Abstract 3513: CC312, a trispecific CD19-targeting co-stimulatory T cell engager, for the treatment of B cell malignancies and autoimmune diseases

Abstract Background: B cell depletion therapy (BCDT), such as monoclonal antibodies, bispecific T cell engagers(TCE) and CAR-T,has an extensive history of effectively treating B cell malignancies. Certain BCDT monoclonal antibodies,e.g. rituximab,are also approved to treat autoimmune diseases(ADs), however demonstrate poor B cells depletion in deep tissue which may limit the long-term disease control or remission in patients. Recently, anti-CD19 CAR-T, through thorough depletion and “resetting” of B cell populations, have achieved multi-year drug-free remission in systemic lupus erythematosus (SLE),idiopathic inflammatory myopathy(IIM)and systemic sclerosis(SSc). Here, we developed a trispecific TCE CC312, targeting CD3 and CD28 on T cells and CD19 on B cells. Consistent with CAR-T, CC312 showed potent T cell activation and B cell depletion in a prior study in B cell malignancies. In the current study, the potential of CC312 in treating ADs was explored in translational models and in the clinical setting. Methods: B cell killing of CC312 was assessed in ex vivo cytotoxicity assays using PBMC isolated from AD patients. T cell activation, proliferation and differentiation were also evaluated with patient PBMC. The in vivo efficacy for SLE was investigated in mice engrafted with SLE patient PBMC. In addition, clinical safety, tolerability, and efficacy of CC312 in refractory SLE, IIM, SSc, and other B cell-related ADs was evaluated in an ongoing investigator-initiated clinical trial. Results: In vitro,CC312 induced a concentration-dependent potent depletion of B cells in PBMCs derived from donors with ADs, with EC50 in pM range across donors and disease types. Compared with anti-CD3/CD19 bispecific benchmark, CC312 significantly enhanced T cell activation, proliferation, and memory T cell differentiation due to CD28 co-stimulation. In vivo, CC312 thoroughly depleted peripheral B and plasmablast cells,as well as eliminated IgG and anti-dsDNA in serum. At the end of this study, neither IgG deposits nor CD20+B cell infiltrates were observed within kidney tissues. In the ongoing clinical study of ADs, CC312 is well-tolerated, with no Grade 3+ CRS or ICANS. Even at the lowest dose level(5 μg/dose), peripheral B cells and B cell subgroups can be comprehensively depleted, accompanied with improvement or remission of disease. Conclusion: CC312’s capacity to potently and thoroughly eliminate B cells has been demonstrated in in vitro and in vivo studies as well as in the clinical setting, indicating the potential benefit in treating B cell-related ADs. As the first CD28 co-stimulatory TCE to be explored in ADs, additional clinical studies will be conducted to further evaluate the efficacy and safety in autoimmune patients. Citation Format: Yingfeng Huang, Ruixia Zhang, Xiaofang Zhang, Zhen Jing, Caizhi Zhao, Fangfang Pan, Beibei Zheng, Ruixue Dai, Li Zeng. CC312, a trispecific CD19-targeting co-stimulatory T cell engager, for the treatment of B cell malignancies and autoimmune diseases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3513.