JP6251477B2 - ヒト前立腺特異的膜抗原(psma)をターゲッティングするj591ミニボディおよびcysダイアボディならびにこれらを使用するための方法 - Google Patents
ヒト前立腺特異的膜抗原(psma)をターゲッティングするj591ミニボディおよびcysダイアボディならびにこれらを使用するための方法 Download PDFInfo
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Description
本発明は、米国国立癌研究所(NCI)により授与された契約番号HHSN261200900051 Cの下、米国政府の支援により行われた。政府は本発明における一定の権利を有する。
本出願は、2009年12月2日に出願された米国仮出願第61/266,134号の利益を主張するものであり、前記出願の主題は、本明細書に完全に記載されているかのように参照により本明細書に組み込まれる。
PSMA抗体または機能的PSMA抗体フラグメントが、本明細書に記載された実施形態により本明細書で提供される。PSMA抗体または機能的抗体フラグメントは、PSMAに特異的に結合する、またはPSMAと免疫学的に反応する免疫グロブリンまたは免疫グロブリン関連分子の1つもしくは複数の部分を含む分子である。用語「修飾抗体」には、細胞内抗体、キメラ抗体、完全ヒト抗体、ヒト化抗体、およびヘテロコンジュゲート抗体(例えば、二重特異性抗体、ダイアボディ、トリアボディ、およびテトラボディ)など、免疫グロブリンの遺伝子改変形態または他の修飾形態が含まれるが、これらに限定されない。用語「機能的抗体フラグメント」には、Fab'、F(ab')2、Fab、Fv、rIgG、scFvフラグメント、単一ドメインフラグメント、ペプチボディ、ミニボディおよびcysダイアボディを含むがこれらに限定されない、抗体の1つもしくは複数の抗原結合フラグメント単独または他の分子との組み合わせが含まれる。用語scFvとは、伝統的な二本鎖抗体の重鎖および軽鎖の可変ドメインが結合されて一本鎖を形成する一本鎖Fv抗体を指す。
幾つかの実施形態では、PSMA抗体または機能的抗体フラグメントは、修飾される抗体誘導体を含んでもよい。例えば、抗体誘導体には、グリコシル化、アセチル化、ペグ化、リン酸化、アミド化、既知の保護/ブロッキング基による誘導体化、タンパク質分解切断、および細胞リガンドまたは他のタンパク質への連結により修飾された抗体が含まれるが、これらに限定されない。数多くの化学的修飾はいずれも、既知の技法(特定の化学的切断、アセチル化、ホルミル化およびツニカマイシンの代謝合成を含むが、これらに限定されない)により実行することができる。さらに、誘導体は、1つまたは複数の非天然アミノ酸を含有してもよい。
PSMA抗体、機能的PSMA抗体フラグメントまたは抗PSMAコンジュゲートは、PSMAを過剰発現する癌細胞などのPSMA陽性細胞をターゲッティングするのに使用することができる。したがって、PSMA発現に関連する癌または他の状態を診断、検出、可視化、モニタリングまたは治療する方法は、PSMA抗体、機能的PSMA抗体フラグメントまたは抗PSMAコンジュゲートを、癌またはPSMA発現に関連する他の状態を有するまたは有することが疑われる被験者に投与するステップを含み得る。本明細書では、用語「被験者」とは、ヒト、ヒト以外の霊長類、齧歯類、イヌ、ブタ等を含むがこれらに限定されない任意の動物(例えば、哺乳動物)を指す。
幾つかの実施形態では、PSMAの過剰発現に関連する癌または他の状態の治療方法が提供される。このような方法は、上記のようなPSMA抗体、または機能的PSMA抗体フラグメントを含む医薬組成物の治療有効量を被験者に投与するステップを含む。1つの実施形態では、PSMA抗体、または機能的PSMA抗体フラグメントは、本明細書に記載されたようなJ591ミニボディおよびJ591 CysDBなどのJ591抗体由来のミニボディまたはCysDBである。
J591ミニボディ構築物。第3世代J591ミニボディは、完全長親huJ591抗体の修飾可変領域を組み込む改変抗体フラグメントである。ミニボディフォーマットは、各単量体がヒトIgG1 CH3ドメインに連結された一本鎖可変フラグメント(scFv)である、ホモ二量体である(図1A)。scFvは、VHVLまたはVLVH配向を有することができる。図1Bに示された通り、VHVL配向を有するscFvのJ591ミニボディ発現構築物は、18アミノ酸リンカー(L)配列により可変軽鎖(VL)領域に連結された可変重鎖(VH)ドメインを有する。VLVH配向では、VLおよびVHは、VL領域がVHドメインの上流となるように図1Bにおいて入れ替わることになる。
1) VHVL配向を有するJ591ヒト複合体(HC) (J591 HC VHVL;配列番号1)、
2) VLVH配向を有するJ591ヒト複合体(HC) (J591 HC VLVH)、
3) VHLV配向を有する2プロリン置換(2P)を有するJ591(J591 2P VHVL;配列番号2)、および
4) VLVH配向を有する2プロリン置換(2P)を有するJ591(J591 2P VLVH)。
上記発現および結合データに基づき、J591ヒト複合体VHVL (HC VHVL)ミニボディを有力候補として選択して、この後の下記in vivoイメージング試験のための大規模(およそ低ミリグラム量)タンパク質産生に進んだ。下記実施例は、J591 HC VHVLミニボディに特有であるが、しかし、本明細書に記載されたJ591ミニボディまたはcysダイアボディはいずれも、類似の試験において精製および使用され得ることが留意される。
高発現安定細胞プールは、無血清CHO-S細胞のレンチウイルス形質導入を用いてCatalent社の専有GPEx技術により生成した。イオン交換クロマトグラフィーを用いて、J591ミニボディを、下流の実験に向けて純度が十分に高い状態で細胞上清から精製した。生成物の高純度は、SDS-PAGEおよびSEC分析により確認した(>85%純度)。精製タンパク質は、著しいバイオバーデンが全くなく(0cfu/ml)、および比較的低い内毒素レベル(8から16EU/mgの間)を有する。この産生実行バッチからの総収量は、J591ミニボディタンパク質65mgであった。
ヨウ素131によるJ591ミニボディの放射性標識。精製J591ミニボディタンパク質(50μg)を、Pierce Thermo Scientific社製のヨードゲン方法(Olafsenら 2006年に記載されているような)を用いて約50μCiの131Iで放射性標識した。この試薬は、J591ミニボディの利用可能なチロシン残基に131Iを付着させる化学的酸化反応を可能にする。Table 2(表1)は、放射性標識効率、精製後の結合放射能のパーセンテージ、および比放射能を含む、J591ミニボディ放射性標識結果の概要である。放射性標識効率は、該タンパク質に結合した対結合しない放射能のパーセンテージを測定するための即時薄層クロマトグラフィー(ITLC)を用いて、約51%と判定された(以下のTable 2(表1)参照)。比放射能は、用量校正器を用いた放射性標識タンパク質の合計放射能の測定、および標識効率に基づく比放射能の計算により、0.46μCi/μgと判定された(Table 2(表1))。過剰な非結合131Iを除去するため、放射性標識タンパク質を、スピンカラムを用いてさらに精製した。精製後にJ591ミニボディに結合した放射能のパーセンテージは、精製後に約96%まで劇的に増加した(Table 2(表1))。
ヨウ素124によるJ591ミニボディの放射性標識。精製J591ミニボディタンパク質(合計量300μg)を、Pierce Thermo Scientific社製のヨードゲン方法(Olafsenら 2006年に記載されているような)を用いて約1.3mCiの124Iで放射性標識した。この方法は、J591ミニボディの利用可能なチロシン残基に124I放射性同位体を付着させる化学的酸化反応を伴う。以下のTable 3(表2)は、放射性標識効率、精製後の結合放射能のパーセンテージ、比放射能、および免疫反応性を含む、J591ミニボディ放射性標識結果の概要である。標識反応後、放射性標識効率は、即時薄層クロマトグラフィー(ITLC)を用いて約62%(該タンパク質に結合した対結合しない放射能のパーセンテージ)と判定された(Table 3(表2)参照)。放射性標識J591ミニボディを、Sephadex G-25スピンカラムを用いて部分的に精製し、およびITLCにより再評価して結合放射能のパーセンテージを判定した。放射性標識タンパク質の比放射能は、用量校正器を用いて該タンパク質の合計放射能を測定して判定した、2.6μCi/μgであった(Table 3(表2))。過剰な非結合124Iを反応から除去するため、放射性標識タンパク質を、スピンカラムを用いてさらに精製した。精製後にJ591ミニボディに結合した放射能のパーセンテージは、約98%まで劇的に増加した(Table 3(表2))。124I-J591ミニボディの免疫反応性は、CWR22rv1 vs PC3細胞への結合をテストして48%と判定された(表3(表2))。この免疫反応性は予想より低かったが、ミニボディの以前の結合成績に基づき、124I J591ミニボディをイメージングおよび体内分布実験へ進めることを決定した。放射性標識条件(pH、時間、温度等)およびより高いタンパク質純度の獲得に対する今後の最適化が、免疫反応性を潜在的に改善し得るであろう。
64Cu-DOTA J591ミニボディ。64Cu-DOTA-J591ミニボディの腫瘍ターゲッティングおよび結合特異度を評価するため、マイクロPETイメージングおよび体内分布分析を、CWR22rv1 (PSMA+)およびPC3 (PSMA-)異種移植片の両方を移植したマウスを用いて行った。両方の異種移植片腫瘍は、イメージング実験の開始前に39〜223mgの間のサイズまで成長した。注入後4時間でのCTおよびPET/CT画像は、PC3腫瘍と比較してCWR22rv1腫瘍での迅速な腫瘍局在化を示した(図21Aおよび21Bは代表的なマウスを示す)。放射性金属標識ミニボディについて予想した通り、顕著な放射能が胸部で検出され、特に肝臓に局在化していた。64Cuなどの放射性金属の局在化は、文献(Yazakiら 2001年)で十分に研究されている。肝臓を除いて、バックグラウンド放射能は注入後4時間でも比較的低く、顕著なコントラストを有するPET/CT画像を可能にした(図21Bおよび21C)。強い腫瘍局在化は、注入後19時間およびさらに43時間でも持続した(図21D)。全体的なバックグラウンド放射能は経時的にわずかに減少したが、肝臓は強い放射能源のままであった(図21D)。
以下に列挙された参考文献、特許および公開特許出願、ならびに上記明細書に引用された全ての参考文献は、本明細書に完全に記載されているかのように、その全体が参照により本明細書に組み込まれる。
[参考文献]
Claims (60)
- 抗PSMAミニボディまたは抗PSMA cysダイアボディを、PSMA発現に関連する状態を有するまたは有することが疑われる被験者に投与するステップと、
標識されたミニボディまたはcysダイアボディをin vivoで可視化するイメージング方法に被験者を曝すステップと、
標識されたミニボディまたはcysダイアボディが腫瘍部位に局在化する場合、被験者が、PSMA発現に関連する状態を有すると判定するステップと
を含む方法により、被験者におけるPSMA発現に関連する状態の診断における使用のための、診断剤にコンジュゲートされ、PSMAに結合することができる抗PSMAミニボディまたは抗PSMA cysダイアボディであって、
前記ミニボディが、
配列番号10のアミノ酸配列;または
配列番号11のアミノ酸配列;または
配列番号10中にある可変重鎖ドメインおよび配列番号10中にある可変軽鎖ドメイン;または
配列番号11中にある可変重鎖ドメインおよび配列番号11中にある可変軽鎖ドメイン;または
配列番号3を含む可変重鎖ドメインおよび配列番号17を含む可変軽鎖ドメイン
のいずれかを含む、あるいは
前記cysダイアボディが
配列番号12のアミノ酸配列;または
配列番号13のアミノ酸配列;または
配列番号14のアミノ酸配列;または
配列番号15のアミノ酸配列;または
配列番号12中にある可変重鎖ドメインおよび配列番号12中にある可変軽鎖ドメイン;または
配列番号13中にある可変重鎖ドメインおよび配列番号13中にある可変軽鎖ドメイン;または
配列番号14中にある可変重鎖ドメインおよび配列番号14中にある可変軽鎖ドメイン;または
配列番号15中にある可変重鎖ドメインおよび配列番号15中にある可変軽鎖ドメイン;または
配列番号3を含む可変重鎖ドメインおよび配列番号17を含む可変軽鎖ドメイン
を含む、抗PSMAミニボディまたは抗PSMA cysダイアボディ。 - 固形腫瘍の新生血管系をターゲッティングする、請求項1に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
- 被験者におけるPSMA発現に関連する状態が、前立腺癌、肺癌、結腸直腸癌、乳癌、腎臓
癌、肝臓癌、膀胱癌、膵臓癌またはメラノーマである、請求項2に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。 - 抗PSMAミニボディまたは抗PSMA cysダイアボディを含む、医薬組成物の治療有効量を被験者に投与するステップを含む方法により、被験者におけるPSMA発現に関連する状態の治療における使用のための抗PSMAミニボディまたは抗PSMA cysダイアボディであって、
前記ミニボディが、
配列番号10のアミノ酸配列;または
配列番号11のアミノ酸配列;または
配列番号10中にある可変重鎖ドメインおよび配列番号10中にある可変軽鎖ドメイン;または
配列番号11中にある可変重鎖ドメインおよび配列番号11中にある可変軽鎖ドメイン;または
配列番号3を含む可変重鎖ドメインおよび配列番号17を含む可変軽鎖ドメイン
のいずれかを含む、あるいは
前記cysダイアボディが
配列番号12のアミノ酸配列;または
配列番号13のアミノ酸配列;または
配列番号14のアミノ酸配列;または
配列番号15のアミノ酸配列;または
配列番号12中にある可変重鎖ドメインおよび配列番号12中にある可変軽鎖ドメイン;または
配列番号13中にある可変重鎖ドメインおよび配列番号13中にある可変軽鎖ドメイン;または
配列番号14中にある可変重鎖ドメインおよび配列番号14中にある可変軽鎖ドメイン;または
配列番号15中にある可変重鎖ドメインおよび配列番号15中にある可変軽鎖ドメイン;または
配列番号3を含む可変重鎖ドメインおよび配列番号17を含む可変軽鎖ドメイン
を含む、抗PSMAミニボディまたは抗PSMA cysダイアボディ。 - 治療剤にコンジュゲートされる、請求項4に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
- 治療剤が、化学治療剤、治療抗体または抗体フラグメント、毒素、放射性同位体、酵素、ヌクレアーゼ、ホルモン、免疫調節物剤、アンチセンスオリゴヌクレオチド、キレート剤、ホウ素化合物、光活性剤および色素から成る群から選択される、請求項5に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
- 固形腫瘍の新生血管系をターゲッティングする、請求項4に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
- 被験者におけるPSMA発現に関連する状態が、前立腺癌、肺癌、結腸直腸癌、乳癌、腎臓癌、肝臓癌、膀胱癌、膵臓癌またはメラノーマである、請求項4に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
- 前立腺特異的膜抗原(PSMA)に結合することができるscFv配列であって、scFvが、リンカー配列により可変軽鎖ドメイン(VL)に連結された可変重鎖ドメイン(VH)を含むscFv配列と、
人工ヒンジ配列と、
ヒトIgG CH3配列と
を含むミニボディであって、
(a)可変軽鎖ドメインが配列番号10中にある可変軽鎖ドメインアミノ酸配列を含む、および可変重鎖ドメインが配列番号10中にある可変重鎖ドメインアミノ酸配列を含む、または
(b)可変軽鎖ドメインが配列番号11中にある可変軽鎖ドメインアミノ酸配列を含む、および可変重鎖ドメインが配列番号11中にある可変重鎖ドメインアミノ酸配列を含む
ミニボディ。 - 細胞で発現される時にミニボディの分泌を可能にするN末端シグナル配列をさらに含む、請求項9に記載のミニボディ。
- scFvが、VHがVLの上流になるようなVHVL配向にある、請求項9に記載のミニボディ。
- 配列番号1または配列番号2を含むヌクレオチド配列でコードされる、請求項11に記載のミニボディ。
- scFvが、VLがVHの上流になるようなVLVH配向にある、請求項9に記載のミニボディ。
- 可変軽鎖ドメインが、配列番号17を含み、可変重鎖ドメインが、配列番号3を含む、ミニボディ。
- 配列番号10のアミノ酸配列を含む、請求項9に記載のミニボディ。
- 配列番号11のアミノ酸配列を含む、請求項9に記載のミニボディ。
- 少なくとも1つの治療剤にコンジュゲートされる、請求項9に記載のミニボディ。
- 少なくとも一つの治療剤が、化学治療剤、治療抗体または抗体フラグメント、毒素、放射性同位体、酵素、ヌクレアーゼ、ホルモン、免疫調節物剤、アンチセンスオリゴヌクレオチド、キレート剤、ホウ素化合物、光活性剤および光活性色素から成る群から選択される、請求項17に記載のミニボディ。
- 少なくとも1つの診断剤にコンジュゲートされる、請求項9に記載のミニボディ。
- 診断剤が、放射性物質、色素、造影剤、蛍光化合物、蛍光分子、生物発光化合物、生物発光分子、酵素、増強剤、量子ドット、および金属ナノ粒子から成る群から選択される、請求項19に記載のミニボディ。
- PSMA発現に関連する状態を診断するための医薬の製造のための、診断剤にコンジュゲートされ、PSMAに結合することができる抗PSMAミニボディまたは抗PSMA cysダイアボディの使用であって、
ミニボディが、
配列番号10のアミノ酸配列;または
配列番号11のアミノ酸配列;または
配列番号10中にある可変重鎖ドメインおよび配列番号10中にある可変軽鎖ドメイン;または
配列番号11中にある可変重鎖ドメインおよび配列番号11中にある可変軽鎖ドメイン;または
配列番号3を含む可変重鎖ドメインおよび配列番号17を含む可変軽鎖ドメイン
のいずれかを含む、あるいは
前記cysダイアボディが
配列番号12のアミノ酸配列;または
配列番号13のアミノ酸配列;または
配列番号14のアミノ酸配列;または
配列番号15のアミノ酸配列;または
配列番号12中にある可変重鎖ドメインおよび配列番号12中にある可変軽鎖ドメイン;または
配列番号13中にある可変重鎖ドメインおよび配列番号13中にある可変軽鎖ドメイン;または
配列番号14中にある可変重鎖ドメインおよび配列番号14中にある可変軽鎖ドメイン;または
配列番号15中にある可変重鎖ドメインおよび配列番号15中にある可変軽鎖ドメイン;または
配列番号3を含む可変重鎖ドメインおよび配列番号17を含む可変軽鎖ドメイン
を含む、抗PSMAミニボディまたは抗PSMA cysダイアボディの使用。 - 抗PSMAミニボディまたは抗PSMA cysダイアボディが固形腫瘍の新生血管系をターゲッティングする、請求項21に記載の使用。
- 被験者におけるPSMA発現に関連する状態が、前立腺癌、肺癌、結腸直腸癌、乳癌、腎臓癌、肝臓癌、膀胱癌、膵臓癌またはメラノーマである、請求項21に記載の使用。
- ミニボディが
配列番号10のアミノ酸配列;または
配列番号11のアミノ酸配列;または
配列番号10中にある可変重鎖ドメインおよび配列番号10中にある可変軽鎖ドメイン;または
配列番号11中にある可変重鎖ドメインおよび配列番号11中にある可変軽鎖ドメイン;または
配列番号3を含む可変重鎖ドメインおよび配列番号17を含む可変軽鎖ドメイン
のいずれかを含む、あるいは
前記cysダイアボディが
配列番号12のアミノ酸配列;または
配列番号13のアミノ酸配列;または
配列番号14のアミノ酸配列;または
配列番号15のアミノ酸配列;または
配列番号12中にある可変重鎖ドメインおよび配列番号12中にある可変軽鎖ドメイン;または
配列番号13中にある可変重鎖ドメインおよび配列番号13中にある可変軽鎖ドメイン;または
配列番号14中にある可変重鎖ドメインおよび配列番号14中にある可変軽鎖ドメイン;または
配列番号15中にある可変重鎖ドメインおよび配列番号15中にある可変軽鎖ドメイン;または
配列番号3を含む可変重鎖ドメインおよび配列番号17を含む可変軽鎖ドメイン
を含む、
PSMA発現に関連する状態を治療するための医薬の製造のための、抗PSMAミニボディまたは抗PSMA cysダイアボディの使用。 - 抗PSMAミニボディまたは抗PSMA cysダイアボディが治療剤にコンジュゲートされる、請求項24に記載の使用。
- 治療剤が、化学治療剤、治療抗体または抗体フラグメント、毒素、放射性同位体、酵素、ヌクレアーゼ、ホルモン、免疫調節物剤、アンチセンスオリゴヌクレオチド、キレート剤、ホウ素化合物、光活性剤および色素から成る群から選択される、請求項25に記載の使用。
- 抗PSMAミニボディまたは抗PSMA cysダイアボディが固形腫瘍の新生血管系をターゲッティングする、請求項24に記載の使用。
- 被験者におけるPSMA発現に関連する状態が、前立腺癌、肺癌、結腸直腸癌、乳癌、腎臓癌、肝臓癌、膀胱癌、膵臓癌またはメラノーマである、請求項24に記載の使用。
- ミニボディが、
配列番号10のアミノ酸配列;または
配列番号11のアミノ酸配列;または
配列番号10中にある可変重鎖ドメインおよび配列番号10中にある可変軽鎖ドメイン;または
配列番号11中にある可変重鎖ドメインおよび配列番号11中にある可変軽鎖ドメイン;または
配列番号3を含む可変重鎖ドメインおよび配列番号17を含む可変軽鎖ドメイン
のいずれかを含む、あるいは
前記cysダイアボディが
配列番号12のアミノ酸配列;または
配列番号13のアミノ酸配列;または
配列番号14のアミノ酸配列;または
配列番号15のアミノ酸配列;または
配列番号12中にある可変重鎖ドメインおよび配列番号12中にある可変軽鎖ドメイン;または
配列番号13中にある可変重鎖ドメインおよび配列番号13中にある可変軽鎖ドメイン;または
配列番号14中にある可変重鎖ドメインおよび配列番号14中にある可変軽鎖ドメイン;または
配列番号15中にある可変重鎖ドメインおよび配列番号15中にある可変軽鎖ドメイン;または
配列番号3を含む可変重鎖ドメインおよび配列番号17を含む可変軽鎖ドメイン
を含む、
PSMA発現に関連する状態を診断するための医薬の製造における使用のための、診断剤にコンジュゲートされ、PSMAに結合することができる抗PSMAミニボディまたは抗PSMA cysダイアボディ。 - 固形腫瘍の新生血管系をターゲッティングする、請求項29に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
- 被験者におけるPSMA発現に関連する状態が、前立腺癌、肺癌、結腸直腸癌、乳癌、腎臓癌、肝臓癌、膀胱癌、膵臓癌またはメラノーマである、請求項29に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
- ミニボディが、
配列番号10のアミノ酸配列;または
配列番号11のアミノ酸配列;または
配列番号10中にある可変重鎖ドメインおよび配列番号10中にある可変軽鎖ドメイン;または
配列番号11中にある可変重鎖ドメインおよび配列番号11中にある可変軽鎖ドメイン;または
配列番号3を含む可変重鎖ドメインおよび配列番号17を含む可変軽鎖ドメイン
のいずれかを含む、あるいは
前記cysダイアボディが
配列番号12のアミノ酸配列;または
配列番号13のアミノ酸配列;または
配列番号14のアミノ酸配列;または
配列番号15のアミノ酸配列;または
配列番号12中にある可変重鎖ドメインおよび配列番号12中にある可変軽鎖ドメイン;または
配列番号13中にある可変重鎖ドメインおよび配列番号13中にある可変軽鎖ドメイン;または
配列番号14中にある可変重鎖ドメインおよび配列番号14中にある可変軽鎖ドメイン;または
配列番号15中にある可変重鎖ドメインおよび配列番号15中にある可変軽鎖ドメイン;または
配列番号3を含む可変重鎖ドメインおよび配列番号17を含む可変軽鎖ドメイン
を含む、
PSMA発現に関連する状態を治療するための医薬の製造における使用のための、抗PSMAミニボディまたは抗PSMA cysダイアボディ。 - 治療剤にコンジュゲートされる、請求項32に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
- 治療剤が、化学治療剤、治療抗体または抗体フラグメント、毒素、放射性同位体、酵素、ヌクレアーゼ、ホルモン、免疫調節物剤、アンチセンスオリゴヌクレオチド、キレート剤、ホウ素化合物、光活性剤および色素から成る群から選択される、請求項32に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
- 固形腫瘍の新生血管系をターゲッティングする、請求項32に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
- 被験者におけるPSMA発現に関連する状態が、前立腺癌、肺癌、結腸直腸癌、乳癌、腎臓癌、肝臓癌、膀胱癌、膵臓癌またはメラノーマである、請求項32に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
- PSMAに結合することができるscFv配列であって、scFvが、リンカー配列により可変軽鎖ドメイン(VL)に連結された可変重鎖ドメイン(VH)を含むscFv配列〔ここで、VLは配列番号17を含み、VHは配列番号3を含む〕と、
システインテールと
を含むcysダイアボディ。 - 細胞で発現される時にcysダイアボディの分泌を可能にするN末端シグナル配列をさらに含む、請求項37に記載のcysダイアボディ。
- scFvが、VHがVLの上流になるようなVHVL配向にある、請求項37に記載のcysダイアボディ。
- 配列番号6、7、8または9を含むヌクレオチド配列によって、コードされる、請求項39に記載のcysダイアボディ。
- scFvが、VLがVHの上流になるようなVLVH配向にある、請求項37に記載のcysダイアボディ。
- 配列番号12、13、14または15のアミノ酸配列を含む、請求項37に記載のcysダイアボディ。
- PSMAに結合することができるscFv配列であって、リンカー配列により可変軽鎖ドメイン(VL)に連結された可変重鎖ドメイン(VH)を含むscFv配列と、システインテールとを含むcysダイアボディ(CysDB)であって、
可変軽鎖ドメインが配列番号12中にある可変軽鎖ドメインアミノ酸配列を含み、可変重鎖ドメインが配列番号12中にある可変重鎖ドメインアミノ酸配列を含む、cysダイアボディ。 - PSMAに結合することができるscFv配列であって、リンカー配列により可変軽鎖ドメイン(VL)に連結された可変重鎖ドメイン(VH)を含むscFv配列と、システインテールとを含むcysダイアボディ(CysDB)であって、
可変軽鎖ドメインが配列番号13中にある可変軽鎖ドメインアミノ酸配列を含み、可変重鎖ドメインが配列番号13中にある可変重鎖ドメインアミノ酸配列を含む、cysダイアボディ。 - PSMAに結合することができるscFv配列であって、リンカー配列により可変軽鎖ドメイン(VL)に連結された可変重鎖ドメイン(VH)を含むscFv配列と、システインテールとを含むcysダイアボディ(CysDB)であって、
可変軽鎖ドメインが配列番号14中にある可変軽鎖ドメインアミノ酸配列を含み、可変重鎖ドメインが配列番号14中にある可変重鎖ドメインアミノ酸配列を含む、cysダイアボディ。 - PSMAに結合することができるscFv配列であって、リンカー配列により可変軽鎖ドメイン(VL)に連結された可変重鎖ドメイン(VH)を含むscFv配列と、システインテールとを含むcysダイアボディ(CysDB)であって、
可変軽鎖ドメインが配列番号15中にある可変軽鎖ドメインアミノ酸配列を含み、可変重鎖ドメインが配列番号15中にある可変重鎖ドメインアミノ酸配列を含む、cysダイアボディ。 - 配列番号12のアミノ酸配列を含む、請求項37に記載のcysダイアボディ。
- 配列番号13のアミノ酸配列を含む、請求項37に記載のcysダイアボディ。
- 配列番号14のアミノ酸配列を含む、請求項37に記載のcysダイアボディ。
- 配列番号15のアミノ酸配列を含む、請求項37に記載のcysダイアボディ。
- 少なくとも1つの治療剤にコンジュゲートされる、請求項37に記載のcysダイアボディ。
- 少なくとも1つの治療剤が、化学治療剤、治療抗体、抗体フラグメント、毒素、放射性同位体、酵素、ヌクレアーゼ、ホルモン、免疫調節物剤、アンチセンスオリゴヌクレオチド、キレート剤、ホウ素化合物、光活性剤および光活性色素から成る群から選択される、請求項51に記載のcysダイアボディ。
- 少なくとも1つの診断剤にコンジュゲートされる、請求項37に記載のcysダイアボディ。
- 診断剤が、放射性物質、色素、造影剤、蛍光化合物、蛍光分子、生物発光化合物、生物発光分子、酵素、増強剤、量子ドット、および金属ナノ粒子から成る群から選択される、請求項53に記載のcysダイアボディ。
- PSMA発現に関連する状態がPSMA発現に関連する癌である、請求項21に記載の使用。
- PSMA発現に関連する状態がPSMA発現に関連する癌である、請求項1に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
- PSMA発現に関連する状態がPSMA発現に関連する癌である、請求項4に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
- 対象におけるPSMA発現に関連する状態がPSMA発現に関連する癌である、請求項24に記載の使用。
- PSMA発現に関連する状態がPSMA発現に関連する癌である、請求項29に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
- PSMA発現に関連する状態がPSMA発現に関連する癌である、請求項32に記載の抗PSMAミニボディまたは抗PSMA cysダイアボディ。
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