# Targeting dipeptidyl peptidase 3 (DPP3) in extreme-critically ill patients with refractory shock: First-in-human report on the safety and efficacy of an anti-DPP3 antibody

Dominik Jarczak, Axel Nierhaus, Alexandre Mebazaa, Antoine Herpain, Peter

Pickkers, Sanchir Anar, Stefan Kluge

► To cite this version:

Dominik Jarczak, Axel Nierhaus, Alexandre Mebazaa, Antoine Herpain, Peter Pickkers, et al. Targeting dipeptidyl peptidase 3 (DPP3) in extreme-critically ill patients with refractory shock: First-in-human report on the safety and efficacy of an anti-DPP3 antibody. European Journal of Heart Failure, 2025, 27 (8), pp.1483-1485. 10.1002/ejhf.3718. inserm-05353720

HAL Id: inserm-05353720

https://inserm.hal.science/inserm-05353720v1

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Distributed under a Creative Commons Attribution 4.0 International License
doi:10.1002/ejhf.3718
Online publish-ahead-of-print 10 July 2025

Targeting dipeptidyl
peptidase 3 (DPP3) in
extreme-critically ill patients
with refractory shock:
First-in-human report on the
safety and efficacy of an
anti-DPP3 antibody

Refractory shock originates from severely
depressed myocardial contractility – mostly

due to septic shock, septic cardiomyopa-
thy, sepsis-induced vascular dysfunction and
vascular hyporesponsiveness to vasoconstric-
tors (vasoplegia), acute myocardial infarction
(AMI), or acute heart failure. It thereby
initiates progressive worsening of systolic and
diastolic dysfunction and results in systemic
hypoperfusion, coronary ischaemia, increased
ventricular filling pressures, multi-organ sys-
tem failure, and often death. ¹,² Moreover, this
leads to inflammatory activation, anaerobic
metabolism, and oxidative stress, resulting in
systemic inflammatory response syndrome in
one out of three patients. ³

While specific therapies for refractory
shock are missing, just recently dipeptidyl
peptidase 3 (DPP3) has been validated as a
druggable biotarget: DPP3 is an intracellular
aminopeptidase and is released upon cell
death – like in sepsis and AMI and degrades
angiotensin II (Ang2) and related peptides,
disrupts the renin–angiotensin–aldosterone
system (RAAS) and thereby perpetuates
shock. ⁴,⁵ Recently, a humanized monoclonal
antibody that binds DPP3 and inhibits its
enzymatic activity, has entered clinical evalu-
ation. This anti-DPP3 antibody was designed
to block the enzymatic activity of circulating
DPP3 in the bloodstream, thereby inhibiting
DPP3-dependent angiotensin peptide degra-
dation and restoring RAAS homeostasis.
This blockade is intended to rapidly stabilize
haemodynamics and therefore cardiovascu-
lar and renal functions, improving clinical
outcomes in affected patients. It showed
excellent pre-clinical safety and efficacy in
mice, rats, pigs and monkeys, including nor-
malization of cardiovascular, pulmonary and
renal function, with drastically reduced mor-
tality.⁶ A phase 1 study in healthy subjects
(NCT06331884) was recently completed.

Here we report the treatment of three
terminally critically ill patients with refrac-
tory shock and multi-organ failure due to
septic cardiomyopathy, using the anti-DPP3
antibody. The treatment was conducted in
the Department of Intensive Care Medicine,
at the University Medical Center Hamburg-
Eppendorf in Hamburg, Germany. Patients
were eligible, if they were (i) in refractory
shock with continuous clinical deteriora-
tion, (ii) in utmost critical condition with
signs of multi-organ failure, and (iii) upon
exhaustion of all therapeutic options. The
treatment on a named-patient basis approach
relies on article 37 of the Declaration of
Helsinki and article 41 of the German
Pharmaceuticals Act.⁷ Accordingly, while

approvals by the ethics committee and reg-
ulatory bodies are not applicable for this
approach, informed consent was obtained
from the patients, their relatives, or legal
representatives.

Lactate, C-reactive protein and interleukin-6 were determined in the routine lab. DPP3 activity was measured using a customized assay. Follow-up was pre-specified as 48 h, with efficacy read-out defined as shock reversal, indicated by a norepinephrine dose ≤0.2 µg/kg body weight/min or halving of initial dose.

Two female patients (patients 1 and 3) and
one male patient (patient 2) were treated.
Detailed information on patient characteris-
tics and concomitant therapy are provided
in online supplementary Tables S1–S3. The
patients’ age ranged between 64 and 84 years.
All three patients had pre-existing condi-
tions and were in utmost critical condition
with signs of multi-organ failure, including
high plasma lactate level, due to refractory
septic shock. In addition, patient 1 had
an AMI, which could not be immediately
revascularized due to severe haemodynamic
instability, while patient 3 was suffering from
right-sided cardiogenic shock. All three were
suffering from acute kidney injury, in need
of renal replacement therapy, two out of
three (patients 1 and 2) were intubated
and under invasive mechanical ventilation.
Activity of DPP3 was strongly elevated in
all three patients (≥99th percentile of a
general population) (Figure 1). All three
patients were approved for treatment with
the anti-DPP3 antibody by an independent
international patient selection board. The
board confirmed exhaustion of all conven-
tional therapeutic options with no further
options for escalation of conventional therapy
in the presence of a high chance of immediate
mortality.

Patients received a single dose of the
anti-DPP3 antibody at a dose of 10 mg/kg
body weight over a 2-h period. The anti-
DPP3 antibody was administered between 1
and 3 days after admission to the intensive
care unit, separately from any concomitant
drugs using a dedicated lumen of a central
venous catheter. All patients were on stable
medication at time of anti-DPP3 antibody
dosing and thereafter, and the antibody
remained the only novel therapeutic inter-
vention introduced during the 48-h follow-up
period.

The therapy was well tolerated in all three
patients, no immediate adverse reactions
were noted, and no adverse events judged
to be associated with the administration
<figure><img src="image_2.png" /><figcaption>**Figure 1** Effect of the anti-dipeptidyl peptidase 3 (DPP3) antibody on DPP3 activity (upper panel), norepinephrine infusion rate, lactate concentration, and respiratory function (mid panel), renal function and inflammatory markers (lower panel). CRP, C-reactive protein; P/F, ratio of partial pressure of oxygen in arterial blood to the fraction of inspiratory oxygen concentration.</figcaption></figure>

of anti-DPP3 antibody. Figure 1 shows the effect of the intervention on DPP3 activity, norepinephrine infusion rate and lactate concentration. The mode-of-action observations from animal models were confirmed, as DPP3 enzyme activity was strongly reduced upon anti-DPP3 antibody administration (reduction of median DPP3 activity from 7 µmol/min*L at baseline to 2 µmol/min*L at day 2). The anti-DPP3 antibody demonstrated therapeutic efficacy in all clinical parameters investigated: the reduction of DPP3 activity was mirrored by a strong decrease of norepinephrine need and shock reversal in all three patients, as well as normalization of

lactate concentrations within the 48-h follow-up period. There was also an improvement in respiratory and kidney function during follow-up, as indicated by clearly improved P/F ratio and decreasing creatinine levels in all three patients (Figure 7). Finally, there was a profound decrease in circulating interleukin-6 from median 893.5 ng/L (upper limit of normal 4.4 ng/L) to 27.2 ng/L, in line with previous observations from animal studies.⁶ In line, median C-reactive protein values decreased from 298 mg/L (upper limit of normal <5 mg/L) to 179 mg/L.

While follow-up was pre-specified as 48 h, mid-term follow-up was assessed

retrospectively and is provided in online supplementary Tables S1–S3.

This first experience on DPP3-based biotherapy indicates that the specific humanized monoclonal anti-DPP3 antibody holds great promise for treatment of refractory shock and the findings are in line with the proposed mode-of-action: the specific inhibition of DPP3 enzyme activity restores RAAS homeostasis and thereby prevents Ang2 degradation, resulting in reducing norepinephrine doses and increased lactate clearance through improved perfusion. This restoration of perfusion and circulatory function may improve renal function, as evidenced
by decreased creatinine concentrations. We assume that besides improvement of kidney perfusion, the restoration of RAAS pathway also contributes to renal improvement, as animals and patients receiving Ang2 exhibited improved urinary output and creatinine clearance.⁶,⁸ As for the improvement in lung function, it was shown that the pulmonary vascular endothelium, where angiotensin-converting enzyme (ACE) is primarily (+90%) located in humans, is essential for the synthesis and degradation of Ang2, and it has been demonstrated that ACE activity is altered in severe lung injury, and this dysfunction correlates with the severity of the disease.⁹⁻¹¹ Finally, it is known that RAAS is involved in pro-inflammatory and pro-fibrotic effects at cellular and molecular levels, and therefore the strong effect on inflammation, as an independent driver of morbidity and mortality in shock, was anticipated and already observed in a pre-clinical study: anti-DPP3 antibody treated pigs had strongly decreased interleukin-6 heart expression in comparison to placebo-treated controls in a septic shock model.⁶

## Conclusions

In this preliminary uncontrolled case series of terminally critically ill patients with refractory shock due to septic shock and septic cardiomyopathy, the administration of the specific inhibitory anti-DPP3 antibody was well tolerated and followed by improvements in clinical parameters. It is important to note that the non-controlled design and the small sample size preclude any definitive statements about the safety and potential efficacy of the anti-DPP3 antibody in refractory shock patients, and that no causality can be claimed between the application of the anti-DPP3 antibody and the shock reversal observed in the three patients. Still, the results of this case series are encouraging for the ongoing clinical development programme.

## Supplementary Information

Additional supporting information may be found online in the Supporting Information section at the end of the article.

## Acknowledgements

We thank 4TEEN4 Pharmaceuticals GmbH (Hennigsdorf, Brandenburg, Germany) for the cost-free provision of the anti-DPP3 antibody and technical support in biomarker measurements. 4TEEN4 Pharmaceuticals GmbH (Hennigsdorf, Brandenburg, Germany) was not involved in the preparation, writing, review and approval of the manuscript. Conflict of interest: D.J., A.H., and S.A. have nothing to disclose. A.N. received travel reimbursement and lecture honoraria from ADVITOS and CytoSorbents Europe GmbH and travel reimbursement from Biotest AG and Thermo Fisher. A.M. received research contracts from 4TEEN4, Roche, Sphingotec, Abbott Diagnostics, Windtree; consultation fee from Roche, Corteria, Adrenomed, Fire; honorarium for lecture from Merck, Novartis, Roche, Bayer; co-inventor of a patent on combined therapies to treat dyspnoea; a co-inventor of a patent owned by S-Form Pharma; member of committees of trials for Secret-HF, sponsored by the French Government, for S-Form Pharma and Implicit. P.P. received travel reimbursement and honoraria from 4TEEN4, AM-Pharma and EBI. S.K. received research support from Cytosorbents and Daiichi Sankyo; lecture fees from ADVITOS, Biotest, Daiichi Sankyo, Fresenius Medical Care, Gilead, Mitsubishi Tanabe Pharma, MSD, Pfizer, Shionogi and Zoll; consultant fees from ADVITOS, Fresenius, Gilead, MSD and Pfizer.

Dominik Jarczak¹, Axel Nierhaus¹, Alexandre Mebazaa²,³, Antoine Herpain⁴, Peter Pickkers⁵, Sanchir Anar¹, and Stefan Kluge¹*

¹Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany; ²Université Paris Cité, INSERM UMR-S 942 (MASCOT), Paris, France;

³Department of Anesthesiology and Critical Care and Burn Unit, Saint-Louis and Lariboisière Hospitals, FHU PROMICE, DMU Parabol, APHP Nord, Paris, France; ⁴Department of Intensive Care, Saint-Pierre University Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium; and

⁵Department of Intensive Care, Radboud University Medical Centre, PO Box 9101, NL, 6500, HB, Nijmegen, The Netherlands

*Email: s.kluge@uke.de

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