RT Journal Article
SR Electronic
T1 Pan-cancer distribution of cleaved cell-surface Amphiregulin, the target of the GMF-1A3 antibody drug conjugate
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.03.10.483840
DO 10.1101/2022.03.10.483840
A1 Kristopher A. Lofgren
A1 Nicolette C. Reker
A1 Sreeja Sreekumar
A1 Paraic A. Kenny
YR 2022
UL http://biorxiv.org/content/early/2022/03/12/2022.03.10.483840.abstract
AB Amphiregulin (AREG) is a transmembrane protein which, following TACE/ADAM17-dependent cleavage, releases a soluble Epidermal Growth Factor Receptor ligand domain that promotes proliferation of normal and malignant cells. Expression of Amphiregulin has been described by immunohistochemistry in several tumor types, including lung, prostate, head and neck, gastric, pancreatic and breast cancers but evidence for a functional requirement for Amphiregulin in these malignancies is more limited. We have previously described the development of a monoclonal antibody, GMF-1A3, that selectively recognizes the Amphiregulin epitope that is revealed following cleavage by TACE/ADAM17 and demonstrated that drug conjugates of this antibody have anti-tumor activity in mouse models. By directly evaluating Amphiregulin cleavage, immunohistochemistry on tissue specimens using this antibody can be used to evaluate the extent to which Amphiregulin is being proteolytically processed in cancer, which is a more direct measure of Amphiregulin activity. As a potential companion diagnostic for this antibody-drug conjugate, this immunohistochemistry assay allows identification of tumors with high levels of the cleaved Amphiregulin target. Here we evaluate levels of cleaved Amphiregulin in 370 specimens from 10 tumor types and demonstrate that it is widely expressed in solid tumors and is especially common (more than 50% of cases) in breast, prostate, liver and lung cancer.Competing Interest StatementKL, SS and PK are inventors on a patent application (US 63/211,356) describing the antibodies used in this manuscript.