Definition

A tetra-specific natural killer (NK) cell engager composed of antibody fragments directed against the two NK cell activating receptors NKp46 and CD16a (FcgammaRIIIa), an antibody fragment against the tumor-associated antigen (TAA) CD20 and a non-alpha interleukin-2 variant (IL-2v), composed of the beta chain (CD122) of the interleukin-2 receptor (IL-2R), with potential immunomodulating and antineoplastic activities. Upon administration, the NKp46/CD16/CD20/IL-2-variant-specific NK cell engager IPH6501 targets and binds with the anti-NKp46 moiety to the activating receptor NKp46 expressed on tumor-infiltrating NK cells, and with Fc gamma to the activating receptor CD16, also expressed on NK cells. In addition, IPH6501 targets and binds, with its IL-2v moiety, to IL-2Rbeta on NK cells, and with its anti-CD20 antibody moiety to CD20 that is expressed on tumor cells. This bridges cancer cells and NK cells, stimulates NK cell proliferation and activation, and allows for NK cell-mediated cytokine secretion and cytotoxicity against CD20-expressing cancer cells. This depletes CD20-expressing tumor cells. CD20 is overexpressed on a variety of tumor cell types. IL-2R enhances NK cell proliferation. NKp46 enhances NK cytokine production. IL-2v does not bind to the IL-2R-alpha chain (CD25) and does not interact with regulatory T cells (Tregs). Co-engagement of NKp46 and CD16 triggers strong NK cell activation.