Authors’ Reply: “On the Importance of Considering Glycosylation when Evaluating Biologic Therapies”

We thank Dr. Lemaire for the interest in our work and for the relevant observations. He reported that anti-CD20 mAbs, due to their generation in Golgi animal cell lines, may bring the sialic acid N-glycolylneuraminic (Neu5Gc), activated via linkage to cytidine monophosphate (CMP) by the enzyme cytidine monophosphate N-acetylneuraminic acid hydroxylase (Cmah), to be added to the terminal of glycans by sialyl transferases. In humans, the activated Neu5Gc is not present due to the deletion of the CMAH gene. In addition, exposure to animal proteins may have stimulated amplification of anti-Neu5Gc.1 Moreover, rituximab and ofatumumab are produced in CHO (Chinese hamster ovary) and NS0 (murine myeloma) cells, respectively. NSO express higher Cmah than CHO, with consequent significantly higher immunogenic profile of ofatmumab than rituximab. The immunogenicity of fully human anti-CD20 mAbs is not often considered in clinical practice but is relevant because it may affect efficacy. Further studies might address possible relevance of meat-heavy Western diets.2 We hypothesized that ofatumumab would be more effective than rituximab in a cohort of patients with steroid-dependent nephrotic syndrome on the basis of the stronger binding with CD20 and higher activation of complement that Lemaire reports. We observed equivalence between the two anti-CD20 mAbs,3 with rituximab superior in subjects aged <9 years.3 We also observed that previous exposure to rituximab results in production of anti-rituximab antibodies, which persists for a limited time but does not affect response to further administration. Lemaire posits that anti-Neu5GC antibodies may limit ofatumumab efficacy. Therefore, stratification of subjects enrolled in the ofatumumab arm, on the basis of the presence of circulating anti-Neu5Gc antibodies, may affect the results of our clinical trial. A goal of our present research is development of techniques to detect anti-Neu5Gc antibodies. The application will be extended to other ongoing studies with second-generation anti-CD20 mAbs. The introduction of anti-CD20 mAbs in 20114 has revolutionized the therapeutic approach to idiopathic nephrotic syndrome in children and to primary and secondary autoimmune glomerulonephritis in adults, such as membranous nephropathy and glomerulonephritis secondary to ANCA-vasculitis. It is fundamental to confirm the hypothesis in our large cohort and to determine how long circulating anti-Neu5Gc antibodies persist. Detection of anti-Neu5Gc antibodies prior to and during treatment with chimeric, human, or humanized anti-CD20 mAbs would promote a more personalized therapeutic approach. Disclosures All authors have nothing to disclose. Funding P. Ravani and G.M. Ghiggeri were supported by the Italian Ministry of Health, Ricerca Finalizzata (Grant: WFR: PE/Number: 2016-02361576).

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