A Bispecific Antibody Engineering Strategy for Effective Dual-Target Degradation of Cell-Surface and Secreted...

Area of Science:

• Oncology
• Immunology
• Biotechnology

Background:

• Tumor progression relies on complex signaling between cancer cells and the tumor microenvironment (TME).
• Targeting oncogenic drivers and their ligands is crucial for effective cancer therapy.
• Current antibody therapies often face limitations in achieving comprehensive signaling blockade.

Purpose of the Study:

• To develop a novel bispecific antibody-based strategy for simultaneous degradation of membrane-bound and secreted proteins.
• To engineer a dual degradation system targeting HER2 and VEGF-A for enhanced anti-cancer effects.
• To evaluate the efficacy of this new therapeutic modality in preclinical cancer models.

Main Methods:

• Engineered a human bispecific IgG1 antibody, termed BsST (Bi-SignalTAC), incorporating a lysosome-targeting peptide.
• BsST was designed to simultaneously bind HER2 (oncogenic driver) and VEGF-A (TME-derived ligand).
• Utilized the intrinsic cellular lysosomal degradation pathway for simultaneous protein depletion.

Main Results:

• BsST achieved efficient, simultaneous degradation of both HER2 and VEGF-A.
• This dual degradation led to significant tumor growth shutdown and potent antiangiogenic effects.
• BsST demonstrated superior efficacy compared to the combination of trastuzumab and bevacizumab in xenograft models.

Conclusions:

• Bispecific signal-mediated lysosome-targeting chimera (BsST) offers a powerful dual degradation strategy for targeting cancer drivers and TME ligands.
• This approach surpasses conventional antibody blockade by leveraging cellular degradation machinery.
• The modular design of BsST allows for adaptability to target other extracellular antigen pairs in various diseases.