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, 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), or systemic sclerosis (SSc), who are refractory to primary therapy or relapse, were eligible. CC312 was administered intravenously twice per week for four consecutive weeks at 3 different dose levels (5 to 20 µg). After 4 weeks of administration, the researchers will decide whether to continue the treatment based on the efficacy and B cell depletion data of the patients. Safety, primary efficacy, PK and PD parameters including circulating B cell counts, autoantibodies, and other disease- related biomarkers, are evaluated for up to 52 weeks. Efficacy of SLE will be assessed by means of Definition of Remission in SLE (DORIS) remission criteria, IIM by American College of Rheumatology-European League against Rheumatism (ACR–EULAR) major clinical response, RA by the ACR 20/50 scores and composite index of RA disease activity (DAS28-CRP) scores and SSc by the score on the European Scleroderma Trials and Research Group (EUSTAR).

Results: Currently, Two patients (patient 1, patient 2) with relapsed and refractory moderate SLE have been enrolled. Patient 1, a 37-year-old woman with a 18-year history of SLE, presented arthritis, alopecia, and pleurisy. The SLEDAI-2K score of patient 1 at baseline was 8 points. Patient 2, a 39-year-old woman with a 12-year history of SLE, presented arthritis, alopecia, low complement and high anti-dsDNA level. The SLEDAI-2K score of patient 2 at baseline was 10 points. Both patients had been administered with CC312 ( i.v ) at 5 μg for 4 weeks. Rapid and deep depletion of circulating CD19 ⁺ B cells and subpopulations were observed during the treatment cycle. A trend of T cell activation and expansion were also observed during that cycle. SRI-4 response was achieved in both patients after 4 weeks treatment with obvious improvement of clinical symptoms. Arthritis, alopecia, and chest pain were disappeared or relieved, and SLEDAI-2K score was dropped to 4 in patient 1. Arthritis and alopecia also disappeared, and SLEDAI-2K score was dropped to 4 in patient 2. In this study, CC312 is well-tolerated. Drug-related adverse events were only included minimal grade 1 cytokine release syndrome and hematologic changes, and no grade 3 or greater CRS at any dose.

Conclusion: In the ongoing clinical study of autoimmune diseases, CC312 is evaluated at ascending dose levels via step-up regimen. After short-term treatment, CC312 is well-tolerated, with no grade 3+ CRS or ICANS. Even at the lowest dose level, peripheral B cells and B cells subsets can be rapid and comprehensively depleted, accompanied with improvement or even remission of disease. Both patients achieved SRI-4 clinical response.

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.