Development of Novel Lysosome-Targeting Chimera by Non-covalent-Type Fc-IGF2 Complex (Fc-LYTAC) for Target Membrane...

The development of selective inducers of extracellular or membrane protein degradation has attracted attention as next-generation drugs. Herein, we report a novel lysosome-targeting chimera (LYTAC) comprising a fusion protein (G67-(GGGGS)_n-IGF2), in which insulin-like growth factor 2 (IGF2) is linked to an Fc-binding peptide derived from protein G (G67) via several repeats of a GGGGS linker (n = 0-3). G67-(GGGGS)_n-IGF2 forms non-covalent complexes with the Fc region of the Fc domain-containing proteins. The trastuzumab-based human epidermal growth factor receptor 2 (HER2) targeting Fc-LYTAC (FcL-2) markedly induced HER2 degradation. The HER2 degradation activity of FcL-2 was inhibited by the inhibition of lysosomal activities, indicating that Fc-LYTAC induces target protein degradation via the endocytosis-lysosomal pathway. The Fc-LYTAC methodology could be extended to epidermal growth factor receptor-binding antibodies and even Fc-tagged HER2-binding single-chain variable fragments. These results provide an innovative strategy for the conversion of membrane protein-binding molecules with an Fc region into efficient target protein degradation inducers.