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

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.

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“…Amphiregulin and IL-10 are involved in muscular regeneration [ 71 ], epithelial regeneration [ 72 ] neural repair [ 73 ], and wound healing [ 74 ]. However, their role in the development of tumours has also been shown [ 75 ]. Recent studies revealed that amphiregulin is produced by senescent cells and its presence is a negative background provoking expression of programmed cell death 1 ligand (PD-L1) and cancer development [ 76 , 77 ], ( Figure 2 ).…”