Increasing Serum Half-life and Extending Cholesterol Lowering in Vivo by Engineering Antibody with pH-sensitive Binding to PCSK9

被引：135

作者：

Chaparro-Riggers, Javier ^{[1
]}

Liang, Hong ^{[1
]}

DeVay, Rachel M. ^{[1
]}

Bai, Lanfang ^{[1
]}

Sutton, Janette E. ^{[1
]}

Chen, Wei ^{[1
]}

Geng, Tao ^{[1
]}

Lindquist, Kevin ^{[1
]}

Casas, Meritxell Galindo ^{[1
]}

Boustany, Leila M. ^{[1
]}

Brown, Colleen L. ^{[1
]}

Chabot, Jeffrey ^{[1
]}

Gomes, Bruce ^{[2
]}

Garzone, Pamela ^{[1
]}

Rossi, Andrea ^{[1
]}

Strop, Pavel ^{[1
]}

Shelton, Dave ^{[1
]}

Pons, Jaume ^{[1
]}

Rajpal, Arvind ^{[1
]}

机构：

[1] Rinat Pfizer Inc, San Francisco, CA 94080 USA

[2] Novartis Inst BioMed Res Inc, Cambridge, MA 02139 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2012年 / 287卷 / 14期

关键词：

THERAPEUTIC MONOCLONAL-ANTIBODIES; DENSITY-LIPOPROTEIN CHOLESTEROL; POPULATION PHARMACOKINETICS; NONHUMAN-PRIMATES; LDL-CHOLESTEROL; RECEPTOR; HYPERCHOLESTEROLEMIA; PHARMACODYNAMICS; MECHANISMS; DEPENDENCE;

D O I：

10.1074/jbc.M111.319764

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Background: An antagonistic anti-PCSK9 antibody exhibits target- mediated clearance, resulting in a dose-dependent PK. Results: Engineering of an antibody with pH-sensitive binding to PCSK9 decreases target-mediated clearance, resulting in increased PK and efficacy in vivo. Conclusion: pH-sensitive anti-PCSK9 antibodies are excellent candidates for therapeutic development. Significance: pH-sensitive antibodies may enable less frequent or lower dosing of antibodies hampered by target-mediated clearance and high antigen load.

引用

页码：11090 / 11097

页数：8

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