A humanized single-chain antibody against beta 3 integrin inhibits pulmonary metastasis by preferentially fragmenting activated platelets in the tumor microenvironment.

Abstract

Platelets play a supportive role in tumor metastasis. Impairment of platelet function within the tumor microenvironment may provide a clinically useful approach to inhibit metastasis. We developed a novel humanized single-chain antibody (scFv Ab) against integrin GPIIIa49-66 (named A11) capable of lysing activated platelets. In this study, we investigate the effect of A11 on the development of pulmonary metastases. In the Lewis lung carcinoma (LLC) metastatic model, A11 decreases the mean number of surface nodules and mean volume of pulmonary nodules. It protects against lung metastases in a time window that extended 4 hours before and 4 hours after the IV injection of LLCs. Coinjection of GPIIIa49-66 albumin reverses the antimetastatic activity of A11 in the B16 melanoma model, consistent with the pathophysiologic relevance of the platelet GPIIIa49-66 epitope. Significantly, A11 had no effect on angiogenesis using both in vitro and in vivo assays. The underlying molecular mechanisms are a combination of inhibition of each of the following interactions: between activated platelets and tumor cells, platelets and endothelial cells, and platelets and monocytes, as well as disaggregation of an existing platelet/tumor thrombus. Our observations may provide a novel antimetastatic strategy through lysing activated platelets in the tumor microenvironment using humanized anti-GPIIIa49-66 scFv Ab.

• Authors: Wei Zhang, Suying Dang, Tao Hong, Jian Tang, Jing Fan, Dawei Bu, Yanjie Sun, Zhugang Wang, Thomas Wisniewski
• Journal: Blood (Blood) Vol. 120 Issue 14 Pg. 2889-98 (Oct 04 2012) ISSN: 1528-0020 [Electronic] United States
• PMID: 22879538 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Peptide Fragments
• Platelet Glycoprotein GPIIb-IIIa Complex
• Single-Chain Antibodies

Topics

• Animals
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Carcinoma, Lewis Lung (immunology, prevention & control, secondary)
• Cell Adhesion
• Cell Movement
• Female
• Human Umbilical Vein Endothelial Cells (cytology, immunology)
• Humans
• Melanoma, Experimental (immunology, prevention & control, secondary)
• Mice
• Mice, Inbred C57BL
• Neovascularization, Pathologic
• Peptide Fragments (immunology)
• Platelet Activation (immunology)
• Platelet Glycoprotein GPIIb-IIIa Complex (immunology)
• Single-Chain Antibodies (therapeutic use)
• Tumor Microenvironment (immunology)