Vascular endothelial effects of collaborative binding to platelet/endothelial cell adhesion molecule-1 (PECAM-1)

Area of Science:

• Vascular Biology
• Drug Delivery
• Immunology

Background:

• Targeting endothelial cells can improve outcomes in vascular diseases.
• Collaborative Enhancement of Paired Affinity Ligands (CEPAL) utilizes paired antibodies for enhanced binding to PECAM-1, enabling simultaneous drug delivery.
• PECAM-1 is known to maintain endothelial quiescence and junction integrity.

Purpose of the Study:

• To investigate potential unintended vascular effects of CEPAL targeting PECAM-1.
• To compare the vascular effects of PECAM-1 targeted CEPAL with antibodies targeting VE-Cadherin.

Main Methods:

• In vitro and in vivo studies using human and mouse endothelial cells.
• Assessment of endothelial permeability, vascular activation, and systemic cytokine release.
• Evaluation of antibody binding to PECAM-1 and VE-Cadherin.

Main Results:

• Antibodies targeting PECAM-1, alone or in pairs (CEPAL), induced only modest or non-significant vascular effects.
• Antibody binding to VE-Cadherin significantly increased endothelial permeability, vascular activation, and cytokine release.
• PECAM-1-targeted CEPAL demonstrated relatively well-tolerated endothelial drug delivery.

Conclusions:

• PECAM-1-targeted CEPAL is a promising strategy for endothelial drug delivery with a favorable safety profile.
• VE-Cadherin targeting carries a risk of inducing vascular inflammation and permeability.
• This study provides a framework for evaluating the toxicity of vascular-targeted therapeutics.