B32

Activation of the pro-apoptotic receptor DR5 triggers apoptosis through the cell-extrinsic pathway. We have generated fully human, optimized IgG1/l3 monoclonal antibody (Apomab) that induces tumor cell apoptosis through DR5, and investigated its anti-tumor activity in xenograft models of non-Hodgkin’s lymphoma (NHL). Initially, a panel of NHL cell lines that included Burkitt’s lymphomas, follicular lymphomas (FL) and diffuse large B cell lymphomas (DLBCL) were tested for DR5 expression. All of the NHL cell lines tested were found to express DR5, and thus, were rational candidates for analysis of Apomab activity in vitro. We tested Apomab on the NHL cell lines in vitro and observed apoptosis in a subset of the lines, including BJAB, SU-DHL-4 and OCI-Ly19. Furthermore, apoptosis in those cell lines was accompanied by activation of the effector caspases, caspase-3 and -7. In vivo, Apomab showed single-agent activity against several types of NHL xenografts grown in SCID mice. Rituximab is a CD20 antibody used to treat FL and DLBCL in humans. We observed significant cooperation between Apomab and rituximab in vivo against BJAB, SU-DHL-4 xenografts. Remarkably, Toledo cells were resistant to Apomab in vitro, but sensitive in vivo to the combination of Apomab and rituximab. These findings demonstrate activity of Apomab against NHL xenografts and provide a strong rationale for clinical investigation of Apomab in combination with rituximab as a novel strategy for NHL therapy.

AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics-- Oct 22-26, 2007; San Francisco, CA