Inert Natural Killer Group 2 Member D receptor (iNKG2D) (iNKG2D.YA)

The Inert Natural Killer Group 2 Member D (iNKG2D.YA) receptor is a synthetic, engineered version of the human NKG2D receptor designed for use in modular CAR-T cell therapies [Woods et al., 2020, Nature Communications]. It contains a specific Y74A (YA) mutation in its extracellular domain that renders it "inert" to all naturally occurring NKG2D ligands, such as MICA and MICB, thereby preventing unintended activation by endogenous stress signals [Astellas Pharma]. This receptor serves as the foundation of the "convertibleCAR" platform, where it exclusively binds to a complementary "orthogonal" ligand—a mutated version of MICA—that is incorporated into bispecific adapter molecules called MicAbodies [Xyphos Biosciences]. When a MicAbody is introduced, it acts as a molecular bridge, linking the iNKG2D-expressing T cells to tumor cells expressing a specific target antigen. This modular design allows a single engineered T cell product to be redirected toward different antigens by simply changing the MicAbody, offering a programmable and controllable approach to immunotherapy [ClinicalTrials.gov, NCT04107116]. The system is currently being investigated for its ability to treat various malignancies while providing a safety switch, as T cell activity is dependent on the presence and concentration of the MicAbody. The iNKG2D.YA receptor is typically co-expressed with signaling domains like DAP10 or CD3-zeta to facilitate downstream T-cell activation upon engagement. This technology aims to overcome challenges such as antigen escape and off-target toxicity associated with conventional CAR-T cells.

Other names

iNKG2DOrthogonal NKG2DconvertibleCAR receptoriNKG2D-YAInert NKG2D receptor

The iNKG2D.YA receptor is an engineered T-cell receptor that remains signaling-inert until engaged by a bispecific adapter molecule (MicAbody). The MicAbody bridges the receptor's orthogonal binding site to a specific tumor antigen, inducing T-cell activation and tumor cell lysis.