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. Bergmann was one of the founders and managers of B.R.A.H.M.S. AG where the sepsis marker Procalcitonin (PCT®) was developed under his responsibility as Chief Research Officer. Andreas Bergmann is inventor holding 204 patent rights and co-author of over 180 peer-reviewed scientific publications.

Dr. Bergmann went on to establish sphingotec GmbH and Sphingotec Therapeutics GmbH, which are 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 focussing on the discovery and development of monoclonal antibody therapies that target the vasoactive Adrenomedullin system as a new strategy for causative and safe treatment of acute circulatory failure, e.g. septic shock. Their lead product is the first-in-class drug candidate ADRECIZUMAB, a humanized monoclonal Adrenomedullin-specific antibody, which after successful completion of phase I clinical studies is now entering phase II.

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. We have currently open positions for highly motivated and engaged scientists, technical assistants, and a business development manager.

For more information please check the “Career” section above. 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].

Additional studies in cardiogenic shock patients showed that high cDPP3 is associated with heart and kidney dysfunction within 48 h, need of vasopressor therapy within 96 h, high rates of refractory shock and high short-term mortality [7]. We also observed that dynamic changes of cDPP3 levels during the first 24h were significantly associated with outcome. Patients that showed a decrease in cDPP3 levels in 24h had lower risk of refractory shock, organ failure and mortality in comparison to patients that kept their cDPP3 levels high [7].

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.
[7] Takagi et al. (2019) Circulating dipeptidyl peptidase-3 and alteration in hemodynamics in cardiogenic shock: results from the OptimaCC trial.

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, cardiogenic shock, 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).

Echocardiogram of rat heart with cardiovascular failure before PROCIZUMAB treatment

Echocardiogram of rat heart with cardiovascular failure after PROCIZUMAB treatment

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 edema, 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

4TEEN4 Pharmaceuticals reports first results on Procizumab, a novel therapeutic anti-DPP3 antibody for treatment of acute myocardial depression

  • 4TEEN4 Pharmaceuticals GmbH demonstrates that targeting the enzyme Dipeptidyl Peptidase 3 (DPP3) with its first-in-class therapeutic antibody Procizumab normalises heart and kidney function in a preclinical models of acute heart failure with depressed contraction.
  • Clinical data presented by Prof. Alexandre Mebazaa at ESC Congress 2019 in Paris provide evidence for a novel disease mechanism in which circulating DPP3 degrades central mediators of heart and kidney function, rapidly leading to fatal organ dysfunction.
  • 4TEEN4 Pharmaceuticals GmbH licensed its diagnostic biomarker test DPP3 to SphingoTec GmbH, which today launched the IB10 sphingotest® DPP3 assay for use with the Nexus IB10 point-of-care analyser, the first CE-IVD test for DPP3.

Paris, France, and Hennigsdorf/Berlin, Germany, August 31, 2019

4TEEN4 Pharmaceuticals GmbH (“4TEEN4”, former Sphingotec Therapeutics GmbH, Hennigsdorf/Berlin, Germany) today for the first time reported preclinical data on its lead product Procizumab, a therapeutic antibody targeting circulating Dipeptidyl Peptidase 3 (DPP3) for the treatment of patients with acute myocardial depression including acute heart failure and cardiogenic shock. The published data further emphasizes the medical utility of DPP3 as a biomarker predicting organ dysfunction and outcome in critically ill patients.

 

DPP3 is at the core of a recently discovered patho-mechanism of acute myocardial depression reported for the first time by Prof. Alexandre Mebazaa (Hôpital Lariboisière, Paris) at ESC Congress 2019 (organised by the European Society of Cardiology ESC, Paris) [1]. Data from two clinical studies (OptimaCC [2] and CardShock [3]) presented by Prof. Mebazaa demonstrate that pathological concentrations of the newly identified myocardial depressant factor DPP3 were clearly associated with organ failure and short-term outcome of patients with cardiogenic shock, an emergency that affects around 10% [4] of patients with myocardial infarction. Mebazaa’s team hypothesizes that intracellular DPP3 is released from cells into the bloodstream during cell death. They provided striking evidence that DPP3 degrades the cardiovascular mediators angiotensin II and enkephalin, which are central to heart and kidney

function.

 

In pre-clinical models, injections of DPP3 decreased cardiac output, as well as kidney hemodynamics. Administration of Procizumab, a humanized monoclonal antibody designed to block peptidase activity of DPP3, immediately normalized heart and kidney function in a pre-clinical model for acute heart failure. “Procizumab is a novel treatment approach targeting a recently identified DPP3-mediated disease mechanism in critically ill patients”, said Prof. Mebazaa, whose results were also published today in the European Journal of Heart Failure [5,6].

 

4TEEN4 is currently setting up a GMP process for Procizumab manufacturing and is expected to enter regulatory non-clinical safety studies next year.

 

“In ongoing preclinical efficacy studies, Procizumab has shown high therapeutic potential in certain indications, including heart failure, that are triggered by dysfunction in the cardiorenal axis mediated by low angiotensin II and enkephalin levels. Supported by excellent clinical cohort results on the DPP3 biomarker, we are now preparing for first-in-men clinical trials” said Dr. Andreas Bergmann, CEO of 4TEEN4.

 

The studies published today and further on-going retrospective studies show promising clinical utility of DPP3 as a biomarker in emergency settings. The company has licensed the global rights to develop DPP3-based diagnostics for near-patient and central laboratory testing to SphingoTec GmbH (“sphingotec”; Hennigsdorf, Germany). 4TEEN4 and sphingotec, together with Nexus Dx Inc. and Adrenomed AG, are part of the Medicine4Future Initiative established by serial entrepreneur Dr. Andreas Bergmann.

 

References

[1] Circulating dipeptidyl peptidase-3 is a myocardial depressant factor: Procizumab promptly and sustainably restored

hemodynamics in heart failure, Prof. Alexandre Mebazaa at ESC Congress 2019, Paris

[2] clinicaltrial.gov NCT 01367743

[3] clinicaltrial.gov NCT 1374867

[4] van Diepen (2017) Contemporary Management of Cardiogenic Shock: A Scientific Statement From the American Heart Association, Circulation

[5] Takagi (2019) Circulating dipeptidyl-peptidase 3 and alteration in hemodynamics in cardiogenic shock: Results from the OptimaCC Trial, European Journal of Heart Failure

[6] Deniau (2019) Circulating dipeptidyl peptidase-3 is a myocardial depressant factor: DPP3 inhibition rapidly and sustainably improves hemodynamics, European Journal of Heart Failure

Read More 

Article in European Journal of Heart Failure: Circulating dipeptidyl peptidase-3 is a myocardial depressant factor: DPP3 inhibition rapidly and sustainably improves hemodynamics

Benjamin Deniau, Linda Rehfeld, Karine Santos, Anke Dienelt, Feriel Azibani, Malha Sadoune, Paul Robert Kounde, Jane Lise Samuel, Heli Tolpannen, Johan Lassus, Veli-Pekka Harjola, Nicolas Vodovar, Andreas Bergmann, Oliver Hartmann, Alexandre Mebazaa, Alice Blet

 

Article in European Journal of Heart Failure: Circulating dipeptidyl-peptidase 3 and alteration in hemodynamics in cardiogenic shock: Results from the OptimaCC Trial

Koji Takagi, Alice Blet, Bruno Levy, Benjamin Deniau, Feriel Azibani, Elodie Feliot, Andreas Bergmann, Karine Santos, Oliver Hartmann, Etienne Gayat, Alexandre Mebazaa, Antoine Kimmoun

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 21, 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.

Read More 

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

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