Development of recombinant Mesozumab-CPTin that dual-targets mesothelin and CP2c for anticancer therapy.

Current pharmacotherapeutics using antibody-drug conjugates (ADCs) for cancer therapy present limitations, such as off-target effects and safety concerns. To address them, we have developed CPTin, a cell-penetrating, cancer cell-specific cytotoxic peptide that disrupts the oncogenic properties of CP2c, and have established an ADC-like, single-protein platform, named dual-targeting anti-cancer therapeutics (DTAT). DTAT is composed of cancer cell-specific monoclonal antibodies (mAbs) attached to a cell-penetrating cytotoxic payload targeting an addictive oncoprotein CP2c (CPTin) via a cleavable linker, recognized by the matrix metalloproteinase-11. Based on this DTAT platform, we designed an anti-mesothelin (MSLN) mAb extended to include two CPTins, herein referred to as Mesozumab-CPTin. Mesozumab-CPTin exhibited remarkable utility with high productivity and stability. It efficiently promoted pancreatic cancer cell death without causing non-cancerous cytotoxicity from the early phase, showing anti-cancer properties than the commercial therapies including Cisplatin, Abraxane, Gemcitabine, and their combination treatment. In xenograft mice models for pancreatic cancer, Mesozumab-CPTin displayed lower average values in tumor volume and well-tolerated without significant side effects in a single high-dose acute toxicity assessment, compared to the anti-MSLN ADC Anetumab ravtansine. Mesozumab-CPTin is a genetically engineered peptide-based biomaterial to overcome limitations of traditional ADCs, which is a novel therapeutic candidate with stability and safety for pancreatic cancer.