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

J Lipid Res. 2015 Nov;56(11):2124-32. doi: 10.1194/jlr.M061903. Epub 2015 Sep 20.


Lilly PCSK9 antibody LY3015014 (LY) is a monoclonal antibody (mAb) that neutralizes proprotein convertase subtilisin-kexin type 9 (PCSK9). LY decreases LDL cholesterol in monkeys and, unlike other PCSK9 mAbs, does not cause an accumulation of intact PCSK9 in serum. Comparing the epitope of LY with other clinically tested PCSK9 mAbs, it was noted that the LY epitope excludes the furin cleavage site in PCSK9, whereas other mAbs span this site. In vitro exposure of PCSK9 to furin resulted in degradation of PCSK9 bound to LY, whereas cleavage was blocked by other mAbs. These other mAbs caused a significant accumulation of serum PCSK9 and displayed a shorter duration of LDL-cholesterol lowering than LY when administered to mice expressing the WT human PCSK9. In mice expressing a noncleavable variant of human PCSK9, LY behaved like a cleavage-blocking mAb, in that it caused significant PCSK9 accumulation, its duration of LDL lowering was reduced, and its clearance (CL) from serum was accelerated. Thus, LY neutralizes PCSK9 and allows its proteolytic degradation to proceed, which limits PCSK9 accumulation, reduces the CL rate of LY, and extends its duration of action. PCSK9 mAbs with this property are likely to achieve longer durability and require lower doses than mAbs that cause antigen to accumulate.

Keywords: drug therapy; dyslipidemias; low density lipoprotein/metabolism; mass spectrometry; pharmacokinetics; pharmacology; proprotein convertase subtilisin-kexin type 9.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / pharmacokinetics
  • Antibodies, Monoclonal / pharmacology*
  • Anticholesteremic Agents / chemistry
  • Anticholesteremic Agents / pharmacokinetics
  • Anticholesteremic Agents / pharmacology*
  • Cholesterol, LDL / blood
  • Drug Evaluation, Preclinical
  • Drug Stability
  • Furin / chemistry
  • Half-Life
  • Humans
  • Hypercholesterolemia / drug therapy
  • Macaca fascicularis
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Proprotein Convertase 9
  • Proprotein Convertases / antagonists & inhibitors*
  • Proprotein Convertases / immunology
  • Protein Binding
  • Proteolysis
  • Serine Endopeptidases / immunology
  • Treatment Outcome


  • Antibodies, Monoclonal
  • Anticholesteremic Agents
  • Cholesterol, LDL
  • frovocimab
  • Pcsk9 protein, mouse
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases
  • Furin