Abstract 2140: Beyond antibodies and CAR-T: CC312, a first-in-class, anti-CD19, anti-CD3, anti-CD28 trispecific antibody in treatment with relapsed and/or refractory B-cell malignancies

Background: Depletion of B cells has resulted in major therapeutic benefits in hematological malignancies. Several FDA-approved B cell-depleting therapies are available, including CAR-T and T cell engagers (TCE). Blinatumomab, the only CD19-targeting bispecific T cell engager approved for B cell malignancies, has disadvantages in clinical setting including sub-optimal pharmacokinetics, neurotoxicity, CRS, and lack of long-term efficacy. In this study we present CC312, a trispecific antibody engineered for better efficacy by leveraging “Two Signal” co-stimulation, as well as improved safety via target-dependent activation and high potency / low dosage leading to low off-target effects. Methods: Effects of CC312 on T cell activation, proliferation, central memory T cell differentiation/proliferation and T cell killing activity were compared with blinatumomab in ex vivo assays. In vivo efficacy for CC312 was investigated in a Raji-luc s.c. engraftment CD34+ HSC-NCG mouse model. Moreover, a Phase Ia, open-label study is currently ongoing, and is designed to characterize the safety and tolerability of CC312 in patients with R/R B-NHL and R/R lymphocytic leukemia, to determine recommended dose(s), schedule(s), and route(s) of administration for future studies, and to estimate the preliminary anti-tumor activity of CC312. Results: In vitro, CC312 exhibited more robust T cell activation, higher proliferation and ∼10-fold greater potency versus blinatumomab. Additionally, CC312 induced a higher proportion of central memory T cells, and resulted in longer target cell killing relative to blinatumomab. In vivo, CC312 demonstrated similar tumor growth inhibition versus blinatumomab when dosed twice-weekly and more potent tumor growth inhibition when dosed once-weekly. In the ongoing Ph1a trial, CC312 has completed five levels of priming dose escalation as well as upper levels of treatment dose escalation, and has exhibited a favorable clinical safety profile to date with no DLTs or grade 3+ CRS/ICANS. CC312 achieved multi-fold depletion of peripheral blood B cells across dosages as well as ignited CD4 and CD8 T cell expansion and activation in B cell lymphoma patients. Conclusion: In this study, CC312 exhibited key advantages over leading CD3xCD19 TCE blinatumomab in multiple clinically relevant in vitro functional assays, demonstrated robust tumor growth inhibition in B cell lymphoma mouse models and achieved thorough depletion of CD19+ B cells and potent activation of T cells in B cell lymphoma patients across dosages while maintaining a favorable safety/tolerability profile. Therefore, via its “Two Signal” co-stimulation approach, CC312 represents a promising candidate for treatment of B cell lymphoma. CC312’s clinical benefit will continue to be explored at higher doses as part of ongoing Ph1a dose escalation study. Citation Format: Yingfeng Huang, Xiaofang Zhang, Ruixia Zhang, Zhen Jing, Caizhi Zhao, Fangfang Pan, Beibei Zheng, Ruixue Dai, Yingying Yang, Li Zeng. Beyond antibodies and CAR-T: CC312, a first-in-class, anti-CD19, anti-CD3, anti-CD28 trispecific antibody in treatment with relapsed and/or refractory B-cell malignancies [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 2140.