Multibody-Enabled Lysosome-Targeting Drug Conjugates for Target Protein Degradation and Combination Therapy

Current lysosome-targeting chimeras (LYTACs) and antibody-drug conjugates (ADCs) face inherent limitations, including reliance on monospecific binders and target-dependent internalization efficiency. Here, we report a versatile therapeutic platform that overcomes these constraints by engineering a novel class of multivalent, multispecific binding proteins, termed Multibodies . Using the fungal immunomodulatory protein LZ-8 as a scaffold, we developed a lysosome-targeting chimera-drug conjugates (LYTAC-DCs) system capable of mediating the degradation of multiple membrane proteins while enabling site-specific drug release. While wild-type LZ-8 demonstrated potent lysosomal targeting, it induced significant off-target toxicity and lysosomal dysfunction. Through rational protein engineering, we identified a key residue (Y84) responsible for promiscuous receptor binding and generated an optimized variant, LZ-8-2.3 (Y84A), which eliminated toxicity while preserving efficient lysosomal trafficking. The resulting LYTAC-DC platform mediated high-fidelity degradation of EGFR, PD-L1, and HER2 across diverse cancer models, concurrently delivering cytotoxic (e.g., MMAE) or immunogenic (e.g., doxorubicin) payloads. Efficacy was validated in patient-derived organoids and murine xenografts, including against osimertinib-resistant lung cancer. Furthermore, AI-assisted directed evolution enabled the development of non-chimeric lysosome-targeting drug conjugates (LYTA-DCs), highlighting the modularity and engineerability of the Multibody scaffold. Our work establishes a unified and programmable strategy for targeted protein degradation and drug delivery, significantly expanding the therapeutic landscape beyond conventional LYTAC and ADC technologies.