In a recent paper published in Science, the researchers at the University of Washington School of Medicine and the Fred Hutchinson Cancer Research Center in Seattle report a novel designed protein that can target a therapeutic agent only to cells with specific, predetermined combinations of cell surface markers.
The remarkable tool is named colocalization-dependent protein switches (Co-LOCKR). It is formed by multiple synthetic proteins that can only function when gathering on the surface of a targeted cell. They can change shapes when coming together, thereby activating a sort of molecular beacon. The presence of these beacons on a cell surface can lead to a predetermined biological activity — like cell killing — to a specific, targeted cell. The researchers demonstrated that Co-LOCKR can focus the cell-killing activity of CAR T cells. In the lab, they mixed Co-LOCKR proteins, CAR T cells, and a soup of potential target cells. Some of these had just one marker, others had two or three. Only the cells with the predetermined marker combination were killed by the T cells. If a cell also had a predetermined “healthy marker,” then that cell was spared.
Although their present work is focused on development of the Co-LOCKR system and CAR T cell applications, the Co-LOCKR system should be powerful for engineering biology in any setting that requires proximity-based activation or targeting of specific sub-populations of cells.
Lajoie, Marc J., et al. "Designed protein logic to target cells with precise combinations of surface antigens." Science (2020).