依洛尤单抗 (Repatha)

概览

Evolocumab is a PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor antibody used as an adjunct to LDL cholesterol reducing therapies, aiding in the prevention of cardiovascular events and cardiovascular revascularization procedures.

作用机制

Evolocumab is a human IgG monoclonal antibody which targets PCSK9 (proprotein convertase subtilisin/kexin type 9). PCSK9 is a serine protease produced by the liver which binds LDL receptors and creates a complex to be targeted for lysosomal degradation. LDL receptors typically bind LDL-cholesterol ("bad" cholesterol) for cellular reuptake, therefore the formation of these complexes with PCSK9 inhibits LDL receptor recycling to the cell surface, resulting in decreased cellular reuptake of LDL-C and increased levels of free LDL-C in the plasma. Individuals with familial hypercholesterolemia often may have "gain of function" mutations in the PCSK9 molecules in their body, resulting in increased LDL-C plasma levels and a consequent cardiovascular risk. Evolocumab is able to bind both the normal PCSK9 and the "gain of function" mutant, D374Y. The exact mechanism of the binding has not been published, however the precursor molecule, mAb1, is indicative of the interaction. The mAb1 molecule binds on the catalytic site of PCSK9 next to the binding site for the LDL receptor and creates hydrogen bonds and hydrophobic interactions, resulting in the steric inhibition of binding between PCSK9 and the LDL receptor. Because the formation of complexes between LDL receptor and PCSK9 are prevented, the internalized LDL receptors are less likely to be degrated by lysosomes and may recycle to the surface of the cell to serve their function of removing LDL from the blood.

适应症

Evolocumab is indicated in adult patients with established cardiovascular disease to reduce the risk of myocardial infarction, stroke, and coronary revascularization. It is also indicated as an adjunct to diet, alone or in combination with other hypolipidemic treatments, in adults with primary hyperlipidemia (and in pediatric patients ≥10 years old with heterozygous familial hypercholesterolemia) to reduce LDL-C. In addition, it is indicated adjunctly to other hypolipidemic treatments in patients ≥10 years old with homozygous familiar hypercholesterolemia to reduce LDL-C.

• Coronary Revascularization
• Myocardial Infarction
• Stroke
• Increases in serum total low-density lipoprotein (LDL)