Abstract 538: A PCSK9 Antibody that Blocks Binding to LDLR while Allowing Normal PCSK9 Inactivation by Furin is Afforded a Reduced Clearance Rate and a Longer Duration of Effect in Mice

Introduction: Monoclonal antibodies (Mabs) that neutralize proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to lower LDL-C in human trials. It is known that PCSK9 is cleaved by furin at Arg218 and that the cleaved PCSK9 is inactive in modulating LDLR. Antibodies whose epitopes are near the EGFA binding domain are more efficacious in increasing LDLR but may interfere with furin cleavage and thus normal PCSK9 clearance. Here we describe a unique antibody (LY) that both lowers LDL-C and allows for normal PCSK9 cleavage by furin. Hypothesis: An antibody with an epitope that permits furin cleavage of PCSK9 will show more durable LDL lowering compared to one with an epitope that interferes with cleavage. Methods: Furin cleavage of recombinant PCSK9 was evaluated by electrophoresis in the presence of antibodies. Antibodies were studied in mice expressing wild-type or a non-cleavable variant of human PCSK9. Results: We determined that LY3015014 (LY) permits furin cleavage of PCSK9 while Mab A...