Clinical activity, tolerability, and pharmacodynamics of ulviprubart in patients with T-cell large granular lymphocytic leukemia: Interim Results of A phase 1 trial

Abstract Background T-cell large granular lymphocytic leukemia (T-LGLL) is a rare cause of anemia and neutropenia characterized by clonal expansion of cytotoxic CD8+CD57+ T cells. It is typically treated with immunosuppressants, however, significant off-target effects can limit treatment. CD8+CD57+ T cells can also express killer cell lectin-like receptor subfamily G member 1 (KLRG1), and depletion of KLRG1+ cells may be useful for the treatment of T-LGLL. Ulviprubart is an afucosylated monoclonal antibody specific for KLRG1. Here, we detail interim results of a phase 1/2 study of 21 subjects investigating the safety, tolerability, and activity of ulviprubart. Methods In this open-label, ascending dose, adaptive clinical trial, subjects received subcutaneous injections of ulviprubart at 0.25, 0.75, 1.5, or 3 mg/kg in five cohorts. Subjects were first dosed every 8 weeks (Q8W) in cohorts 1-3 at dosages of 0.25, 0.75, and 1.5 mg/kg. Cohorts 4 and 5 were dosed every 4 weeks (Q4W) at dosages of 1.5 and 3 mg/kg respectively. PK/PD and safety were regularly assessed.Data is presented for subjects who attained and maintained Q4W dosing at 1.5mg/kg or 3mg/kg for at least 12 weeks. Amelioration of neutropenia was defined as a 4-week ANC increase ≥ 50% from baseline and amelioration of anemia was defined as a 4-week Hgb increase ≥ 1 g/dL not attributable to transfusion or growth factor. Results 21subjects were enrolled. Mean age (range) was 57 (22,87) years, 14 were female, 20 presented with neutropenia and 12 with anemia. Only 1 treatment related SAE was reported (Grade 3 infusion related reaction hours after a 3 mg/kg dose and a blood transfusion that occurred before dosing). There were no discontinuations due to adverse events. 13 subjects achieved 12 weeks of Q4W dosing. Of these, all of whom had neutropenia at baseline, 7 (53%) had improvement of neutropenia of > 50% or greater than 1000 neutrophils/dL; of the 9 with anemia at baseline, 2 (22%) had increased hemoglobin of at least 1 g/dL. Pharmacodynamic response was variable. Of the 13 subjects evaluated, an effect of at least 50% depletion of CD8+CD57+ T cells was observed in 7 (54%); of these 7 subjects, 3 had a sustained depletion of > 90% and 4 had a sustained depletion of between 50-75%. 1 subject achieved a sustained depletion of 70% of the CD8+ KLRG1+ and CD8+ CD57+ KLRG1+ T cells, but this extent of depletion was not reflected in the respective parent populations of CD8+ and CD8+CD57+ T cells. 5 subjects did not achieve any significant level of depletion. Notably, of the 5 subjects without a significant PD effect, 2 had no detectable KLRG1 expression at baseline and 1 was profoundly lymphopenic. Conclusion In this small study, Q4W dosing of ulviprubart (1.5 or 3 mg/kg) was active in depleting cytotoxic KLRG1+ T cells and was well tolerated. There was a 53% response rate for patients with neutropenia and 22% response in patients with anemia with Q4 week dosing, supporting further clinical study.