Under the scope of this EU-funded project, we performed two major preclinical studies in which we developed novel therapeutic antibodies that demonstrated superior efficacy compared to their parental versions.
1) Next-generation immune cell engagers
Checkpoint inhibitors represent a class of therapeutic antibodies that activate the immune system, primarily by engaging effector T cells, to combat cancer cells. The current checkpoint inhibitors typically target a single immune pathway; they do not adequately address the intricate cell-cell interactions of the immune system that eventually converge in producing specific immune response outcomes. Therefore, immunotherapy by checkpoint inhibitors is insufficient for potentiating an effective anti-tumor immunity in most cancers. We tackled this challenge by creating a novel bi-specific monoclonal antibody that engineers immune cell communication as a novel immunotherapeutic approach. On one hand, it acts as a checkpoint inhibitor that stimulates tumor-reactive T cells by targeting an immune pathway termed PD-1. On the other hand, it binds a subpopulation of immune cells termed conventional type 1 dendritic cells. These dendritic cells play a key role in cancer cell recognition and promoting PD-1-positive T cell-mediated activity. The interplay between these two immune cell subpopulations in the tumor microenvironment and tumor-draining lymph nodes has been found to be a crucial limiting factor for effective immunotherapy. We characterized this novel antibody in various tumor-bearing mouse models. We observed increased migration of dendritic cells towards the tumor-draining lymph nodes, increased infiltration of activated T cells into the tumor, as well as enhanced physical interactions between these two cell subpopulations. It enabled the reprogramming of the immune cell network towards a more pro-inflammatory, effective anti-tumor immunity. We observed superior tumor growth control and anti-metastasis effect compared to the respective checkpoint inhibitor. Improved efficacy was also observed in tumor models that are otherwise resistant to checkpoint inhibitors.
The manuscript of this study, titled “Bispecific dendritic-T cell engager potentiates antitumor immunity,” by Shapir Itai et al. was recently published in the prestigious journal Cell in 2024.
2) A redesigned antibody to enhance anti-tumor potency
The manuscript of this study, titled “Fc-optimized GITR antibody enhances a CD4 T cell-dendritic cell crosstalk to promote anti-tumor immunity,” by Avraham et al. is currently under review for publication
