1. Cholesterol reduction by immunization with a PCSK9 mimic.
- Author
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Zhang B, Chuang GY, Biju A, Biner D, Cheng J, Wang Y, Bao S, Chao CW, Lei H, Liu T, Nazzari AF, Yang Y, Zhou T, Chen SJ, Chen X, Kong WP, Ou L, Parchment DK, Sarfo EK, SiMa H, Todd JP, Wang S, Woodward RA, Cheng C, Rawi R, Mascola JR, and Kwong PD
- Subjects
- Animals, Humans, Mice, Receptors, LDL metabolism, Female, Mice, Inbred C57BL, Proprotein Convertase 9 immunology, Proprotein Convertase 9 metabolism, Cholesterol metabolism, Cholesterol blood, Immunization methods, Macaca fascicularis
- Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a plasma protein that controls cholesterol homeostasis. Here, we design a human PCSK9 mimic, named HIT01, with no consecutive 9-residue stretch in common with any human protein as a potential heart attack vaccine. Murine immunizations with HIT01 reduce low-density lipoprotein (LDL) and cholesterol levels by 40% and 30%, respectively. Immunization of cynomolgus macaques with HIT01-K21Q-R218E, a cleavage-resistant variant, elicits high-titer PCSK9-directed antibody responses and significantly reduces serum levels of cholesterol 2 weeks after each immunization. However, HIT01-K21Q-R218E immunizations also increase serum PCSK9 levels by up to 5-fold, likely due to PCSK9-binding antibodies altering the half-life of PCSK9. While vaccination with a PCSK9 mimic can induce antibodies that block interactions of PCSK9 with the LDL receptor, PCSK9-binding antibodies appear to alter homeostatic levels of PCSK9, thereby confounding its vaccine impact. Our results nevertheless suggest a mechanism for increasing the half-life of soluble regulatory factors by vaccination., Competing Interests: Declaration of interests B.Z., G.-Y.C., W.-P.K., Y.W., C.W.C., J.R.M., L.O., T.Z., Y.Y., T.L., and P.D.K. are inventors on a United States provisional patent application submitted by the NIH describing PCSK9-mimicking vaccine immunogens., (Published by Elsevier Inc.)
- Published
- 2024
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