n-Dodecyl-β-d-Maltoside Inhibits Aggregation of Human Interferon-β-1b and Reduces Its Immunogenicity

Abstract

The development of neutralizing antibodies to the protein drug interferon-β is a significant impediment to its use in the treatment of multiple sclerosis. Neutralizing antibodies to interferon-β arise from aggregation of the peptide during manufacturing and storage. We tested the ability of dodecylmaltoside, a nontoxic alkylsaccharide surfactant, to reduce aggregation of interferon-β in vitro and to reduce its immunogenicity in vivo. Interferon-β, in solution with and without dodecylmaltoside, was periodically evaluated for aggregation by light scatter for 1 month. Interferon-β, with and without dodecylmaltoside, was given 3 days/week for 1 month to mice; the sera of these mice were analyzed for anti-interferon-β antibodies by ELISA. Dodecylmaltoside reduces the aggregation of interferon-β in vitro and its immunogenicity in vivo. Our positive findings warrant additional tests of dodecylmaltoside as a therapeutic adjuvant in rodent models of multiple sclerosis.

Formation, Clearance, Deposition, Pathogenicity, and Identification of Biopharmaceutical-related Immune Complexes

“…In mice, aggregation also can affect human IgG1 mAb biodistribution and immunogenicity with SC administration leading to persistence of aggregates in the injection site, faster clearance of aggregates after plasma uptake, and greater increases in cytokine levels compared with IV administration (Filipe et al 2014). Similarly, aggregates in rh interferon b drugs were associated with increased induction of neutralizing ADA in both humans and transgenic mice with lessening of immunogenicity by inclusion of a surfactant (Rifkin et al 2011). Finally, it is plausible that residual aggregates in mAb or IgG Fc fusion drug formulation could act as IC even without an ADA component.…”

Solution Properties of Alkyl β‐D‐Maltosides

“…From a chemical point of view, alkyl D‐maltosides are stable under neutral and alkaline conditions because they are comprised of bulkier and rigid sugar headgroups and flexible alkyl chain tail groups connected via an ether linkage rather than an ester linkage or an amide linkage (Faramarzi et al, ). Therefore, they have a wide range of applications and development in food, cosmetic, pharmaceutical industries, and scientific research (de Foresta et al, ; Jastrzebska et al, ; Ni et al, ; Pillion et al, ; Raman et al, ; Rifkin et al, ; Santonicola et al, ; Weber and Benning, ; Zhang et al, ). They have been used in drug delivery (Ahmad et al, ), thermal stabilization (Ahmad et al, ), hydrolytic metabolism (Weber and Benning, ), salt tolerance (Zhang et al, ), formation of higher‐ordered structure (Jastrzebska et al, ), co‐immunoprecipitation (Lee et al, ), and structure analysis (Ni et al, ), as well as therapeutic adjuvants (Rifkin et al, ), permeation enhancers (Pillion et al, ), absorption enhancers (Gradauer et al, ), and membrane protein stabilizers against denaturation (Das et al, ; de Foresta et al, ; Jastrzebska et al, ; Klammt et al, ; Newby et al, ; Raman et al, ; Santonicola et al, ; Whorton and MacKinnon, ).…”

Amino-Acid-Incorporating Nonionic Surfactants for Stabilization of Protein Pharmaceuticals

“…N-dodecyl-β-D-maltoside, a surfactant that has been explored elsewhere for protein stabilization, was also included in this study and did not perform qualitatively differently than either polysorbate control ( Figure S2). 16 Protein aggregates often have large amounts of β-sheet structure as hydrophobic regions come together, and as a result, circular dichroism (CD) can be used to track aggregation through monitoring of the β-sheet signal. 17,18 Figure 1b shows the evolution of the β-sheet signal (218 nm) for IgG samples formulated alone or with Polysorbate 20 or FM1000.…”