Journal
BLOOD
Volume 121, Issue 14, Pages 2804-2813Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-12-468363
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency (JST)
- Swiss Federal Institute of Technology Zurich
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Monoclonal antibodies (mAbs) that are internalized into cells are a current focus in the development of antibody-drug conjugates (ADCs). We describe a phage display-based high-throughput screening system to rapidly isolate cell-internalizing mAbs. We simultaneously examined the cell-internalizing activities of several hundred independent mAbs and successfully isolated cell-internalizing mAbs against the tumor endothelial markers Roundabout homolog 4 (Robo4) and vascular endothelial growth factor receptor 2 (VEGFR2). Tumor accumulation of mAbs with high cell-internalizing activity was significantly higher than that of mAbs with low cell-internalizing activity. Furthermore, the antitumor effects of ADCs of mAbs with high cell-internalizing activity were significantly stronger than those of mAbs with low cell-internalizing activity. Although anti-VEGFR2 therapy caused a significant loss of body weight, anti-Robo4 therapy did not. These findings indicate that cell-internalizing activity plays an important role in the biodistribution and therapeutic effects of ADCs. Further, Robo4 can be an effective marker for tumor vascular targeting. (Blood. 2013; 121(14):2804-2813)
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