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Overcoming resistance to HER2-targeted therapy with a novel HER2/CD3 bispecific antibody
Andres Lopez-Albaitero1, Hong Xu2, Hongfen Guo2
1Department of Surgery, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
Abstract:
T-cell-based therapies have emerged as one of the most clinically effective ways to target solid and non-solid tumors. HER2 is responsible for the oncogenesis and treatment resistance of several human solid tumors. As a member of the HER family of tyrosine kinase receptors, its over-activity confers unfavorable clinical outcome. Targeted therapies directed at this receptor have achieved responses, although development of resistance is common. We explored a novel HER2/CD3 bispecific antibody (HER2-BsAb) platform that while preserving the anti-proliferative effects of trastuzumab, it recruits and activates non-specific circulating T-cells, promoting T cell tumor infiltration and ablating HER2(+) tumors, even when these are resistant to standard HER2-targeted therapies. Its in vitro tumor cytotoxicity, when expressed as EC50, correlated with the surface HER2 expression in a large panel of human tumor cell lines, irrespective of lineage or tumor type. HER2-BsAb-mediated cytotoxicity was relatively insensitive to PD-1/PD-L1 immune checkpoint inhibition. In four separate humanized mouse models of human breast cancer and ovarian cancer cell line xenografts, as well as human breast cancer and gastric cancer patient-derived xenografts (PDXs), HER2-BsAb was highly effective in promoting T cell infiltration and suppressing tumor growth when used in the presence of human peripheral blood mononuclear cells (PBMC) or activated T cells (ATC). The in vivo and in vitro antitumor properties of this BsAb support its further clinical development as a cancer immunotherapeutic.
Insights
A novel HER2/CD3 bispecific antibody (BsAb) effectively targets HER2(+) tumors by recruiting T-cells. This immunotherapy shows promise against resistant cancers and warrants further clinical development.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Biology
Background:
- T-cell-based therapies are effective against various cancers.
- HER2 receptor tyrosine kinase overactivity drives oncogenesis and treatment resistance.
- Standard HER2-targeted therapies often face resistance.
Purpose of the Study:
- To explore a novel HER2/CD3 bispecific antibody (HER2-BsAb) platform.
- To evaluate HER2-BsAb's efficacy in overcoming resistance to standard therapies.
- To assess HER2-BsAb's potential as a cancer immunotherapeutic.
Main Methods:
- Developed and tested a HER2/CD3 bispecific antibody (HER2-BsAb).
- Assessed in vitro tumor cell line cytotoxicity and correlation with HER2 expression.
- Evaluated HER2-BsAb efficacy in humanized mouse models (xenografts and PDXs) with human PBMCs or ATCs.
- Investigated insensitivity to PD-1/PD-L1 immune checkpoint inhibition.
Main Results:
- HER2-BsAb demonstrated potent in vitro tumor cell killing, correlating with HER2 expression.
- Cytotoxicity was largely unaffected by PD-1/PD-L1 blockade.
- In vivo studies showed significant T-cell infiltration and tumor growth suppression in breast, ovarian, and gastric cancer models.
- Effective in both cell line xenografts and patient-derived xenografts (PDXs).
Conclusions:
- The HER2-BsAb platform preserves anti-proliferative effects while enhancing T-cell-mediated tumor ablation.
- HER2-BsAb shows broad efficacy across tumor types and models, including resistant ones.
- The study supports further clinical development of HER2-BsAb as a cancer immunotherapy.