anti-EGFR/anti-CD3 tumor protease-activated T-cell engager JANX008

A protease-activated, double masked tumor activated T-cell engager (TCE) composed of a tumor-associated antigen (TAA) binding domain that targets epidermal growth factor receptor (EGFR) and a T-cell binding domain that targets CD3, that are both conjugated, via a tumor protease-cleavable linker, to a peptide mask that prevents binding of the EGFR-binding domain to EGFR-expressing tumor cells and binding of the CD3-binding domain to T cells, respectively, and an albumin-binding domain that extends circulating half-life, with potential immunomodulating and antineoplastic activities. Upon intravenous administration of anti-EGFR/anti-CD3 tumor protease-activated TCE JANX008, the tumor protease-cleavable linkers are proteolytically cleaved in the tumor microenvironment (TME), which separates both the EGFR-binding domain and the CD3-binding domain of JANX008 from their respective peptide masks, thereby allowing the binding domains to bind to their respective targets. The EGFR-binding domain targets and binds to EGFR expressed on tumor cells. The CD3-binding domain targets and binds to T cells. The resulting cross-linkage triggers a cytotoxic T-lymphocyte (CTL) response against EGFR-expressing tumor cells in the TME. EGFR, a receptor tyrosine kinase, is overexpressed on the surfaces of various tumor cell types. The albumin-binding domain, which is attached to the CD3-binding domain mask, binds to albumin in the circulation, thereby extending the half-life of JANX008. While in circulation, the two tumor protease-cleavable peptide masks inhibit EGFR and CD3 binding and may prevent cytokine release syndrome (CRS) and on-target EGFR healthy tissue toxicity while increasing its efficacy when activated in the TME.