The rGel/BLyS Fusion Toxin Inhibits Diffuse Large B-cell Lymphoma Growth In Vitro and In Vivo

Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma (NHL) and accounts for 30% to 40% of NHL. Molecules targeting nuclear factor-kappa B (NF-kappa B) are expected to be of therapeutic value in those tumors where NF-kappa B seems to play a unique survival role such as activated B-cell (ABC)-subtype DLBCL. We previously generated a rGel/BLyS fusion toxin for receptor-mediated delivery of the rGel toxin specifically to malignant B cells. In this study, we examined this fusion toxin for its ability to suppress DLBCL growth in vitro and in vivo. rGel/BLyS was specifically cytotoxic to DLBCL lines expressing all three BLyS receptors and constitutively active NF-kappa B. Treatment with rGel/BLyS induced down-regulation of the phosphorylation of inhibitory subunit of NF-kappa B (I kappa B-alpha), inhibition of NF-kappa B DNA-binding activity, and accumulation of I kappa B-alpha. In agreement with these results, we additionally found that rGel/BLyS downregulated levels of several NF-kappa B targets including Bcl-x(L), Mcl-1, survivin, and x-chromosome linked inhibitor-of-apoptosis. Treatment also induced up-regulation of Bax and apoptosis through caspase-3 activation and poly ADP-ribose polymerase cleavage. Importantly, rGel/BLyS significantly inhibited tumor growth (P<.05) in a DLBCL xenograft model. Thus, our results indicate that rGel/BLyS is an excellent candidate for the treatment of aggressive NHLs that are both dependent on NF-kappa B and are resistant to conventional chemotherapeutic regimens.