Large granular lymphocyte leukemia (LGLL) is a rare type of leukemia that is most prevalent in the elderly population. Standard-of-care treatments include immunosuppressive therapies such as methotrexate, cyclosporine, or cyclophosphamide, but response rates are only modest, and toxicity such as cytopenias and carcinogenic potential limit their use, thus highlighting the critical need for more novel and effective therapies for LGLL patients.
CD94 is a type II transmembrane receptor exclusively expressed on mature, cytotoxic lymphocytes such as natural killer (NK) cells, terminally differentiated CD8+ and Vd2 gamma-delta T cells. In LGLL patients we report the upregulation of CD94, along with its associated cytotoxic markers, on LGLL cells relative to their normal CD8+ T cell and NK cell counterparts in peripheral blood mononuclear cells (PBMCs) from 138 LGLL cases. DR-01, an antibody against CD94 that exhibits enhanced antibody-dependent cellular cytotoxicity (ADCC), induced potent and dose-dependent depletion of CD94+ cells in PBMCs in vitro from both healthy individuals and LGLL patients, and in cynomolgus monkeys and LGLL cells engrafted into NSG-Tg (hIL-15) mice. Importantly, purified leukemic cells from LGLL patient PBMCs, in the absence of other immune effector cells, were efficiently depleted by DR-01, thus identifying antibody-induced fratricide as a novel treatment approach for this disease. Robust pharmacodynamic activity was observed in a LGLL patient in a phase I clinical study of DR-01 (NCT05475925). Our findings identify CD94 as a bona fide target on LGLL cells and highlight anti-CD94 antibody-induced fratricide as a potential novel therapeutic option for LGLL patients.
