What question did this study set out to answer?

To determine how antibody epitope selection and proteolytic cleavage of PCSK9 influence circulating antigen accumulation, antibody clearance, and the duration of cholesterol-lowering efficacy.

September 21, 2015Journal of Lipid ResearchOpen Access

Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody

View Full Paper

Ask AI

Bookmark

Authors

KSKrista SchroederEli Lilly (United States)TBThomas P. BeyerEli Lilly (United States)RHRyan J. HansenUniversity of Washington

Discussion

Member takes

Implication

Preclinical study reveals that permitting antigen cleavage extends antibody durability in animal models, suggesting a design strategy for longer-acting PCSK9 therapeutics.

Key Points

To determine how antibody epitope selection and proteolytic cleavage of PCSK9 influence circulating antigen accumulation, antibody clearance, and the duration of cholesterol-lowering efficacy.
Mapped the binding epitope of LY3015014 relative to the furin cleavage site and assessed furin-mediated in vitro degradation of antibody-bound PCSK9.
Administered LY3015014 and comparator cleavage-blocking antibodies to wild-type human PCSK9-expressing mice and nonhuman primates to quantify serum antigen accumulation, clearance, and LDL-lowering duration.
Evaluated the pharmacokinetics and pharmacodynamics of LY3015014 in transgenic mice expressing a furin-resistant, noncleavable variant of human PCSK9.
Unlike comparator antibodies that span and protect the furin cleavage site, LY3015014 leaves the site accessible, permitting furin-mediated degradation of bound PCSK9 and preventing intact antigen accumulation in serum.
In wild-type human PCSK9 mice, LY3015014 exhibited a longer duration of LDL-cholesterol lowering than cleavage-blocking antibodies.
In mice expressing noncleavable PCSK9, LY3015014 demonstrated accelerated serum clearance, substantial antigen accumulation, and shortened duration of LDL reduction.

Cite This Study

Schroeder et al. (2015) studied this question.

synapsesocial.com/papers/6a71ee9df44fa9f079df9608 https://doi.org/10.1194/jlr.m061903

View Full Paper

Ask AI

Bookmark

Implication

Preclinical study reveals that permitting antigen cleavage extends antibody durability in animal models, suggesting a design strategy for longer-acting PCSK9 therapeutics.

Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody

Discussion

Member takes

Implication

Key Points

Cite This Study

Proteolytic cleavage of antigen extends the durability of an anti-PCSK9 monoclonal antibody

Discussion

Member takes

Implication

Key Points

Cite This Study

Also Consider

Also Consider