Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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A Novel Therapeutic Effect of a New Variant of CTLA4-Ig with Four Antennas That Are Terminally Capped with Sialic Acid in the CTLA4 Region

  • Piao, Yongwei (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Yun, So Yoon (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Kim, Hee Soo (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Park, Bo Kyung (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Ha, Hae Chan (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Fu, Zhicheng (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Jang, Ji Min (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Back, Moon Jung (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Shin, In Chul (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Won, Jong Hoon (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University) ;
  • Kim, Dae Kyong (Department of Environmental & Health Chemistry, College of Pharmacy, Chung-Ang University)
  • Received : 2022.05.21
  • Accepted : 2022.07.16
  • Published : 2022.11.01
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Abstract

Rheumatoid arthritis (RA) is a multifactorial immune-mediated disease, the pathogenesis of which involves different cell types. T-cell activation plays an important role in RA. Therefore, inhibiting T-cell activation is one of the current therapeutic strategies. Cytotoxic T-lymphocyte antigen 4-immunoglobulin (CTLA4-Ig), also known as abatacept, reduces cytokine secretion by inhibiting T-cell activation. To achieve a homeostatic therapeutic effect, CTLA4-Ig has to be administered repeatedly over several weeks, which limits its applicability in RA treatment. To overcome this limitation, we increased the number of sialic acid-capped antennas by genetically engineering the CTLA4 region to increase the therapeutic effect of CTLA4-Ig. N-acetylglucosaminyltransferase (GnT) and α2,6-sialyltransferase (α2,6-ST) were co-overexpressed in Chinese hamster ovary (CHO) cells to generate a highly sialylated CTLA4-Ig fusion protein, named ST6. The therapeutic and immunogenic effects of ST6 and CTLA4-Ig were compared. ST6 dose-dependently decreased paw edema in a mouse model of collagen-induced arthritis and reduced cytokine levels in a co-culture cell assay in a similar manner to CTLA4-Ig. ST6- and CTLA4-Ig-induced T cell-derived cytokines were examined in CD4 T cells isolated from peripheral blood mononuclear cells after cell killing through irradiation followed by flow- and magnetic-bead-assisted separation. Interestingly, compared to CTLA4-Ig, ST6 was substantially less immunogenic and more stable and durable. Our data suggest that ST6 can serve as a novel, less immunogenic therapeutic strategy for patients with RA.

Keywords

Acknowledgement

This study was supported by a Chung-Ang University Young Scientist Scholarship in 2015. The samples used in this study were provided by Inha University (ICN, KR). This study was supported by a grant from the National Research Foundation of Korea (NRF-2017M3A9D8048414) funded by the Korean government (Ministry of Science and ICT).

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