title: Collaborative enhancement of antibody binding to distinct PECAM-1 epitopes modulates endothelial targeting.
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 enhancement" of mAb binding is affirmed in vivo, as manifested by enhanced pulmonary accumulation of intravenously administered radiolabeled PECAM-1 mAb when co-injected with an unlabeled paired mAb in mice. This is the first demonstration of a positive modulatory effect of endothelial binding and vascular immunotargeting provided by the simultaneous binding a paired mAb to adjacent distinct epitopes. The "collaborative enhancement" phenomenon provides a novel paradigm for optimizing the endothelial-targeted delivery of therapeutic agents.
authors.affiliation: Department of Radiology, Division of Nuclear Medicine and Clinical Molecular Imaging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Chacko
authors.forename: Madhura
authors.initials: M
authors.lastname: Nayak
authors.forename: Colin F
authors.initials: CF
authors.lastname: Greineder
authors.forename: Horace M
authors.initials: HM
authors.lastname: Delisser
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Muzykantov
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000276:immunology* / Q000378:metabolism; D011863:Radioimmunoassay
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D019408:Platelet Endothelial Cell Adhesion Molecule-1