STAT3-Specific Single Domain Nanobody Inhibits Expansion of Pathogenic Th17 Responses and Suppresses Uveitis in Mice

• Published in: Frontiers in immunology Vol. 12; p. 724609
• Main Authors: Mbanefo, Evaristus C, Yan, Ming, Kang, Minkyung, Alhakeem, Sahar A, Jittayasothorn, Yingyos, Yu, Cheng-Rong, Parihar, Ashutosh, Singh, Sunanda, Egwuagu, Charles E
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 15-09-2021
• Subjects: Adoptive Transfer; Animals; Autoantigens - immunology; Autoantigens - metabolism; Autoimmune Diseases - immunology; Autoimmune Diseases - prevention & control; Cell Proliferation - drug effects; Cytokines - metabolism; Disease Models, Animal; EAU; Electroretinography; Eye Proteins - immunology; Eye Proteins - metabolism; Humans; Immunology; Mice; Mice, Inbred C57BL; nanobody; Retinol-Binding Proteins - immunology; Retinol-Binding Proteins - metabolism; STAT3; STAT3 Transcription Factor - immunology; STAT3 Transcription Factor - metabolism; Th1; Th17; Th17 Cells - immunology; Th17 Cells - pathology; uveitis; Uveitis - immunology; Uveitis - prevention & control; EAU; nanobody; Th1; uveitis; Th17; STAT3
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.724609

STAT3 activates transcription of genes that regulate cell growth, differentiation, and survival of mammalian cells. Genetic deletion of
in T cells has been shown to abrogate Th17 differentiation, suggesting that STAT3 is a potential therapeutic target for Th17-mediated diseases. However, a major impediment to therapeutic targeting of intracellular proteins such as STAT3 is the lack of efficient methods for delivering STAT3 inhibitors into cells. In this study, we developed a novel antibody (SBT-100) comprised of the variable (V) region of a STAT3-specific heavy chain molecule and demonstrate that this 15 kDa STAT3-specific nanobody enters human and mouse cells, and induced suppression of STAT3 activation and lymphocyte proliferation in a concentration-dependent manner. To investigate whether SBT-100 would be effective in suppressing inflammation
, we induced experimental autoimmune uveitis (EAU) in C57BL/6J mice by active immunization with peptide from the ocular autoantigen, interphotoreceptor retinoid binding protein (IRBP
). Analysis of the retina by fundoscopy, histological examination, or optical coherence tomography showed that treatment of the mice with SBT-100 suppressed uveitis by inhibiting expansion of pathogenic Th17 cells that mediate EAU. Electroretinographic (ERG) recordings of dark and light adapted a- and b-waves showed that SBT-100 treatment rescued mice from developing significant visual impairment observed in untreated EAU mice. Adoptive transfer of activated IRBP-specific T cells from untreated EAU mice induced EAU, while EAU was significantly attenuated in mice that received IRBP-specific T cells from SBT-100 treated mice. Taken together, these results demonstrate efficacy of SBT-100 in mice and suggests its therapeutic potential for human autoimmune diseases.