Background: CD19-targeting chimeric antigen receptor (CAR) T-cell therapy can induce long-term drug-free remission in patients with autoimmune diseases (AIDs) [1]. However, the CAR-T modality is associated with significant safety risks and logistical challenges [2]. CD19-targeted TCEs have the potential to induce B-cell depletion with potential better safety than CAR-T therapy and off-the-shelf convenience [3]. However, T cell dysfunction，exhaustion and less T cell proliferation contribute to treatment failure following anti-CD19 bispecific T-cell engager and CAR-T therapies [4, 5]. To circumvent this issue, we have developed a first-in-class anti-CD19, anti-CD3, anti-CD28 tri-specific antibody, CC312, that simultaneously engages CD19+ on tumor cells, CD3 (TCR signaling component) and CD28 (a costimulatory receptor) on T cells, which leads to redirected T-cell cytotoxicity towards CD19-positive malignant B cells. CD28 signaling has been associated with non-exhausted T cell phenotype [6], as well as enhances T cell proliferation, survival and cytokine secretion, priming naïve T cells, and inducing IL-2 production.

Objectives: The potential of CC312 in treating autoimmune diseases will be explored in the clinical setting.

Methods: This 3 + 3 design, dose-escalation study determined adverse events and the maximum tolerated dose (MTD) of intravenous infusion CC312 in patients with relapsed/refractory autoimmune diseases. Patients with moderate to severe systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), rheumatoid arthritis (RA), systemic sclerosis (SSc), etc., who are refractory to primary therapy or relapse were eligible. CC312 was administered intravenously twice per week at 3 different dose levels (5 to 20 µg). Safety, pharmacokinetic (PK)/pharmacodynamic (PD) profiles, and primary efficacy parameters—including longitudinal monitoring of peripheral B-lymphocyte counts, disease-associated autoantibodies, and disease-specific biomarkers—will be evaluated over a 48-week study period. Primary efficacy endpoints are disease-specific: SLE via the SLE Responder Index 4 (SRI-4) criteria; IIM by the American College of Rheumatology–European League Against Rheumatism (ACR-EULAR) major clinical response criteria; RA using ACR20/50 response rates and the composite Disease Activity Score 28 using C-reactive protein (DAS28-CRP); and SSc assessed through the European Scleroderma Trials and Research Group (EUSTAR) activity index.

Results: Five patients with refractory moderate-to-severe systemic lupus erythematosus (SLE) have been enrolled to date, stratified into two dosing cohorts: three patients administered 5 μg and two patients receiving 10 μg CC312. Treatment duration spanned 1-3 cycles across the five enrolled patients. The safety profile remained favorable, with no observed dose-limiting toxicities (DLT), immune effector cell-associated neurotoxicity syndrome (ICANS), or cytokine release syndrome (CRS) of grade ≥2. CC312-related adverse events (AEs) of grade ≥3 were restricted to transient lymphopenia, neutropenia, and leukopenia, all resolving spontaneously without intervention. No treatment-related serious adverse events (SAEs) were reported. Rapid and deep depletion of circulating CD19-positive B lymphocytes and their cellular subsets was observed throughout the treatment phase. The 10 μg dosing cohort demonstrated more robust B-cell depletion kinetics compared to the 5 μg cohort. All five patients achieved SRI-4 response post-intervention, demonstrating significant clinical improvement, including complete symptom resolution in a subset. Among four patients with baseline proteinuria, all exhibited marked post-treatment amelioration. In the 10 μg cohort, both participants showed great reductions in anti-dsDNA autoantibody levels (normalization to reference range in one patient), accompanied by complement level elevation.

Conclusion: In this active clinical investigation evaluating CC312 for autoimmune diseases, dose-escalation cohorts (5-10 μg) exhibited favorable safety profiles following 1-3 treatment cycles, with no immune effector cell-associated neurotoxicity syndrome (ICANS) or grade ≥2 cytokine release syndrome (CRS). Rapid, near-complete depletion of peripheral CD19-positive B lymphocytes and their effector subsets was achieved at all dose levels, including the minimum tested dose, correlating with clinically meaningful disease improvement. Universal SRI-4 response was observed across the cohorts.

REFERENCES: [1] Fabian Müller, et al. N Engl J Med. 2024 Feb 22;390(8):687-700.

[2] Shah K, et al. Clin Exp Immunol. 2024;217(1):15-30.

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

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

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

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

Acknowledgements: NIL.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.