Establishment of a glycoengineered CHO cell line for enhancing antennary structure and sialylation of CTLA4-Ig

Lim, Jin-Hyuk; Kim, Jihye; Cha, Hyun-Myoung; Kang, Seung‐Hoon; Han, Hyejin; Ji, Minkyoo; Cheon, Su-Hwan; Kang, Minju; Kim, Ha Hyung; Kim, Dong-Il

doi:10.1016/j.enzmictec.2022.110007

Cited by 5 publications

(4 citation statements)

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“…CTLA4-Ig primarily has two-to tri-antennary structures in the CTLA4 region (Bora de Oliveira et al, 2017). Therefore, a recent study investigated the cooverexpression of GnT and α2,6-ST as a means to produce a highly sialylated CTLA4-Ig fusion protein (Lim et al, 2017;Lim et al, 2022). The authors successfully created a four-antennastructured fusion protein with an increased number of sialic acids in the CTLA4 region by covering the antenna tips with sialic acids (Lim et al, 2017(Lim et al, , 2022.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, a recent study investigated the cooverexpression of GnT and α2,6-ST as a means to produce a highly sialylated CTLA4-Ig fusion protein (Lim et al, 2017;Lim et al, 2022). The authors successfully created a four-antennastructured fusion protein with an increased number of sialic acids in the CTLA4 region by covering the antenna tips with sialic acids (Lim et al, 2017(Lim et al, , 2022. We expected that ST6 would have a better therapeutic effect than CTLA4-Ig in RA treatment; however, the results showed that ST6 has similar effects as CTLA4-Ig when used at the same concentration.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we compared the therapeutic potentials of CTLA4-Ig, known as abatacept, and ST6, a variant of the CTLA4-Ig fusion protein having more sialic acid caps, for RA treatment. ST6 is a novel fusion protein generated via overexpression of GnT, α2,6-ST, and CTLA4-Ig in CHO cells ( Lim et al ., 2022 ). CTLA4-Ig is widely regarded as the first in a new class of drugs for the treatment of RA and as a co-stimulation blocker.…”

Section: Discussionmentioning

confidence: 99%

“…The sialic acid caps in the CTLA4 region improve the half-life of the protein ( Ngantung et al ., 2006 ). To enhance the therapeutic effect of CTLA4-Ig, CTLA4 has to be modified with an optimal number of antennas that are terminally capped with sialic acid ( Lim et al ., 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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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

Yun

Kim

et al. 2022

Biomol Ther (Seoul)

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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-beadassisted 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.

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