TfR1)(またはCD71)に特異的に結合する。場合によっては、抗トランスフェリン受容体抗体は、ヒトトランスフェリン受容体1(TfR1)(またはヒトCD71)に特異的に結合する。
いくつかの実施形態では、本明細書に記載されるポリペプチド(例えば、抗体とその結合フラグメント)は、とりわけ、化学合成によって、また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では、上記の抗トランスフェリン受容体抗体はさらにペイロードにコンジュゲートする。いくつかの例では、ペイロードは小分子を含む。他の例では、ペイロードはタンパク質またはペプチドを含む。さらなる例では、ペイロードはポリ核酸分子を含む。
式中、
Aは抗トランスフェリン受容体抗体を含み、
Bはペイロードを含み、
Cはポリマーからなり、
X1は単結合または第1のリンカーからなり、
X2は単結合または第2のリンカーからなり、および、
nは1-12から選択された平均値である。
いくつかの実施形態では、Bは化学的なライゲーションプロセスによってAにコンジュゲートする。いくつかの例では、Bは天然のライゲーションによってAにコンジュゲートする。いくつかの例では、コンジュゲーションは、Dawson, et al. ”Synthesis of proteins by native chemical ligation,” Science 1994, 266, 776-779; Dawson, et al. ”Modulation of Reactivity in Native Chemical Ligation through the Use of Thiol Additives,” J. Am. Chem. Soc. 1997, 119, 4325-4329; Hackeng, et al. ”Protein synthesis by native chemical ligation:Expanded scope by using straightforward methodology.,” Proc. Natl. Acad. Sci. USA 1999, 96, 10068-10073;あるいは、Wu, et al. ”Building complex glycopeptides: Development of a cysteine-free native chemical ligation protocol,” Angew. Chem. Int. Ed. 2006, 45, 4116-4125に記載される通りである。いくつかの例では、コンジュゲーションは米国特許第8,936,910号に記載されるとおりである。いくつかの実施形態では、ポリ核酸分子は、天然のライゲーション化学を介して、結合部分に部位特異的または非特異的にコンジュゲートする。
ポリ核酸分子
いくつかの実施形態では、ペイロードはポリ核酸分子である。いくつかの例では、ポリ核酸分子は、RNA干渉(RNAi)または遺伝子発現抑制(例えば、アンチセンスオリゴヌクレオチド)治療などの遺伝子治療に関与する。いくつかの例では、ポリ核酸分子は、mRNAのスプライシングを調節し、それによってコードされたタンパク質のその後の生成を調節する。
いくつかの実施形態では、ペイロードは小分子である。いくつかの例では、小分子は細胞傷害性ペイロードである。例示的な細胞傷害性ペイロードは、限定されないが、微小管破壊剤、DNA修飾剤、またはAkt阻害剤を含む。
いくつかの実施形態では、本明細書に記載された抗トランスフェリン受容体抗体コンジュゲートは、高分子(ポリマー部分C)をさらに含む。いくつかの例では、ポリマー部分は、分岐したまたは分枝していない単量体の長鎖、および/または、二次元あるいは三次元の単量体の架橋したネットワークからなる、天然または合成のポリマーである。いくつかの例では、ポリマー部分は多糖、リグニン、ゴム、またはポリアルキルエンオキシド(例えば、ポリエチレングリコール)を含む。いくつかの例では、少なくとも1つのポリマー部分としては、限定されないが、アルファ-ジヒドロキシルポリエチレングリコール、オメガ-ジヒドロキシルポリエチレングリコール、生物分解性ラクトンベースのポリマー、例えば、ポリアクリル酸、ポリラクチド酸(PLA)、ポリ(グリコール酸)(PGA)、ポリプロピレン、ポリスチレン、ポリオレフィン、ポリアミド、ポリシアノアクリレート、ポリイミド、ポリエチレンテレフタラート(PET、PETG)、ポリエチレンテレフタレート(PETE)、ポリテトラメチレングリコール(PTG)、またはポリウレタン、およびこれらの混合物が挙げられる。本明細書で使用されるように、混合物は、ブロックコポリマーに関連する場合と同様に、同じ化合物内の様々なポリマーの使用を指す。場合によっては、ブロックコポリマーは、ポリマーの少なくとも1つの部分が別のポリマーの単量体から構築されるポリマーである。いくつかの例では、ポリマー部分はポリアルキレンオキシドを含む。いくつかの例では、ポリマー部分はPEGを含む。いくつかの例では、ポリマー部分はポリエチレンイミド(PEI)またはヒドロキシエチルデンプン(HES)を含む。
いくつかの実施形態では、抗トランスフェリン受容体抗体コンジュゲートは、追加のコンジュゲート化部分をさらに含む。いくつかの例では、追加の結合部分はエンドソーム溶解部分である。場合によっては、エンドソーム溶解部分は、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、また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区画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、また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、エンドソーム溶解部分はエンドソーム溶解性ポリマーを含む。
いくつかの実施形態では、抗トランスフェリン受容体抗体コンジュゲートはさらに、エンドソーム溶解性ポリペプチドとコンジュゲートする。いくつかの実施形態では、式(I):A-(X1-B)n、または、式(II):A-X1-(B-X2-C)nのコンジュゲートは、エンドソーム溶解性ポリペプチドとさらにコンジュゲートする。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。さらなる場合には、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。いくつかの例では、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)、またはそのそれぞれの誘導体を含む。いくつかの例では、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では、式(I):A-(X1-B)n、または、式(II):A-X1-(B-X2-C)nのコンジュゲートは、エンドソーム溶解性ポリマーとさらにコンジュゲートする。本明細書で使用される場合、エンドソーム溶解性ポリマーは、線形、分岐ネットワーク、星形、くし形、またはしご型のポリマーを含む。いくつかの例では、エンドソーム溶解性ポリマーは、2つ以上の異なる型の単量体を含むホモポリマーまたはコポリマーであある。場合によっては、エンドソーム溶解性ポリマーはポリカチオンポリマーである。他の場合において、エンドソーム溶解性ポリマーはポリアニオンポリマーである。
いくつかの実施形態では、エンドソーム溶解部分は脂質(例えば、融合性脂質)である。いくつかの実施形態では、式(I):A-(X1-B)n、または、式(II):A-X1-(B-X2-C)nのコンジュゲートは、エンドソーム溶解性脂質(例えば、融合性脂質)とさらにコンジュゲートする。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)、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)、および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、エンドソーム溶解部分は小分子である。いくつかの実施形態では、式(I):A-(X1-B)n、または、式(II):A-X1-(B-X2-C)nの分子は、エンドソーム溶解性小分子とさらにコンジュゲートする。エンドソーム溶解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(カルノキン(carnoquines))、アモピロキン、プリマキン、メフロキン、ニバキン(nivaquines)、ハロファントリン、キノンイミン、またはそれらの組み合わせを含む。いくつかの例では、キノリンエンドソーム溶解部分としては、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、およびそのアミノ、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アナログが挙げられる。いくつかの例では、エンドソーム溶解部分は、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、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。いくつかの例では、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。
いくつかの実施形態では、本明細書に記載された抗トランスフェリン受容体抗体の使用によって、対象となる標的部位にペイロードを送達する方法が本明細書に記載されている。いくつかの例では、対象となる標的部位は、疾患または疾病に関連付けられる原因となるタンパク質を過剰発現する細胞である。いくつかの例では、対象となる標的部位は、非機能的なタンパク質、または、疾患あるいは疾病につながる発現が低下したタンパク質をコードする正しく処理されていないmRNAを含む細胞である。いくつかの例では、対象となる標的部位は腫瘍部位である。さらなる例では、対象となる標的部位は脳にある部位である。
いくつかの実施形態では、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。いくつかの例では、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、または頭蓋内)投与のために製剤化される。他の例では、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。また他の例では、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では、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では、医薬組成物は、1日に1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回、1週おき、月2週間、月3週間、月1回、月2回、月3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。
特定の実施形態では、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、包装容器、または容器を含み、容器の各々は、本明細書に記載されている方法で使用される別の要素の1つを含む。適切な容器は、例えば、ボトル、バイアル、注射器、および試験管を含む。1つの実施形態では、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。
他に定義されていない限り、本明細書で使用されているすべての技術的および科学的用語は、主張された主題が属する技術分野の当業者によって一般的に理解されてい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、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、「含む(including)」という用語の使用は、「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。
例示的な抗TfR抗体をコードする核酸をCHOK1SV GSKO細胞へと安定的にトランスフェクトし、生成物1つにつき3つの安定プールを作製した。この安定プールでは、トランスフェクション後8日目以降の細胞増殖とプロテインAの力価をモニタリングした。培養物が一旦、生存率70%で閾値0.6×10e6細胞/mLに到達したとき、安定プールを継代した。細胞の生存率が97%を超えると、試験済みのプール中の最高産生プールを用いて、生成物1つにつき600mLの流加過剰成長培養(fed-batch overgrow cultures)(FOG)を0.2×10e6細胞/mLで蒔いた。4日目と8日目にFOG培養物に給餌し、11日目に遠心分離と濾過滅菌により採取した。滅菌細胞培養上清を、AKTA清浄器(10mL/分で実行)上で並行して3×5ml MabSelectSuREカラムを用いたプロテインA精製により精製した。リン酸ナトリウム50mMでカラムを平衡化した。pH7.0の塩化ナトリウム250mMをリン酸ナトリウム50mMとpH7.0の塩化ナトリウム1Mで洗浄し、pH3.5のギ酸ナトリウム10mMで溶出した。溶出した分画を2×PBSで1:2に希釈することで中和し、次いで希釈したNaOHを用いてpHを7.4に調整した。
a)%A %B カラム体積
b)100 0 1
c)811 9 0.5
d)50 50 13
e)40 60 0.5
f)0 100 0.5
g)100 0 2
a)時間 %A %B
b).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
例示的な抗TfR抗体でのカニクイザルの処置を試験して、腓腹筋でのSSB mRNAダウンレギュレーションの割合を求める。30mg/kg、10mg/kg、および3mg/kgの投与量を試験する。抗体コンジュゲートの活性を投与後21および/または28日目に調査する。血液学と臨床化学の解析によりカニクイザルの安全性もモニタリングする。
hIgG1 TfR-Var2iiおよびhIgG1 TfR-Var9iiは、hTfR1を標的とするヒト化IgG1抗体であり、IgG1重鎖のヒンジ領域に突然変異を含有しており、作用因子機能(LALA+L328R)を取り除くように設計されている。キメラhIgG2 TfR1抗体とは対照的に、hIgG1 TfR-Var2iiおよびhIgG1 TfR-Var9iiのSSBコンジュゲートをカニクイザルへ投与後、網状赤血球値は低下しない。この結果は、TfR1標的化抗体による未成熟網状赤血球の枯渇が、抗体のADCC/CDC活性を取り除く突然変異により上手く抑えることができることを実証する他者の試験と一致している(WO2014/189973A2)。
投与前のSSB mRNA値と比較して、1または6mg/kg(siRNA)のhIgG1 TfR-Var2iiまたはhIgG1 TfR-Var9ii SSBコンジュゲートの単回投与により、投与後21日目で腓腹筋と大腿四頭筋におけるSSB mRNA値を最大72%ダウンレギュレートした(図19)。ヒト化抗体の活性は親キメラIgG2 TfR1抗体の活性と同様である。60mg/kg(6mg/kgのAOC投与量に等しい)で投与したコンジュゲートされていないTfR-Var2ii Abでは、SSBの有意なダウンレギュレーションを認めなかった。
6mg/kgのhIgG1 TfR-Var2ii-SSBを単回投与して21日目、大半の組織に10~100nMのSSB siRNA濃度を認めた。最高siRNA値は肝臓と副腎であり(1000nM以下)、最低値は脳であった(2nM)。骨格筋のsiRNA濃度は3~20nMであった。siRNA曝露は比較的低いにもかかわらず、骨格筋と心臓のみに50%を超えるSSB mRNA値の低下を認めた。この結果から、TfR1標的化抗体によるオリゴヌクレオチドペイロードの送達は筋肉に特異的であり、siRNA曝露ではなく細胞特異的輸送経路により導かれることを実証する。
Claims (106)
- 可変重鎖(VH)領域と可変軽鎖(VL)領域を含む、抗トランスフェリン受容体抗体であって、VH領域は、配列番号:1を含むHCDR1配列と、HCDR2配列EINPIX1GRSNYAX2KFQGであって、X1がNまたはQから選択され、X2がQまたはEから選択される、HCDR2配列と、配列番号:3を含むHCDR3配列とを含む、抗トランスフェリン受容体抗体。
- VH領域は、配列番号:1を含むHCDR1配列、配列番号:2を含むHCDR2配列、および配列番号:3を含むHCDR3配列を含む、請求項1に記載の抗トランスフェリン受容体抗体。
- VH領域は、配列番号:1を含むHCDR1配列、配列番号:4を含むHCDR2配列、および配列番号:3を含むHCDR3配列を含む、請求項1に記載の抗トランスフェリン受容体抗体。
- VH領域は、配列番号:1を含むHCDR1配列、配列番号:5を含むHCDR2配列、および配列番号:3を含むHCDR3配列を含む、請求項1に記載の抗トランスフェリン受容体抗体。
- VL領域は、LCDR1配列RTSENIYX3NLA、LCDR2配列AX4TNLAX5、およびLCDR3配列QHFWGTPLTX6を含み、ここで、X3はNまたはSから選択され、X4はAまたはGから選択され、X5はDまたはEから選択され、および、X6は存在し、または存在せず、存在する場合にはFである、請求項1-4のいずれか1つに記載の抗トランスフェリン受容体抗体。
- VL領域は、配列番号:6を含むLCDR1配列、LCDR2配列AATNLAX5、およびLCDR3配列QHFWGTPLTX6を含み、ここで、X5はDまたはEから選択され、X6は存在し、または存在せず、存在する場合にはFである、請求項1-5のいずれか1つに記載の抗トランスフェリン受容体抗体。
- VL領域は、配列番号:6を含むLCDR1配列、配列番号:7を含むLCDR2配列、および配列番号:8を含むLCDR3配列を含む、請求項1-6のいずれか1つに記載の抗トランスフェリン受容体抗体。
- VL領域は、配列番号:6を含むLCDR1配列、配列番号:9を含むLCDR2配列、および配列番号:10を含むLCDR3配列を含む、請求項1-5のいずれか1つに記載の抗トランスフェリン受容体抗体。
- VL領域は、配列番号:11を含むLCDR1配列、配列番号:12を含むLCDR2配列、および配列番号:10を含むLCDR3配列を含む、請求項1-5のいずれか1つに記載の抗トランスフェリン受容体抗体。
- VH領域は、配列番号:1を含むHCDR1配列、配列番号:2を含むHCDR2配列、および配列番号:3を含むHCDR3配列を含み、ならびに、VL領域は、配列番号:6を含むLCDR1配列、配列番号:7を含むLCDR2配列、および配列番号:8を含むLCDR3配列を含む、請求項1-9のいずれか1つに記載の抗トランスフェリン受容体抗体。
- VH領域は、配列番号:1を含むHCDR1配列、配列番号:4を含むHCDR2配列、および配列番号:3を含むHCDR3配列を含み、ならびに、VL領域は、配列番号:6を含むLCDR1配列、配列番号:7を含むLCDR2配列、および配列番号:8を含むLCDR3配列を含む、請求項1-9のいずれか1つに記載の抗トランスフェリン受容体抗体。
- VH領域は、配列番号:1を含むHCDR1配列、配列番号:5を含むHCDR2配列、および配列番号:3を含むHCDR3配列を含み、ならびに、VL領域は、配列番号:6を含むLCDR1配列、配列番号:9を含むLCDR2配列、および配列番号:10を含むLCDR3配列を含む、請求項1-9のいずれか1つに記載の抗トランスフェリン受容体抗体。
- VH領域は、配列番号:1を含むHCDR1配列、配列番号:4を含むHCDR2配列、および配列番号:3を含むHCDR3配列を含み、ならびに、VL領域は、配列番号:11を含むLCDR1配列、配列番号:12を含むLCDR2配列、および配列番号:10を含むLCDR3配列を含む、請求項1-9のいずれか1つに記載の抗トランスフェリン受容体抗体。
- VH領域は、配列番号:13-16から選択される配列に対する少なくとも80%、85%、90%、95%、99%、または100%の配列同一性を含む、請求項1-13のいずれか1つに記載の抗トランスフェリン受容体抗体。
- VL領域は、配列番号:18-21から選択される配列に対する少なくとも80%、85%、90%、95%、99%、または100%の配列同一性を含む、請求項1-14のいずれか1つに記載の抗トランスフェリン受容体抗体。
- 抗トランスフェリン受容体抗体は、ヒト化抗体またはその結合フラグメント、あるいはキメラ抗体またはその結合フラグメントを含む、請求項1-15のいずれか1つに記載の抗トランスフェリン受容体抗体。
- 抗トランスフェリン受容体抗体は、多特異性抗体またはその結合フラグメントを含む、請求項1-16のいずれか1つに記載の抗トランスフェリン受容体抗体。
- 抗トランスフェリン受容体抗体は、二重特異性抗体またはその結合フラグメントを含む、請求項1-17のいずれか1つに記載の抗トランスフェリン受容体抗体。
- 抗トランスフェリン受容体抗体は、IgG-scFv、ナノボディ、BiTE、ダイアボディ、DART、TandAb、scダイアボディ、scダイアボディ-CH3、トリプルボディ、ミニ抗体、ミニボディ、TriBiミニボディ、scFv-CH3 KIH、Fab-scFv-Fc KIH、Fab-scFv、scFv-CH-CL-scFv、F(ab’)2、F(ab’)2-scFv2.scFv-KIH、Fab-scFv-Fc、四価HCAb、scダイアボディ-Fc、ダイアボディ-Fc、タンデムscFv-Fc、またはイントラボディを含む、請求項1-18のいずれか1つに記載の抗トランスフェリン受容体抗体。
- 抗トランスフェリン受容体抗体は、IgG1フレームワークを含む、請求項1-19のいずれか1つに記載の抗トランスフェリン受容体抗体。
- 抗トランスフェリン受容体抗体はIgG2フレームワークを含む、請求項1-19のいずれか1つに記載の抗トランスフェリン受容体抗体。
- IgG2フレームワークはIgG2bフレームワークである、請求項21に記載の抗トランスフェリン受容体抗体。
- 抗トランスフェリン受容体抗体はIgG4フレームワークを含む、請求項1-19のいずれか1つに記載の抗トランスフェリン受容体抗体。
- 抗トランスフェリン受容体抗体は、Fc領域中に少なくとも1つの突然変異をさらに含む、請求項1-23のいずれか1つに記載の抗トランスフェリン受容体抗体。
- 少なくとも1つの突然変異はエフェクター機能を調節する、請求項24に記載の抗トランスフェリン受容体抗体。
- 少なくとも1つの突然変異は、Fc-γ受容体結合を弱めるか、または取り除く、請求項24または25に記載の抗トランスフェリン受容体抗体。
- 少なくとも1つの突然変異は、残基位置D265、N297、K322、L328、またはP329にあり、ここで、残基位置はIgG1を基準としている、請求項24-26のいずれか1つに記載の抗トランスフェリン受容体抗体。
- Fc領域は2以上、3以上、または4以上の突然変異を含む、請求項24-27のいずれか1つに記載の抗トランスフェリン受容体抗体。
- Fc領域はL233とL234において突然変異を含み、ここで、残基は配列番号:23の位置233と位置234に対応する、請求項24-28のいずれか1つに記載の抗トランスフェリン受容体抗体。
- Fc領域は、D265とN297において突然変異を含む、請求項24-28のいずれか1つに記載の抗トランスフェリン受容体抗体。
- 抗トランスフェリン受容体抗体は、配列番号:23-46から選択された重鎖(HC)配列と、配列番号:47-50から選択された軽鎖(LC)配列とを含む、請求項1-30のいずれか1つに記載の抗トランスフェリン受容体抗体。
- 抗トランスフェリン受容体抗体は、ヒトトランスフェリン受容体(TfR)に特異的に結合する、請求項1-31のいずれか1つに記載の抗トランスフェリン受容体抗体。
- 請求項1-32の抗トランスフェリン受容体抗体とペイロードとを含む、抗トランスフェリン受容体抗体コンジュゲート。
- ペイロードは小分子、ペプチド、タンパク質、またはポリ核酸分子を含む、請求項33に記載の抗トランスフェリン受容体抗体コンジュゲート。
- ペイロードはポリ核酸分子を含む、請求項33に記載の抗トランスフェリン受容体抗体コンジュゲート。
- ポリ核酸分子は、短干渉核酸(siNA)、低分子干渉RNA(siRNA)、二本鎖RNA(dsRNA)、マイクロRNA(miRNA)、低分子ヘアピン型RNA(shRNA)、アンチセンスオリゴヌクレオチド(ASO)、PMO、またはmRNAを含む、請求項35に記載の抗トランスフェリン受容体抗体コンジュゲート。
- ペイロードはdsRNAを含む、請求項34-36のいずれか1つに記載の抗トランスフェリン受容体抗体コンジュゲート。
- ペイロードはアンチセンスオリゴヌクレオチド(ASO)を含む、請求項34-36のいずれか1つに記載の抗トランスフェリン受容体抗体コンジュゲート。
- ペイロードは小分子、ペプチド、またはタンパク質を含む、請求項33に記載の抗トランスフェリン受容体抗体コンジュゲート。
- ペイロードは、微小管破壊剤、DNA修飾剤、またはAkt阻害剤を含む、請求項39に記載の抗トランスフェリン受容体抗体コンジュゲート。
- ペイロードは、オーリスタチンまたはその誘導体、ドラスタチンまたはその誘導体あるいはアナログ、メイタンシノイド、もしくは、ピロロベンゾジアゼピンまたはその誘導体を含む、請求項39に記載の抗トランスフェリン受容体抗体コンジュゲート。
- オーリスタチンまたはその誘導体は、モノメチルオーリスタチンE(MMAE)またはモノメチルオーリスタチンF(MMAF)である、請求項41に記載の抗トランスフェリン受容体抗体コンジュゲート。
- メイタンシノイドはDM1またはDM4である、請求項41に記載の抗トランスフェリン受容体抗体コンジュゲート。
- ピロロベンゾジアゼピンは、ピロロベンゾジアゼピン二量体である、請求項41に記載の抗トランスフェリン受容体抗体コンジュゲート。
- ペイロードは免疫調節剤または免疫調節薬を含む、請求項39に記載の抗トランスフェリン受容体抗体コンジュゲート。
- 免疫調節薬はサイトカインを含む、請求項45に記載の抗トランスフェリン受容体抗体コンジュゲート。
- ペイロードはタンパク質またはペプチドトキシンあるいはそのフラグメントを含む、請求項39に記載の抗トランスフェリン受容体抗体コンジュゲート。
- ペイロードは、リンカーを介して抗トランスフェリン受容体抗体にコンジュゲートする、請求項33-47のいずれか1つに記載の抗トランスフェリン受容体抗体コンジュゲート。
- 抗トランスフェリン受容体抗体はさらに、2つ以上のペイロードにコンジュゲートする、請求項33-48のいずれか1つに記載の抗トランスフェリン受容体抗体コンジュゲート。
- 抗トランスフェリン受容体抗体に対するペイロードの比率は、約1:1、2:1、3:1、4:1、5:1、6:1、7:1、8:1、9:1、10:1、11:1、または12:1である、請求項33-49のいずれか1つに記載の抗トランスフェリン受容体抗体コンジュゲート。
- ペイロードはポリ核酸分子である、請求項51に記載の抗トランスフェリン受容体抗体コンジュゲート。
- ポリ核酸分子は、パッセンジャー鎖とガイド鎖とを含む、請求項52に記載の抗トランスフェリン受容体抗体コンジュゲート。
- ガイド鎖は、少なくとも1つの修飾されたヌクレオチド間結合、少なくとも1つの反転脱塩基部分、少なくとも1つの5’-ビニルホスホネート修飾された非天然のヌクレオチド、あるいは、これらの組み合わせを含む、請求項53に記載の抗トランスフェリン受容体抗体コンジュゲート。
- 少なくとも1つの5’-ビニルホスホネート修飾された非天然のヌクレオチドは、ガイド鎖の5’末端から、約1、2、3、4、または5つの塩基離れて位置する、請求項54に記載の抗トランスフェリン受容体抗体コンジュゲート。
- ポリ核酸分子は、2’位置での糖部分の修飾をさらに含む、請求項51-55のいずれか1つに記載の抗トランスフェリン受容体抗体コンジュゲート。
- 2’-位置での修飾は、2’-O-メチル、2’-O-メトキシエチル(2’-O-MOE)、2’-デオキシ、T-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)、T-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)修飾されたヌクレオチドから選択される、請求項56に記載の抗トランスフェリン受容体抗体コンジュゲート。
- パッセンジャー鎖は、少なくとも6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、またはそれ以上のホスホロジアミデートモルホリノオリゴマー修飾された非天然のヌクレオチドを含む、請求項53に記載の抗トランスフェリン受容体抗体コンジュゲート。
- パッセンジャー鎖はガイド鎖よりも長さが短く、それによって、5’オーバーハング、3’オーバーハング、1つの末端の平滑末端、またはこれらの組み合わせを生成する、請求項52-58のいずれか1つに記載の抗トランスフェリン受容体抗体コンジュゲート。
- パッセンジャー鎖はガイド鎖と長さが等しく、それによって、ポリ核酸分子の各末端で平滑末端を生成する、請求項52-58のいずれか1つに記載の抗トランスフェリン受容体抗体コンジュゲート。
- パッセンジャー鎖はA-X1にコンジュゲートする、請求項52-60のいずれか1つに記載の抗トランスフェリン受容体抗体コンジュゲート。
- A-X1はパッセンジャー鎖の5’末端にコンジュゲートする、請求項61に記載の抗トランスフェリン受容体抗体コンジュゲート。
- A-X1はパッセンジャー鎖の3’末端にコンジュゲートする、請求項61に記載の抗トランスフェリン受容体抗体コンジュゲート。
- Cはポリエチレングリコールである、請求項64に記載の抗トランスフェリン受容体抗体コンジュゲート。
- ポリ核酸分子は、パッセンジャー鎖とガイド鎖とを含む、請求項64に記載の抗トランスフェリン受容体抗体コンジュゲート。
- パッセンジャー鎖はA-X1とX2-Cにコンジュゲートする、請求項66に記載の抗トランスフェリン受容体抗体コンジュゲート。
- A-X1はパッセンジャー鎖の5’末端へコンジュゲートし、X2-Cはパッセンジャー鎖の3’末端へコンジュゲートする、請求項67に記載の抗トランスフェリン受容体抗体コンジュゲート。
- X2-Cはパッセンジャー鎖の5’末端へコンジュゲートし、A-X1はパッセンジャー鎖の3’末端へコンジュゲートする、請求項67に記載の抗トランスフェリン受容体抗体コンジュゲート。
- X1とX2はそれぞれ独立して非ポリマーリンカーである、請求項51-69のいずれか1つに記載の抗トランスフェリン受容体抗体コンジュゲート。
- さらにDを含む、請求項64に記載の抗トランスフェリン受容体抗体コンジュゲート。
- Dはエンドソーム溶解部分である、請求項71に記載の抗トランスフェリン受容体抗体コンジュゲート。
- 請求項1-32の抗トランスフェリン受容体抗体をコードする核酸ポリマー。
- 請求項73に記載の核酸ポリマーを含むベクター。
- 請求項1-32の抗トランスフェリン受容体抗体、または、請求項33-72の抗トランスフェリン受容体抗体コンジュゲート、および、
薬学的に許容可能な賦形剤、
を含む、医薬組成物。 - 前記医薬組成物は全身投与のために製剤化される、請求項75に記載の医薬組成物。
- 前記医薬組成物は非経口投与のために製剤化される、請求項75または76に記載の医薬組成物。
- 被験体の対象となる標的部位にペイロードを送達する方法であって、
前記方法は、
対象となる標的部位にペイロードを送達するために、請求項33-72の抗トランスフェリン受容体抗体コンジュゲート、または、請求項75-77の医薬組成物を、被験体に投与する工程を含む、方法。 - 対象となる標的部位は、過剰発現された原因となるタンパク質を含む細胞である、請求項78に記載の方法。
- 対象となる標的部位は腫瘍部位である、請求項78に記載の方法。
- 対象となる標的部位は脳にある部位である、請求項78に記載の方法。
- 被験体の癌を処置する方法であって、
前記方法は、
対象となる被験体の癌を処置するために、請求項33-72の抗トランスフェリン受容体抗体コンジュゲート、または、請求項75-77の医薬組成物を、被験体に投与する工程を含む、方法。 - 癌は固形癌である、請求項82に記載の方法。
- 癌は血液悪性腫瘍である、請求項82に記載の方法。
- 癌は、膀胱癌、肺癌、脳癌、黒色腫、乳癌、非ホジキンリンパ腫、子宮頚癌、卵巣癌、大腸癌、膵臓癌、食道癌、前立腺癌、腎臓癌、皮膚癌、白血病、甲状腺癌、肝臓癌、または子宮癌である、請求項82-84のいずれか1つに記載の方法。
- 癌は転移性癌である、請求項82-85のいずれか1つに記載の方法。
- 癌は再発性または難治性の癌である、請求項82-85のいずれか1つに記載の方法。
- 被験体の筋萎縮症または筋緊張性ジストロフィーを処置する方法であって、
前記方法は、
請求項33-72の抗トランスフェリン受容体抗体コンジュゲート、または、請求項75-77の医薬組成物を、被験体に投与する工程を含み、ここで、ポリ核酸分子はアトロジーンの標的配列にハイブリダイズし、および、ポリ核酸分子は、アトロジーンに対するRNA干渉を媒介し、それによって被験体の筋萎縮症を処置する、方法。 - 筋萎縮症は、糖尿病に関連する筋萎縮症または癌性悪液質に関連する筋萎縮症である、請求項88に記載の方法。
- 筋萎縮症は、インスリン欠損症、慢性腎不全、うっ血性心不全、慢性呼吸病、慢性感染症、絶食、除神経、サルコペニア、または1型筋緊張性ジストロフィー(DM1)に関連する、請求項88に記載の方法。
- 筋緊張性ジストロフィーはDM1である、請求項88に記載の方法。
- 被験体の網状赤血球レベルは、抗トランスフェリン受容体抗体の投与後に減少しない、請求項88に記載の方法。
- 抗トランスフェリン受容体抗体コンジュゲートの投与は、被験体のSSB siRNAまたはSSB mRNAのレベルをダウンレギュレートする、請求項88に記載の方法。
- SSB siRNAまたはSSB mRNAのダウンレギュレーションは、筋肉内におけるものである、請求項93に記載の方法。
- 筋肉は骨格筋である、請求項94に記載の方法。
- 筋肉は心筋である、請求項94に記載の方法。
- アトロジーンは、IGF1-Akt-FoxO経路、グルココルチコイド-GR経路、PGC1α-FoxO経路、TNFα-NFκB経路、またはミオスタチン-ActRIIb-Smad2/3経路内のアップレギュレートされた遺伝子を含む、請求項88に記載の方法。
- アトロジーンはE3リガーゼをコードする、請求項88に記載の方法。
- アトロジーンはフォークヘッドボックス転写因子をコードする、請求項88に記載の方法。
- アトロジーンはアトロジン-1遺伝子(FBXO32)、MuRF1遺伝子(TRIM63)、FOXO1、FOXO3、またはMSTNを含む、請求項88に記載の方法。
- アトロジーンはDMPKを含む、請求項88に記載の方法。
- 被験体の筋ジストロフィーを処置する方法であって、
前記方法は、
請求項33-72の抗トランスフェリン受容体抗体コンジュゲート、または、請求項75-77の医薬組成物を、被験体に投与する工程であって、それによって、被験体の筋ジストロフィーを処置する、工程、を含む、方法。 - 筋ジストロフィーは、デュシェンヌ型筋ジストロフィー、ベッカー型筋ジストロフィー、顔面肩甲上腕型筋ジストロフィー、先天性筋ジストロフィー、または筋緊張性ジストロフィーである、請求項102に記載の方法。
- 筋ジストロフィーはデュシェンヌ型筋ジストロフィーである、請求項102に記載の方法。
- 被験体はヒトである、請求項78-104のいずれか1つに記載の方法。
- 請求項1-32の抗トランスフェリン受容体抗体、請求項33-72の抗トランスフェリン受容体抗体コンジュゲート、請求項73の核酸ポリマー、請求項74のベクター、または請求項75-77の医薬組成物を含むキット。
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