Abrocitinib reduces circulating, skin homing, and resident memory T-cells in atopic dermatitis samples in vitro and ex vivo, and disease flare severity in a humanized mouse model

Summary: Abstract Body: In patients suffering from moderate to severe atopic dermatitis (AD), Abrocitinib treatment efficiently reduced clinical signs and itch, and impacted breakthrough disease flare frequency. Memory T-cells are postulated to mediate disease reappearance, and therefore we experimentally assessed the effect of Abrocitinib on circulating (CI-) and resident (R) memory (M) T-cells in AD. Treatment of PBMCs isolated from AD patients with Abrocitinib did not alter the number of TCI-M but prevented anti-CD3/CD28 induced expansion of central and/or effector TCI-M, including CLA+ (skin homing) and CCR4+ (skin tropic) CD4+ and CD8+ subpopulations. Similar to clinical outcomes, RNAseq and cytokine array analyses demonstrated diseased phenotype amelioration in treated AD peri-lesional and lesional samples ex vivo. Additionally, abrocitinib reduced the number of CD3+CD45RO+CD69+ cells, and CD3+CD45RO+CLA+ TRM in peri-lesional and/or lesional AD samples predominantly in the epidermis, and tended to restore filaggrin expression, as shown by quantitative (immuno-)histomorphometry. Furthermore, application of the abrocitinib surrogate molecule (ASM) resolved disease manifestation, and alleviated the phenotype of flares induced by sonic stress in a humanized mouse model of AD. This was revealed by transcriptomic and histological analysis, as well as the detection of higher filaggrin and claudin-1 expression, and lower CD3+ cells in treated versus control xenotransplants. Taking together, our data indicate that Abrocitinib impacts breakthrough AD flare severity potential and possess interesting disease modifying properties linked, at least in part, also to its ability to interfere with the expansion/survival of TM. Sofoklis Koudounas¹, Lisa Zondler¹, Markus Fehrholz¹, Amos Gilhar², Ralf Ludwig¹, Kristian Reich³, Melissa Watkins⁴, Ilaria Piccini¹, Karin I. Pappelbaum¹, Marta Bertolini¹ 1. QIMA Life Sciences, QIMA Monasterium, Münster, Germany. 2. Technion-Israel Institute of Technology, Haifa, Israel. 3. University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 4. Pfizer Inc, New York, NY, United States. Adaptive and Auto-Immunity