Prof. Alexandre Mebazaa Head of the Department of Anesthesia and Critical Care

Sepsis: Monoclonal Antibody Procizumab Improves Cardiac Function in Animal Model Study Interview with:

Prof. Alexandre Mebazaa Head of the Department of Anesthesia and Critical Care

Prof. Mebazaa

Prof. Alexandre Mebazaa
Head of the Department of Anesthesia and Critical Care
Hôpital Lariboisiere and of the Research group MASCOT supported by Inserm and the Université de Paris (Paris, France).
Prof. Mebazaa is the principle investigator of the recently published preclinical experiments on Procizumab, a potent, pre-clinical drug candidate targeting DPP3 in patients with acute mycardial depression. What is the background for this study? What is the significance of DPP3? 

Response: The global burden of sepsis counts for one in three deaths world-wide. Recent findings have shown that circulating Dipeptidyl Pepidase 3 (cDPP3) is elevated in critical patients, including cardiogenic shock and septic patients, with the highest DPP3 blood levels found in non-survivors.

Dipeptidyl Peptidase 3 (DPP3) is an intracellular peptidase that is released into the bloodstream upon cell injury and death, where it inactivates many circulating peptides including angiotensin II. This process likely leads to cardiac depression. Procizumab is a humanized monoclonal antibody in preclinical development that targets and modulates DPP3. The aim of the current study was to evaluate the benefits of inhibiting circulating DPP3 by Procizumab in a preclinical model of sepsis-induced myocardial depression. What are the main findings? 

Response: We have found that high DPP3 blood values are associated with decreased heart function in this sepsis-induced myocardial depression model, and the inhibition of DPP3 with Procizumab has immediately and significantly improved the heart function by increasing the cardiac output, the stroke volume and the left ventricular shortening fraction of all tested animals in comparison to the placebo group. What should readers take away from your report? 

Response: Our study demonstrates that Procizumab inhibits the circulating DPP3 and consequently restores cardiac contractility in preclinical septic models. These data indicate that circulating DPP3 plays an important part in sepsis-induced myocardial depression and suggest Procizumab as a promising, under development therapeutic option in this context. What recommendations do you have for future research as a result of this work?

Response: The current study extends the previously proven role of circulating DPP3 in cardiogenic shock to septic cardiomyopathy. By inhibiting circulating DPP3, Procizumab could potentially be a therapeutic option in patients with septic shock, an indication with very limited efficient therapies. Furthermore, the use of Procizumab could possibly limit the use of high doses of vasopressors during septic shock treatment, which has been associated with deleterious effects. Is there anything else you would like to add?

Response: Circulating DPP3 is at the core of a newly discovered disease mechanism, which remained unknown until recently. The recent findings show that circulating DPP3 is involved in pathophysiological processes that trigger cardiac depression in various clinical settings, and its inhibition by Procizumab efficiently restores heart function.

My team at Université de Paris is specialized in cardiovascular markers in stressed conditions (MASCOT Unit) and was strongly involved in the project. For the animal experiments, my team worked in close contact with the team of 4TEEN4 Pharmaceuticals GmbH that developed the therapeutic antibody and were involved in all scientific discussions. The study was financed by Inserm and Université de Paris and partly 4TEEN4 Pharmaceuticals GmbH via an unrestricted grant that allowed to support a PhD student salary.

Citation: Inhibition of circulating dipeptidyl-peptidase 3 restores cardiac function in a sepsis-induced model in rats: A proof of concept study

Benjamin Deniau,Alice Blet ,Karine Santos,Prabakar Vaittinada Ayar,Magali Genest,Mandy Kästorf,Malha Sadoune,Andreia de Sousa Jorge,Jane Lise Samuel,Nicolas Vodovar,Andreas Bergmann,Alexandre Mebazaa ,Feriel Azibani

Published: August 27, 2020


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Last Updated on September 17, 2020 by Marie Benz MD FAAD