title: Antibodies that neutralize cellular uptake of elosulfase alfa are not associated with reduced efficacy or pharmacodynamic effect in individuals with Morquio A syndrome.
abstract: 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.
authors: BioMarin Pharmaceutical Inc., Novato, CA, United States. Electronic address: AMelton@bmrn.com.
authors: Andrew C
authors: AC
authors: Melton
authors: BioMarin Pharmaceutical Inc., Novato, CA, United States.
authors: Russell K
authors: RK
authors: Soon
authors: BioMarin Pharmaceutical Inc., Novato, CA, United States.
authors: Troy
authors: T
authors: Tompkins
authors: BioMarin Pharmaceutical Inc., Novato, CA, United States.
authors: Brian
authors: B
authors: Long
authors: BioMarin Pharmaceutical Inc., Novato, CA, United States.
authors: Becky
authors: B
authors: Schweighardt
authors: BioMarin Pharmaceutical Inc., Novato, CA, United States.
authors: Yulan
authors: Y
authors: Qi
authors: BioMarin Pharmaceutical Inc., Novato, CA, United States.
authors: Catherine
authors: C
authors: Vitelli
authors: BioMarin Pharmaceutical Inc., Novato, CA, United States.
authors: Anil
authors: A
authors: Bagri
authors: BioMarin Pharmaceutical Inc., Novato, CA, United States.
authors: Celeste
authors: C
authors: Decker
authors: BioMarin Pharmaceutical Inc., Novato, CA, United States.
authors: Charles A
authors: CA
authors: O'Neill
authors: BioMarin Pharmaceutical Inc., Novato, CA, United States.
authors: Stephen J
authors: SJ
authors: Zoog
authors: BioMarin Pharmaceutical Inc., Novato, CA, United States.
authors: Lynne
authors: L
authors: Jesaitis
mesh_terms: D057134:Antibodies, Neutralizing / Q000097:blood* / Q000276:immunology; D001692:Biological Transport; D002811:Chondroitinsulfatases / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004311:Double-Blind Method; D056947:Enzyme Replacement Therapy / Q000379:methods*; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D018613:Microscopy, Confocal; D009085:Mucopolysaccharidosis IV / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D017527:Receptor, IGF Type 2 / Q000276:immunology* / Q000378:metabolism; D012698:Serologic Tests / Q000379:methods*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D057134:Antibodies, Neutralizing; D017527:Receptor, IGF Type 2; C034304:cation-dependent mannose-6-phosphate receptor; D002811:Chondroitinsulfatases; C102295:GALNS protein, human
keywords: Elosulfase alfa; Enzyme replacement therapy; Lysosomal storage disease; Morquio A; Neutralizing antibody titer