JP2017520572A - 抗hsv抗体の外用適用 - Google Patents
抗hsv抗体の外用適用 Download PDFInfo
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- JP2017520572A JP2017520572A JP2016575171A JP2016575171A JP2017520572A JP 2017520572 A JP2017520572 A JP 2017520572A JP 2016575171 A JP2016575171 A JP 2016575171A JP 2016575171 A JP2016575171 A JP 2016575171A JP 2017520572 A JP2017520572 A JP 2017520572A
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- hsv
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- infection
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Abstract
Description
1.対象、材料、方法
1.1 HSV中和性ヒト化モノクローナル抗体の作製および産生
最近、マウスモノクローナル抗体mAb 2cによるHSV-1/2の高度に保存された糖タンパク質Bエピトープの架橋は、遊離ビリオンの高効率な中和をもたらすだけでなく、感染細胞から非感染細胞への直接的なウイルス伝播の阻害ももたらすことが証明された(Krawczyk A, et al., Journal of virology 2011;85(4):1793-1803)。これらのユニークな性質をヒトでの治療的使用に活用するために、本発明者らはmAb 2cのヒト化誘導体を作製した。
2010年〜2013年の間に、口腔ヘルペス感染(単純疱疹)の急性再発を患った12人の健常な30〜59歳のボランティア(女性7人、男性5人)を処置した。ボランティアは、最初のHSV症状(口唇のかゆみ、口唇部近くまたは口腔部近くの灼熱感または刺痛)の開始が起きた時または最初のHSV症状の開始が外唇上の明白な皮膚疾患に進行してから来診した。観察された皮膚疾患には、透明な帯黄色体液で満たされた小〜大水疱または漏出性の赤い水疱を含む外側ヘルペス性病変が含まれた。
ZOVIRAXクリームは2つの二重盲検ランダム化プラセボ(媒体)対照治験で評価されている(Zovirax N-. Zovirax処方情報http://wwwaccessdatafdagov/drugsatfda_docs/label/2002/21478_zovirax_lblpdf#paqe=1&zoom=auto,0,792を参照されたい)。
200μgのmAb hu2c(5mg/ml)で単回外用処置した後に免疫不全マウスにおける急性性器HSV-2感染症の臨床経過を変化させるヒト化モノクローナル抗体hu2cの能力を調べた。明白な病変および腟洗浄液の培養により評価される場合において、100%のマウスを感染させるために、5×105PFUのHSV-2Gのウイルス接種材料を麻酔下のマウスの腟に送達した。
Claims (18)
- 口唇単純ヘルペス、外陰部単純ヘルペス、慢性または播種性皮膚単純ヘルペス感染症、剣状ヘルペス、およびヘルペス性湿疹からなる群より選択される、HSV-1またはHSV-2が引き起こす対象における粘膜組織または表皮組織の急性感染症の治療における使用のための、外用投与される抗HSV抗体またはその抗原結合断片。
- 抗HSV抗体がモノクローナル抗体またはポリクローナル抗体である、請求項1記載の使用のための抗HSV抗体またはその抗原結合断片。
- 抗HSV抗体がヒト化抗体または完全ヒト抗体である、請求項1または2記載の使用のための抗HSV抗体またはその抗原結合断片。
- 抗HSV抗体がHSV-1および/またはHSV-2の糖タンパク質B(gB)を認識する、請求項1〜3のいずれか一項記載の使用のための抗HSV抗体またはその抗原結合断片。
- 抗体が、感染細胞から隣接する第2の非感染細胞へのHSVの伝播(細胞間伝播)を阻害する能力を有する、請求項4記載の使用のための抗HSV抗体またはその抗原結合断片。
- 抗体が、抗体依存性細胞性細胞傷害(ADCC)および/または補体依存性細胞傷害(CDC)に依存せずに細胞間伝播を阻害する能力を有する、請求項4または5記載の使用のための抗HSV抗体またはその抗原結合断片。
- SEQ ID NO:1を含むVHCDR1、SEQ ID NO:2を含むVHCDR2、SEQ ID NO:3を含むVHCDR3、SEQ ID NO:4を含むVLCDR1、SEQ ID NO:5を含むVLCDR2、およびSEQ ID NO:6を含むVLCDR3の相補性決定領域を含む、請求項4〜6のいずれか一項記載の使用のための抗HSV抗体またはその抗原結合断片。
- 抗体が、SEQ ID NO:7の位置1〜30、38〜51、68〜99、および112〜122、ならびにSEQ ID NO:8の位置1〜23、41〜55、63〜94、および104〜114に示されるアミノ酸残基に対して少なくとも70%の配列同一性を有するアミノ酸配列を含む、請求項7記載の使用のための抗HSV抗体またはその抗原結合断片。
- 抗体がSEQ ID NO:9のVHおよびSEQ ID NO:10のVLを含む、請求項7または8のいずれか一項記載の使用のための抗HSV抗体またはその抗原結合断片。
- 抗体がmAb 2cと同じエピトープを認識し、該エピトープがHSV-1およびHSV-2の糖タンパク質Bのアミノ酸172〜195および295〜313に位置する、請求項7〜9のいずれか一項記載の使用のための抗HSV抗体またはその抗原結合断片。
- 抗体がmAb 2c抗体である、請求項6〜10のいずれか一項記載の使用のための抗HSV抗体またはその抗原結合断片。
- 抗体が、口唇、外陰部、鼻、耳、眼、手指、足指、および/または身体全体の皮膚部、好ましくは頭、顎部、首、胸、顔、胃、および/または脚上の皮膚部の感染粘膜組織または感染表皮組織に外用適用される、請求項1〜10のいずれか一項記載の使用のための抗HSV抗体またはその抗原結合断片。
- 抗体が感染粘膜組織または感染表皮組織の周辺部に外用適用される、請求項1〜12のいずれか一項記載の使用のための抗HSV抗体またはその抗原結合断片。
- 抗体がウイルス抑制剤と組み合わせて投与される、請求項1〜13のいずれか一項記載の使用のための抗HSV抗体またはその抗原結合断片。
- ウイルス抑制剤が、ヌクレオシド類似体、ピロホスフェート類似体、ヌクレオチド類似体、アマンタジン誘導体、およびヘリカーゼ-プライマーゼ阻害剤の薬物クラスからなる群より選択される、請求項14記載の使用のための抗HSV抗体またはその抗原結合断片。
- ヌクレオシド類似体が、アシクロビル、ペンシクロビル、バラシクロビル、およびファムシクロビルからなる群より選択され;
ピロホスフェート類似体がフォスカーネットであり;
ヌクレオチド類似体がシドフォビルであり;
アマンタジン誘導体がトロマンタジンであり;かつ
ヘリカーゼ-プライマーゼ阻害剤がプリテリビル(Pritelevir)である、
請求項15記載の使用のための抗HSV抗体またはその抗原結合断片。 - 完全長抗体/完全抗体である、請求項1〜16のいずれか一項記載の使用のための抗HSV抗体。
- 有効量の請求項1〜17のいずれか一項記載の使用のための抗体またはその抗原結合断片と少なくとも1種類の薬学的に許容される賦形剤とを含む薬学的組成物。
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KR20170020423A (ko) | 2017-02-22 |
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WO2015197763A1 (en) | 2015-12-30 |
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