Biologics, including proteins, antibodies, and vaccines, are therapeutic products derived from living organisms and produced using microbial systems. In these systems, a host microorganism is engineered to carry a plasmid encoding the biologic of interest, along with an antimicrobial resistance (AMR) gene for selection purposes. The use of AMR genes allows only cells containing the plasmid to survive under antibiotic pressure, enabling large-scale production of the biologic.
Regulatory agencies are currently discouraging the use of selection markers that could confer resistance to antibiotics to minimize theoretical risk of spreading antibiotic resistance traits to environmental microbial organisms. Agencies suggest that newly licensed biologics products should not contain any AMR genes. This includes removal of naturally occurring AMR genes from live bacteria through genetic modification.
In response, a global fortune 500 company is seeking novel, cost-effective, antibiotic-free, endotoxin-free microbial expression systems for production of a wide range of biologics, including recombinant proteins, peptides, antigens, Fc-fusion proteins, and monoclonal antibodies. Additionally, the company seeks partners/technology to support removal of AMR genes through genetic modification.
We are seeking microbial expression systems which do not contain AMR genes and/or technologies to engineer microbial cells to produce biologics without the use of antibiotics. The system should eventually support industrial-scale (1000L) bioreactors, ensure high protein yields, and maintain control over contamination and genetic stability during fermentation.
- Use of essential gene(s) to select for expression plasmids which can be complemented by media additives during strain construction
- Nutrient-dependent protein expression strains where only plasmid-carrying cells can survive in a nutrient-deficient medium (auxotrophic markers)
- Plasmid addiction systems, such as metabolic burden-based and replication control systems
- Other non-antibiotic selectable markers
- Plasmid-free expression systems (e.g. genomic integration of target genes) which produce similar high yields as plasmid-based expression systems
- Laboratories capable of gene editing/deletion in biosafety level 2 (BSL-2) pathogens
- Control of contamination and genetic drift
- Avoid bovine/transmissible spongiform encephalopathies (BSE/TSE) risks and potential exposure to foreign animal diseases (FAD) of concern
- Host strain and expression system free of AMR genes
- High biologic yield
- Cost-effective
- Scalable manufacturing capability
- Low or endotoxin-free host strains for protein expression
- Plasmid selection relying on toxin/anti-toxin maintenance
- CHO (Chinese hamster ovary) cells and other mammalian cell lines
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