Acuitas Therapeutics unveiled significant advancements in lipid nanoparticle (LNP) technology at the 13th International mRNA Health Conference in Berlin, presenting next-generation formulations designed to enhance therapeutic potency, expand delivery beyond the liver, and enable broader clinical applications. The Vancouver-based company, whose LNP technology enabled the Pfizer-BioNTech COVID-19 vaccine, demonstrated multiple breakthrough innovations that could accelerate the development of mRNA-based therapeutics across diverse disease areas.
Enhanced Potency and Safety Profiles
Chief Scientific Officer Dr. Ying Tam presented comprehensive data on the company's next-generation LNP platform, showcasing novel candidates engineered for significantly improved potency. The new formulations demonstrated up to fourfold increases in effectiveness for gene editing and vaccine applications compared to current standards. Importantly, optimized lipid structures achieved reduced liver exposure while preserving therapeutic activity in preclinical mouse models, leading to increased tolerability and lowered liver enzyme levels.
"Commercial validation of our technology has provided both an important milestone of success and the impetus for continued advancement," said Dr. Thomas Madden, CEO of Acuitas Therapeutics. "Our research, presented at the mRNA Health Conference, is focused on two key goals: expanding the application of our technology into new therapeutic areas and enhancing the potency and safety of the platform itself."
Targeted Delivery Breakthroughs
The company achieved significant progress in targeted delivery systems, developing DARPin-conjugated LNP candidates that demonstrated highly targeted delivery to immune cells, specifically T-lymphocytes. A long-circulating format further enhanced uptake efficiency and expression levels, potentially enabling more precise therapeutic interventions.
For respiratory applications, Acuitas developed mucous penetrant mRNA-LNP candidates capable of extrahepatic delivery to airway epithelial cells in cystic fibrosis lung models. These formulations enabled effective gene editing compared to control LNPs, suggesting potential applications for treating genetic lung diseases.
Manufacturing Innovation
The company introduced an alternative LNP manufacturing approach called pre-formed vesicles (PFV), which demonstrated equivalent potency to standard benchmark manufacturing methods while offering significant improvements in cost, storage, distribution, and manufacturing flexibility. This innovation could prove particularly valuable for personalized mRNA-LNP therapies, where manufacturing scalability and cost-effectiveness are critical considerations.
Cancer Vaccine Applications
Acuitas conducted extensive research on applying its clinically approved ALC-315™ ionizable lipid—used in the Pfizer-BioNTech COVID-19 vaccine—for cancer vaccine development. The studies directly compared Acuitas' LNP formulations to lipoplexes and evaluated different mRNA modifications.
Key findings revealed that unmodified RNA delivered via ALC-315™-based LNPs induced stronger antigen-specific CD8 T-cell responses compared to nucleoside-modified mRNA incorporating N1methylpseudouridine-encoding OVA payload as a model tumor antigen. Remarkably, this superior response was maintained at one-tenth of the initially tested dose, suggesting improved therapeutic efficiency.
When comparing delivery methods, intramuscular administration of mRNA using ALC-315™-based LNPs induced equal or superior cellular and humoral immunity compared to intravenously administered mRNA lipoplexes, despite the lipoplexes being administered at four-fold higher doses with additional booster injections.
Novel Lipid Development
The company identified and validated six novel proprietary lipids that demonstrated superior performance characteristics compared to ALC-315™. These candidates induced equivalent neutralizing antibody titers at five-fold lower doses while maintaining favorable reactogenicity profiles comparable to ALC-315™. The novel lipids also elicited stronger cellular and B-cell responses and achieved higher in vivo expression in secondary lymphoid organs with reduced liver expression.
Translational Safety Research
Acuitas conducted important translational research examining how body weight, premedications, and concomitant medications impact LNP activity and tolerability in nonhuman primates. The study used intravenously administered mRNA-LNP encoding human IgG and revealed several clinically relevant findings.
LNP tolerability was reduced in larger monkeys weighing more than 6 kg, while premedications including steroids and H1/H2 blockers helped reduce liver transaminase elevation. However, these premedications improved tolerability at the cost of reduced IgG mRNA expression levels. Platelet count decreases were most pronounced in large monkeys and those receiving meloxicam.
Clinical Impact and Future Directions
The research represents a significant advancement in mRNA delivery technology, building on Acuitas' established clinical success. The company's LNP technology has already enabled multiple groundbreaking therapeutics, including ONPATTRO® for transthyretin amyloidosis, the first in-human proof of concept for genome base editing, and the first personalized CRISPR therapy.
These next-generation improvements could accelerate the development of targeted LNPs for extrahepatic and in vivo CAR T-cell therapies, epigenetic medicines, multivalent vaccines for infectious diseases including malaria, HIV/AIDS, and tuberculosis, as well as personalized cancer vaccines. The enhanced potency, improved safety profiles, and expanded targeting capabilities position the technology to address a broader range of therapeutic applications while potentially reducing dosing requirements and associated costs.
