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Blockade of ErbB2 and PD-L1 using a bispecific antibody to improve targeted anti-ErbB2 therapy
Deepak Mittal1, Dipti Vijayan1, Joost Neijssen2
1Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland Australia.
Abstract:
A significant proportion of human epidermal growth factor receptor 2 (Her2/ErbB2)-positive metastatic breast cancer patients are refractory to Her2-targeted trastuzumab-like therapy. Some of this resistance has been attributed to the upregulation of immune checkpoints such as programmed cell death-1 (PD-1) and its ligand, PD-L1 in Her2-positive breast cancer patients. Therefore, therapies targeting both the PD-1/PD-L1 interaction and oncogenic Her2 signaling are of significant clinical interest. Here, we constructed a mouse bispecific antibody targeting PD-L1 and rat Her2 (referred to as BsPD-L1xrErbB2) aiming to redirect the anti-PD-L1 response toward Her2-expressing tumor cells. BsPD-L1xrErbB2 demonstrated additive binding to interferon (IFN)-γ treated Her2+ TUBO tumor cells, but it did not affect the proliferation of tumor cells in-vitro. BsPD-L1xrErbB2 also blocked the PD-1/PD-L1 interaction. This bispecific antibody was constructed with a mouse IgG2a Fc backbone and interacted with Fcγ receptors and resulted in complement deposition (C3). ADCC and complement action could be potential mechanisms of action of this molecule. BsPD-L1xrErbB2 successfully reduced TUBO tumor growth and increased tumor rejection rate compared to the monovalent anti-PD-L1, monovalent anti-ErbB2 or the combination of anti-PD-L1 and anti-ErbB2 monotherapies. The enhanced anti-tumor effect of BsPD-L1xrErbB2 was dependent on CD8+ T lymphocytes and IFN-γ, as depletion of CD8+ T lymphocytes and neutralization of IFN-γ completely abolished the antitumor activity of the bispecific antibody. Consistently, BsPD-L1xrErbB2 treatment also increased the frequency of intratumor CD8+ T lymphocytes. Taken together, our data support a bispecific antibody approach to enhance the anti-tumor efficacy of PD-1/PD-L1 checkpoint blockade in Her2-positive metastatic breast cancers.
Insights
A novel bispecific antibody targeting programmed cell death-1 ligand 1 (PD-L1) and human epidermal growth factor receptor 2 (Her2) effectively reduced tumor growth in Her2-positive breast cancer models. This therapy enhanced anti-tumor immunity mediated by CD8+ T cells, offering a promising strategy for treatment-resistant cancers.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Many Her2-positive metastatic breast cancers are resistant to Her2-targeted therapies like trastuzumab.
- Upregulation of immune checkpoints, including programmed cell death-1 (PD-1) and its ligand PD-L1, contributes to this resistance.
- Targeting both PD-1/PD-L1 interaction and Her2 signaling presents a potential therapeutic strategy.
Purpose of the Study:
- To construct and evaluate a bispecific antibody (BsPD-L1xrErbB2) targeting PD-L1 and Her2 (ErbB2).
- To assess the efficacy of BsPD-L1xrErbB2 in overcoming resistance to Her2-targeted therapy in Her2-positive breast cancer.
- To investigate the mechanisms underlying the anti-tumor activity of the bispecific antibody.
Main Methods:
- Construction of a mouse bispecific antibody (BsPD-L1xrErbB2) targeting PD-L1 and rat Her2.
- In vitro assessment of antibody binding, PD-1/PD-L1 interaction blockade, and tumor cell proliferation.
- In vivo evaluation of BsPD-L1xrErbB2 efficacy in reducing tumor growth and increasing tumor rejection in a Her2-positive mouse model (TUBO).
- Assessment of the role of CD8+ T lymphocytes and interferon-gamma (IFN-γ) in the bispecific antibody's anti-tumor effect.
Main Results:
- BsPD-L1xrErbB2 demonstrated additive binding to Her2-positive tumor cells and blocked the PD-1/PD-L1 interaction.
- The bispecific antibody significantly reduced TUBO tumor growth and increased tumor rejection rates compared to monotherapies or combination therapies.
- The anti-tumor efficacy of BsPD-L1xrErbB2 was dependent on CD8+ T lymphocytes and IFN-γ, with increased intratumor CD8+ T cell frequency observed.
- Potential mechanisms of action include antibody-dependent cell-mediated cytotoxicity (ADCC) and complement activation.
Conclusions:
- The developed bispecific antibody BsPD-L1xrErbB2 shows significant potential for enhancing anti-tumor efficacy in Her2-positive metastatic breast cancer.
- This approach effectively combines Her2-targeted therapy with immune checkpoint blockade.
- The findings support the use of bispecific antibodies as a promising strategy to overcome treatment resistance in Her2-positive breast cancers.
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