Abstract
Antibody drug conjugate (ADC) therapy has become one of the most promising approaches in cancer immunotherapy. Bispecific targeting could enhance the efficacy and safety of ADC by improving its specificity, affinity and internalization. In this study we constructed a HER2/HER3-targeting bispecific ADC (BsADC) and characterized its physiochemical properties, target specificity and internalization in vitro, and assessed its anti-tumor activities in breast cancer cell lines and in animal models. The HER2/HER3-targeting BsADC had a drug to antibody ratio (DAR) of 2.89, displayed a high selectivity against the target JIMT-1 breast cancer cells in vitro, as well as a slightly higher level of internalization than HER2- or HER3-monospecific ADCs. More importantly, the bispecific ADC potently inhibited the viability of MCF7, JIMT-1, BT474, BxPC-3 and SKOV-3 cancer cells in vitro. In JIMT-1 breast cancer xenograft mice, a single injection of bispecific ADC (3 mg/kg, i.v.) significantly inhibited the tumor growth with an efficacy comparable to that caused by combined injection of HER2 and HER3-monospecific ADCs (3 mg/kg for each). Our study demonstrates that the bispecific ADC concept can be applied to development of more potent new cancer therapeutics than the monospecific ADCs.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 81773621 and 82073751 to JWZ) and Shanghai Science and Technology Commission Project (No. 20S11904900 to BHZ). Authors would like to thank Lei Ma, Ai-ying Nie and Lan-kun Song at Waters Technology (Shanghai) Co. Ltd for their analytical support with mass spectrometry analysis.
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HFZ and LH conceptualized the study. HFZ and XL designed and performed the in vitro experiments and analyzed the data. LW, JJL, YLY, JC, YK performed the in vivo experiments. HJ, YQX, BHZ and JWZ supervised the study. BHZ and JWZ provided financial support. HFZ and XL wrote the original draft. BHZ, JWZ and YQX reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.
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Zong, Hf., Li, X., Han, L. et al. A novel bispecific antibody drug conjugate targeting HER2 and HER3 with potent therapeutic efficacy against breast cancer. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01279-8
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DOI: https://doi.org/10.1038/s41401-024-01279-8