Immune check-points (ICPs) are multiple signaling pathways involved in the maintenance of immune homeostasis. The interaction between a transmembrane receptor expressed on immune cells and its ligand induces anti-inflammatory responses, allowing the control of the intensity and duration of physiological immune responses.
This mechanism is hijacked by tumor cells, which express the ICPs ligands and therefore inhibit the immune system, resulting in tumor proliferation and invasion.
Blocking antibodies targeting ICPs have proven their efficacy as cancer immunotherapy and the work of James P. Allison and Tasuku Honjo on this topic has been awarded the medicine Nobel Prize in 2018(1).
However, treatment resistance emerges in certain patients. This is due to another immune escape mechanism by which tumor cells lower the expression of the targeted ICP and enhance the expression of other ICPs. There is therefore a need to develop new antibodies targeting novel ICPs, to be used alone or in combination with current available treatments.
Our project focuses on the development of a blocking nanobody targeting an immune receptor largely described as an ICP. Nanobodies (or VHHs) are small antibodies engineered from camelids antibodies. Their originality resides in the fact that they comprise only a single heavy chain but present high specificities and affinities to their target. (2) Their small size and simple tertiary structure make them easier to produce and they demonstrate interesting features especially for solid tumor treatments compared to conventional antibodies.
Using a macrophage cellular model, we want to assess if our blocking nanobody is able to reprogram macrophages from an anti-inflammatory type 2 to a pro-inflammatory type 1 phenotype.
1. Pradill et al., The blockade of immune checkpoints in immunotherapy, Nat Rev Cancer. (2012)
2. Chanier et al, Nanobody engineering: Towards Next Generation Immunotherapies and Immunoimaging of Cancer, Antibodies (2019)
