Mondego Bio to test AI-designed PTPN2 inhibitor ZE00-0388 in first study

Portugal-based Mondego Bio has selected ZE00-0388, a highly selective small-molecule inhibitor of PTPN2, as its lead clinical candidate, formally transitioning the Portugal-based biotech into clinical-stage development and setting up a first-in-human Phase 1 trial in H1 2026. The candidate nomination follows completion of a broad preclinical evaluation package that demonstrated a favorable safety and tolerability profile in relevant animal models. With this milestone, Mondego Bio said it will initiate clinical operations focused on early safety, pharmacokinetics and translational biomarker exploration in oncology.

The planned Phase 1 study will employ a dual-track design, beginning with a healthy volunteer cohort to assess safety, tolerability and pharmacokinetics and to inform dose selection. The program will then expand into oncology patient cohorts to evaluate ZE00-0388 as both a monotherapy and in combination with immune checkpoint inhibitors, alongside exploratory biomarker analyses in patients with solid tumors.

PTPN2 as a drug target

ZE00-0388 is an AI-designed, highly selective inhibitor of Protein Tyrosine Phosphatase Non-Receptor Type 2 (PTPN2), an intracellular regulator of cytokine and interferon signaling. PTPN2 functions as a negative regulator of the JAK–STAT pathway and has been implicated in immune suppression within the tumor microenvironment. Preclinical findings suggest that modulation of PTPN2 activity may enhance interferon signaling and immune cell function, providing a mechanistic rationale for combination strategies with established immuno-oncology agents.

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As a regulator of immune signaling, PTPN2 is also viewed as a potential target in several other disease areas, including auto-immune diseases, type 1 diabetes, to support immunotherapies by making tumors more susceptible to immune attack and more.

Several academic centers are actively engaged in PTPN2-targeted research:

  • The Manguso Lab at Massachusetts General Hospital (MGH) and the Broad Institute has pioneered CRISPR-based screens to identify PTPN2 as a regulator of anti-tumor immunity, and is involved in clinical trials and translational research on PTPN2 inhibitors.
  • University of Colorado, Denver, has conducted genetic studies on PTPN2 in autoimmune thyroid disease.
  • Princess Máxima Center for Pediatric Oncology (Netherlands) is sponsoring ongoing trials in pediatric hematological malignancies, with sites in the Netherlands, Sweden, and Italy.

Besides Mondego’s ZE00-0388, other PTPN2 inhibitors in or approaching clinical trials include:

  • ABBV-CLS-484: Developed by AbbVie in collaboration with the Broad Institute and Calico Life Sciences, this first-in-class PTPN2/PTPN1 inhibitor is in Phase 1 trials for advanced solid tumors (NCT047779946; Nature, 20231).
  • ABBV-CLS-579: Another AbbVie asset targeting PTPN2, also in early-phase clinical development for solid tumors.