Shannon Sirk and the Sirk Research Group.
Urbana, Ill. – An Illinois research team is developing a method of producing and delivering monoclonal antibody treatments for breast cancer through commensal microbes in the gut. If successful, this approach could increase accessibility and dramatically decrease the cost of monoclonal antibodies.
Shannon Sirk, Cancer Center at Illinois researcher and assistant professor of bioengineering, was recently awarded a Foundation for Women’s Wellness (FWW) Women’s Health Research Award for her work in this area, with her project titled, “Democratizing breast cancer bio-therapeutics.”
The use of bioengineered commensal microbes, bacteria that have a neutral or beneficial effect on our bodies, to produce therapeutics could be incredibly efficacious since they are already perfectly suited to the gut microenvironment. However, there remains a major issue to be solved: how to get the microbially-produced drugs out of the gut and into the bloodstream to the target breast tumor.
“We have to engineer not only microbial delivery but also the antibody fragments that are being delivered with specific modifications so that when they are produced in the gut, they can engage with cell-surface receptors, enabling them to move through the gut wall and into the bloodstream,” Sirk said.
The funding from the FWW was awarded to support Sirk and her lab members to engineer both the microbes and the antibody fragments to enable this movement, allowing the sustained production of monoclonal antibodies from within the body and their transport into systemic circulation.
This new delivery method could remove the necessity for injections of high dose treatments, providing patients with a low-level, steady state rather than a single, large dose.
Previous work with commensal microbes has focused on delivering therapeutics for gastrointestinal diseases, as it can be easier to facilitate delivery to local targets. However, Sirk’s project requires a different approach, with incremental engineering steps to achieve gut wall penetration and determine the optimal dosage.
Normally, antibodies are Y-shaped, with an Fc domain (the long “stem” of the Y) that engages with cellular receptors to protect the antibody from degradation and mediate transport across membranes like the gut wall. The shorter arms of the antibody are comprised of antigen binding sites that bind to proteins like HER2, marking diseases or cancerous cells for immune cells to attack.
Sirk’s project will develop antibody fragments that are made up of the antigen binding sites without Fc domains, since bacterial cells have difficulty producing full-length antibodies and these smaller pieces have higher tumor penetration. However, this means that these fragments will not engage the cellular receptors that prevent degradation and facilitate transport out of the gut, so Sirk’s lab is modifying the fragments with small peptides that mimic the function of the Fc domain.
Image of Shannon Sirk.
“We have an opportunity here to develop a technology that will increase access and decrease cost. The antibodies we are working with have been around for a long time and have impacted so many breast cancer patients positively, but they are still incredibly expensive and require infusions,” Sirk said. “Our immediate concern is our local community, but the goal is to increase accessibility of these incredible treatments in lower-resource communities across the globe.”
This technology will be developed using a genetic toolbox created within Sirk’s lab that enables the specific bioengineering needed to produce effective antibody fragments in gut commensal bacterial species. This toolbox is similar to those commonly used to manipulate E. coli, but allows the researchers to manipulate microbial species outside of the standard lab strains.
Eventually, Sirk hopes to make a clinical impact with this novel therapeutic delivery method. Rather than feeling overwhelmed by the many parameters that must first be characterized, Sirk remains excited by the possibilities of establishing microbial colonies to surveil and treat diseases including breast and other cancers.
– Written by the CCIL Communications Team
Shannon Sirk is a Cancer Center at Illinois (CCIL) researcher, and an assistant professor of bioengineering and the Carle Illinois College of Medicine. She is a co-leader of the CCIL’s Cancer and Microbes Working Group. Sirk is also affiliated with the Microbiome Metabolic Engineering Theme at the Carl R. Woese Institute for Genomic Biology, leads the Sirk Research Group, and is the Associate Director of the Illinois Microbial Systems Initiative.
The Sirk Research Group is also supported by a Cancer Center at Illinois Seed Grant award.