The fully human anti-CD30 antibody 5F11 activates NF-κB and sensitizes lymphoma cells to bortezomib-induced apoptosis

Abstract

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 B (NF-B) and the anti-

TNF-α-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species

“…In agreement with our previous data, the combination of bortezomib and MDX-060 showed synergistic cytotoxicity in L540 cells but not in the control cells lacking CD30. 8 Pretreatment with Ab is essential for synergy which is not seen after bortezomib coapplication or pretreatment. However, inhibition of CD30 shedding by Ro32-7315 suppressed this failure of synergy.…”

“…7 We previously tested the combination of bortezomib and the fully human anti-CD30 antibody (Ab), MDX-060, in the anti-CD30 Ab-responsive HL cell line L540, both in vitro and in a SCID mouse model. 8 Although preincubation with MDX-060 enhanced the cytotoxic potency of bortezomib, simultaneous or preincubation with bortezomib failed to improve Ab therapy. Currently, there is no explanation for this defect.…”

Bortezomib in combination with dexamethasone for patients with relapsed Hodgkin's lymphoma: results of a prematurely closed phase II study (NCT00148018)

“…10 Further studies of bortezomib in Hodgkin's lymphoma might therefore only be justified with combinations of bortezomib. However, the use of bortezomib combined with dexamethasone is not encouraged in patients with relapsed Hodgkin's lymphoma.…”

Immunotherapies for Hodgkin's lymphoma

“…For example, in vitro data suggest that the anti-tumor activity of 5F11 is limited because of CD30-mediated activation of NF-kB and its target, c-flip [66]. In an HL cell line, evidence of enhanced NF-kB activation was likewise seen shortly after treatment with SGN-30 [67], which could in turn increase chemotherapeutic resistance.…”

“…In an HL cell line, evidence of enhanced NF-kB activation was likewise seen shortly after treatment with SGN-30 [67], which could in turn increase chemotherapeutic resistance. In tumor cell lines and an HL xenograft model, giving bortezomib (a proteosome inhibitor that suppresses NK-kB activation) after 5F11 helped to overcome apoptotic resistance and had cytotoxic synergy [66]. In vitro data also suggest enhanced cytotoxicity when 5F11 is combined with chemotherapy including gemcitabine and etoposide [68].…”