Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an attractive therapeutic target for cardiovascular disease. Monoclonal antibodies (mAbs) that bind PCSK9 and prevent PCSK9:LDLR complex formation reduce serum LDL-C in vivo. PCSK9-mediated lysosomal degradation of bound mAb, however, dramatically reduces mAb exposure and limits duration of effect. Administration of high affinity mAb1:PCSK9 complex (1:2) to mice resulted in significantly lower mAb1 exposure compared to mAb1 dosed alone in normal mice or in PCSK9 knock-out mice lacking antigen. To identify mAb binding characteristics that minimize lysosomal disposition, the pharmacokinetic behavior of four mAbs representing a diverse range of PCSK9 binding affinities at neutral (serum) and acidic (endosomal) pH was evaluated in cynomolgus monkeys. Results revealed an inverse correlation between affinity and both mAb exposure and duration of LDL-C lowering. High affinity mAb1 exhibited the lowest exposure and shortest duration of action (6 days), while mAb2 displayed prolonged exposure and LDL-C reduction (51 days) as a consequence of lower affinity and pH-sensitive PCSK9 binding. mAbs with shorter endosomal PCSK9:mAb complex dissociation half-lives (<20 seconds) produced optimal exposure-response profiles. Interestingly, incorporation of previously reported Fc-region amino acid substitutions or novel "loop-insertion" peptides that enhance in vitro FcRn binding led to only modest PK improvements for mAbs with pH-dependent PCSK9 binding, with only limited augmentation of PD activity relative to native mAbs. A pivotal role for PCSK9 in mAb clearance was demonstrated, more broadly suggesting that therapeutic mAb binding characteristics require optimization based on target pharmacology.