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Chitnis, Tanuja; Kaskow, Belinda J.; Case, Junning; Hanus, Katherine; Li, Zhenhua; Varghese, Johnna F.; Healy, Brian C.; Gauthier, Christian; Saraceno, Taylor J.; Saxena, Shrishti; Lokhande, Hrishikesh; Moreira, Thais G.; Zurawski, Jonathan; Roditi, Rachel E.; Bergmark, Regan W.; Giovannoni, Federico; Torti, Maria F.; Li, Zhaorong; Quintana, Francisco; Clementi, William A.; Shailubhai, Kunwar; Weiner, Howard L.; Baecher-Allan, Clare M.

Nasal administration of anti-CD3 monoclonal antibody modulates effector CD8+ T cell function and induces a regulatory response in T cells in human subjects

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  • Medientyp: E-Artikel
  • Titel: Nasal administration of anti-CD3 monoclonal antibody modulates effector CD8+ T cell function and induces a regulatory response in T cells in human subjects
  • Beteiligte: Chitnis, Tanuja; Kaskow, Belinda J.; Case, Junning; Hanus, Katherine; Li, Zhenhua; Varghese, Johnna F.; Healy, Brian C.; Gauthier, Christian; Saraceno, Taylor J.; Saxena, Shrishti; Lokhande, Hrishikesh; Moreira, Thais G.; Zurawski, Jonathan; Roditi, Rachel E.; Bergmark, Regan W.; Giovannoni, Federico; Torti, Maria F.; Li, Zhaorong; Quintana, Francisco; Clementi, William A.; Shailubhai, Kunwar; Weiner, Howard L.; Baecher-Allan, Clare M.
  • Erschienen: Frontiers Media SA, 2022
  • Erschienen in: Frontiers in Immunology, 13 (2022)
  • Sprache: Nicht zu entscheiden
  • DOI: 10.3389/fimmu.2022.956907
  • ISSN: 1664-3224
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: BackgroundParenteral anti-CD3 Mab (OKT3) has been used to treat transplant rejection and parental administration of a humanized anti-CD3 Mab (Teplizumab) showed positive effects in diabetes. Nasal administration of anti-CD3 Mab has not been carried out in humans. Nasal anti-CD3 Mab suppresses autoimmune diseases and central nervous system (CNS) inflammation in animal models. We investigated the safety and immune effects of a fully humanized, previously uncharacterized nasal anti-CD3 Mab (Foralumab) in humans and its in vitro stimulatory properties.MethodsIn vitro, Foralumab were compared to UCHT1 anti-human CD3 mAb. For human administration, 27 healthy volunteers (9 per group) received nasal Foralumab or placebo at a dose of 10ug, 50ug, or 250ug daily for 5 days. Safety was assessed and immune parameters measured on day 1 (pre-treatment), 7, 14, and 30 by FACS and by scRNAseq.ResultsIn vitro, Foralumab preferentially induced CD8+ T cell stimulation, reduced CD4+ T cell proliferation and lowered expression of IFNg, IL-17 and TNFa. Foralumab induced LAP, TIGIT, and KLRG1 immune checkpoint molecules on CD8+ and CD4+ T cells in a mechanism independent of CD8 T cells. In vivo, nasal Foralumab did not modulate CD3 from the T cell surface at any dose. Immune effects were primarily observed at the 50ug dose and consisted of reduction of CD8+ effector memory cells, an increase in naive CD8+ and CD4+ T cells, and reduced CD8+ T cell granzyme B and perforin expression. Differentially expressed genes observed by scRNAseq in CD8+ and CD4+ populations promoted survival and were anti-inflammatory. In the CD8+ TEMRA population there was induction of TIGIT, TGFB1 and KIR3DL2, indicative of a regulatory phenotype. In the memory CD4+ population, there was induction of CTLA4, KLRG1, and TGFB whereas there was an induction of TGF-B1 in naïve CD4+ T cells. In monocytes, there was induction of genes (HLA-DP, HLA-DQ) that promote a less inflammatory immune response. No side effects were observed, and no subjects developed human anti-mouse antibodies.ConclusionThese findings demonstrate that nasal Foralumab is safe and immunologically active in humans and presents a new avenue for the treatment of autoimmune and CNS diseases.
  • Zugangsstatus: Freier Zugang