Structure-guided and phage-assisted evolution of a therapeutic anti-EGFR antibody to reverse acquired resistance.

ABSTRACT: Acquired resistance to cetuximab in colorectal cancers is partially mediated by the acquisition of mutations located in the cetuximab epitope in the epidermal growth factor receptor (EGFR) ectodomain and hinders the clinical application of cetuximab. We develop a structure-guided and phage-assisted evolution approach for cetuximab evolution to reverse EGFR^S492R- or EGFR^G465R-driven resistance without altering the binding epitope or undermining antibody efficacy. Two evolved cetuximab variants, Ctx-VY and Ctx-Y104D, exhibit a restored binding ability with EGFR^S492R, which harbors the most common resistance substitution, S492R. Ctx-W52D exhibits restored binding with EGFR harboring another common cetuximab resistance substitution, G465R (EGFR^G465R)

SUBMITTER: Zhuang X 

PROVIDER: S-EPMC9338999 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature