Preclinical Proof of Concept for the Single-Protein Anticancer Molecule Targeting Both a Tumor Surface Antigen and an Intracellular Oncoprotein

초록

Although antibody-drug conjugates (ADCs) are a widely used platform for developing various anticancer immunotherapeutics, the use of cancer non-selective chemicals is recognized as a drawback of ADC development. To address the issues regarding the safety and manufacturing complexity of ADCs, this study conceptualizes a single-protein platform, named dual-targeting anticancer therapeutics (DTAT), that links a cancer cell-selective cytotoxic peptide to an antibody via a linker peptide cleavable on cancer cells. As a model molecule for preclinical proof of the concept, an anti-Her2 single-chain variable fragment (scFv)-based DTAT protein named DTAT-D311 is established, which contains a recently developed anticancer peptide, herein named CPTin, as its cell-penetrating payload. This recombinant single protein efficiently induces the apoptotic death of cancer cells, which is characterized by a very early onset. In terms of in vivo efficacy in suppressing tumor growth, DTAT-D311 outperforms the anti-Her2 therapeutic antibody, trastuzumab (Herceptin). By targeting an intracellularly addictive oncoprotein, CP2c, CPTin exhibits broad-spectrum anticancer activity. In conclusion, this study demonstrates that DTAT provides an innovative pharmaceutical modality to target both a tumor surface antigen and an intracellular oncoprotein. In addition, DTAT-D311 is suggested to be a promising biopharmaceutical agent for targeted immunotherapy against Her2-positive cancers, exhibiting favorable safety profile. © 2025 Wiley-VCH GmbH.

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