Blockade of ErbB2 and PD-L1 using a bispecific antibody to improve targeted anti-ErbB2 therapy.
Deepak MittalDipti VijayanJoost NeijssenJoost KreijtzMaurice M J M HabrakenHans Van EenennaamAndrea Van ElsasMark J SmythPublished in: Oncoimmunology (2019)
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.
Keyphrases
- tyrosine kinase
- epidermal growth factor receptor
- immune response
- squamous cell carcinoma
- dendritic cells
- small cell lung cancer
- cancer therapy
- wastewater treatment
- signaling pathway
- endothelial cells
- machine learning
- advanced non small cell lung cancer
- oxidative stress
- dna damage
- risk assessment
- cell proliferation
- climate change
- poor prognosis
- electronic health record
- long non coding rna
- nk cells
- deep learning
- cell therapy
- newly diagnosed