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Project

Development of anti-checkpoint strategies using nanobodies (FWOKN318)

Cytotoxic T lymphocytes (CTLs) can kill cancer cells, however, are often functionally compromised in cancer patients, because of the expression of inhibitory immune checkpoints. Treatment with antibodies that target these checkpoints induces durable responses in various cancer types. We study nanobodies, the smallest fragment from Camelid antibodies, as novel checkpoint inhibitors, since their single-domain nature offers many advantages over conventional antibodies. We so far
developed nanobodies that target PD-L1, the ligand of the inhibitory receptor PD-1, because PD-L1 is often upregulated on cancer cells to shield them from CTL-responses. During this study, we observed that expression of PD-L1 on cancer cells is closely linked to expression of Gal-3, a not yet described phenomenon. As Gal-3 is a ligand for LAG-3, an inhibitory receptor that is highly co-expressed on PD-
1 expressing CTLs, we will study whether Gal-3 provides a means to cancer cells to escape anti-
tumor immunity during PD-1/PD-L1 blocking therapy. In analogy to the PD-L1 study, we will generate LAG-3 binding nanobodies and evaluate their immune activating properties. We will also study different anti-PD-L1 and anti-LAG-3 nanobody formats, focusing on valence, stability and
bispecificity. This project therefore proposes to study and evaluate novel immune checkpoint drugs with a strong potential for translation from bench to bedside.
Date:1 Jan 2019 →  31 Dec 2019
Keywords:cancer
Disciplines:Cancer therapy