Antibody-Targeted Covalent Inhibitor Conjugate (Ab-TCI) Bridged by an Arsenic-Thiol Bond Enables "Double Insurance" Targeting of Cancer Cells and Kinase for Effective Cancer Treatment.

Targeted covalent inhibitors (TCIs), a class of pharmaceuticals that specifically recognize disease-related proteins and form covalent bonds for precise therapy, still suffer from side effects and diminished efficacy due to poor tumor cell specificity. To address this, we present a new cell/protein "Double Insurance" targeting strategy through constructing a novel antibody-TCI conjugate (Ab-TCI), which comprises a monoclonal antibody (Loncastuximab), a TCI (As-Ibt) for Bruton's tyrosine kinase (BTK), and between them an arsenic-thiol bond as a new cleavable linker. This Ab-TCI enables B-cell lymphoma cell recognition, internalization, and release of As-Ibt by intracellular GSH, efficiently inhibiting BTK, and effectively suppressing the growth of xenograft tumors. To our knowledge, this is the first Ab-TCI enabling simultaneous dual targeting capabilities for cancer cells and kinase, achieving a remarkable improvement in drug efficacy. New potent dual-targeting Ab-TCIs could be inspired by integrating different FDA approved TCIs and antibodies through our strategy for cancer treatment.