Distinct apoptotic signaling characteristics of the anti-CD40 monoclonal antibody dacetuzumab and rituximab produce enhanced antitumor activity in non-Hodgkin lymphoma.

Abstract

PURPOSE:

Individually targeting B-cell antigens with monoclonal antibody therapeutics has improved the treatment of non-Hodgkin lymphoma (NHL). We examined if the antitumor activity of rituximab, CD20-specific antibody, could be improved by simultaneously targeting CD40 with the humanized monoclonal antibody dacetuzumab (SGN-40).

EXPERIMENTAL DESIGN:

Dacetuzumab was dosed with rituximab to determine the in vivo activity of this combination in a subcutaneous Ramos xenograft model of non-Hodgkin lymphoma (NHL). The effect of dacetuzumab on rituximab antibody-dependent cell mediated-cytotoxicity (ADCC), antiproliferative, and apoptotic activities were evaluated in vitro using NHL cell lines. Western blotting and flow cytometry were used to contrast the signaling pathways activated by dacetuzumab and rituximab in NHL cells.

RESULTS:

The dacetuzumab-rituximab combination had significantly improved antitumor activity over the equivalent dose of rituximab in the Ramos xenograft model (P = 0.0021). Dacetuzumab did not augment rituximab-mediated ADCC activity; however, these antibodies were additive to synergistic in cell-proliferation assays and produced increased apoptosis in combination. Rituximab signaling downregulated BCL-6 oncoprotein in a cell line-specific manner, whereas dacetuzumab strongly downregulated BCL-6 in each cell line. Dacetuzumab induced expression of the proapoptotic proteins TAp63 and Fas, whereas rituximab did not affect basal expression of either protein. Finally, rituximab partially blocked dacetuzumab-mediated upregulation of the prosurvival protein BCL-x(L).

CONCLUSIONS:

Targeting CD40 with dacetuzumab enhanced the antitumor activity of rituximab in cell line and xenograft NHL models. The distinct but complementary apoptotic signal transduction profiles of dacetuzumab and rituximab are an important mechanism behind the improved activity of this combination.

• Authors: Timothy S Lewis, Renee S McCormick, Kim Emmerton, Jeffrey T Lau, Shang-Fan Yu, Julie A McEarchern, Iqbal S Grewal, Che-Leung Law
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 14 Pg. 4672-81 (Jul 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21610152 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antibodies, Monoclonal, Murine-Derived
• Antineoplastic Agents
• CD40 Antigens
• Rituximab
• dacetuzumab

Topics

• Animals
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antibodies, Monoclonal, Murine-Derived (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Apoptosis (drug effects)
• CD40 Antigens (antagonists & inhibitors)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Synergism
• Humans
• Kaplan-Meier Estimate
• Lymphoma, Non-Hodgkin (drug therapy, metabolism, mortality, pathology)
• Mice
• Mice, SCID
• Rituximab
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays