Abstract
PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed. The authors used the scrambled disulfide bond technique to generate conformationally-altered isomers of the catalytic domain of mouse PCSK9. The focus was on the immune response of four X-isomers and their effects on plasma cholesterol and triglyceride levels in both C57BL/6J and Apoe−/− mice. The authors showed that the four immunogens produced significant immunogenicity against native PCSK9 to day 120 after immunization of C57BL/6J and Apoe−/− mice. This resulted in significantly decreased plasma cholesterol levels in C57BL/6J mice, and to a lesser degree in Apoe−/− mice. The X-PCSK9-B1 treated mice had increased LDL receptor mRNA and protein levels at day 120 after treatment. Thus, this study provides a new, potentially promising approach that uses long-term immunotherapy for a treatment of hypercholesterolemia.
Highlights
PCSK9 (Proprotein convertase subtilisin/kexin type 9) is synthesized in the liver and secreted into plasma [1,2]
The authors determined the low-density lipoproteins (LDL) receptor levels by quantitative PCR at day-120 after the treatment of immunogens of X-PCSK9-A1, A2 and B1, B2 in C57BL/6J and Apoe−/− mice. Both C57BL/6J and Apoe−/− mice, had the levels of LDLR mRNA significantly increased after immunogen X-PCSK9-B1 treatment, compared to the phosphate-buffered saline (PBS)-treated group (Figure 6, p = 0.0363 and 0.0030, respectively). These results suggest that X-PCSK9-B1 antibody increases LDLR mRNA levels, resulting from the inhibition of the interaction of PCSK9 with LDLR
The authors used a disulfide scrambling method [17] to produce defined non-native conformational isomers of disulfide proteins (X-isomers), and showed that non-native isomers of vascular endothelial growth factor (VEGF) produced an immune response against native VEGF [18]. These results provide a basis for the development of a vaccine strategy for immunotherapy to treat diseases
Summary
PCSK9 (Proprotein convertase subtilisin/kexin type 9) is synthesized in the liver and secreted into plasma [1,2]. The laboratory of JY Chang has used this method to show an increased immune response of non-native isomers (X-isomers) to vascular endothelial growth factor (VEGF) in mice [18], demonstrating that X-VEGF isomers are potentially useful compounds for developing active immunotherapy for cancer treatment The authors used this scrambled disulfide bond technique to generate conformationally changed isomers of the catalytic domain (residues 152−452) of mouse PCSK9 in this study. The treatment effect of X-PCSK9 immunogens, A1, A2, and B1, B2, on Apoe−/− mice all produced significantly decreased plasma cholesterol levels (Table 3, treatment effect p < 0.0001) compared to the PBS group. The treatment effect of immunogens did not reach significant values for plasma triglyceride levels in Apoe−/− mice, but the time effects reached statistical significance for all three immunogens, including X-PCSK9-A1, A2 and B1 (Table 5, p = 0.0038, 0.0029, 0.0033, respectively). The data of the effect of the X-PCSK9 isomers on plasma cholesterol and triglyceride levels demonstrates that X-PCSK9 isomers, X-PCSK9-B1, significantly decrease plasma cholesterol and triglyceride levels
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