By modifying a protein in the cell’s normal elimination pathway, researchers targeted specific cells for destruction.
Image credit:Mindy Takamiya/Kyoto University iCeMS
When cells die or the body no longer needs them, phagocytic cells arrive to engulf them. This process relies upon the cells destined for destruction to express a protein that serves as an “eat me” signal. An adaptor molecule grabs onto this signal and then tethers itself to a protein on phagocytes, bridging the two cells. This binding activates the phagocyte to pull in the unwanted cell and chow down on it.
A research team at Kyoto University wondered whether they could adapt this cell removal system as a therapeutic to eliminate cells involved in disease. They modified the adaptor protein to recognize an antigen on a target cell of their choosing and demonstrated that this promoted selective elimination by phagocytes.1 The findings, published in Nature Biomedical Engineering, offer a potential new approach to treat a variety of diseases.
To test their idea, the team first replaced the antigen-target domain on the adaptor protein with an antibody fragment, a nanobody, that recognized green fluorescent protein (GFP). They dubbed this new construct: connector for removal of unwanted cell habitat (Crunch). They showed that GFP-targeting Crunch bound to GFP on cell membranes in vitro and activated engulfment of these cells by phagocytes.
Next, they assessed whether GFP-targeting Crunch also promoted elimination in vivo. They showed that their Crunch construct reduced GFP-expressing splenocytes as well as melanoma tumors expressing GFP injected into otherwise healthy mice.
To evaluate whether they could adapt this system to disease-relevant antigens, they fused different small antibody constructs to their antigen-binding domain. They targeted two different antigens: one against a melanoma protein, while the other bound to CD19, a B cell marker.
Both Crunch constructs recognized their targets in mice. The melanoma-targeting Crunch reduced tumor growth, increasing the animals’ survival. Meanwhile, the CD19-targeting Crunch promoted engulfment of CD19+ splenocytes in mouse blood and spleens. When the team injected this construct into mice that modeled systemic lupus erythematosus, which is driven by autoantibodies, they observed decreased numbers of CD19+ B cells in the animals’ blood and spleens. This also decreased the accumulation of antibodies in the kidneys and the presence of autoantibodies in the serum.
“We think this could become a new kind of therapy that can be adapted to many conditions. We can also adopt the targeting sensors from antibodies and CAR-T. It’s the ecosystem for the various therapeutic tools,” said Jun Suzuki, a biochemist at Kyoto University and study coauthor, in a press release.
