Cancer immunotherapy relies on the activation and sustained function of cancer-specific effector T cells. Multiple pathways control the activity of these cells. The inhibitory receptor LAG-3 takes part in this regulation. This CD4-like molecule has garnered substantial interest because of its pleiotropic roles. LAG-3 is expressed on activated effector T cells and down-regulates their activity.
LAG-3 is also expressed on activated regulatory T cells (Tregs), endowing them with suppressive capacity. Moreover, LAG-3 binds to MHC-II on antigen-presenting cells, inhibiting their maturation and as such T-cell activation. Tregs can also acquire MHC-II, enabling them to suppress LAG-3+ effector T cells. Finally, MHC-II expression on melanoma cells protects them against T cells.
Consequently, LAG-3 has become an important immunological target. The aim of this study is to evaluate single domain antibodies or nanobodies (Nbs), the smallest functional fragments from Camelid antibodies, to image and block LAG-3 signaling. We propose to generate Nbs specific for mouse and human LAG-3. Upon radiolabeling these will be evaluated for diagnostics. As a therapy
we propose to deliver the Nbs under the form of mRNA to tumors. This allows prolonged production of Nbs that inhibit LAG-3 signals and as such will impact on the different processes that impair effector T cells. In conclusion, this project is a preclinical evaluation of LAG-3 specific Nbs as novel cancer medicines.