From Bee Venom to Blood-Brain Barrier Shuttles. Development of Minimized Apamin Derivatives for Brain Delivery of Antibodies and other Cargoes

Benjamí Oller Salvia

Dra.Meritxell Teixidó Prof. Erenest Giralt

This research led to the development of novel brain-targeting peptide shuttles inspired by apamin, a bee venom peptide capable of crossing the blood-brain barrier (BBB). Through rational design, non-toxic and low-immunogenic analogues—termed mini-apamins—were engineered, retaining the ability to cross the BBB via active transport. Among these, MiniAp-4 showed superior permeability and was able to enhance the transport of various molecules in both in vitro human BBB models and in vivo murine systems. The work has resulted in a patent application and publication in Angewandte Chemie. A second part of the project applied these shuttle peptides to improve brain delivery of therapeutic antibodies targeting glioblastoma (GBM), a highly aggressive brain tumor. Since the BBB remains intact in the invasive front of GBM, conventional therapies fail to reach these regions. The project developed and optimized peptide–antibody conjugates, ensuring stability and preservation of therapeutic activity. These conjugates showed enhanced BBB translocation in cellular models. Production is now being scaled to provide material for in vivo testing in patient-derived GBM mouse models at VHIO under the direction of Prof. Joan Seoane.

A new peptide capable of transporting a wide range of substances to the brain has been discovered. This peptide has been patented and the application proposal described here consists of demonstrating that it is capable of increasing the therapeutic efficiency of a relevant drug in order to license the patent to a company. In this way, the investment made up to this point could have a social and economic return for the country. The diseases chosen are two types of glioma and Friedreich's ataxia because, being rare pathologies, they would facilitate development in clinical phases. Furthermore, the technology discovered has the potential to be applied to most brain conditions, in which the blood-brain barrier prevents existing drugs from reaching their targets in sufficient concentrations. In this way, it is hoped that the project can, firstly, improve the quality of life of many patients and, secondly, generate economic activity around the development and potential commercialization of drugs.

ovel Brain-Targeting Peptide Shuttles; Apamin; Bee Venom Peptide; Blood-Brain Barrier (BBB); Rational Design; Non-Toxic Analogues; Low-Immunogenic Analogues; Mini-apamins; Active Transport; MiniAp-4; Superior Permeability; Enhanced Transport; In Vitro Human BBB Models; In Vivo Murine Systems; Patent Application; Publication; Angewandte Chemie; Shuttle Peptides; Brain Delivery; Therapeutic Antibodies; Glioblastoma (GBM); Aggressive Brain Tumor; BBB Intact; Invasive Front; Conventional Therapies; Peptide–Antibody Conjugates; Stability; Preservation of Therapeutic Activity; Enhanced BBB Translocation; Cellular Models; Production Scaling; In Vivo Testing; Patient-Derived GBM Mouse Models;