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Temporal Patterns of Novel Circulating Biomarkers in IL-2-mediated Vascular Injury in the Rat
Natalie D Keirstead1, Cristina Bertinetti-Lapatki2, Denise Knapp3
1Hoffmann La-Roche Inc., Nutley, New Jersey, USA Present address: Alnylam Pharmaceuticals Inc., Cambridge, Massachusetts, USA.
Abstract:
Recombinant interleukin-2 (rIL-2) administration in oncology indications is hampered by vascular toxicity, which presents as a vascular leak syndrome. We used this aspect of the toxicity of rIL-2 to evaluate candidate biomarkers of drug-induced vascular injury (DIVI) in rats given 0.36 mg/kg rIL-2 daily. Groups of rats were given either 2 or 5 doses of rIL-2 or 5 doses of rIL-2 followed by a 7-day recovery. The histomorphologic lexicon and grading scheme developed by the Vascular Injury Working Group of the Predictive Safety Testing Consortium of the Critical Path Institute were utilized to enable semiquantitative integration with circulating biomarker levels. The administration of rIL-2 was associated with time-dependent endothelial cell hyperplasia and hypertrophy and perivascular inflammation that correlated with increases in circulating angiopoietin-2, lipocalin-2, monocyte chemotactic protein-1, tissue inhibitor of metalloproteinase-1, vascular endothelial growth factor A, E-selectin, and chemokine (C-X-C motif) ligand-1, and the microRNAs miR-21, miR-132, and miR-155. The dose groups were differentially identified by panels comprising novel candidate biomarkers and traditional hematologic parameters. These results identify biomarkers of the early stages of DIVI prior to the onset of vascular smooth muscle necrosis.
Insights
Recombinant interleukin-2 (rIL-2) causes vascular leak syndrome. This study identified novel biomarkers, including angiopoietin-2 and specific microRNAs, indicating early drug-induced vascular injury in rats.
Area of Science:
- Pharmacology
- Toxicology
- Biomarker Discovery
Background:
- Recombinant interleukin-2 (rIL-2) is used in oncology but causes vascular toxicity, presenting as vascular leak syndrome.
- Understanding and predicting this drug-induced vascular injury (DIVI) is crucial for patient safety.
Purpose of the Study:
- To evaluate candidate biomarkers for early detection of rIL-2-induced vascular injury in a rat model.
- To correlate histopathological findings of vascular injury with circulating biomarker levels.
Main Methods:
- Rats received daily doses of rIL-2 (0.36 mg/kg) for 2 or 5 days, with one group having a 7-day recovery period.
- Histomorphologic evaluation used the Vascular Injury Working Group lexicon and grading scheme.
- Circulating biomarker levels (proteins and microRNAs) were measured and correlated with vascular changes.
Main Results:
- rIL-2 administration led to time-dependent endothelial cell hyperplasia/hypertrophy and perivascular inflammation.
- Increased circulating levels of angiopoietin-2, lipocalin-2, MCP-1, TIMP-1, VEGF-A, E-selectin, CXCL1, miR-21, miR-132, and miR-155 were observed.
- Biomarker panels differentiated dose groups and identified early DIVI stages before smooth muscle necrosis.
Conclusions:
- Novel circulating biomarkers, including angiopoietin-2, lipocalin-2, and specific microRNAs, can detect early-stage drug-induced vascular injury.
- These biomarkers show potential for monitoring rIL-2 toxicity and improving patient safety in oncology.
- The findings provide a foundation for developing predictive assays for vascular injury.
