A novel immunotoxin reveals a new role for CD321 in endothelial cells.
There are currently several antibody therapies that directly target tumors, and antibody-drug conjugates represent a novel moiety as next generation therapeutics. Here, we used a unique screening probe, DT3C, to identify functional antibodies that recognized surface molecules and functional epitopes...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5640210?pdf=render |
| _version_ | 1811232070419087360 |
|---|---|
| author | Takeshi Fukuhara Jia Kim Shintaro Hokaiwado Makiko Nawa Hayato Okamoto Tomohiko Kogiso Tetsuro Watabe Nobutaka Hattori |
| author_facet | Takeshi Fukuhara Jia Kim Shintaro Hokaiwado Makiko Nawa Hayato Okamoto Tomohiko Kogiso Tetsuro Watabe Nobutaka Hattori |
| author_sort | Takeshi Fukuhara |
| collection | DOAJ |
| description | There are currently several antibody therapies that directly target tumors, and antibody-drug conjugates represent a novel moiety as next generation therapeutics. Here, we used a unique screening probe, DT3C, to identify functional antibodies that recognized surface molecules and functional epitopes, and which provided toxin delivery capability. Accordingly, we generated the 90G4 antibody, which induced DT3C-dependent cytotoxicity in endothelial cells. Molecular analysis revealed that 90G4 recognized CD321, a protein localized at tight junctions. Although CD321 plays a pivotal role in inflammation and lymphocyte trans-endothelial migration, little is known about its mechanism of action in endothelial cells. Targeting of CD321 by the 90G4 immunotoxin induced cell death. Moreover, 90G4 immunotoxin caused cytotoxicity primarily in migratory endothelial cells, but not in those forming sheets, suggesting a critical role for CD321 in tumor angiogenesis. We also found that hypoxia triggered redistribution of CD321 to a punctate localization on the basal side of cells, resulting in functional impairment of tight junctions and increased motility. Thus, our findings raise the intriguing possibility that endothelial CD321 presented cellular localization in tight junction as well as multifunctional dynamics in several conditions, leading to illuminate the importance of widely-expressed CD321 as a potential target for antitumor therapy. |
| first_indexed | 2024-04-12T10:57:10Z |
| format | Article |
| id | doaj.art-b9c7099ed63744b5a5bd0a6843df65c8 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T10:57:10Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b9c7099ed63744b5a5bd0a6843df65c82022-12-22T03:36:04ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-011210e018150210.1371/journal.pone.0181502A novel immunotoxin reveals a new role for CD321 in endothelial cells.Takeshi FukuharaJia KimShintaro HokaiwadoMakiko NawaHayato OkamotoTomohiko KogisoTetsuro WatabeNobutaka HattoriThere are currently several antibody therapies that directly target tumors, and antibody-drug conjugates represent a novel moiety as next generation therapeutics. Here, we used a unique screening probe, DT3C, to identify functional antibodies that recognized surface molecules and functional epitopes, and which provided toxin delivery capability. Accordingly, we generated the 90G4 antibody, which induced DT3C-dependent cytotoxicity in endothelial cells. Molecular analysis revealed that 90G4 recognized CD321, a protein localized at tight junctions. Although CD321 plays a pivotal role in inflammation and lymphocyte trans-endothelial migration, little is known about its mechanism of action in endothelial cells. Targeting of CD321 by the 90G4 immunotoxin induced cell death. Moreover, 90G4 immunotoxin caused cytotoxicity primarily in migratory endothelial cells, but not in those forming sheets, suggesting a critical role for CD321 in tumor angiogenesis. We also found that hypoxia triggered redistribution of CD321 to a punctate localization on the basal side of cells, resulting in functional impairment of tight junctions and increased motility. Thus, our findings raise the intriguing possibility that endothelial CD321 presented cellular localization in tight junction as well as multifunctional dynamics in several conditions, leading to illuminate the importance of widely-expressed CD321 as a potential target for antitumor therapy.http://europepmc.org/articles/PMC5640210?pdf=render |
| spellingShingle | Takeshi Fukuhara Jia Kim Shintaro Hokaiwado Makiko Nawa Hayato Okamoto Tomohiko Kogiso Tetsuro Watabe Nobutaka Hattori A novel immunotoxin reveals a new role for CD321 in endothelial cells. PLoS ONE |
| title | A novel immunotoxin reveals a new role for CD321 in endothelial cells. |
| title_full | A novel immunotoxin reveals a new role for CD321 in endothelial cells. |
| title_fullStr | A novel immunotoxin reveals a new role for CD321 in endothelial cells. |
| title_full_unstemmed | A novel immunotoxin reveals a new role for CD321 in endothelial cells. |
| title_short | A novel immunotoxin reveals a new role for CD321 in endothelial cells. |
| title_sort | novel immunotoxin reveals a new role for cd321 in endothelial cells |
| url | http://europepmc.org/articles/PMC5640210?pdf=render |
| work_keys_str_mv | AT takeshifukuhara anovelimmunotoxinrevealsanewroleforcd321inendothelialcells AT jiakim anovelimmunotoxinrevealsanewroleforcd321inendothelialcells AT shintarohokaiwado anovelimmunotoxinrevealsanewroleforcd321inendothelialcells AT makikonawa anovelimmunotoxinrevealsanewroleforcd321inendothelialcells AT hayatookamoto anovelimmunotoxinrevealsanewroleforcd321inendothelialcells AT tomohikokogiso anovelimmunotoxinrevealsanewroleforcd321inendothelialcells AT tetsurowatabe anovelimmunotoxinrevealsanewroleforcd321inendothelialcells AT nobutakahattori anovelimmunotoxinrevealsanewroleforcd321inendothelialcells AT takeshifukuhara novelimmunotoxinrevealsanewroleforcd321inendothelialcells AT jiakim novelimmunotoxinrevealsanewroleforcd321inendothelialcells AT shintarohokaiwado novelimmunotoxinrevealsanewroleforcd321inendothelialcells AT makikonawa novelimmunotoxinrevealsanewroleforcd321inendothelialcells AT hayatookamoto novelimmunotoxinrevealsanewroleforcd321inendothelialcells AT tomohikokogiso novelimmunotoxinrevealsanewroleforcd321inendothelialcells AT tetsurowatabe novelimmunotoxinrevealsanewroleforcd321inendothelialcells AT nobutakahattori novelimmunotoxinrevealsanewroleforcd321inendothelialcells |