CD33 / CLL-1 (CLEC12A)

Class

Antibody-conjugated NK cell therapy (off-the-shelf, dual-target)

Pathway

NK cell-mediated cytotoxicity, antigen bridging via chemically conjugated bispecific antibody

CD33 and CLEC12A (also called CLL-1) are surface proteins found on the blasts of acute myeloid leukemia (AML), a cancer of the bone marrow's myeloid blood-forming cells. This mechanism uses natural killer (NK) cells, an arm of the innate immune system capable of killing abnormal cells without prior sensitization, as an off-the-shelf (pre-manufactured, not patient-specific) cellular therapy. Rather than genetically engineering the NK cells, a bispecific antibody is chemically attached to their surface, creating a physical bridge between the NK cell and the tumor cell: one antibody arm engages an NK activating receptor, while the other two arms recognize CD33 and CLEC12A on the leukemic cell. This dual targeting addresses a core problem in AML immunotherapy, antigen heterogeneity: individual leukemic clones can vary in which surface markers they display, and single-antigen approaches risk leaving antigen-low subpopulations unharmed, allowing relapse. By bridging to two independent AML-associated antigens, the therapy broadens tumor coverage and lowers the chance that a leukemic cell escapes recognition entirely. This general strategy, engaging innate immune effector cells against myeloid leukemia markers, is relevant across AML and related myelodysplastic conditions where malignant clones share a myeloid lineage origin.