Following the established objectives during Polybraint, first, the validation of the technical feasibility and effectiveness of our nanocarrier platform for the i.n. delivery of biologics was achieved. We conjugated the antibody PD-1, fully characterized, and studied its efficacy and safety in a wild-type murine model after intranasal administration, demonstrating that the presence of the polymeric nanocarrier, as well as the vehicle (a permeation enhancer hydrogel), are key to achieving enhanced performance compared with the standard of care (free PD-1 antibody in the clinics intranasally as well as intraperitoneally, a normal administration route for this antibody in preclinical studies). For oxytocin transportation, conjugation was not possible due to oxytocin stability issues, and an alternative PGA nanocarrier with capabilities for drug encapsulation was developed. Studies in vivo (biodistribution as well as pharmacological activity) are ongoing. Alternatively to oxytocin and through an extended collaboration with research teams at VHIR and Univ Autonoma Barcelona, the conjugation with the protein GBA with an adapted strategy and the demonstration of its effectiveness as enzyme replacement therapy in a Parkinson's disease murine model were also achieved (patent filed). Again, as in the case of PD-1, demonstrating the need for the use of both components, the polypeptidic nanocarriers and the hydrogel acting as a vehicle for intranasal delivery.
In parallel, we have studied brain distribution by optical imaging, showing differences depending on the brain area, mainly due to the different cell population (deeper understanding in this line is ongoing). In addition, to overcome the resolution limitation of this technique, the conjugates were labeled with DTPA-Gd, and their brain biodistribution is being explored also by MRI at Univ Barcelona with our collaborators. Both immunoconjugates tested in vivo maintain cargo functionality: in PD-1 in the wild-type animal and now it is being explored in a glioblastoma model (Univ Barcelona); and the GBA protein in a Parkinson's disease model (VHIR). Additional experiments not planned but enriching those results obtained include the implementation of microfluidics to control crosslinking strategies and optimized biologic conjugate synthesis towards industrial scale-up and cost-effective manufacture. With all these experiments, it is believed that the readiness of the technology moves from TRL 2-3 to TRL 5-6.
Work performed under objectives/tasks 2 and 3 include a patentability report for the hydrogel/nanocarrier as an i.n. platform and a Freedom to Operate study, both of them positive. Together with a possible market study for i.n. strategies, we are currently discussing possibilities to advance towards translation.
In summary, In Polybraint, we have (1) confirmed the transportation of the biologic cargo with pharmacological functionality; (2) conducted benchmark studies with the parent biologics after intranasal and also intravenous (GBA) and intraperitoneal (PD-1) administration; (3) established an IP strategy, acquired IP protection for GBA derivatives and performed freedom to operate analysis as well as started to assess the future commercialization feasibility to move this interesting technology forward as the vehicle as well as the nanconjugate part of the intranasal formulation are key elements to effectively deliver biologics to the brain.
