Abstract
Sets of modular proteins enabled targeting of cells with specific combinations of surface markers.
Major Finding: Sets of modular proteins enabled targeting of cells with specific combinations of surface markers.
Concept: This system was used to target CAR T cells against a mixed population of target and bystander cells.
Impact: This provides a technique that may allow targeting of diseased cells with minimal collateral damage.
A hindrance to targeting cancer cells based on the presence of specific surface markers is that it is rare that a single marker can distinguish one cell type from all others. Lajoie, Boyken, Salter, and colleagues developed a system featuring a colocalization-dependent protein switch (Co-LOCKR), which can target cells based on their precise combination of surface markers. The system includes a Cage protein composed of a targeting domain with affinity to a specific cell-surface marker linked to a Cage domain and a Latch domain; the Latch has a functional peptide that can recruit a therapeutic agent (e.g., a CAR T cell). When inactive, the Cage binds the Latch, sequestering the functional peptide. A second protein, called a Key, has affinity for a separate cell-surface marker and, when the Cage and Key are in proximity, the Key displaces the Latch from the Cage, displaying the functional peptide. Thus, recruitment of the therapeutic agent occurs only when both markers are present on the cell surface. To enable the targeting of cells with another combination of surface markers, an additional Key can be included. Further, to avoid undesired recruitment of the therapeutic agent to healthy cells, a second surface marker can be targeted by a Decoy protein that binds and sequesters the Key, preventing the Key's engagement with the Cage. Using this system, the Boolean logic operations AND, OR, and NOT can be applied: A cell can be targeted if it expresses marker 1 AND marker 2 OR marker 3 but NOT marker 4, where marker 1 and either 2 or 3 are expressed by diseased cells and marker 4 is expressed by healthy cells. Lajoie, Boyken, Salter, and colleagues demonstrated that this system can be used for selective CAR T-cell targeting in mixed-cell populations in vitro, killing target cells and sparing bystander cells that share a subset of the same markers. Future work on this technique must focus on optimizing pharmacodynamics and minimizing immunogenicity in vivo.
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