Cornell Researchers Engineer Bacteria to Produce Therapeutic Antibodies at Lower Cost
核心洞察
Cornell researchers have bioengineered bacteria with a unique enzyme from Desulfovibrio marinus to attach glycans to monoclonal antibodies (搜索), potentially democratizing access to therapeutic antibody drugs.
The breakthrough addresses a key limitation of bacterial production systems by enabling protein glycosylation, which impacts over 50% of human proteins and is critical for antibody immune function.
The engineered E. coli bacteria could offer dramatically accelerated production speeds and significantly lower costs compared to conventional Chinese hamster ovary cell manufacturing methods.
A Cornell-led research team has developed a potentially transformative method for producing therapeutic antibodies using bioengineered bacteria, addressing a major bottleneck in antibody drug manufacturing. The breakthrough, published July 4 in Nature Communications, could significantly reduce costs and accelerate production of monoclonal antibody treatments.
Novel Enzyme Discovery Enables Bacterial Glycosylation
The researchers identified a unique oligosaccharyltransferase (搜索) (OST (搜索)) enzyme in the bacterial species Desulfovibrio marinus that can attach complex sugars, known as glycans, to monoclonal antibodies (搜索). This discovery came after mining the genomes of more than 50 different bacterial species.
"That's a very unique property. Most enzymes from this family are incapable of catalyzing this specific reaction. In fact, none of them that we've tested do, except for this one special enzyme," said Matt DeLisa, the William L. Lewis Professor of Engineering in Cornell Engineering and the paper's senior author. "It was quite a surprise. The genome of D. marinus is the last place we would have expected to find an enzyme that possesses this functionality."
The enzyme specifically installs glycans at the required location on immunoglobulin G (IgG (搜索)) subtype monoclonal antibodies (搜索), a critical modification for therapeutic efficacy.
Addressing Manufacturing Limitations
Current antibody drug production relies heavily on Chinese hamster ovary (CHO) cells, a slow and expensive process that poses challenges during emergency situations requiring rapid response. Bacterial systems offer faster growth, division, and protein production compared to CHO cells, but have been limited by their inability to perform protein glycosylation naturally.
"Glycosylation is super important for the structure and function of the antibody drug itself. Without their attached glycans, the antibodies lack important immune functions," DeLisa explained. "So if you're not able to install these glycans, then you really don't have access to a therapeutically relevant product."
Glycosylation impacts more than 50% of all proteins produced in the human body, making this modification critical for human protein drug development.
Engineering E. coli for Antibody Production
The research team transferred the D. marinus gene into E. coli bacteria, described by DeLisa as "a major workhorse of the biotechnology enterprise," effectively providing the machinery for executing protein glycosylation reactions. After producing glycosylated IgG (搜索)-type antibodies in the engineered bacteria, the researchers used a chemoenzymatic remodeling technique to modify the glycan structure for human compatibility.
Mass spectrometry analysis performed by a team at the University of Georgia's Complex Carbohydrate Research Center confirmed the successful glycosylation results.
Broad Therapeutic Applications
Because all IgG (搜索) antibodies share structural similarities, the researchers' engineered E. coli system could enable biosynthesis of virtually any antibody drug product. These products have potential applications in treating cancer (搜索), autoimmune diseases (搜索), and infectious diseases (搜索).
"We think this is a really crucial step towards democratizing access of therapeutic antibody drugs by engineering their biosynthesis in low-cost production technologies like recombinant bacteria," DeLisa said. "These engineered bacteria are amenable to large-scale biomanufacturing schemes that afford dramatically accelerated production speeds. Another advantage is that the cost of goods associated with making protein products in bacterial cells is significantly lower versus with conventional technology."
Production Optimization Challenges
Despite the breakthrough, challenges remain in scaling production to compete with existing CHO cell technology. "CHO cells are slow and expensive, but they're really good at making antibody drugs at incredibly high production titers," DeLisa noted. "So although we now have the machinery for executing these reactions, next steps would certainly have to focus on optimizing the production of these glycosylated antibody proteins in order to become competitive with existing CHO cell technology."
The research involved collaboration with Michael Jewett of Stanford University and included co-authors from the University of Maryland, University of Georgia, and Johns Hopkins University. The study was supported by the Defense Advanced Research Projects Agency, Defense Threat Reduction Agency, National Science Foundation, and National Institutes of Health.