JP6990667B2 - 眼性新血管形成を低減するための組成物および方法 - Google Patents
眼性新血管形成を低減するための組成物および方法 Download PDFInfo
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Description
本願は、2016年6月16日に出願された米国仮出願第62/351,231号の利益を主張し、その開示全体が参照によって本明細書に組み込まれる。
本明細書に言及されているあらゆる刊行物、特許および特許出願は、あたかも個々の刊行物、特許または特許出願のそれぞれが、参照により組み込まれていると特にかつ個々に示されているのと同じ程度まで、参照により本明細書に組み込まれている。
特定の実施形態では、例えば以下の項目が提供される。
(項目1)
眼疾患または状態を処置する方法であって、眼への注射によって単位用量の薬学的懸濁物を霊長類被験体に投与するステップを含み、前記単位用量の薬学的懸濁物が、
AAV2におけるカプシドタンパク質VP1のアミノ酸570~611に対応する位置に、LGETTRP、NETITRP、KAGQANN、KDPKTTN、KDTDTTR、RAGGSVG、AVDTTKFおよびSTGKVPNから選択されるアミノ酸配列の挿入を含むバリアントカプシドタンパク質;ならびに抗血管内皮増殖因子(抗VEGF)ポリペプチドをコードする異種配列を有する、1E12~1E13の間のベクターゲノムのrAAV
を含む、方法。
(項目2)
前記単位用量が、2E12~6E12の間のベクターゲノムを含む、項目1に記載の方法。
(項目3)
前記被験体が、非ヒト霊長類である、項目1に記載の方法。
(項目4)
前記被験体が、ヒトである、項目1に記載の方法。
(項目5)
前記眼状態または疾患が、新生血管(滲出型)加齢性黄斑変性(AMD)、網膜静脈閉塞後の黄斑浮腫、糖尿病性黄斑浮腫(DME)、網膜静脈閉塞またはDMEに伴う糖尿病性網膜症である、項目1に記載の方法。
(項目6)
前記眼状態または疾患が、脈絡膜新血管形成またはAMDである、項目1に記載の方法。
(項目7)
前記懸濁物を投与するステップが、カラー眼底写真撮影によって測定された場合に、ビヒクル対照と比較して、グレードIV病変のパーセンテージの少なくとも5%の低下をもたらす、項目1に記載の方法。
(項目8)
グレードIV病変のパーセンテージの前記低下が、少なくとも10%である、項目7に記載の方法。
(項目9)
前記単位用量が、100μL以下の容量を含む、項目1に記載の方法。
(項目10)
前記単位用量が、50μL以下の容量を含む、項目1に記載の方法。
(項目11)
前記挿入が、AAV2におけるアミノ酸587および588の間の位置におけるLGETTRPである、項目1に記載の方法。
(項目12)
前記被験体が、ラニビズマブ、ベバシズマブおよびsVEGFR-1のうち少なくとも1種に対して応答性である、項目1に記載の方法。
(項目13)
前記被験体が、ラニビズマブまたはベバシズマブで前処置されている、項目1に記載の方法。
(項目14)
前記注射が、硝子体内である、項目1に記載の方法。
(項目15)
前記注射が、網膜下である、項目1に記載の方法。
(項目16)
注射による前記投与が、少なくとも2年間で1回以下行われる、項目1に記載の方法。
(項目17)
注射による前記投与が、少なくとも5年間で1回以下行われる、項目1に記載の方法。
(項目18)
前記投与が、一度限りの投与である、項目1に記載の方法。
(項目19)
前記投与ステップに先立ち、前記懸濁物を撹拌して均一な分布を確実にするステップをさらに含む、項目1に記載の方法。
(項目20)
前記投与ステップに先立ち、前記懸濁物を室温に温めるステップをさらに含む、項目1に記載の方法。
(項目21)
前記懸濁物が、界面活性物質をさらに含む、項目1に記載の方法。
(項目22)
前記界面活性物質が、ポリソルベート、ドデシル硫酸ナトリウム、ラウリル硫酸ナトリウム、ラウリルジメチルアミンオキシド、ポリエトキシ化アルコール、ポリオキシエチレンソルビタン、オクトキシノール、Brij、プルロニックおよびポリオキシルヒマシ油から選択される、項目21に記載の方法。
(項目23)
前記懸濁物が、フェノール、マンニトール、ソルビトールまたは塩化ナトリウムをさらに含む、項目1に記載の方法。
(項目24)
前記注射後に抗生物質溶液または硫酸アトロピン軟膏を投与するステップをさらに含む、項目1に記載の方法。
(項目25)
前記抗生物質溶液が、シプロフロキサシンを含む、項目24に記載の方法。
(項目26)
前記抗VEGFポリペプチドが、ヒト化モノクローナル抗体である、項目1に記載の方法。
(項目27)
前記抗VEGFポリペプチドが、抗体断片またはFabである、項目1に記載の方法。
(項目28)
前記ヒト化モノクローナル抗体が、ラニビズマブまたはベバシズマブである、項目1に記載の方法。
(項目29)
前記抗VEGFポリペプチドが、可溶性トランケート型のVEGF受容体1(sVEGFR-1)である、項目1に記載の方法。
(項目30)
眼状態または疾患を処置する方法であって、
(a)AAV2におけるカプシドタンパク質VP1のアミノ酸570~611に対応する位置に、LGETTRP、NETITRP、KAGQANN、KDPKTTN、KDTDTTR、RAGGSVG、AVDTTKFおよびSTGKVPNから選択されるアミノ酸配列の挿入を含むバリアントカプシドタンパク質;ならびに抗血管内皮増殖因子(抗VEGF)ポリペプチドをコードする異種配列を有するrAAVを含む懸濁組成物を撹拌するステップと、
(b)注射によりヒト被験体の眼に前記懸濁組成物を投与するステップと
を含む、方法。
(項目31)
前記挿入が、AAV2のアミノ酸587および588の間のLGETTRPである、項目30に記載の方法。
(項目32)
前記被験体が、ラニビズマブまたはベバシズマブで前処置されていることによって特徴付けられる、項目30に記載の方法。
(項目33)
前記被験体が、ラニビズマブおよびベバシズマブのうち少なくとも1種に対して応答性である、項目30に記載の方法。
(項目34)
前記抗VEGFポリペプチドが、ヒト化モノクローナル抗体である、項目30に記載の方法。
(項目35)
前記抗VEGFポリペプチドが、抗体断片またはFabである、項目30に記載の方法。
(項目36)
前記ヒト化モノクローナル抗体が、ラニビズマブまたはベバシズマブである、項目34に記載の方法。
(項目37)
前記抗VEGFポリペプチドが、可溶性トランケート型のVEGF受容体1(sVEGFR-1)である、項目30に記載の方法。
(項目38)
前記被験体に投与される容量が、50μL以下である、項目30に記載の方法。
(項目39)
前記被験体に投与される容量が、100μL以下である、項目30に記載の方法。
(項目40)
容量が、1E12~1E13の間のベクターゲノムの単位用量を含む、項目30に記載の方法。
(項目41)
容量が、2E12~6E12の間のベクターゲノムの単位用量を含む、項目30に記載の方法。
(項目42)
前記投与ステップが、少なくとも2年間で1回以下行われる、項目30に記載の方法。
(項目43)
前記投与ステップが、一度限りの注射である、項目30に記載の方法。
(項目44)
前記組成物を投与する前に、少なくとも1種の承認された治療法に対する応答性に関して前記被験体をアッセイするステップをさらに含む、項目30に記載の方法。
(項目45)
前記承認された治療法が、ラニビズマブおよびベバシズマブを含む、項目44に記載の方法。
(項目46)
前記懸濁物が、薬学的に許容される賦形剤を含む、項目30に記載の方法。
(項目47)
前記賦形剤が、界面活性物質または安定剤を含む、項目46に記載の方法。
(項目48)
前記界面活性物質が、ポリソルベート、ドデシル硫酸ナトリウム、ラウリル硫酸ナトリウム、ラウリルジメチルアミンオキシド、ポリエトキシ化アルコール、ポリオキシエチレンソルビタン、オクトキシノール、Brij、プルロニックおよびポリオキシルヒマシ油から選択される、項目47に記載の方法。
(項目49)
前記薬学的に許容される賦形剤が、フェノール、マンニトール、ソルビトールまたは塩化ナトリウムを含む、項目46に記載の方法。
(項目50)
前記眼状態または疾患が、新生血管(滲出型)加齢性黄斑変性(AMD)、網膜静脈閉塞後の黄斑浮腫、糖尿病性黄斑浮腫(DME)、網膜静脈閉塞またはDMEに伴う糖尿病性網膜症である、項目30に記載の方法。
(項目51)
前記眼状態または疾患が、脈絡膜新血管形成またはAMDである、項目30に記載の方法。
(項目52)
前記注射が、硝子体内である、項目30に記載の方法。
(項目53)
前記注射が、網膜下である、項目30に記載の方法。
(項目54)
前記挿入が、AAV2におけるアミノ酸587および588の間の位置におけるLGETTRPである、項目30に記載の方法。
(項目55)
投与前に前記懸濁物を室温に温めるステップをさらに含む、項目30に記載の方法。
(項目56)
AAV2におけるカプシドタンパク質VP1のアミノ酸570~611に対応する位置に、LGETTRP、NETITRP、KAGQANN、KDPKTTN、KDTDTTR、RAGGSVG、AVDTTKFおよびSTGKVPNから選択されるアミノ酸配列の挿入を含むバリアントカプシドタンパク質;ならびに抗血管内皮増殖因子(抗VEGF)ポリペプチドをコードする異種配列を有するrAAVを含む、単位用量の懸濁物を含む薬学的組成物。
(項目57)
前記単位用量が、1E12~1E13の間のベクターゲノムである、項目56に記載の薬学的組成物。
(項目58)
前記単位用量が、2E12~6E12の間のベクターゲノムである、項目56に記載の薬学的組成物。
(項目59)
前記懸濁物が、冷蔵されている、項目56に記載の薬学的組成物。
(項目60)
項目56に記載の薬学的組成物および前記薬学的組成物を希釈するための溶液を含むキット。
(項目61)
前記溶液が、緩衝液、塩、アルコール、界面活性物質またはこれらのいずれかの組み合わせを含む、項目60に記載のキット。
(項目62)
シリンジをさらに含む、項目60に記載のキット。
(項目63)
前記抗VEGFポリペプチドが、ヒト化モノクローナル抗体である、項目56に記載の薬学的組成物。
(項目64)
前記抗VEGFポリペプチドが、抗体断片またはFabである、項目56に記載の薬学的組成物。
(項目65)
前記ヒト化モノクローナル抗体が、ラニビズマブまたはベバシズマブである、項目56に記載の薬学的組成物。
(項目66)
前記抗VEGFポリペプチドが、可溶性トランケート型のVEGF受容体1(sVEGFR-1)である、項目56に記載の薬学的組成物。
(項目67)
前記挿入が、AAV2におけるアミノ酸587および588の間の位置におけるLGETTRPである、項目56に記載の薬学的組成物。
アデノウイルス、アデノ随伴ウイルス、レトロウイルスおよびレンチウイルスを含む、様々なウイルスベクターを遺伝子療法において使用することができる。
一部の実施形態では、遺伝子療法は、非ヒト霊長類またはヒト被験体の眼または眼の硝子体への投与に適したまたは適応された抗VEGF活性を有する治療用導入遺伝子の送達に使用される。一部の実施形態では、本明細書に記載されているカプシドバリアント(例えば、AAV2.7m8)を含むrAAVは、抗VEGF剤をコードする異種核酸配列を含み、被験体への硝子体内または網膜下注射の際に、網膜細胞への抗VEGF遺伝子の配列の送達に使用される。一部の実施形態では、抗VEGF遺伝子を含むrAAVは、遺伝子療法および硝子体内注射のために製剤化される。一部の実施形態では、抗VEGF遺伝子は、その機能的断片またはバリアントを指す。一部の実施形態では、sFLT-1、ラニビズマブまたはベバシズマブ等の抗VEGF剤の核酸配列は、直ちに利用できるそのアミノ酸配列に由来する。一部の実施形態では、sFLT-1、ラニビズマブまたはベバシズマブ等の抗VEGF剤の核酸配列を、さらにコドン最適化して、被験体におけるその発現を改善する。一部の実施形態では、抗VEGF剤の核酸配列および/またはアミノ酸配列は、in vivoでのその活性、発現、安定性および/または溶解度を増強するように修飾される。
一部の実施形態では、薬学的組成物は、1種または複数の活性成分、例えば、抗VEGF剤またはその断片もしくはバリアントをコードする核酸配列を含むAAV2.7m8と共に、所望の治療または予防的効果を達成するための硝子体内または網膜下注射によるヒト患者への投与に適した1種または複数の賦形剤、担体、安定剤または増量剤を含有する製剤である。
一部の事例では、本明細書に記載されているバリアントカプシドタンパク質および治療用導入遺伝子を含むいずれかの血清型のrAAVビリオン、またはその薬学的組成物は、眼の新血管形成またはCNVに関連する眼状態または疾患を少なくとも部分的に好転させることができる。一部の実施形態では、カプシドバリアントタンパク質を含むrAAVビリオンは、ヒト被験体の眼への抗VEGF導入遺伝子の送達に使用される。
一部の実施形態では、本開示は、病理学的血管新生関連眼疾患を処置するための方法であって、斯かる処置を必要とするヒト被験体に薬学的に有効な量の本明細書に提供される薬学的組成物を投与するステップを含む方法を提供する。一部の実施形態では、疾患は、加齢性黄斑変性(AMD)、滲出型AMD、乾性AMD、網膜新血管形成、脈絡膜新血管形成糖尿病性網膜症、増殖性糖尿病性網膜症、網膜静脈閉塞、網膜中心静脈閉塞、網膜静脈分枝閉塞、糖尿病性黄斑浮腫、糖尿病性網膜虚血、虚血性網膜症および糖尿病性網膜浮腫ならびにこれらのいずれかの組み合わせを含む眼性新生血管疾患の群から選択される。
Claims (15)
- (a)カプシドタンパク質VP1の位置587および588の間に挿入されたアミノ酸配列LGETTRPと、配列番号9に対して少なくとも95%の相同性を有する第一のポリペプチドをコードする配列、および配列番号10に対して少なくとも95%の相同性を有する第二のポリペプチドをコードする配列を含む核酸とを含むrAAV2バリアント、ならびに
(b)薬学的に許容される賦形剤
を含む、眼の血管新生に関連する眼疾患または状態の処置の方法において使用するための薬学的組成物であって、前記方法は、単位用量の前記薬学的組成物を、処置を必要とする霊長類被験体の眼に硝子体内注射により投与することを含む、薬学的組成物。 - 前記単位用量が、1E8~3E14のベクターゲノム、または1E9~3E13のベクターゲノム、または1E10~3E13のベクターゲノム、または2E12~6E12のベクターゲノムである、請求項1に記載の使用のための組成物。
- 前記被験体がヒトである、請求項1または請求項2に記載の使用のための組成物。
- 前記眼状態または疾患が、新生血管(滲出型)加齢性黄斑変性(AMD)、網膜静脈閉塞後の黄斑浮腫、糖尿病性黄斑浮腫(DME)、網膜静脈閉塞またはDMEに伴う糖尿病性網膜症である、請求項1~3のいずれか一項に記載の使用のための組成物。
- 前記眼状態または疾患が、脈絡膜新血管形成または滲出型AMDである、請求項1~3のいずれか一項に記載の使用のための組成物。
- 前記組成物の投与が、カラー眼底写真撮影によって測定された場合に、ビヒクル対照と比較して、グレードIV病変のパーセンテージの少なくとも5%、または少なくとも10%の低下をもたらす、請求項1~5のいずれか一項に記載の使用のための組成物。
- 前記単位用量が、(a)100μL以下の容量を有する;または(b)50μL以下の容量を有する、請求項1~6のいずれか一項に記載の使用のための組成物。
- 前記被験体が、ラニビズマブ、ベバシズマブおよびsVEGFR-1のうち少なくとも1種に対して応答性である、請求項1~7のいずれか一項に記載の使用のための組成物。
- 前記被験体が、ラニビズマブまたはベバシズマブで前処置されている、請求項1~8のいずれか一項に記載の使用のための組成物。
- (a)注射による前記投与が、少なくとも2年間で1回以下、もしくは少なくとも5年間で1回以下行われる;または(b)前記投与が、一度限りの投与である、請求項1~9のいずれか一項に記載の使用のための組成物。
- 前記薬学的組成物が懸濁物である、請求項1~10のいずれか一項に記載の使用のための組成物。
- (a)前記投与ステップに先立ち、前記懸濁物を撹拌して均一な分布を確実にするステップ;および/または(b)前記投与ステップに先立ち、前記懸濁物を室温に温めるステップ、をさらに含む、請求項11に記載の使用のための組成物。
- 前記懸濁物が、(a)界面活性物質をさらに含み、必要に応じて、前記界面活性物質が、ポリソルベート、ドデシル硫酸ナトリウム、ラウリル硫酸ナトリウム、ラウリルジメチルアミンオキシド、ポリエトキシ化アルコール、ポリオキシエチレンソルビタン、オクトキシノール、Brij、プルロニックおよびポリオキシルヒマシ油から選択される;および/または(b)フェノール、マンニトール、ソルビトールまたは塩化ナトリウムをさらに含む、請求項11または請求項12に記載の使用のための組成物。
- 前記注射後に、抗生物質溶液、例えばシプロフロキサシンを含む抗生物質溶液、または硫酸アトロピン軟膏を投与するステップをさらに含む、請求項1~13のいずれか一項に記載の使用のための組成物。
- 前記rAAV2バリアントが、配列番号9の配列を含む第一のポリペプチドおよび配列番号10の配列を含む第二のポリペプチドをコードする核酸を含む、請求項1~14のいずれか一項に記載の使用のための組成物。
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Publication number | Priority date | Publication date | Assignee | Title |
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JP2014518614A (ja) | 2011-04-22 | 2014-08-07 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 変異体キャプシドを有するアデノ関連ウイルスビリオンおよびその使用方法 |
JP2015523060A (ja) | 2012-05-15 | 2015-08-13 | アバランチ オーストラリア プロプライエタリー リミテッド | Aavsflt−1を用いたamdの処置 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014518614A (ja) | 2011-04-22 | 2014-08-07 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 変異体キャプシドを有するアデノ関連ウイルスビリオンおよびその使用方法 |
JP2015523060A (ja) | 2012-05-15 | 2015-08-13 | アバランチ オーストラリア プロプライエタリー リミテッド | Aavsflt−1を用いたamdの処置 |
Non-Patent Citations (2)
Title |
---|
Journal of Ocular Pharmacology and Therapeutics,2015年,Vol.31,No.5,pp.269-276 |
Science Translational Medicine,2013年,Vol.5,No.189,pp.189ra76 |
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