Development of First-in-class Drugs for Triple Negative Breast Cancer based on Antibody-mimic Recombination Proteins

Abstract

TNBC, the term triple-negative breast cancer, describes a subtype of breast cancer that lacks expression of estrogen (ER), progesterone receptor (PR), and human epidermal growth factor 2 receptor (HER2). In recent, Antibody-drug conjugate (ADC) is emerging as a promising agent for treating TNBC. It enables selective delivery to tumors by using the properties of antibodies that recognize specific antigens. However, developing ADCs requires overcoming high hurdles in synthesis and purification with antibodies. Therefore, herein, a novel TNBC treatment system has been developed that overcomes the disadvantages of ADC. The synthesis and purification process was shortened through supramolecular binding using substrate-specific binding. Since this recombinant protein has a binding pocket that can specifically bind to the substrate attached to the linker, the structure of “anticancer drug-linker-affibody attached recombinant protein” can be constructed. The anticancer drug-linker was designed for self-assembly. The hydrophobic drug is located on the core, and the hydrophilic substrate is exposed to the surface of a self-assembly form, and when recombinant protein is bound to this surface, a "protein-coated self-assembled structure" can be formed which can target TNBC. The camptothecin (CPT) was modified to form a disulfide bond with cysteine of Glutathione (GSH). It can convert to the original parent CPT drug when the disulfide bond is cleavaged. GSH was used as the substrate, and Glutathione-S-Transferase (GST) having a binding pocket with GSH was used as the recombinant protein. The GST used in this study has an EGFR binding affibody that can bind to the EGFR receptor overexpressed in TNBC, and thus has a targeted ability against TNBC.