Collaborative enhancement of antibody binding to distinct PECAM-1 epitopes modulates endothelial targeting.
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 epito...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3325922?pdf=render |
| _version_ | 1818381793895645184 |
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| author | Ann-Marie Chacko Madhura Nayak Colin F Greineder Horace M Delisser Vladimir R Muzykantov |
| author_facet | Ann-Marie Chacko Madhura Nayak Colin F Greineder Horace M Delisser Vladimir R Muzykantov |
| author_sort | Ann-Marie Chacko |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T02:40:14Z |
| format | Article |
| id | doaj.art-1bd6ddcf87c94f36979ca7459425613c |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T02:40:14Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-1bd6ddcf87c94f36979ca7459425613c2022-12-21T23:20:02ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0174e3495810.1371/journal.pone.0034958Collaborative enhancement of antibody binding to distinct PECAM-1 epitopes modulates endothelial targeting.Ann-Marie ChackoMadhura NayakColin F GreinederHorace M DelisserVladimir R MuzykantovAntibodies 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.http://europepmc.org/articles/PMC3325922?pdf=render |
| spellingShingle | Ann-Marie Chacko Madhura Nayak Colin F Greineder Horace M Delisser Vladimir R Muzykantov Collaborative enhancement of antibody binding to distinct PECAM-1 epitopes modulates endothelial targeting. PLoS ONE |
| title | Collaborative enhancement of antibody binding to distinct PECAM-1 epitopes modulates endothelial targeting. |
| title_full | Collaborative enhancement of antibody binding to distinct PECAM-1 epitopes modulates endothelial targeting. |
| title_fullStr | Collaborative enhancement of antibody binding to distinct PECAM-1 epitopes modulates endothelial targeting. |
| title_full_unstemmed | Collaborative enhancement of antibody binding to distinct PECAM-1 epitopes modulates endothelial targeting. |
| title_short | Collaborative enhancement of antibody binding to distinct PECAM-1 epitopes modulates endothelial targeting. |
| title_sort | collaborative enhancement of antibody binding to distinct pecam 1 epitopes modulates endothelial targeting |
| url | http://europepmc.org/articles/PMC3325922?pdf=render |
| work_keys_str_mv | AT annmariechacko collaborativeenhancementofantibodybindingtodistinctpecam1epitopesmodulatesendothelialtargeting AT madhuranayak collaborativeenhancementofantibodybindingtodistinctpecam1epitopesmodulatesendothelialtargeting AT colinfgreineder collaborativeenhancementofantibodybindingtodistinctpecam1epitopesmodulatesendothelialtargeting AT horacemdelisser collaborativeenhancementofantibodybindingtodistinctpecam1epitopesmodulatesendothelialtargeting AT vladimirrmuzykantov collaborativeenhancementofantibodybindingtodistinctpecam1epitopesmodulatesendothelialtargeting |