Neuendorfstraße 15A, 16761 Hennigsdorf
03302 205650

About Us

4TEEN4 Pharmaceuticals GmbH is a company with a clear mission: Improving the management of critically ill patients, which suffer from diseases related to massive cell death and thus uncontrolled Dipeptidyl peptidase 3 (DPP3) release into the bloodstream. Based on data that prove the reliability of DPP3 as a marker associated with short-term patient outcome, we identified DPP3 as a druggable target. The long-term vision is to provide a therapeutic solution for critically ill patients that neutralizes circulating DPP3 in order to restore proper organ function and improve survival.
To achieve this mission, we develop monoclonal antibody therapies accompanied by a targeted diagnostic. Our lead product is a first-in-class drug candidate, the humanized monoclonal antibody Procizumab, accompanied by different diagnostics.
The 4TEEN4 Pharmaceuticals GmbH, former Sphingotec Therapeutics GmbH, was established in 2013 and is managed by Andreas Bergmann, Ph.D.. The company is located in Hennigsdorf near Berlin, Germany.

The diagnostic assay measures DPP3 concentrations in the blood, assessing the risk of short-term organ dysfunction and mortality. The antibody therapy neutralizes DPP3 in the blood, rescuing organ function.

Our target – Dipeptidyl Peptidase 3

In a screening for biotargets in acute cardiovascular diseases, we identified a novel biomarker candidate: Dipeptidyl peptidase 3. DPP3 is a zinc dependent metallopeptidase that cleaves dipeptides sequentially from the N-terminus of various bioactive peptide substrates (1). The most prominent substrate of DPP3 is angiotensin II (Ang II), which modulates many cardiovascular functions including blood pressure and cardiac remodeling (4–6). The release of DPP3 from dying cells, and DPP3’s potential implications in the cardiovascular system lead us to develop a blood-based immunoassay to quantify DPP3 in the bloodstream.

Management

Andreas Bergmann, Ph.D. | Managing Director

Andreas Bergmann has worked in the diagnostic industry for over 30 years. With an outstanding track record, he has spearheaded the discovery, validation and the development of blood biomarkers. Andreas Bergmann is an inventor holding 204 patent rights and co-author of over 180 peer-reviewed scientific publications.

Dr. Bergmann established sphingotec GmbH and 4TEEN4 Pharmaceuticals GmbH, which are both located in Hennigsdorf. He leads the development of diagnostic methods for the prediction, prevention, intervention strategies and early treatment of diseases in the fields of cardiovascular diseases, cancer and acute care. Focusing on plasma biomarkers to indicate the susceptibility of a specific disease, the resulting information can enable monitoring, prevention and intervention strategies.

Dr. Bergmann is also Chief Scientific Officer (CSO) of the Adrenomed AG. Adrenomed is a biopharmaceutical company focused on therapies targeting vascular integrity. The Company’s lead product candidate is Adrecizumab, a clinical-stage, first-in-class monoclonal antibody. Adrecizumab targets the vasoprotective peptide Adrenomedullin, an essential regulator of vascular integrity to treat life-threatening conditions associated with increased vascular leakage, congestion and shock. For more information, please see https://adrenomed.com/

Senior Management

Anke Dienelt, PhD. | Project Manager
Karine Santos, PhD. | Head of Research and Development

Our Team

Mandy Kaestorf, BSc. | Scientist

Oliver Hartmann, PhD. | Biostatistician

Career

Our company is continually looking for highly motivated team members.

If you are interested in joining our innovative team, please contact us at career@4teen4.de

DPP3

Dipeptidyl peptidase 3

In a screening to find targets related to acute cardiovascular diseases, we identified a novel biomarker candidate, Human dipeptidyl peptidase 3 (DPP3).

DPP3 (EC 3.4.14.4), also known as red cell angiotensinase, is a zinc dependent metallopeptidase that cleaves dipeptides sequentially from the N-terminus of various bioactive peptide substrates [1].

DPP3 is mainly a ubiquitously expressed cytosolic enzyme that is evolutionarily conserved among prokaryotes and eukaryotes. DPP3 was first identified and its activity measured by Ellis and Nuenke in 19672 and since then DPP3 has been reported in organ homogenates and several bodily fluids, such as retroplacental serum, seminal plasma and cerebrospinal fluid [1].

In vitro, DPP3 sequentially cleaves dipeptides from the free N terminus of several bioactive peptide substrates and has been shown to cleave angiotensins and enkephalins, peptides that regulate heart and kidney function, respectively [1]. Despite the first identification of DPP3 in bovine pituitary gland more than 50 years ago [2], the exact physiological role of intracellular DPP3 remains unclear since its currently known substrates are extracellular bioactive peptides.

The most prominent substrate of DPP3 is angiotensin II (Ang II) – the main effector of the renin-angiotensin system (RAS). The RAS is activated in cardiovascular diseases and Ang II, in particular, has been shown to modulate many cardiovascular functions including the control of blood pressure and cardiac remodeling [3, 4]. Recently, it was shown that DPP3 degrades Ang II in vivo, reducing blood pressure in hypertensive mice [5]. The release of DPP3 from dying cells, and DPP3’s potential implications in blood pressure regulation and pain modulation based on its extracellular substrate specificity (Ang II and Enkephalins), lead us to develop a blood-based immunoassay to quantify DPP3 in the bloodstream

With this immunoassay we determined the normal DPP3 levels in the blood or plasma of healthy volunteers, which we refer to as circulating DPP3 (cDPP3) to differentiate it from intracellular DPP3. Using this as a reference value, we first observed an increase of cDPP3 levels in severely ill septic patients. Furthermore, high cDPP3 levels were associated with disease severity and high short-term mortality risk [6].

In order to understand if cDPP3 directly causes organ dysfunction, we natively purified DPP3 from human blood cell lysate and intravenously injected it in healthy mice. Upon DPP3 injection, we observed an impaired heart function within 15 min and a reduction of kidney function within 60 min. These results indicate that cDPP3 directly affects heart and kidney hemodynamics and steers organ dysfunction. Our current model suggests that, upon cell death, DPP3 is released in the extracellular space and reaches the bloodstream. This leads to uncontrolled degradation of DPP3 substrates, such as Ang II and enkephalin, and organ dysfunction. DPP3 is not only a powerful biomarker for short-term organ dysfunction and mortality but also a biotarget.

 

REFERENCES

[1] Prajapati et al. (2011) Dipeptidyl peptidase 3: a multifaceted oligopeptide N-end cutter. FEBS J.

[2] Ellis and Neunke (1967) Dipeptidyl arylamidase 3 of the pituitary: purification and characterization. JBC.

[3] Dostal et al. (1997) Molecular mechanisms of angiotensin II in modulating cardiac function: Intracardiac effects and signal transduction pathways. J Mol Cell Cardiol

[4] Abramić M et al. (1988) Dipeptidyl Peptidase III from Human Erythrocytes. Biol Chem Hoppe Seyler.

[5] Pang et al. (2016) Novel therapeutic role for dipeptidyl peptidase III in the treatment of hypertension. Hypertension

[6] Rehfeld et al. (2018) Novel Methods for the Quantification of Dipeptidyl Peptidase 3 (DPP3) Concentration and Activity in Human Blood Samples. JALM.

Diagnostics

Diagnostics

Cardiovascular diseases (CVDs) and sepsis are the leading cause of death worldwide. There is an unmet medical need for a reliable measure to determine the risk status and to guide treatment strategies.

One part of our research focuses on the development of novel biomarkers. Diagnostic tools can aid patient stratification and help identify patients that will benefit most from targeted therapies. Our novel biomarker candidate DPP3 effectively predicts short-term organ dysfunction and mortality in patients with cardiovascular failure and can be used to monitor disease progression as well as indicate treatment strategies. This newly developed immunoassay can be used alone or in combination with Procizumab treatment.

IB10 sphingotest® DPP3

DPP3  is a highly conserved, ubiquitously expressed cytosolic peptidase. Upon diseases that are associated with necrotic events and cell death, as seen e.g. in acute heart failure, myocardial infarction, sepsis, stroke or trauma, DPP3 is released into the bloodstream. There, circulating DPP3 degrades uncontrolled its substrates, such as Angiotensin II and Enkephalin. As a result, the hormonal regulation by these bioactive peptides is disrupted, which culminates in organ failure. Therefore, high DPP3 plasma concentrations have been shown to predict short-term organ dysfunction and mortality, while a normalization of circulating DPP3 concentrations within 24 hours immensely improves patient prognosis.

The IB10 sphingotest® DPP3 allows the early diagnosis and monitoring of clinically relevant DPP3 released upon necrotic events in critically ill patients with a simple blood draw [1]. With the IB10 sphingotest® DPP3 an early prediction of short-term multi-organ failure is possible. The biomarkers dynamic nature enables close patient monitoring and risk startification, leading to improved outcome. For more information, please see: https://sphingotec.com/nexus-ib10/

 

REFERENCES

[1] Rehfeld et al. (2018) Novel Methods for the Quantification of Dipeptidyl Peptidase 3 (DPP3) Concentration and Activity in Human Blood Samples. JALM.

Therapy

Procizumab

Procizumab has an innovative mode of action, relevant in acute diseases that are associated with massive cell death and uncontrolled release of intracellular DPP3 into the bloodstream. Translocated DPP3 remains active in the circulation where it cleaves bioactive peptides in an uncontrolled manner. Procizumab neutralized circulating DPP3, leading to an inhibition of bioactive peptide degradation in the bloodstream, and stabilization of cardiovascular and renal function, while lowering associated short-term mortality.

Preclinical studies of Procizumab in animal models of cardiovascular failure showed impressive and instant efficacy. As an example, injection of PROCIZUMAB in rats with shock-induced cardiovascular failure, lead to an instant normalization of shortening fraction (see videos).

  • PROCIZUMAB is a humanized monoclonal IgG1 antibody specifically binding circulating DPP3. It will be a first-in-class drug that targets and modulates DPP3, an essential regulator of cardiovascular function.
    High Preclinical Efficacy: In several preclinical cardiovascular failure models, PROCIZUMAB has shown to improve all clinically relevant endpoints in vivo. It improves blood pressure, normalizes ejection fraction and reduces mortality.
  • GMP material development ongoing: A generic Good Manufacturing Practice (GMP) process is under development

Acute Heart Failure

Acute heart failure (AHF) is a relevant public health problem causing the majority of unplanned hospital admissions in patients 65 years of age and above. Despite major achievements in the treatment of chronic heart failure (HF) over the last decades, which led to improvement in long-term survival, outcomes of AHF remain poor with 90-day re-hospitalization and 1-year mortality rates reaching up to 30%. Persistence of poor outcomes in AHF might be related to the paucity of improvements in the acute management of those patients. Despite lacking evidence of beneficial effects on outcome, critical treatment of AHF still mainly consists of non-invasive ventilation in case of pulmonary oedema, intravenous diuretics and/or vasodilators. In addition, AHF is not a specific disease but the shared clinical presentation of different, heterogeneous cardiac abnormalities. Therefore, there is an unmet need for increased individualization of AHF treatment according to the predominant underlying pathophysiological mechanisms to improve patient’s outcome1.

[1] Arrigo et al. (2016) Understanding acute heart failure: pathophysiology and diagnosis. European Heart Journal Supplements

News and Events

Article in PLoS One: A novel and highly efficient purification procedure for native human dipeptidyl peptidase 3 from human blood cell lysate

Paul Kaufmann, Matthias Muenzner, Mandy Kaestorf, Karine Santos, Tobias Hartmann, Anke Dienelt, Linda Rehfeld, Andreas Bergmann

PLoS One. 2019 Aug 7;14(8):e0220866. doi: 10.1371/journal.pone.0220866. eCollection 2019.

4TEEN4 Pharmaceuticals participates in three upcoming conferences

Hennigsdorf (Germany), August , 2019 – 4TEEN4 Pharmaceuticals announced today its participation in three upcoming conferences in Europe. 4TEEN4 representatives will be available for one-on-one meetings at these events.

ESC Congress 2019 together with World Congress of Cardiology

August 31st – September 4th, 2019, Paris, France

Prof. Alexandre Mebazaa (Department of Anesthesia, Burn and Critical Care, University Hospitals Saint-Louis – Lariboisière, AP-HP, Paris, France) will give a presentation about “Circulating dipeptidyl peptidase-3 is a myocardial depressant factor: Procizumab promptly and sustainably restored hemodynamics in heart failure”, in the session “Late Breaking Basic and Translational Science – Acute Coronary Syndromes and Heart Failure”, on Saturday August 31st, 14:46 CET, room Pristina – Village 3.

Dr. Karine Santos, Head of Research and Development at 4TEEN4 Pharmaceuticals, will also be present at this congress and available for meetings.

 

Weimar Sepsis Update 2019 – Tribute to Translation

September 11th – 13th, 2019, Weimar, Germany

Dr. Karine Santos, Head of Research and Development at 4TEEN4 Pharmaceuticals, will be present at this congress and available for meetings.

 

32nd European Society of Intensive Care Medicine (ESICM) LIVES

September 28th – October 2nd, 2019, Berlin, Germany

Benjamin Deniau will give a presentation about “Circulating dipeptidyl peptidase 3 is a myocardial depressant factor quickly and promptly reversed by Procizumab”, in the session “CD/AKI – Haemodynamic and kidney issues in the ICU”, on Wednesday October 2nd, 10:13 CET, area Dortmund.

Dr. Karine Santos, Head of Research and Development at 4TEEN4 Pharmaceuticals, will also be present at this congress and available for meetings.

Article in The Journal of Applied Laboratory Medicine – Novel Methods for the Quantification of Dipeptidyl Peptidase 3 (DPP3) Concentration and Activity in Human Blood Samples

Linda Rehfeld, Eugenia Funk, Shalinee Jha, Peter Macheroux, Olle Melander, Andreas Bergmann

doi: 10.1373/jalm.2018.027995 Published November 2018

Funding

DPP3-Antibody – Programm zur Förderung von Forschung, Innovation und Technologien (ProFIT Brandenburg), Nr. 8016982, 8016983

The main goal of the project is the development and characterization of the novel DPP3 neutralizing therapeutic antibody Procizumab. Within the scope of the project, we develop a GMP conform cell line for Procizumab production and characterize the antibody with different preclinical and biochemical methods. In addition, we develop different immunoassays to detect DPP3 and Procizumab in different samples and matrices.

Location

Neuendorfstraße 15A, 16761 Hennigsdorf
Phone: 03302 205650 
Email: info@4teen4.de

Cookie Preference

Please select an option. You can find more information about the consequences of your choice at Help. Privacy Policy / Datenschutzerklärung | Imprint / Impressum

Select an option to continue

Your selection was saved!

More information

Help

To continue, you must make a cookie selection. Below is an explanation of the different options and their meaning.

  • Accept all cookies:
    All cookies such as tracking and analytics cookies.
  • Accept first-party cookies only:
    Only cookies from this website.
  • Reject all cookies:
    No cookies except for those necessary for technical reasons are set. Borlabs Cookie already set a necessary cookie.

You can change your cookie setting here anytime: Privacy Policy / Datenschutzerklärung. Imprint / Impressum

Back