Complement activation mediates cetuximab inhibition of non-small cell lung cancer tumor growth in vivo

Abstract

BackgroundCetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), increases survival in patients with advanced EGFR-positive non-small cell lung cancer when administrated in combination with chemotherapy. In this study, we investigated the role of complement activation in the antitumor mechanism of this therapeutic drug.ResultsEGFR-expressing lung cancer cell lines were able to bind cetuximab and initiate complement activation by the classical pathway, irrespective of the mutational status of EGFR. This activation led to deposition of complement components and increase in complement-mediated cell death. The influence of complement activation on the activity of cetuximab in vivo was evaluated in xenografts of A549 lung cancer cells on nude mice. A549 cells express wild-type EGFR and have a KRAS mutation. Cetuximab activity against A549 xenografts was highly dependent on complement activation, since complement depletion completely abrogated the antitumor efficacy of cetuximab. Moreover, cetuximab activity was significantly higher on A549 cells in which a complement inhibitor, factor H, was genetically downregulated.ConclusionsWe demonstrate for the first time that the in vivo antitumor activity of cetuximab can be associated with a complement-mediated immune response. These results may have important implications for the development of new cetuximab-based therapeutic strategies and for the identification of markers that predict clinical response.

An in vitro chemoresponse assay defines a subset of colorectal and lung carcinomas responsive to cetuximab

“…32 In addition, this study provides the justification for future studies to both cetuximab-IR cell lines (H1666 and HCC827), express wild type K-ras. 24,25 These results are consistent with clinical demonstrations that tumors which express K-ras mutations are more likely to be resistant to treatment with cetuximab. 26 In addition, the results also support the idea that some wild type K-ras tumors are non-responsive to cetuximab.…”

Impact of Epidermal Growth Factor Receptor (EGFR) Cell Surface Expression Levels on Effector Mechanisms of EGFR Antibodies

“…Thus, complement activation triggered by combinations of two noncompetitive EGFR-or EGFRvIII-directed mAbs or individual CDC-optimized (K326A/E333A) variants was observed in vitro (20,33). Additionally, complement activation induced by cetuximab treatment was suggested to play a crucial role in tumor growth inhibition in vivo (34). However, the incompatibility of membrane-bound complement-regulatory proteins expressed on human tumor cell lines with murine complement components limits the interpretation of data received from such mouse xenograft models.…”

Characterization and Immunotherapeutic Implications for a Novel Antibody Targeting Interleukin (IL)-13 Receptor α2

“…Although the underlying mechanism for this antitumor effect remains unclear, the result suggests a possible therapeutic applicability for this antibody alone or as a therapeutic carrier with regard to the future treatment of IL13R␣2-expressing glial and other lineage tumors. Several antibodies have been shown to mediate a cytotoxic effect in tumors through Fc-mediated activation of complement (39). Antibody-dependent cell-mediated cytotoxicity-induced activation of effector cells can also contribute to the cytotoxic effect of antibodies against targeted cells (40,41).…”