Abstract 957: A novel therapeutic modality integrating antibody therapy and oncolytic virotherapy for enhanced tumor targeting and treatment
Authors: Wenxin Xu, Can Chen, Huan Zheng, Jieying Xu, Mengshi Jiang, Li Zhang, Deyu Xu, Hongjie Cheng, Yang Zhang, Mengmeng Liu, Jinlu Cai, Fang Hu, Lieming Ding
Journal: Cancer Research (2025)

Abstract Background: In contemporary oncopharmacology, antigenic targets remain a pivotal focus, especially within the realm of immunotherapy, where tumor-specific antigens are of critical importance. Extensive research on these antigens has spurred the development of innovative therapeutic modalities, such as antibody therapies, CAR-T/NK cell therapies, XDC conjugate drug therapies, tumor neoantigen therapies, and gene therapies. However, these therapeutic strategies encounter significant challenges related to antigen target specificity. Although engineered antigen-targeting drugs typically provide high specificity and low toxicity, they can still disrupt normal signaling pathways and produce off-target effects, leading to adverse reactions that may compromise treatment duration and patient outcomes.To mitigate these challenges, we have devised a novel oncological strategy that synergizes antibody therapy with oncolytic virotherapy. This approach uses a genetically modified oncolytic virus to present a human-absent antigen on the surface of tumor cells, which is then targeted by a CD3 bispecific antibody to achieve the desired therapeutic effect. This combinatorial approach could expand treatment options for cancer patients, especially those with resistant tumors. It may also alter the tumor microenvironment, creating a bystander effect that boosts treatment effectiveness. Methods: Through comprehensive mega data analytics, non-primate endogenous antigenic proteins were identified. Advanced genetic engineering techniques were employed to integrate the antigenic complex TT3 into the genome of a genetically modified oncolytic vaccinia virus, ensuring stable expression on the surface of virus-infected tumor cells. Then a TT3/CD3 bispecific antibody, designated BK-001, was developed. The binding affinity of BK-001 was rigorously evaluated using ELISA, FACS, and BLI methodologies. The functional potency was determined using RGA, and in vitro cytotoxicity assessed via RTCA. Anti-tumor efficacy of BK-001 was validated using preclinical models, and a comprehensive non-clinical safety assessment was conducted on cynomolgus monkeys. Results and Conclusion: BK-001 is a bispecific T-cell engager antibody designed to boost the immune response against tumors infected by oncolytic viruses, promoting the destruction of cancer cells and improving the tumor microenvironment. The activation of BK-001 relies on the presence of TT3 antigen, which guarantees targeted immune response against tumors. In efficacy studies, BK-001 demonstrated robust tumor growth inhibition at minimal doses, with statistically significant differences compared to control groups. Furthermore, BK-001 exhibited prolonged activity and a favorable safety profile, underpinning its clinical development potential when used in conjunction with oncolytic virus therapy. Citation Format: Wenxin Xu, Can Chen, Huan Zheng, Jieying Xu, Mengshi Jiang, Li Zhang, 1 Deyu Xu, Hongjie Cheng, Yang Zhang, Mengmeng Liu, Jinlu Cai, Fang Hu, Lieming Ding. A novel therapeutic modality integrating antibody therapy and oncolytic virotherapy for enhanced tumor targeting and treatment [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 957.