Abstract 1317: A Proprotein Convertase Subtilisin-like/Kexin Type 9 (PCSK9)-binding Antibody, That Structurally Mimics the Egf-a Domain of the LDL-receptor, Lowers LDL-cholesterol in a Transgenic Mouse Model and in Rhesus Monkeys
Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) regulates LDL-C levels by binding to cell surface LDL-receptor protein (LDLR) and is an important therapeutic target for treating coronary heart disease (CHD). Using phage library panning and a PCSK9 binding ELISA, we have identified a human antibody antigen binding fragment (Fab) 1D05 as a potent binder (Kd=3 nM) of PCSK9, a full antagonist of the PCSK9-LDLR interaction, and an effective inhibitor of PCSK9-dependent effects on LDL-uptake in cell culture. The crystal structure of Fab-1D05 bound to PCSK9 shows that the loops of the heavy and light chains of 1D05 make extensive contacts with the LDLR-binding epitope on PCSK9. Interestingly, the CDR-H3 and CDR-H2 on 1D05 structurally mimic EGF-A (a LDLR domain required for PCSK9 binding), suggesting that 1D05 inhibits PCSK9 by sterically preventing it from binding to LDLR. In a transgenic mouse model (CETPtg(LDLR+/−), with a lipid profile and circulating levels of PCSK9 comparable to humans, the fully human antibody 1D05-IgG (≥1 mpk) lowers LDL-C by ~40% and raises hepatic LDLR protein levels ~5 fold. In healthy rhesus monkeys 1D05-IgG (3 mpk) effectively lowers LDL-C by ~50% and despite its short t1/2 (77 hr), ≥20% LDL-C lowering is observed for ~2 weeks post a single IV dose. Additionally, 1D05-IgG treatment in monkeys promotes a transient increase (2–3 fold) of circulating levels of PCSK9 in the first 2 days post dose; however maximal target engagement is maintained from 1 hr - 10 days post dosing. Similarly, 1D05 treatment of hepatocytes inhibits cell internalization of PCSK9 and promotes an increase in circulating levels of PCSK9. These studies indicate that anti-PCSK9 antibodies could be effective LDL-C lowering therapeutic agents in the clinic.