New Publication by Yumab: Novel bispecific T-cell engagers overcoming acquired EGFR resistance

In a paper newly published in mAbs, Universität Stuttgart-, Technical University of Braunschweig-, and YUMAB GmbH-based authors reveal research results for novel antagonistic anti-EGFR antibodies that have potential to overcome resistance to current T-cell engagers against the same target.

ABSTRACT

Epidermal growth factor receptor (EGFR) is a validated therapeutic target in several human cancers harboring wild-type KRAS. However, intrinsic and acquired resistance to EGFR-targeted antibody therapies such as cetuximab remains a major limitation to achieving broad and durable treatment responses. Extensive clinical and translational studies have shown that resistance frequently arises from missense mutations within the extracellular domain (ECD) of EGFR. In this study, we developed novel antagonistic EGFR antibodies that bind epitopes overlapping but distinct from the cetuximab-binding site while retaining high affinity for all major EGFR ECD escape variants. Antibody binding effectively inhibited EGFR phosphorylation, downstream signaling, and tumor cell proliferation. The antibodies were further engineered into bispecific EGFR × CD3 T-cell engagers (TCEs) with either 1 + 1 or 2 + 1 stoichiometries. In contrast to cetuximab-based TCEs, the newly developed EGFR-directed TCEs efficiently induced T cell-mediated cytotoxicity against tumor cells expressing wild-type EGFR as well as the clinically relevant ECD escape variants S492R and G465R. Anti-tumor activity was additionally demonstrated in an EGFR-expressing CT-26 syngeneic tumor model in vivo. Collectively, these findings define a promising therapeutic strategy to overcome resistance to current EGFR-targeted therapies and provide a strong rationale for the development of next-generation T-cell – redirecting therapies in patients with EGFR-positive malignancies.

Kühl, L., Löffler, A. K., Seifert, O., Michler, D., Kuhlmann, M., Russo, G., … Kontermann, R. E. (2026). Novel bispecific T-cell engagers overcoming acquired EGFR resistance. mAbs, 18(1). https://doi.org/10.1080/19420862.2026.2674236

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