Biochimie, 2025

Bispecific targeting system based on DARPins-modified light-chain ferritin for cancer chemotherapy

Cancer continues to be one of the leading causes of death worldwide. Due to genome instability, solid tumors are characterized by high heterogeneity of tumor-associated antigen expression, which makes a great challenge for targeted tumor therapy. Targeting two molecular receptors overexpressed on tumor cells is a way to overcome this problem and improve therapeutic efficacy. In this study we used truncated ferritin L-subunit (FTLsh, lacking 34 a.a. at the carboxyl terminus) as a scaffold for creating a hybrid protein for simultaneous targeting on human epidermal growth factor receptor 2 (HER2) and epithelial cell adhesion molecule (EpCAM), both of which are frequently overexpressed in epithelial carcinomas. As HER2/EpCAM-specific binders we use proteins of non-IgG nature based on ankyrin repeats (Designed Ankyrin Repeat Proteins) - DARPin_9-29 and DARPin-EC1. The hybrid protein DARP_9-29-FTLsh-EC1 generated by genetic method was conjugated to monomethyl auristatin E (MMAE). The protein-drug conjugate DARP_9-29-FTLsh-EC1/MMAE was shown to be mainly composed of dimeric form. The receptor-specific binding and internalization properties of DARP_9-29-FTLsh-EC1 fusion protein were confirmed by flow cytometry and confocal microscopy. In vitro cytotoxicity was shown to be HER2/EpCAM specific and strongly correlated to receptor density. In vivo studies have shown that DARP_9-29-FTLsh-EC1/MMAE is selectively accumulated in HER2/EpCAM-positive tumors in a mouse xenograft model causing significant tumor reduction. Our results demonstrate that bispecific targeting opens new prospects for the development of precise anticancer therapy.

Frolova AY, Shramova EI, Kakuev DL, Martynov VI, Pakhomov AA, Deyev SM, Proshkina GM

Department of immunology, Laboratory of molecular immunology, Laboratory of molecular theranostics

: 10.1016/j.biochi.2025.10.003
: 41067694
IBCH: 12204
Ссылка на статью в журнале: https://linkinghub.elsevier.com/retrieve/pii/S0300908425002275
Нет данных о цитировании
Данные статьи проверены модераторами 2025-11-02

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