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Anti-heparanase monoclonal antibody enhances heparanase enzymatic activity and facilitates wound healing

Svetlana Gingis-Velitski^*, Rivka Ishai-Michaeli, Israel Vlodavsky^*,1 and Neta Ilan^*

^* Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Israel; and

Department of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

¹Correspondence: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel. E-mail: vlodavsk{at}cc.huji.ac.il

Heparanase is a mammalian endo-β-D-glucuronidase capable of cleaving HS side chains at a limited number of sites, activity that is strongly implicated in tumor metastasis, neovascularization, inflammation, and autoimmunity. Clinically, up-regulation of heparanase mRNA and protein expression has been documented in a variety of primary human tumors, correlating with reduced postoperative survival and increased lymph node and distant metastasis, thus providing strong clinical support for the prometastatic feature of the enzyme and making it an attractive target for the development of anticancer and anti-inflammatory drugs. Screening a panel of monoclonal antibodies for their ability to inhibit heparanase enzymatic activity, we noted that one hybridoma, 6F8, exhibited the opposite effect and significantly enhanced heparanase activity. Here, we provide evidence that antibody 6F8 enhances the activity of recombinant and cellular heparanase, facilitates invasion of tumor-derived cells in vitro, and improves wound healing in a mouse punch model in vivo. These results support a role of heparanase in the course of wound healing and, moreover, suggest that monoclonal antibodies can be applied clinically for the enhancement, rather than inhibition, of certain enzymes.—Gingis-Velitski, S., Ishai-Michaeli, R., Vlodavsky, I., Ilan, N. Anti-heparanase monoclonal antibody enhances heparanase enzymatic activity and facilitates wound healing.

Key Words: heparan sulfate • cell invasion • cell migration • stimulatory antibody

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