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• W4285492786 abstract "Ravaniand colleagues must be commended for successfully publishing an important randomized controlled trial addressing the role of two anti-CD20 mAbs, rituximab and ofatumumab, for pediatric nephrotic syndrome.1 Rituximab is a chimeric mouse/human mAb, whereas ofatumumab is an entirely human mAb. The authors mention that one major limitation of rituximab-based therapy is that many patients develop antirituximab antibodies, which dramatically reduces efficacy. Further, they posit that ofatumumab may be superior to rituximab because it has a higher affinity for the human CD20 epitope and triggers a more vigorous complement response.1 It would have been necessary to highlight that rituximab is very likely to have a significantly less immunogenic glycosylation profile than ofatumumab. This phenomenon relates to the properties of specific neuraminic acids (also known as sialic acids) that decorate the tip of most glycans.2 There are two major types of neuraminic acids in the animal kingdom: N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). These monosaccharides must be activated via linkage to cytidine monophosphate (CMP) to be added to the termini of glycans by sialyltransferases. Interestingly, cells produce Neu5Gc when the enzyme cytidine monophosphate N-acetylneuraminic acid hydroxylase (CMAH) adds an oxygen atom to CMP-Neu5Ac.2 Due to a deletion in the gene encoding for CMAH, all humans cannot synthesize CMP-Neu5Gc. As a result, most humans have preexisting anti-Neu5Gc antibodies that likely developed after exposure to animal-derived proteins (xeno-antigens).2 This means that intravenous infusion of recombinant antibodies produced in animal cells may significantly reduce the half-life in many patients because of the robust immune response triggered after exposure.3 This phenomenon would be predicted to worsen with additional infusions. Both rituximab and ofatumumab are N-glycosylated in the Golgi of the animal cell lines used to produce them—the CHO (Chinese hamster ovary) and NS0 (murine myeloma) cells, respectively. CHO cells are unusual because they express lower Cmah levels than other commonly used animal cell lines, such as NS0 cells.4 As a result, the proportion of N-linked glycans capped with Neu5Ac is much lower in recombinant proteins produced in CHO cells. On the basis of the above discussion, it would have been essential to share data about the patients who experienced relapses during the trial and were prescribed additional infusions of rituximab or ofatumumab. It would also have been ideal to monitor the titers of antirituximab and anti-Neu5Gc antibodies in both arms of the study. Patients with low preexisting anti-Neu5Gc levels would be predicted to fare better. Disclosures The author has nothing to disclose. Funding None." @default.
• W4285492786 created "2022-07-15" @default.
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• W4285492786 date "2022-08-01" @default.
• W4285492786 modified "2023-10-16" @default.
• W4285492786 title "On the Importance of Considering Glycosylation When Evaluating Biologic Therapies" @default.
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• W4285492786 doi "https://doi.org/10.1681/asn.2022040461" @default.
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