Abstract
Mimotope peptides selected from combinatorial peptide libraries can be used as capture reagents for immunoassay detection of therapeutic monoclonal antibodies (mAbs). We report the use of phage display libraries to identify peptide ligands (VeritopesTM) that bind natalizumab, a therapeutic mAb indicated for use in multiple sclerosis. PKNPSKF is identified as a novel natalizumab-binding motif, and peptides containing this motif demonstrated utility as capture reagents in enzyme-linked immunosorbent assays (ELISAs). A peptide containing the identified motif was shown to be competitive with the natural ligand (α4-integrin) and a neutralizing anti-idiotype antibody for natalizumab binding, indicating that VeritopesTM act as surrogate ligands that bind the antigen binding site of natalizumab. Affinity maturation further confirmed the motif sequence and yielded peptides with greater apparent affinity by ELISA. VeritopesTM are promising assay reagents for therapeutic drug level monitoring.
Highlights
Multiple sclerosis (MS) is a leading cause of neurologic disability that affects approximately 400,000 people in the US and 2.5 million worldwide[1]
The immunosuppressive activity of natalizumab has been associated with opportunistic infection by John Cunningham (JC) virus which may lead to progressive multifocal leukoencephalopathy (PML), a serious and often-fatal opportunistic brain infection
56–58% of MS patients are positive for anti-JC virus antibodies, which puts them at increased risk for developing PML while on natalizumab[5,6,7]
Summary
Multiple sclerosis (MS) is a leading cause of neurologic disability that affects approximately 400,000 people in the US and 2.5 million worldwide[1]. 56–58% of MS patients are positive for anti-JC virus antibodies, which puts them at increased risk for developing PML while on natalizumab[5,6,7]. The estimated incidence of PML in patients positive for anti-JC virus antibodies is 3.87 per 1,000 patients after at least 1 month of natalizumab treatment. It increases to 11.1 per 1,000 patients for JC virus antibody positive patients with prior use of immunosuppressants and long-term use of natalizumab (24–48 months)[8]. Serum natalizumab concentrations have been shown to vary over 100-fold[4]. The performance of VeritopesTM as assay capture reagents for natalizumab is demonstrated by ELISA.
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