학술논문
A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo1[S]
Document Type
article
Author
Yan G. Ni; Stefania Di Marco; Jon H. Condra; Laurence B. Peterson; Weirong Wang; Fubao Wang; Shilpa Pandit; Holly A. Hammond; Ray Rosa; Richard T. Cummings; Dana D. Wood; Xiaomei Liu; Matthew J. Bottomley; Xun Shen; Rose M. Cubbon; Sheng-ping Wang; Douglas G. Johns; Cinzia Volpari; Lora Hamuro; Jayne Chin; Lingyi Huang; Jing Zhang Zhao; Salvatore Vitelli; Peter Haytko; Douglas Wisniewski; Lyndon J. Mitnaul; Carl P. Sparrow; Brian Hubbard; Andrea Carfí; Ayesha Sitlani
Source
Journal of Lipid Research, Vol 52, Iss 1, Pp 78-86 (2011)
Subject
Language
English
ISSN
0022-2275
Abstract
Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) regulates LDL cholesterol levels by inhibiting LDL receptor (LDLr)-mediated cellular LDL uptake. We have identified a fragment antigen-binding (Fab) 1D05 which binds PCSK9 with nanomolar affinity. The fully human antibody 1D05-IgG2 completely blocks the inhibitory effects of wild-type PCSK9 and two gain-of-function human PCSK9 mutants, S127R and D374Y. The crystal structure of 1D05-Fab bound to PCSK9 reveals that 1D05-Fab binds to an epitope on the PCSK9 catalytic domain which includes the entire LDLr EGF(A) binding site. Notably, the 1D05-Fab CDR-H3 and CDR-H2 loops structurally mimic the EGF(A) domain of LDLr. In a transgenic mouse model (CETP/LDLr-hemi), in which plasma lipid and PCSK9 profiles are comparable to those of humans, 1D05-IgG2 reduces plasma LDL cholesterol to 40% and raises hepatic LDLr protein levels approximately fivefold. Similarly, in healthy rhesus monkeys, 1D05-IgG2 effectively reduced LDL cholesterol 20%–50% for over 2 weeks, despite its relatively short terminal half-life (t1/2 = 3.2 days). Importantly, the decrease in circulating LDL cholesterol corresponds closely to the reduction in free PCSK9 levels. Together these results clearly demonstrate that the LDL-lowering effect of the neutralizing anti-PCSK9 1D05-IgG2 antibody is mediated by reducing the amount of PCSK9 that can bind to the LDLr.