Pan-cancer distribution of cleaved cell-surface amphiregulin, the target of the GMF-1A3 antibody drug conjugate

Kristopher A Lofgren; Nicolette C Reker; Sreeja Sreekumar; Paraic A Kenny

doi:10.1093/abt/tbac020

Pan-cancer distribution of cleaved cell-surface amphiregulin, the target of the GMF-1A3 antibody drug conjugate

Antib Ther. 2022 Aug 1;5(3):226-231. doi: 10.1093/abt/tbac020. eCollection 2022 Jul.

Authors

Kristopher A Lofgren¹, Nicolette C Reker¹, Sreeja Sreekumar¹, Paraic A Kenny^{1

2}

Affiliations

¹ Kabara Cancer Research Institute, Gundersen Medical Foundation, La Crosse, WI 54601, USA.
² Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA.

Abstract

Amphiregulin is a transmembrane protein which, when cleaved by the TACE/ADAM17 protease, releases a soluble epidermal growth factor receptor ligand domain that promotes proliferation of normal and malignant cells. We previously described a rabbit monoclonal antibody, GMF-1A3, that selectively recognizes the cell-associated cleaved amphiregulin epitope. Antibody-drug conjugates had anti-tumor activity against human breast cancer xenografts. Several tumor types express amphiregulin, but evidence for a functional requirement for amphiregulin in these malignancies is limited. By directly evaluating amphiregulin cleavage with immunohistochemistry, GMF-1A3 provides a more direct measure of amphiregulin activity. Using 370 specimens from 10 tumor types (as well as normal controls), we demonstrate that cleaved amphiregulin is widely expressed in solid tumors and is especially common (> 50% of cases) in breast, prostate, liver and lung cancer. As a potential companion diagnostic for this antibody-drug conjugate, this assay allows identification of tumors with high levels of the cleaved amphiregulin target.

Keywords: amphiregulin; antibody-drug conjugate; monomethyl auristatin E; tissue microarray.