Mechanism of resistance to cetuximab therapy in colorectal cancer

The response rate to cetuximab, a chimeric (mouse-human) monoclonal antibody directed against epidermal growth factor receptor (EGFR), in colorectal cancer is low (10–15%), with significant inter-individual variability. Mechanisms proposed thus far to explain resistance to this therapy—such as the emergence of EGFR and KRAS mutations and aberrant ERBB2 signaling—do not account for the total inter-individual variation in treatment responses in de novo and in acquired resistance, which suggests involvement of additional mechanisms. I propose that preexisting antibodies to the GM 3/f allotype, a genetic marker of immunoglobulin (Ig) G1 that is present on cetuximab, or such antibodies induced in response to administered cetuximab, could contribute to resistance to cetuximab. This novel mechanism, if supported by experimental observations, could provide an urgently needed biomarker for targeting eligible patients for this therapy. Most manufacturers of mouse-human chimeric antibodies have treated the constant (C) region of human Ig as if it were naturally monomorphic and therefore not immunogenic in humans. The C region of Ig γ chains is highly polymorphic with at least 18 testable specificities (GM allotypes)—4 on γ1, 1 on γ2 and 13 on γ3. With the exception of allelic GM 3 and GM 17 determinants expressed in the Fd region, all other GM alleles are expressed in the Fc region of γ chains. Most GM determinants are highly immunogenic, and the Ig molecules carrying these markers cross the maternal-fetal barrier in both directions, leading to anti-GM antibody production in the mother against the paternal GM markers present in the child, Mechanism of resistance to cetuximab therapy in colorectal cancer Possible role of antibodies to immunoglobulin allotypes