Background/Purpose: Immune reset of autoimmune disease has been proposed to be a potential benefit of T cell engagers (TCEs) and CD19 CAR T therapy. A-319, a highly potent TCE, can deplete CD19+ B cells in patients (pts) with hematological malignancies. We evaluated the safety profile of A-319 in systemic lupus erythematosus (SLE) pts and explored if A-319 has the potential to reset autoimmunity in a dose-finding clinical study.

Methods: Twelve pts were enrolled in the study with baseline characteristics shown in Table 1. In week (W) 1, pts received A-319 at 0.05μg/kg/day(D), on D1, 3 and 5 by 24hr IV infusion. In W2-4, pts received A-319 at 0.3 (cohort 1, n=6), or 0.6 (cohort 2, n=3) or 1.2μg/kg/day (cohort 3, n=3), on D1, 3 and 5 by 6hr IV infusion. Safety, pharmacokinetics (PK) and pharmacodynamics (PD) parameters including peripheral blood (PB) B cell counts, autoantibodies, and other disease-related biomarkers and efficacy are evaluated for up to 1 year. The study, approved by the local hospital IRB, was registered as NCT06400537.

Results: Safety summary is listed in Table 2. No Grade ≥3 cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANs), or hypogammaglobulinemia were reported. One case of Grade 2 CRS was reported and resolved within 12hr without tocilizumab. One pt (P10) in Cohort 3 withdrew on D10 due to renal complications. One pt (P5) in Cohort 1 withdrew from the study at Month(M) 5 due to disease rebound.Dose-dependent peripheral blood B cell depletion was demonstrated. Cohort 1 achieved incomplete B cell depletion with 10±9% remaining at W4. However, B cell counts in Cohorts 2 and 3 were at 0.0 cell/uL at W4 and W2-W6, respectively. B cell recovery observed at ~W6 and M2, except for pts 9 and 11. The B cell subtype analysis and single cell sequence results demonstrated significantly different profiles at baseline, end of dosing and follow-up. Disease-related biomarker changes including autoantibody reduction (e.g., anti-ANA, dsDNA, Sm, SS-A, SS-B, ribosomal P protein, chromatin, Scl-70, Ro-52), normalization of complement levels (C3 and C4), and reduction of 24hr proteinuria, were also observed. The preliminary efficacy (Figure 1) at the last follow-up (LFU, 9 to 3 months) visit showed reduced SLEDAI-2K scores with the achievement of SRI-4 (n=9), SRI-6 (n=8), SRI-8 (n=7), LLDAS (n=4), and DORIS (n=1). Seven pts had reductions in 24hr total urine protein (Utp) levels. Four of 7 pts with baseline Utp ≥0.5 g/24hr achieved levels < 0.5 g/24hr by M6 (3 in Cohort 1, 1 in Cohort 2). All pts reduced glucocorticoid (GC) dose below baseline levels. At the LFU, 8 pts reduced to < =7.5 mg/day, including 6 pts further reduced to < =5 mg/day. Disease rebound in P5 corelated with incomplete B cell depletion and autoantibody level rebound.

Conclusion: A-319 was well tolerated and demonstrated efficacy even at a (low) dose associated with incomplete B cell depletion. These results suggest that A-319 could potentially reset autoimmunity in refractory SLE patients to achieve remission.

Table 1. Baseline characteristics

Table 2. Safety summary

Figure 1. Clinical response (SLEDAI-2K score)

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-319-a-cd3xcd19-t-cell-engager-for-the-treatment-of-refractory-systemic-lupus-erythematosus-preliminary-evidence-of-autoimmune-reset/