YANCOPOULOS, GEORGE D.,洋寇普罗斯 乔治,洋寇普羅斯 喬治,PAPADOPOULOS, NICHOLAS J.,帕帕度普罗斯 尼可拉斯,帕帕度普羅斯 尼可拉斯,MURPHY, ANDREW J.,墨菲 安德鲁,墨菲 安德魯,STAHL, NEIL,史塔贺 尼尔,史塔賀 尼爾
申请号：
TW102128784
公开号：
TW201420605A
申请日:
2013.08.12
申请国别(地区):
TW
年份:
2014
代理人:
摘要：
The present invention provides antibodies and antigen-binding fragments thereof that specifically bind proprotein convertase subtilisin/kexin-9 (PCSK9) with greater affinity at neutral pH than at acidic pH. The antibodies of the invention may possess one or more amino acid changes as compared to antibodies that do not exhibit pH-dependent binding properties. For example, the present invention includes anti-PCSK9 antibodies which possess one or more histidine substitutions in one or more complementarity determining regions. The antibodies of the invention, with pH-dependent binding properties, remain in circulation and exhibit cholesterol lowering activity for prolonged periods of time in animal subjects as compared to anti-PCSK9 antibodies that do not exhibit pH-dependent binding properties. The antibodies of the invention are therefore useful for treating diseases and disorders related to elevated HDL cholesterol, wherein the antibodies of the invention can be administered to a patient at a lower dose and/or with less frequent dosing as compared to antibodies that do not exhibit pH-dependent binding properties.本發明係提供在中性pH比在酸性pH具較大親和力之專一地與前蛋白轉化酶枯草桿菌蛋白酶/kexin 9(PCSK9)結合的抗體及其抗原結合片段。本發明之抗體相較於不具有pH-依賴性結合特性之抗體,係具有一或多個胺基酸改變。例如,本發明包括抗-PCSK9抗體,其在一或多個互補決定區具有一或多個組胺酸取代,本發明之具有pH-依賴性結合性質之抗體,相較於不具有pH-依賴性結合性質之抗-PCSK9抗體,其續留在動物對象的循環中並展現長期降膽固醇之活性。本發明之抗體因此可用於治療與升高的HDL膽固醇有關之疾病和病症,其中本發明之抗體,相較於不具有pH-依賴性結合性質之抗體,可以較低劑量及/或較低頻率投予病患。
