A Bispecific Antibody Engineering Strategy for Effective Dual-Target Degradation of Cell-Surface and Secreted Oncoproteins with Superior Antitumor Activity

Tumor progression is driven by reciprocal signaling between cancer cells and the tumor microenvironment (TME). In this study, we present a bispecific signal-mediated lysosome-targeting chimera (Bi-SignalTAC, BsST), a dual degradation strategy that leverages the intrinsic cellular sorting machinery to concurrently direct membrane-bound oncogenic drivers and their TME-derived protein ligands to lysosomes for degradation. We engineered a human bispecific IgG1 that simultaneously binds to both HER2 and VEGF-A, incorporating a lysosome-targeting peptide at the C-terminus of both heavy and light chains. This knobs-into-holes IgG, designated as BsST, facilitates the efficient dual degradation of HER2 and VEGF, simultaneously achieving tumor growth signaling shutdown and antiangiogenic effects that surpass those of conventional antibody blockade. Our approach demonstrates enhanced efficacy compared to the combination of trastuzumab and bevacizumab in xenograft models. This bispecific degradation strategy serves as a valuable therapeutic modality for the simultaneous depletion of both membrane-bound and secreted proteins. Furthermore, its modular design makes this dual-target degradation technology readily adaptable to other disease-relevant extracellular antigen pairs.