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 [1]. However, T cell dysfunction and exhaustion contribute to treatment failure following anti-CD19 bispecific TCE [2,3]. 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 [4].

Objectives: The potential of CC312 in treating relapsed/refractory autoimmune diseases will be explored in the clinical setting (NCT06888960).

Methods: This open-label study employs a standard 3 + 3 dose-escalation design to assess the safety and tolerability profile and to identify the maximum tolerated dose (MTD) of CC312 in an autoimmune disease population. The trial features two distinct, sequentially enrolled administration cohorts, Intravenous (IV) cohort: CC312 is administered intravenously twice per week at 5 different dose levels (5 to 40 μg). Subcutaneous (SC) cohort: CC312 is administered subcutaneously once per week at different dose levels. 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, IV cohort:12 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-α, and IL-10) was observed. For the current dosages, 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 cohorts (≥20 μg) at week 4 to week 12. The SRI-4 response rates are shown in Table 1. 83.3% of patients (5/6) 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. Importantly, two patients have completed the 52-week follow-up, and both have maintained continuous SRI-4 responses. Patient 5 (Pt5) had concomitant hemolytic anemia with a disease duration of 4 years. In addition to previous treatments with hormones and immunosuppressants, this patient had also received belimumab and rituximab. Following completion of CC312 treatment at a dose of 10 µg, this patient showed a significant clinical response, with proteinuria and hematuria disappearing, and normalization of hemoglobin levels. The other patient, Pt7, had a baseline SLEDAI-2K score of 16 and concomitant lupus nephritis (renal biopsy showing ISN/RPS Class V). After completing CC312 treatment at a dose of 20 µg, this patient demonstrated disappearance of proteinuria and cylindruria. Anti-dsDNA antibodies decreased to within the normal range, complement levels normalized, and the SLEDAI-2K score fell to zero post-treatment and remained stable through week 52. The BILAG score indicated no active organ involvement, achieving DORIS remission.

SC cohort: This cohort has initiated the enrollment. Data collection is underway.

Conclusions: In this study, CC312 demonstrated a favorable safety profiles with no ICANS or grade ≥2 CRS at the highest tested dose. Rapid and near-complete depletion of peripheral CD19 ⁺ B lymphocytes was achieved across all dose cohorts. Notably, CC312 drove 100% depletion of CD19 ⁺ bone marrow plasma cells in SLE patients treated with 20 μg. Long-term (up to 6~13 months) and sustained SRI-4 responses were observed across the cohorts, accompanied by marked and durable improvement in clinical symptoms.

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REFERENCES:

[1] Michaelson JS, Baeuerle PA. J Exp Med. 2024;221(5): e20240499.

[2] Nora Philipp, et al. Blood. 2022 Sep 8;140(10):1104-1118.

[3] Virginie Nägele, et al. Exp Hematol Oncol. 2017 May 18:6:14.

[4] Etienne Humblin, et al. Sci Immunol. 2023 Aug 4;8(86): eadg0878.

Acknowledgments: NIL.

Disclosure of interest: None declared