Generation of a Fully Human High Affinity Neutralizing Antibody Against MT-SP1/Matriptase and Its Potential Role for the Treatment of B Cell Lymphoma.

Membrane-type serine protease 1 (MT-SP1)/Matriptase is a type II transmembrane serine protease that is primarily expressed in epithelial cells and is over-expressed in several cancers. MT-SP1 has been implicated in the processes of tumor cell invasion and metastasis, primarily due to its ability to degrade extracellular matrix proteins and to activate the latent forms of hepatocyte growth factor (HGF), urokinase type plasminogen activator and protease-activated receptor 2. To further explore the role of this protein in human cancer, we developed a fully human IgG1, high affinity, neutralizing antibody against MT-SP1 (95/96) using XenoMax® technology. Using this antibody, we confirmed the expression of MT-SP1 on epithelial cells. In addition, we observed MT-SP1 expression on human peripheral blood B lymphocytes and monocytes. Furthermore, expression was also observed on several B cell lymphomas including Ramos, Raji and Daudi cell lines where, in contrast to epithelial cells, MT-SP1 was found in the absence of its inhibitor and cognate receptor, HGF activator inhibitor -1 (HAI-1). As 95/96 is a potent inhibitor of MT-SP1 enzymatic activity, we used the antibody to examine the functional role of MT-SP1 in B cell lymphoma. Using a tripeptide fluorogenic substrate of MT-SP1, we detected cell surface enzymatic activity on Ramos cells that was completely inhibited by 95/96, implying that the MT-SP1 expressed on Ramos cells is catalytically active. The ability of 95/96 to modulate the invasive properties of Ramos lymphoma cells was evaluated using a rodent hind-limb paralysis model. The median survival of SCID mice systemically inoculated with Ramos lymphoma cells, and receiving 95/96, was significantly extended compared to the animals receiving an isotype-matched control antibody (35 days vs. 26 days, p < 0.01). 95/96 had no effect on the in vitro proliferation or invasion of Ramos cells and was unable to induce cell death in a whole blood assay or by complement-dependent cytolysis. Collectively, these data suggest a role for MT-SP1 catalytic activity in the invasion or metastasis of Ramos B cell lymphoma.