On the surface of every cell are receptors that interact with the cellular world around them. These receptors play a variety of roles. The transferrin receptor 1 (TfR1), for instance, pulls iron into the cell for fuel. It does so rapidly and continuously, as if it were a child spinning in a revolving door. Approximately 500 TfR1 molecules can cycle in and out in a single second, each dropping off any found iron and immediately heading back to the cell surface.
It also turns out that TfR1 is extra abundant on cancer cells to fuel their rapid growth. These unique features got Dana-Farber researcher Xin Zhou, PhD, thinking.
“What if we could repurpose this receptor for another function?” says Zhou. “Instead of using TfR1 to import iron, could we use it to destroy a protein that drives cancer?”
In a recent Nature paper — Zhou’s first as a researcher running her own lab — she and her colleagues describe the bioengineering behind a new platform for potential cancer therapy that turns this rapid refueling system into a protein degradation mechanism. The system uses a bispecific antibody to bind TfR1 and a disease-causing membrane protein of interest together. When the TfR1 receptor is naturally pulled into the cell, it takes the disease-causing protein with it. The protein gets destroyed and the TfR1 molecule heads back to the surface for more.
“We found a way of harnessing an inherent feature of cancer to attack itself,” says Zhou. “Targeting membrane proteins for protein degradation is relatively new, so it’s an exciting opportunity.”
Membrane proteins are common targets for cancer therapeutics, making up approximately 60% of all marketed drug targets. They are not always easy to inhibit, however, so in recent years, researchers have been looking for novel approaches to blocking them, including protein degradation.
Traditional protein degradation marks proteins for destruction by the proteasome, with a focus on the degradation of proteins that work inside a cell. In contrast, Zhou’s platform specifically enables the targeting of membrane proteins and degrades them through a cellular compartment called the lysosome.
Zhou’s lab, which focuses on bioengineering for drug discovery, first started experimenting with ways to bind TfR1 to another membrane protein. They tried various forms of bispecific antibodies, a special type of antibody that can bind to two different proteins, homing in on a design that enabled TfR1 to pull the other protein of interest into the cell with it.
The team then devised a mechanism for the two proteins to separate once inside the cell. This way, the protein of interest is chopped up and degraded while the TfR1 is sent back to the cell surface.
“This approach turned out to be remarkably effective,” says Zhou. “The system is highly modular and doesn’t require too much tailoring for each specific molecule of interest, which makes it a nice platform technology.”
The team experimented with using the platform (called TransTAC, for Transferrin Receptor Targeting Chimeras) to degrade four different membrane proteins with varying physical forms and roles in cancer. Their first experiments resulted in a TransTAC that targets and degrades chimeric antigen receptors or CARs, the engineered receptor on T cells infused as CAR T-cell therapy. The results suggest it could be possible to use the TransTAC to slow or prevent a runaway immune response caused by the therapy.
“This approach could offer an off-the-shelf approach for controlling CAR T cell activity,” says Zhou.
The team also experimented with degrading three naturally occurring receptors: EGFR, which drives multiple forms of cancer, CD20, which is found on B-cells and is a target for lymphoma, and PD-L1, an immune checkpoint ligand that masks cancer cells from the immune system. The custom-made TransTACs for each of these showed between 80% and 98% degradation of these proteins in cellular models.
“We think this platform could really open up opportunities to target membrane proteins, and, in terms of cancer types, we think there is no limit,” says Zhou. “This approach really has broad potential.”
The team studied the degradation of EGFR more deeply. Many cancers are driven by EGFR and multiple EGFR inhibitors exist. However, patients almost always develop resistance to these inhibitors. Zhou tested the EGFR-targeted TransTAC against multiple cell and mouse models of EGFR-resistant cancers with promising results. The tumors shrank, some to barely visible sizes.
As a next step, Zhou is working with the Robert and Renee Belfer Office for Dana-Farber Innovations to develop the TransTAC platform. In addition, she is collaborating with co-author Pasi Jänne, MD, PhD, senior vice president for translational medicine, and Director of the Chen-Huang Center for EGFR Mutant Lung Cancers, to dive more deeply into the mechanisms of action that result in cancer cell death after treatment with a TransTAC.
“We are just beginning to generate preclinical evidence about TransTACs. So far, it’s really encouraging,” says Zhou. “We hope to learn more and ultimately be able to bring this approach to the clinic to help patients with cancer.”
Praise god for the wonderful work and study your doing. Dana Farber saved my life because of this fantastic work. May the lord Jesus bless you for displaying his mercy to those in great need. JohnW.Park