Large granular lymphocytic leukemia (LGLL), a chronic, lymphoproliferative disorder of cytotoxic T (CD8) and natural killer (NK) cells, leads to neutropenia, recurrent infections, and anemia. No approved therapies exist; chronic immunosuppression makes long-term management challenging. DR-01 is a non-fucosylated human IgG antibody targeting CD94-expressing terminal effector CD8+ T cells, γδ T cells, and NK cells, leading to depletion by antibody-dependent cellular cytotoxicity. This Phase 1/2 open-label study (NCT05475925) is assessing DR-01 safety, pharmacokinetics (PK), pharmacodynamics, and efficacy in relapsed/refractory LGLL patients.
As of May 2025, 31 patients (21 [68%] male; median age, 64 [24–86] years) received intravenous DR-01 (0.3–10 mg/kg) in primary (C1D1/D15) or secondary (C1D1/D8/D15) induction regimens, followed by monthly maintenance doses. Prior therapies included methotrexate (29 [94%]), cyclophosphamide (15 [48%]), and cyclosporine (13 [42%]). Most frequent treatment-related adverse events (>15%) were infusion-related reaction (IRR; 23%), fatigue (16%), nausea (16%); most were Grade 1-2. Only one patient, who enrolled before IRR prophylaxis optimization, discontinued due to IRR.
In 23 response-evaluable patients, overall response rate (ORR) was 44%: 6 (26%) complete responses (CR), 4 (17%) partial responses (PR). Longest duration of ongoing response was 15+ months. Time to first response was 0.9–1.8 months. In 15 secondary induction patients, ORR was 60% (33% CR, 27% PR), accompanied by peripheral LGLL cell depletion, dominant LGLL clone eradication, and serum granzyme B reduction.
Preliminary safety and efficacy data show that DR-01 is well-tolerated. A promising response rate and durable responses support continued DR-01 development as an LGLL therapy.
