Innate and Acquired Resistance to Anti-EGFR Therapy—Letter

I read with great interest the recent article by Parseghian and colleagues (1), presenting a review of the mechanisms underlying the innate and acquired resistance to anti-EGFR therapy. This “in-depth review” of the resistance mechanisms, however, does not include the possible host antibody responses to the immunogenic epitopes present on the therapeutic anti-EGFR monoclonal antibodies, such as cetuximab and panitumumab (2). Both cetuximab and panitumumab express GM (γ marker) allotypes that are highly immunogenic in subjects lacking these determinants. For instance, GM 3 allotype is expressed in the CH1 region of cetuximab (3). Subjects lacking GM 3 could have pre-existing anti-GM 3 antibodies because of maternal-fetal incompatibility (4). The administered cetuximab and the pre-existing anti-GM 3 antibodies would form immune complexes that would be removed from the system by phagocytic cells, leading to de novo resistance to cetuximab therapy. Repeated infusion of cetuximab could also generate anti-GM 3 antibodies, leading to acquired resistance to this immunotherapy.

Similar resistance mechanisms could also be envisioned for panitumumab therapy. In summary, effective “personalized immunotherapeutic approaches” must take into account the immunogenicity of GM allotypes expressed on the therapeutic antibodies.