Antibodies that neutralize cellular uptake of elosulfase alfa are not associated with reduced efficacy or pharmacodynamic effect in individuals with Morquio A syndrome
2016
Melton, Andrew | Soon, Russell | Cle, Troy | Long, Brian | Schweighardt, Becky | Qi, Yulan | Vitelli, Catherine | Bagri, Anil | Decker, Celeste | O'Neill, Charles A. | Zoog, Stephen J. | Jesaitis, Lynne
Many enzyme replacement therapies (ERTs) for lysosomal storage disorders use the cell-surface cation-independent mannose-6 phosphate receptor (CI-M6PR) to deliver ERTs to the lysosome. However, neutralizing antibodies (NAb) may interfere with this process. We previously reported that most individuals with Morquio A who received elosulfase alfa in the phase 3 MOR-004 trial tested positive for NAbs capable of interfering with binding to CI-M6PR ectodomain in an ELISA-based assay. However, no correlation was detected between NAb occurrence and clinical efficacy or pharmacodynamics. To quantify and better characterize the impact of NAbs, we developed a functional cell-based flow cytometry assay with a titer step that detects antibodies capable of interfering with elosulfase alfa uptake. Serum samples collected during the MOR-004 trial were tested and titers were determined. Consistent with earlier findings on NAb positivity, no correlations were observed between NAb titers and the clinical outcomes of elosulfase alfa-treated individuals with Morquio A.
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