The fully human anti-CD30 antibody 5F11 activates NF-{kappa}B and sensitizes lymphoma cells to bortezomib-induced apoptosis.
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 1/2 study shows that 5F11 is well tolerated in heavily pretreated patients with relapsed and refractory CD30(+) lymphoma and has some clinical activity. In the present study, we demonstrate that 5F11 activates nuclear factor kappaB (NF-kappaB) and the anti-apoptotic protein cellular FLICE (Fas-associating protein with death domain-like interleukin-1beta-converting enzyme) inhibitory protein (c-flip) in Hodgkin lymphoma (HD)-derived cell lines, which might cause apoptosis resistance, thus limiting the clinical use of 5F11. To overcome this resistance, we combined 5F11 with the proteasome inhibitor bortezomib, which has been shown to suppress NF-kappaB 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-kappaB signaling sensitizes the tumor cells to bortezomib-induced cell death. These data suggest a therapeutic value of this combination for HD patients.
Böll
Boris
B
University Hospital of Cologne, Department of Internal Medicine, Kerpener Str. 62 D-50924 Köln, Germany.
Hansen
Hinrich
H
Heuck
Friederike
F
Reiners
Katrin
K
Borchmann
Peter
P
Rothe
Achim
A
Engert
Andreas
A
Pogge von Strandmann
Elke
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000918:Antibody Specificity / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D004357:Drug Synergism; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects / Q000276:immunology; D017730:Ki-1 Antigen / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D001897:Boronic Acids; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C506387:Cflar protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D017730:Ki-1 Antigen; D016328:NF-kappa B; D011719:Pyrazines; D000069286:Bortezomib