The fully human anti-CD30 antibody 5F11 activates NF-kB and sensitizes lymphoma cells to bortezomib-induced apoptosis.
Boll B, Hansen H, Heuck F, Reiners K, Borchmann P, Rothe A, Engert A, Pogge von Strandmann E.
Laboratory for Immunotherapy, Department I for Internal Medicine, University Hospital of Cologne, Cologne, Germany.
[There was actually a Medarex-authored abstract on this subject at last year's ASH conference. Something I missed.
abstracts2view.com
5F11 is also known as MDX-060].
5F11, a fully human monoclonal antibody directed against CD30 effectively induces killing of CD30-expressing lymphoma cell lines in vitro and in animal models. A recently conducted phase I/II study shows that 5F11 is well tolerated in heavily pre-treated patients with relapsed and refractory CD30-positive lymphoma and has some clinical activity. In the present study we demonstrate that 5F11 activates NF-kB and the anti-apoptotic protein c-flip in HD (Hodgkins lymphoma)-derived cell lines, which might cause apoptosis resistance thus limiting its clinical use. To overcome this resistance we combined 5F11 with the proteasome inhibitor bortezomib which has been shown to suppress NF-kB activity. This combination revealed a synergistic cytotoxic effect in vitro and in a human HD xenograft model provided that 5F11 precedes bortezomib treatment. We conclude that initial 5F11-mediated NF-kB signaling sensitizes the tumor cells to bortezomib-induced cell death. These data suggest a therapeutic value of this combination for HD patients. |
