CD33 and/or FLT3 (activating antigens), EMCN (inhibitory NOT-gate)

Class

Allogeneic, gene circuit-enhanced CAR-NK cell therapy (logic-gated)

Pathway

Dual-antigen (CD33/FLT3) activation combined with an EMCN 'NOT' inhibitory gate to spare healthy hematopoietic stem/progenitor cells while killing AML blasts

CD33 and FLT3 are proteins on the surface of cells within the myeloid blood lineage. Both are commonly found on the malignant blasts of acute myeloid leukemia (AML), but they are also present on normal hematopoietic stem and progenitor cells (HSPCs), the population responsible for continuously replenishing blood and immune cells. This overlap has been a persistent obstacle for antigen-targeted therapies in AML, since eliminating antigen-positive tumor cells risks also destroying the normal blood-forming compartment, a toxicity distinct from the underlying disease. This approach pairs immune effector cells engineered to recognize CD33 and FLT3 as activating signals with a second synthetic receptor that recognizes endomucin (EMCN), a marker enriched on healthy HSPCs, which delivers an inhibitory 'NOT-gate' signal that overrides activation when EMCN is detected. In principle this allows the engineered cells to attack AML blasts, which largely lack EMCN, while sparing normal HSPCs that co-express it alongside CD33/FLT3. The immune effector platform used is natural killer (NK) cells derived from a donor source (allogeneic) rather than the patient's own cells, engineered with the dual-antigen recognition and inhibitory circuit built in. This logic-gated design broadly matters for AML and other myeloid malignancies where disease-associated antigens are shared with essential normal stem cell populations.