Cleaved amphiregulin transmembrane stalk neo-epitope (AREG stalk neo-epitope)

Amphiregulin (AREG) is a member of the epidermal growth factor (EGF) family, synthesized as a single-pass transmembrane precursor known as pro-AREG (UniProt P15514). It is proteolytically processed at the cell surface by the metalloprotease TACE/ADAM17, which releases the soluble EGFR ligand domain to promote proliferation and survival in both normal and malignant cells (Lofgren et al., 2021). This cleavage event leaves behind a residual cell-associated transmembrane stalk that is subsequently internalized by the cell. This stalk contains a neo-epitope that is only revealed after cleavage and is not present in the full-length, uncleaved protein, providing a highly specific target for therapeutic intervention (Kenny, 2023). In cancers with high rates of AREG shedding, such as breast, lung, prostate, and colorectal cancers, this neo-epitope is significantly upregulated. Antibody-drug conjugates (ADCs) targeting this specific fragment, such as GMF-1A3-MMAE, have demonstrated the ability to induce rapid tumor regression in preclinical models by selectively delivering cytotoxic payloads to cells with active AREG processing (Lofgren et al., 2021).

Other names

Pro-amphiregulin stalkCleaved pro-AREGAREG neo-epitopeCell-associated AREG cleavage productAmphiregulin transmembrane stalk

Antibody-drug conjugate (ADC) targeting the neo-epitope for intracellular delivery of a cytotoxin (e.g., MMAE) following target-mediated internalization.