Definition

A protease-activated prodrug T-cell-engager (TCE) composed of two tandem single chain variable fragments (scFvs) targeting the tumor-associated antigen (TAA) human epidermal growth factor receptor 2 (EGFR2; HER2; ErbB2) and CD3, a T-cell surface antigen, and conjugated, via a protease-cleavable linker, to two unstructured polypeptides (XTEN), with potential immunomodulating and antineoplastic activities. Double XTEN masking allows for universal masks that sterically hinder target binding of AMX-818 until cleaved by proteases; it also prolongs half-life. Upon intravenous administration of anti-HER2/CD3/XTEN protease-activated TCE AMX-818, the XTEN masks are proteolytically cleaved in the tumor microenvironment (TME) by dysregulated proteases at the base of the XTEN masks which releases the active TCE. The anti-HER2 scFv moiety targets and binds to HER2 expressed on tumor cells. The CD3 scFv moiety targets and binds to T cells. The resulting cross-linkage may trigger a potent cytotoxic T-lymphocyte (CTL) response against HER2-expressing tumor cells. HER2, a receptor tyrosine kinase (RTK) mutated or overexpressed in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. The XTEN masks allows specific activation of AMX-818 in the TME and limits systemic unmasking; this minimizes systemic toxicity and increases efficacy. In healthy tissues, where protease activity is tightly regulated, the HER2-XTENylated protease-activated T-cell-engager (XPAT) AMX-818 remains predominantly inactive.