Theragnostics
Toward Precision Medicine
We work on identifying the fundamental drivers in critical care diseases and develop a novel therapeutic approaches to help cardiogenic shock patients
Our Biomarker
Dipeptidyl Peptidase 3 (DPP3)
Diagnosis, Prediction and Prognosis:
3 essentials for a novel biomarker
DPP3 at a glance
Upon cell injury and death resultant from hypoperfusion or tissue injury, DPP3, an intracellular peptidase, is released into the bloodstream. In numerous clinical studies, elevated circulating DPP3 levels strongly indicate organ failure and poor outcomes in critically ill patients.
We have demonstrated that the DPP3 biomarker has the potential to advance the prediction of organ function progression in addition to the standard-of-care markers.
Given the rapid advances in the DPP3 biomarker validation pipeline, DPP3 is a promising biomarker, which identifies this biologically active pathway in heterogeneous syndromes, such as cardiogenic shock, and guide therapy escalation.
DPP3 biomarker in clinical practice
Immunoassay for DPP3 is already available as manual laboratory assay and Point-of-Care platform, while further DPP3 determination techniques are under development.
The intended use as a biomarker includes (i) the monitoring of patients with acute coronary syndrome for the identification of patients at immediate risk for development of cardiogenic shock, and (ii) the use as a companion diagnostic to Procizumab.
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Etiology of Shock
DPP3 is located inside the cell
- DPP3 is located intracellularly
- Angiotensin II contributes to maintaining normal heart function and vascular tone
Uncontrolled DPP3 release into the blood
- Uncontrolled DPP3 release into the bloodstream leads into degradation of Angiotensin II
- High DPP3 leads to hemodynamic instability and cardiac depression
Our Drug Procizumab
What is Procizumab?
Procizumab is a humanized monoclonal antibody that specifically binds and inhibits circulating DPP3. Procizumab has an innovative mode of action relevant to acute critical disease entities, such as cardiogenic shock, associated with massive cell death and the uncontrolled release of intracellular DPP3 into the bloodstream.
4TEEN4 Pharmaceuticals identified Dipeptidyl Peptidase 3 (DPP3) as a key biomolecule in the pathophysiology of cardiogenic shock. Heart muscle necrosis leads to cardiac function impairment. Once an acute event causes a critical extent of organ injury and cell death, DPP3 is released into the circulation where it degrades essential hormones, such as Angiotensin II (ANGII) and related peptides, which control vascular tone and cardiac function.
The evidence on the crucial role of DPP3 was recently further confirmed: blood levels of this circulating biomolecule have been proven to indicate severity, poor outcome and impaired organ function in cardiogenic shock (Deniau et al., 2019; Iborra-Egea et al., 2020; Takagi et al., 2020).
The causality of DPP3 for myocardial depression has also been shown recently: when injected intravenously, DPP3 has a cardiac depressant effect in rodents. Several reports indicate that ANGII is the most important substrate of DPP3 (Prajapati and Chauhan, 2011; Pang et al., 2016; Malovan et al., 2022). Elevated DPP3 levels in cardiogenic shock patients lead to an enhanced degradation of ANGII, leading to a perturbation of the renin-angiotensin-aldosterone system (RAAS). Low levels of ANGII lead to low vascular tone, forcing the heart to work harder in order to uphold organ perfusion. Low levels of ANGII also lead to reduced cardiac contractility. In both cases, low organ perfusion leads to organ damage and cell death, which in turn results in more DPP3 release in the bloodstream.
4TEEN4 Pharmaceuticals GmbH developed a humanized monoclonal antibody, Procizumab, for the treatment of adult patients suffering from cardiogenic shock. Procizumab binds DPP3 and inhibits its enzymatic activity. In line with circulating DPP3 being a myocardial depressant factor, the inhibition of excess DPP3 in the blood via Procizumab has shown strong positive hemodynamic effects and improved survival in pre-clinical models, including mice acute heart failure models (Deniau et al., 2019) as well as rat and pig circulatory shock models (Deniau et al., 2020; manuscript in preparation).
Procizumab has been shown to be safe and well tolerated in all preclinical models and toxicology studies. The next step will be the documentation of safety and efficacy in human.
Diseased state and treatment with Procizumab
The renin-angiotensin-aldosterone system (RAAS) is the crucial pathway that controls the cardiovascular function and is dysregulated in case of excessive DPP3 presence. Procizumab blocks excessive DPP3 in the bloodstream, inhibits the degradation of bioactive hormones and related peptides of the RAAS system. This blockade results in hemodynamic stabilization, due to improved cardiovascular function, and reduction of short-term mortality in preclinical models.
Supported by
The project is funded by the European Social Fund (ESF) and the Federal State of Brandenburg via the Brandeburg Ministry for Labor, Social Affairs, Health, Women and Family (MASGF).
