Zero-Shot Design of a Biobetter Cetuximab: Enhanced EGFR Affinity with Preserved Developability

Cetuximab is a chimeric IgG1 monoclonal antibody that has been a cornerstone therapy for EGFR-driven malignancies for nearly two decades. Its therapeutic activity is governed by competitive displacement of endogenous EGFR ligands, making binding affinity a direct determinant of clinical efficacy. We applied ConvergeAB™, a target-aware antibody design platform, in a fully zero-shot configuration to generate a biobetter version of cetuximab. The lead Converge-designed antibody binds EGFR with a mean KD of 315 pM — approximately 2.1-fold tighter than cetuximab (673 pM) and 4.4-fold tighter than a recently published, computationally designed anti-EGFR antibody from Cradle Bio (1.38 nM). The affinity gain arises from six substitutions that leave the global paratope architecture intact (Cα RMSD 0.15 Å vs cetuximab) and instead optimize the binding interface through localized packing and electrostatic adjustments. A panel of biophysical and developability assays — HIC, DLS, DSF, and PSR ELISA — shows that the Converge variant matches or exceeds cetuximab on monomericity, monodispersity, polyspecificity, and thermal stability, while remaining within a developable hydrophobicity envelope. Together, these data demonstrate that a single zero-shot ConvergeAB™ campaign can deliver a biobetter molecule with significantly improved affinity and a clean developability profile, without compromising the parental antibody’s drug-like properties.