CC312——一种新型CD19/CD3/CD28三特异性T细胞衔接器，可实现快速且深度的B细胞清除，在自身免疫性疾病中具有广泛的开发潜力

Background: CD19-targeted T cell engagers (TCEs) have the potential to induce B-cell depletion with potential better safety than CAR-T therapy and off-the-shelf convenience. However, T cell dysfunction and exhaustion contribute to treatment failure following anti-CD19 bispecific TCE. In this study, we developed CC312, a novel tri-specific TCE that integrates CD28 co-stimulation with CD3 and CD19 targeting. CD28 signaling in CC312 has been proved obviously with non-exhausted T cell phenotype. Objective: The potential of CC312 in treating relapsed/refractory autoimmune diseases will be explored in the clinical setting (NCT06888960). Methods: This 3 + 3 design, dose-escalation study determined adverse events and the maximum tolerated dose (MTD) of CC312 in patients with autoimmune diseases. CC312 was administered intravenously twice per week at 5 different dose levels (5 to 40 µg). Safety, pharmacokinetic/pharmacodynamic profiles, and primary efficacy parameters-including B-lymphocyte counts of peripheral blood and bone marrow, autoantibodies and biomarkers-will be evaluated for 48 weeks. Primary efficacy endpoint is the SLE Responder Index 4 (SRI-4) criteria. Results: To date, 10 patients with refractory SLE received 1 to 3 cycles of CC312 treatment. The safety profile remained favorable, with no observed dose-limiting toxicities (DLTs), immune effector cell-associated neurotoxicity syndrome (ICANS), or cytokine release syndrome (CRS) of grade ≥2. A consistent pattern of low-level release for CRS-associated cytokines (IL-6, TNF-alpha, and IL-10) was observed. CC312 consistently and dose-dependently depleted peripheral B cells in most patients. Among those patients who were followed up ≥24 weeks, B cell reconstitution was observed at week 24 without recurrence of clinical symptoms, suggesting immune reconstitution. CD19 + B cells subsets of bone marrow were completely diminished in the 20~30 μg cohorts at week 8 or week 12. 75% of patients (3/4) achieved an SRI-4 response at week 36, with decreased SLEDAI-2K scores and improvement in clinical symptoms, 100% responders have maintained SRI-4 response. In patient 3, the SLEDAI-2K score fell to zero after treatment and remained stable through week 36. C3 levels and anti-dsDNA antibody levels remained stable for most patients. Conclusion: In this study, the highest dose currently administered was 30 μg, and CC312 still exhibited favorable safety profiles, with no ICANS or grade ≥2 CRS. Rapid, near-complete depletion of peripheral CD19 + B lymphocytes was achieved at all cohorts. Furthermore, deep and complete depletion of CD19 + B cells in bone marrow was also achieved for 20 μg and 30 ug cohort. Long-term (up to 6~9 months) SRI-4 response was observed across the cohorts and improvement in clinical symptoms.