CD1a-targeted PD-1 agonists for localized immunosuppression in atopic dermatitis

Summary: Abstract Body: T cells play a central role in the pathogenesis of atopic dermatitis (AD). They respond to environmental allergens in the context of barrier defects and orchestrate the inflammatory response. The PD-1 receptor is a key immune checkpoint that restrains T cell responses. PD-1 inhibitory signals regulate the threshold for T cell activation to limit effector T cell responses, facilitate resolution of inflammation and establish T cell tolerance. We developed a skin-targeted PD-1 agonist as a novel strategy to treat inflammatory skin diseases. These cell-bridging bispecifics comprise a high affinity targeting domain, which binds CD1a, an HLA-related molecule that is highly expressed on skin antigen presenting cells (APCs) and a PD-1 agonist to modulate T cell activity at the immune synapse. In co-culture assays, using CD1a+ or CD1a- APCs and non-targeted PD-1 agonist-control bispecifics, we show that CD1a-directed PD-1 agonists only suppress T cell activation when bound to APCs. The CD1a-targeted PD-1 bispecific does not compete with PD-L1 or PD-L2 binding to PD-1 and co-culture studies, using monocyte-derived Langerhans (MoLCs) cells that express both PD-1 ligands, confirmed the ability of the bispecific to act additively to enhance T cell suppression. Specifically, the bispecific potently inhibits MoLC-stimulated Jurkat NFAT reporter activity and HDM-stimulated IL-13 release in autologous MoLC - T cell assays. Finally, target engagement studies in ex vivo human skin explants demonstrate specific binding of fluorescently labelled molecules to CD1a+ APCs in healthy and AD skin. Furthermore, quantitative immunohistomorphometry and cytokine array analyses show that the bispecifics suppress T cell proliferation and activation in AD lesional and perilesional skin. These studies demonstrate the potential for CD1a-targeted PD-1 agonists to provide localized inhibition of inflammatory T cells in the skin, whilst avoiding systemic immunosuppression. Adam Curnock¹, David Overton¹, Randeep Singh¹, Charlotte Viant¹, Ohannes Mazigi¹, Susan Aungier¹, Onur Egriboz², Ilaria Piccini², Janin Edelkamp², Marta Bertolini², Hussein Al-Mossawi¹ 1. Immunocore Ltd., Abingdon, United Kingdom. 2. QIMA Life Sciences, QIMA Monasterium, Münster, Germany. Adaptive and Auto-Immunity