DUBLIN – Ethris GmbH and Neurimmune AG have formed a collaboration to develop nebulized, mRNA-encoded monoclonal antibodies directed at SARS-CoV-2, which will be delivered directly to the lungs of patients with COVID-19. The two partners aim to start manufacturing mRNA drug product over the summer, in order to start clinical trials – pending regulatory approval – during the fourth quarter of this year.
As well as offering delivery of a therapeutic payload to the main site of infection, the combination of the two technologies offers a precious gain in time. Establishing a conventional cell line for producing a monoclonal antibody takes 12 to months. The mRNA route is a lot quicker.
The 50-50 partnership draws on Neurimmune’s longstanding experience of screening antibody repertoires from recovered patients or from healthy individuals who have never succumbed to a disease of interest with Ethris’ mRNA stabilization and delivery technologies. “We really are combining here two differentiated technologies,” Fabian Buller, chief business officer at Schlieren, Switzerland-based Neurimmune, told BioWorld. “For us, it’s natural to apply our technology to COVID-19 patients who have recovered.”
The resulting antibodies will be encoded in mRNA for localized expression within the lungs, rather than administered directly as biologic drugs. “We are envisaging, out of the box, a relatively short duration of therapy,” Gita Dittmar, CEO of Planegg, Germany-based Ethris, told BioWorld. Ethris’ Stabilized Non-Immunogenic mRNA (Snim RNA) technology has not yet entered the clinic, but it is key to an ongoing drug discovery alliance in chronic lung diseases with Cambridge, U.K.-based Astrazeneca plc. Before the pandemic erupted, its lead program was ETH-42, an mRNA encoding coiled coil domain-containing protein 40 (CCDC40), which is in development for primary ciliary dyskinesia, a severe genetic lung disease. “That's been scheduled to enter the clinic in the second half of 2021,” Dittmar said. The present crisis has dramatically shifted its priorities – and its timelines.
Ethris has already conducted successful in vivo proof-of-concept work in rodents and larger animals, not all of which has been disclosed. Immunogenicity and stability are the two main problems arising from direct administration of mRNA. Naked mRNA is readily degraded by extracellular and intracellular ribonucleases, but what is left can trigger host pattern recognition receptors – such as Toll-like receptor 3 (TLR3), TLR7 and TLR8 and helicase RIG-1 – and induce the production of pro-inflammatory cytokines. Different developers have different ways of minimizing one while maximizing the other, but they generally involve altering the mRNA molecule by replacing all or some uridine and cytidine bases with modified nucleotides. Ethris has not publicly disclosed details of its proprietary approach, but it involves partial replacement of those bases with either natural or unnatural nucleotides.
Efficient delivery is also key to ensuring high levels of mRNA uptake, endosomal escape and translation within the cytoplasm. “We're using a nanoparticle system,” Dittmar said. Once the antibodies are produced, they should be readily available to bind viral particles in the vicinity of the producing cells. “The beauty of the antibody, of course, is it’s a secreted molecule,” she said. Ensuring that therapeutically relevant doses of antibody are administered to the correct regions of the lung in order to reduce the viral load is the overall challenge. As the drug product that will be administered to patients is not the active substance that will deliver that benefit, the whole treatment concept depends on the optimal performance of each step in the process. “That does make it a complex system to evaluate,” Dittmar said.
The company has developed scalable manufacturing processes for GMP production and does not foresee any specific issues with scale-up for commercialization. On the administration side, Ethris is working with standard mesh nebulizers, which are portable and non-invasive. Supply is not likely to be an issue, therefore. “I would not expect that to be a constraint,” Dittmar said.
The companies have not yet determined which patients would be most appropriate for their therapy – much will depend on discussions with clinical opinion leaders and regulators. Whether this type of approach will be needed – or whether conventional antibody delivery routes will suffice – is still an open question. “We don't know yet,” Buller said. “The lung is a complex organ, and COVID-19 is a new disease.” Some preliminary reports on the successful use of convalescent plasma transfusions in critically ill patients suggest that systemic delivery of antibodies may work, but the numbers involved are too low to draw any firm conclusions at this point. Prospective trials of convalescent plasma are underway, as are trials of antibodies that are already approved in other indications, which generally target immune signaling molecules, such as interleukin-6 (IL-6) or IL-2. It is appropriate to take many approaches to combat COVID-19, Dittmar said. “Not all of them will work.”
Neurimmune is best known for its work in developing antibodies for Alzheimer’s disease. Cambridge, Mass.-based Biogen Inc.’s phase III antibody, aducanumab, emerged from a collaboration between Neurimmune and scientists at the University of Zurich. But it has conducted antiviral research, too – five years ago, company scientists reported on the discovery of neutralizing antibodies against JC polyomavirus, the causative agent of progressive multifocal leukoencephalopathy, a lethal side effect in patients undergoing aggressive immunosuppression in multiple sclerosis and other conditions. As well as potentially contributing one solution to the present crisis, this current initiative represents an opportunity to fast-track what is still an emerging technology. “We have a chance to do something really meaningful,” Dittmar said.