Cholesterol reduction by immunization with a PCSK9 mimic.

Autor:	Zhang B; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Chuang GY; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Biju A; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Biner D; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Cheng J; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Wang Y; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Bao S; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Chao CW; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Lei H; Research Technologies Branch, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Liu T; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Nazzari AF; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Yang Y; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Zhou T; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Chen SJ; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Chen X; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Kong WP; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Ou L; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Parchment DK; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Sarfo EK; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., SiMa H; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Todd JP; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Wang S; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Woodward RA; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Cheng C; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Rawi R; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Mascola JR; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA., Kwong PD; Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD 20892, USA; Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: pdkwong@nih.gov.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Jun 25; Vol. 43 (6), pp. 114285. Date of Electronic Publication: 2024 May 30.
DOI:	10.1016/j.celrep.2024.114285
Abstrakt:	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.)
Databáze:	MEDLINE
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