ProAgio

Overview

ProAgio (also known as ACT-50) is an investigational, intravenously administered, rationally designed protein that targets integrin αvβ3. It is being developed primarily for solid tumors with dense fibrotic stroma (notably pancreatic ductal adenocarcinoma; PDAC), and is under evaluation in first‑in‑human trials and additional early-phase combination studies. (cdek.pharmacy.purdue.edu)

Mechanism of action

• Target: Integrin αvβ3 expressed at high levels on cancer‑associated fibroblasts (CAFs) and angiogenic endothelial cells within tumors. (pubmed.ncbi.nlm.nih.gov)
• Binding site and action: ProAgio binds αvβ3 at a site outside the classical RGD ligand pocket and induces apoptosis by recruiting/activating caspase‑8 at the β3 cytoplasmic domain (integrin‑mediated death). This leads to depletion of αvβ3‑expressing cells. (pubmed.ncbi.nlm.nih.gov)
• Tumor microenvironment effects (preclinical): In mouse models of PDAC and TNBC, ProAgio depletes CAFs, reduces stromal collagen, prunes leaky angiogenic vessels, improves perfusion and drug delivery, and enhances chemotherapy activity; it can also shift immune contexture (↓Tregs/MDSCs, ↑CD8+ T cells, ↑M1/M2 ratio). (pmc.ncbi.nlm.nih.gov)

Clinical development and status

• First‑in‑human Phase 1 (NCT05085548): Single‑institution, dose‑escalation study of ProAgio monotherapy in previously treated advanced solid tumors (predominantly PDAC), with planned expansion in PDAC. Dosing is weekly or every 2 weeks across multiple dose levels; optional gemcitabine is allowed in expansion. Primary completion and study completion are estimated in 2025. (ascopubs.org)
• Additional early‑phase trials:
• Metastatic triple‑negative breast cancer (TNBC): Phase I/II study of ProAgio + gemcitabine (NCT06460298), recruiting. (trial.medpath.com)
• Advanced/metastatic colorectal cancer: Phase I/Ib study of ProAgio + FOLFIRI + bevacizumab (NCT06867822), early start-up/registration stage. (ichgcp.net)

Efficacy

• Phase 1 monotherapy (ASCO 2024 dose‑escalation report): Among 28 treated participants (26 PDAC) as of January 30, 2024, five PDAC participants receiving weekly dosing achieved stable disease; two of these showed interval stabilization of CA19‑9. No objective responses were reported in this preliminary readout; recommended Phase 2 dose was pending PK analysis at that time. (ascopubs.org)
• No peer‑reviewed response‑rate data or survival outcomes in humans have been published as of the latest available reports. (ascopubs.org)

Safety

• Phase 1 monotherapy (ASCO 2024): Generally well tolerated across all evaluated dose levels, with mostly transient grade 1–2 treatment‑related adverse events. Noted events included two grade 2 infusion reactions (manageable with premedication). Isolated grade 3 events possibly related to ProAgio included hyperglycemia, acute kidney injury, and anemia, each in separate participants. (ascopubs.org)

Key preclinical evidence

• PDAC models: ProAgio depleted cancer‑associated pancreatic stellate cells, reduced collagen, opened collapsed tumor vessels, improved gemcitabine delivery, and prolonged survival in KPC and orthotopic models. (pubmed.ncbi.nlm.nih.gov)
• TNBC models: Simultaneous depletion of CAFs and angiogenic endothelium reduced tumor growth, metastasis, hypoxia, and improved drug delivery. (pubmed.ncbi.nlm.nih.gov)
• Mechanistic foundation: Demonstrated αvβ3‑dependent, caspase‑8–mediated apoptosis in αvβ3‑expressing cells; anti‑angiogenic activity without affecting established vasculature. (pmc.ncbi.nlm.nih.gov)

Further reading

• Phase 1 clinical abstract (ASCO 2024): Phase I study of ProAgio, an αvβ3 integrin cytotoxin, in advanced pancreatic cancer and other solid tumors. (ascopubs.org)
• Trial record for first‑in‑human study (NCT05085548). (cdek.pharmacy.purdue.edu)
• Mechanism paper: Rational design of a protein that binds integrin αvβ3 outside the ligand‑binding site (Nature Communications). (pmc.ncbi.nlm.nih.gov)
• Preclinical PDAC study (Cellular and Molecular Gastroenterology and Hepatology). (pubmed.ncbi.nlm.nih.gov)
• Preclinical TNBC study (Oncogene). (pubmed.ncbi.nlm.nih.gov)
• Preclinical tumor‑immunity modulation in lung cancer model. (pubmed.ncbi.nlm.nih.gov)

Notes: As of October 7, 2025, publicly available human data consist of an interim Phase 1 dose‑escalation report with preliminary disease‑control observations; no peer‑reviewed, full clinical efficacy results have been published. Trial statuses and estimated completion dates are based on registry listings. (ascopubs.org)

Last updated: Oct 2025