Antibody conjugation of paclitaxel enables aqueous compatibility and enhances tumor-targeted efficacy in vitro and in vivo.

INTRODUCTION

Paclitaxel (PTX) remains a widely used chemotherapeutic agent for treating diverse solid tumors, but its clinical utility is constrained by pronounced hydrophobicity, which necessitates the use of formulation surfactants and contributes to a narrow therapeutic window. To overcome these limitations, we developed a TROP2-targeted antibody-drug conjugate (ADC) designed for selective and solvent-free delivery of PTX.

METHODS

The ADC, designated hRS7-PTX, was generated by conjugating PTX to the humanized anti-TROP2 monoclonal antibody (hRS7) through a rationally engineered, PEGylated, protease-cleavable linker. The conjugate was characterized for its physicochemical stability, solubility, and antigen-dependent cytotoxic activity in vitro. In vivo efficacy and biodistribution were evaluated in murine xenograft models of TROP2-expressing tumors.

RESULTS

hRS7-PTX demonstrated high aqueous stability and maintained favorable physicochemical properties without the need for organic co-solvents. In vitro, the ADC induced potent, antigen-dependent cytotoxicity, preferentially killing TROP2-positive tumor cells while sparing antigen-negative cells. In murine xenograft models, hRS7-PTX treatment produced sustained tumor regression and significantly outperformed weight-equivalent doses of conventional PTX formulations. Fluorescence imaging further confirmed rapid and preferential accumulation of hRS7-PTX within TROP2-rich tumor tissues.

DISCUSSION: These findings establish hRS7-PTX as an effective, solvent-free strategy for targeted PTX delivery that expands the therapeutic index of this widely used drug. The combination of selective tumor targeting, improved tolerability, and robust antitumor activity supports the further development of hRS7-PTX for the treatment of TROP2-positive malignancies.