Front Immunol, 2023, 14:1098302

Single-domain antibody delivery using an mRNA platform protects against lethal doses of botulinum neurotoxin A

Single-domain antibodies (sdAbs, VHHs, or nanobodies) are a promising tool for the treatment of both infectious and somatic diseases. Their small size greatly simplifies any genetic engineering manipulations. Such antibodies have the ability to bind hard-to-reach antigenic epitopes through long parts of the variable chains, the third complementarity-determining regions (CDR3s). VHH fusion with the canonical immunoglobulin Fc fragment allows the Fc-fusion single-domain antibodies (VHH-Fc) to significantly increase their neutralizing activity and serum half-life. Previously we have developed and characterized VHH-Fc specific to botulinum neurotoxin A (BoNT/A), that showed a 1000-fold higher protective activity than monomeric form when challenged with five times the lethal dose (5 LD) of BoNT/A. During the COVID-19 pandemic, mRNA vaccines based on lipid nanoparticles (LNP) as a delivery system have become an important translational technology that has significantly accelerated the clinical introduction of mRNA platforms. We have developed an mRNA platform that provides long-term expression after both intramuscular and intravenous application. The platform has been extensively characterized using firefly luciferase (Fluc) as a reporter. An intramuscular administration of LNP-mRNA encoding VHH-Fc antibody made it possible to achieve its rapid expression in mice and resulted in 100% protection when challenged with up to 100 LD of BoNT/A. The presented approach for the delivery of sdAbs using mRNA technology greatly simplifies drug development for antibody therapy and can be used for emergency prophylaxis.

Panova EA, Kleymenov DA, Shcheblyakov DV, Bykonia EN, Mazunina EP, Dzharullaeva AS, Zolotar AN, Derkaev AA, Esmagambetov IB, Sorokin II, Usachev EV, Noskov AN, Ivanov IA, Zatsepin TS, Dmitriev SE, Gushchin VA, Naroditsky BS, Logunov DY, Gintsburg AL

IBCH: 10592
Ссылка на статью в журнале: https://www.frontiersin.org/articles/10.3389/fimmu.2023.1098302/full
Кол-во цитирований на 10.2026: 31
Данные статьи проверены модераторами 2023-03-13

Список научных проектов, где отмечена публикация

  1. 121102500071-6. . Внебюджетное финансирование.