collaborative enhancement of antibody binding to distinct pecam-1 epitopes modulates endothelial targeting后的协作增强抗体无法绑定到不同的pecam-1调节内皮定位.pdfVIP

Collaborative Enhancement of Antibody Binding to Distinct PECAM-1 Epitopes Modulates Endothelial Targeting 1,4 1 2,4 3 Ann-Marie Chacko , Madhura Nayak , Colin F. Greineder , Horace M. DeLisser , Vladimir R. Muzykantov4* 1 Department of Radiology, Division of Nuclear Medicine and Clinical Molecular Imaging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 2 Department of Emergency Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 3 Pulmonary, Allergy Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 4 Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America Abstract Antibodies to platelet endothelial cell adhesion molecule-1 (PECAM-1) facilitate targeted drug delivery to endothelial cells by ‘‘vascular immunotargeting.’’ To define the targeting quantitatively, we investigated the endothelial binding of monoclonal antibodies (mAbs) to extracellular epitopes of PECAM-1. Surprisingly, we have found in human and mouse cell culture models that the endothelial binding of PECAM-directed mAbs and scFv therapeutic fusion protein is increased by co-administration of a paired mAb directed to an adjacent, yet distinct PECAM-1 epitope. This results in significant enhancement of functional activity of a PECAM-1-targeted scFv-thrombomodulin fusion protein generating therapeutic activated Protein C. The ‘‘collaborative enhan