Abstract 355: A monoclonal antibody against laminin alpha 4 inhibits both MCAM and integrin-a6b1 binding, blocks tumor cell adhesion in vitro and slows melanoma tumor growth in vivo

Abstract Laminin is an extracellular matrix molecule that is secreted as a trimeric protein composed of an α, β and γ chain. There are five distinct laminin α chains that impart distinct binding and signaling activities for cell adhesion, migration, and differentiation in a tissue-specific fashion....

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Published in:	Cancer research (Chicago, Ill.) Vol. 75; no. 15_Supplement; p. 355
Main Authors:	Tam, Stephen J., Li, Lauri E., Lorenzana, Carlos, Liu, Yue, Flanagan, Ken, Dolan, Philip J., Alexander, Lana, Salmans, Josh, Barbour, Robin M., Higaki, Jeffrey N., Nijjar, Tarlochan, Zago, Wagner, Yednock, Ted A., Kinney, Gene
Format:	Journal Article
Language:	English
Published:	01-08-2015
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Summary:	Abstract Laminin is an extracellular matrix molecule that is secreted as a trimeric protein composed of an α, β and γ chain. There are five distinct laminin α chains that impart distinct binding and signaling activities for cell adhesion, migration, and differentiation in a tissue-specific fashion. Laminin a4 (LAMA4) is expressed by vascular endothelial cells throughout the body, but is also overexpressed by cells within tumors of different origin compared to healthy human tissue. LAMA4 serves as a ligand for the cell adhesion receptors MCAM and a6b1 integrin, as well as for cell surface heparin sulfate proteoglycans. In order to probe how the MCAM/Laminin interaction contributes to tumor growth, we screened for LAMA4-specific monoclonal antibodies that block MCAM binding. We identified several such antibodies, and found that a subset also inhibits LAMA4 binding to a6b1 integrin, indicating that MCAM and a6b1 integrin recognize a similar region of LAMA4. Examining cells from multiple types of tumors, we found that these antibodies were potent inhibitors of tumor cell adhesion to LAMA4 in vitro. Finally, with in vivo administration, we demonstrated dose-dependent inhibition of human melanoma tumor growth in a mouse xenograft model, accompanied by morphologic changes in LAMA4 tumor distribution. These findings suggest that the MCAM/a6b1 integrin binding activity of LAMA4 contributes to both tumor adhesion and growth and that LAMA4 may provide a therapeutic drug target for several different oncology indications. Citation Format: Stephen J. Tam, Lauri E. Li, Carlos Lorenzana, Yue Liu, Ken Flanagan, Philip J. Dolan, Lana Alexander, Josh Salmans, Robin M. Barbour, Jeffrey N. Higaki, Tarlochan Nijjar, Wagner Zago, Ted A. Yednock, Gene Kinney. A monoclonal antibody against laminin alpha 4 inhibits both MCAM and integrin-a6b1 binding, blocks tumor cell adhesion in vitro and slows melanoma tumor growth in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 355. doi:10.1158/1538-7445.AM2015-355
ISSN:	0008-5472 1538-7445
DOI:	10.1158/1538-7445.AM2015-355