Figure 1.

Harnessing NK cells to control antigen loss variants: rational for the dual-targeting immunoligand approach. Emergence of antigen loss variants in most cases is seen following targeted therapy and can be associated with lineage switching (A), shaving or trogocytosis of antigen–antibody complexes from the tumor cells (B) or selective outgrowth of antigen-negative cells (C). NK cell activating dual targeting immunoligand (triplebody) consists of two scFvs against distinct antigens on tumor cells and a natural ligand to activate NK cells. As an example, ULBP2-aCD19-aCD33 (dual targeting triplebody) binds not only to the double antigen-positive (CD19⁺CD33⁺) target cells but also to the antigen loss variants. ULBP2, now coated on the target cells, activates NK cell effector functions via NKG2D receptor resulting in the killing of tumor cells by perforin and granzymes and secretion of IFNγ and TNFα. For simplicity, cross-linking is only shown between CD19⁺CD33⁺ target cells and NK cell; however, identical NK cell targeting is possible in response to antigen loss variants.