Researchers here describe an interesting approach to redirecting the immune system to destroy unwanted cells. The membranes of dead cells are distinctively marked and immune cells contain machinery to recognize those marks. This is an important part of the way in which immune cells are directed to engulf and destroy dead cells and cell debris, helping to keep tissue functional. If immune cells are equipped instead with an altered, engineered sensor mechanism, then in principle their well-established behavior of engulfing and destroying dead cells could be repurposed to attack any specific target live cell population. This has applications to many conditions of aging, as researchers have identified many errant, malfunctioning cell populations that contribute to age-related disease and dysfunction. Efficient and safe ways to remove these cells will provide the basis for an important class of future therapies.
During the process of engulfment, phosphatidylserine is exposed on the surface of dead cells as an ‘eat-me’ signal and is recognized by Protein S (ProS), a secreted factor that also binds to the Mer tyrosine kinase (MerTK) on phagocytes. Despite its robust activity, this engulfment mechanism has not been exploited for therapeutic purposes. Here we develop a synthetic protein modality called Crunch (connector for removal of unwanted cell habitat) by modifying ProS, inspired by the high engulfment capability of the ProS-MerTK pathway.
In Crunch, the phosphatidylserine-binding motif of ProS is replaced with a nanobody or single-chain variable fragment that recognizes the surface proteins of targeted cells. Green fluorescent protein nanobody-conjugated Crunch eliminates green fluorescent protein-expressing melanoma cells in transplantation mouse models. In addition, CD19+ B cells are eliminated by anti-CD19 single-chain variable fragment-conjugated Crunch, resulting in a therapeutic effect on systemic lupus erythematosus. Both mouse and human versions of Crunch are effective, establishing this synthetic ligand as a promising tool for the elimination of targeted cells.
