P46 CD1a-targeted PD-1 agonists for localized immunosuppression in atopic dermatitis
Randeep Singh, David Overton, Susan Aungier, Charlotte Viant, Fiona McCann, Tara Mahon, Cristina Oca-Ramirez, Richard Suckling, Ilaria Piccini, Janin Edelkamp, Marta Bertolini, Mariolina Salio, Mathew SleemanAbstract
Introduction and aims
T cells play a central role in the pathogenesis of atopic dermatitis (AD). In the context of skin barrier defects, they respond to environmental allergens and orchestrate the ensuing inflammatory response. Programmed cell death protein-1 (PD-1) is a key immune checkpoint that restrains T-cell activity; PD-1 signalling raises the threshold for T-cell activation, limits effector responses, promotes resolution of inflammation, and contributes to T-cell tolerance. We have developed a skin targeted PD-1 agonist as a novel strategy to treat inflammatory skin diseases. These cell-bridging bispecific molecules combine: (i) a high-affinity VHH targeting domain specific for CD1a, an human leucocyte antigen-related molecule highly expressed on skin antigen presenting cells (APCs), and (ii) a PD-1 agonist VHH to modulate T-cell activity at the immune synapse.
Methods
In coculture assays using CD1a+ or CD1a– APCs, together with nontargeted PD-1 agonist control bispecifics, we show that CD1a directed PD-1 agonists suppress T-cell activation only when target-bound. The CD1a targeted PD-1 bispecific does not compete with PD-L1 or PD-L2 for PD-1 binding. Coculture studies using monocyte-derived Langerhans cells (moLCs), which express both PD-1 ligands, demonstrate that the bispecific acts additively with endogenous PD-1 ligands to enhance T-cell suppression. The bispecific potently inhibits MoLC-stimulated Jurkat NFAT reporter activity and house dust mite-stimulated interleukin-13 release in autologous MoLC–T-cell assays.
Results
Target engagement studies in ex vivo human skin explants show specific binding of fluorescently labelled bispecific molecules to CD1a+ APCs in both healthy and AD skin. Furthermore, quantitative immunohistochemistry and cytokine array analyses demonstrate that the bispecific suppresses T-cell proliferation and activation in AD lesional and perilesional skin.
Conclusions
Collectively, these data support CD1a targeted PD-1 agonists as a promising approach to achieve localized inhibition of inflammatory T cells in the skin while avoiding systemic immunosuppression.