Inert Natural Killer Group 2 Member D receptor (iNKG2D)

The inert Natural Killer Group 2 Member D (iNKG2D) receptor is an engineered, synthetic receptor used in the convertibleCAR-T cell platform for cancer immunotherapy [1]. It is derived from the human NKG2D receptor (KLRK1) but contains specific mutations in its extracellular domain that prevent it from binding to its natural ligands, such as MICA and MICB [1, 2]. Instead, the iNKG2D receptor is designed to bind with high affinity to an 'orthogonal' MICA ligand that has been similarly engineered to avoid binding to wild-type NKG2D [1]. This system functions through the use of bispecific adapter molecules called MicAbodies, which bridge the iNKG2D-expressing T cell to a specific tumor-associated antigen [2]. This modular design allows for the creation of a single 'universal' CAR-T cell product that can be directed against multiple different antigens by simply changing the MicAbody administered to the patient [1, 3]. This approach provides a mechanism to control the timing and dose of CAR-T activity, potentially improving safety and overcoming antigen escape in complex tumors [2]. Sources: [1] Shifrin, N. et al. (2020) Nature Communications; [2] Astellas Pharma/Xyphos Biosciences Technology Overview; [3] Williams, K. et al. (2020) Journal for ImmunoTherapy of Cancer.

Other names

convertibleCARmutated NKG2D receptororthogonal NKG2DiNKG2D-CARInert KLRK1

The iNKG2D receptor acts as a synthetic docking station on T cells that remains signaling-inert until engaged by a bispecific MicAbody adapter. The MicAbody binds the iNKG2D receptor via an orthogonal MICA domain and a tumor antigen via an antibody fragment, inducing T-cell receptor signaling and tumor cell lysis [1, 2].