A study in Nature Communications in March 2024 presents the use of a genetically modified filamentous fungus expression system to produce a human monoclonal antibody that neutralises SARS-CoV-2 variants of concern. One of the workshops at the Congress in Washington considers monoclonal antibodies and they will be explored throughout several other sessions on the agenda, so we examined this article to see what the team behind it have achieved and what implications it might have for global health research.
The importance of monoclonal antibodies
“In recent years, industrially produced immunoglobins have become an important biopharmaceutical tool not only for the treatment of cancer, autoimmune and inflammatory diseases, but also as therapeutics for the prevention and treatment of bacterial and viral infections, such as respiratory syncytial virus and Ebola virus.”
The authors highlight that COVID-19 emphasised the importance of such prophylactics, particularly the early post-infection use of SARS-CoV-2 neutralising human monoclonal antibodies (HuMabs) in people with “high risk of hospitalisation and development of severe COVID-19″. Additionally, HuMabs presented therapeutic opportunities in “reducing fatal outcomes”.
“Although the health benefits of HuMabs necessitates large-scale production and usage, the actual usage in high-risk patients is limited by costly and complicated production procedures, even in high-income countries.”
Furthermore, the “continually evolving capacity” of the emerging variants of concern (VOCs) to “escape neutralising antibodies” complicated the use of HuMabs during the COVID-19 pandemic. Thus, the authors identify an “ongoing need to more rapidly generate HuMabs that are effective against newly emerging VOCs”.
Overcoming limitations
The researchers decided to overcome the limitations of mammalian protein expression systems by exploring an alternative process of recombinant protein production in the filamentous fungus Thermothelomyces heterothallica (C1). This is an expression system with a “naturally high biosynthesis capacity” for secretory, biomass-hydrolyzing enzymes”, and it has been “further enhanced” by genetic engineering of the wild-type fungus to achieve high production yields of industrially used enzymes.
In their work they develop a C1 expression system for the “well-characterised HuMab 87G7”, an antibody derived from H2L2 transgenic mice encoding the human immunoglobulin variable region immunised with the SARS-CoV-2 Spike (S) protein. It binds to a patch of hydrophobic residues within the RBD of the SARS-CoV-2 S protein with broadly neutralising activity against the VOCs Alpha, Beta, Gamma, Delta, and Omicron (BA.1/BA.2). The article reveals that the C1-derived HuMab 87G7 has efficacy for prophylactic and therapeutic use in hamsters and non-human primates, in the absence of antibody-mediated enhanced virus replication.
A promising alternative
The authors describe their alternative expression system as a “promising alternative” for the development of effective treatments against both infectious and non-infectious diseases. Xenogeneic expression from the genetically engineered C1 fungus has “several advantages” over mammalian expression systems. For example, C1 is known for “high biosynthesis activity” of secretory enzymes with engineered modifications that include “several knock-out mutations to inhibit secretion of intrinsic molecules such as proteases”.
Furthermore, production cycles are “much shorter” in comparison with common manufacturing systems, which enables “rapid development and adaption to evolving virus variants”.
“This could enable large-scale production of HuMabs at higher yields, in smaller, less complex production plants with simpler fermentation media compositions, making the process less costly.”
The authors suggest that the technology could be used for the expression of other mAbs, including antibodies against Rift Valley Fever virus or Zika virus. They recommend a comparison with stably transduced CHO cells. Until then, the study offers “proof of principle that HuMabs expressed in genetically engineered C1 filamentous fungus have the potential to supersede mammalian cell-produced HuMabs” for prevention and treatment of acute respiratory virus infections.
Finally, because C1-produced HuMabs “may probably” be expected to be “efficient to manufacture at relatively low cost, with short production cycles”, there are positive implications for overcoming some of the current limitations of HuMab production.
What do you think the research means for global health and mAb development? Don’t forget that you still have time to join us at the Congress to explore mAbs in greater detail, or subscribe here for further research insights.
