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Entresto™ and Neprilysin: Not So Clear Cut of B-type Natriuretic Peptides?

Published: 31.05.2016

A recently introduced heart failure drug Entresto™ (LCZ696) has been suggested to increase the apparent amount of circulating BNP as the drug acts as an inhibitor of neprilysin, a known protease degrading natriuretic peptides. As a consequence, use of Entresto could render the results of BNP measurements diagnostically ambiguous. In this article published in April in Clinical Chemistry, our researchers have studied this question by investigating how different forms of BNP and proBNP are degraded by neprilysin in vitro. This is important because the main form of BNP measured in the blood of heart failure patients is in fact the uncleaved precursor proBNP. On the other hand, commercially available assays utilize different antibody combinations and usage of Entresto may have totally different effects on the assays depending on what epitopes the antibodies used in the assays recognize.

In this study, BNP 1-32 and nonglycosylated and glycosylated forms of proBNP 1-108 were studied for their susceptibility to cleavage by neprilysin. After incubating the proteins with neprilysin for various time periods, the BNP immunoreactivity was analyzed using two different immunoassays utilizing monoclonal antibodies specific to different epitopes of BNP. In addition, the neprilysin cleavage sites were determined using mass-spectrometry.

The in vitro cleavage studies showed that in contrast to BNP, proBNP was not degraded by neprilysin. Glycosylation had no effect on the resistance of proBNP to degradation. Interestingly, the SES-BNP™ assay (specific to region 11-17) was less susceptible to the BNP cleavage by neprilysin than the immunoassays utilizing antibodies specific to region 14-21.

Our data suggest that the effect of Entresto on BNP assay measurements may be assay dependent and that assays utilizing antibodies specific to region Arg17-Ile18 might not fully reflect the cardiac function in patients using the drug. However, in this study we have used an extremely simplified model of a complex biological phenomenon and in order to make any profound conclusions clinical studies are definitely needed in the future.

See the article here.

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