Incidence, characterization, and clinical impact analysis of peginterferon beta1a immunogenicity in patients with multiple sclerosis in the ADVANCE trial

Abstract

Background: Efficacy of interferon beta in multiple sclerosis (MS) can be dampened in patients who develop neutralizing antidrug antibodies (NAbs). Peginterferon beta1a is an interferon conjugated with a polyethylene glycol (PEG) moiety. Pegylation increases a drug's half life and exposure, and may also reduce immunogenicity. Objective: The objective of this study was to characterize the incidence and impact of immunogenicity to peginterferon beta1a over 2 years in patients with MS. Methods: Patients with relapsing-remitting MS (N = 1512) were randomized to subcutaneous peginterferon beta1a 125 μg every 2 or 4 weeks, or placebo, for 1 year; patients in the placebo group were rerandomized to active treatment in year 2. The incidence and titers of binding antibodies (BAbs) and NAbs to interferon and antibodies to PEG (anti-PEG) were assessed in analytically validated assays. The clinical impact of immunogenicity on relapse and magnetic resonance imaging endpoints was evaluated. Results: Over 2 years, 6%, less than 1%, and 7% of patients developed anti-interferon BAbs, NAbs, and anti-PEG antibodies, respectively. There was no discernible clinically meaningful effect of antibody status on the pharmacodynamic, efficacy, or safety parameters evaluated, although these analyses were limited by the low incidence of treatment-emergent antibodies. Conclusion: The treatment effect of peginterferon beta1a in patients with relapsing-remitting MS is not expected to be attenuated by immunogenicity.

Anti-PEG antibodies in the clinic: Current issues and beyond PEGylation

“…This result explains why PEGylated nonhuman enzymes, e.g., uricase and asparaginase, have been reported to present the most severe issues resulting from anti-PEG Abs, whereas others are relatively safer. [49, 51, 52] Another key finding from this study is that the degree of modification is a crucial factor determining PEG-protein conjugate immunogenicity, as more PEG chains on a protein elicited weaker antibody responses, possibly due to better masking of immunogenic epitopes. Finally, it has been determined that anti-PEG Ab binds to 6–7 ethylene glycol repeating units.…”

Recommendations for the Assessment and Management of Pre-existing Drug-Reactive Antibodies During Biotherapeutic Development

“…Pre-existing antibodies to polyethylene glycol (PEG) are reported in various frequencies dependent on the level of prior exposure to PEG-containing commodities or medical procedures, as well as the analytical methods used for pre-existing antibody detection (16,(36)(37)(38)(39). While a high prevalence of anti-PEG preexisting antibodies was not associated with impaired response to PEG-interferon in hepatitis C patients, increased drug clearance, reduced efficacy, and increased infusion reactions have been reported for pegloticase (PEG-porcine uricase) in patients with refractory chronic gout (14,40).…”

Outcome of pediatric patients with acute lymphoblastic leukemia/lymphoblastic lymphoma with hypersensitivity to pegaspargase treated with PEGylated Erwinia asparaginase, pegcrisantaspase: A report from the Children's Oncology Group

“…Initially thought as nonimmunogenic, over 30 years ago Richter and Akerblom clearly demonstrated the development of anti‐PEG antibodies after exposure to PEG‐conjugated allergens in both murine and human experiments . Further, a number of studies have been published documenting anti‐PEG antibodies in normal individuals who have never been exposed to PEGylated pharmaceutical agents, likely attributable to exposure to PEG‐diols, which are increasingly present in processed foods and cosmetics . However, the clinical significance of anti‐PEG antibodies has been debated in the literature.…”

“…In the Richter and Akerblom study, during hyposensitization with PEG‐modified ragweed extract and honey bee venom, the patients showed an anti‐PEG antibody response, however the responses were deemed of no clinical significance . Additionally, while anti‐PEG antibodies have been detected in some patients with hepatitis C treated with PEGylated interferons, no clinically significant hypersensitivity developed . Conversely, in gout patients receiving a PEG‐conjugated porcine uricase, pegloticase, anti‐PEG antibodies were detected in up to 40% of treated patients and were associated with a loss of therapeutic response .…”

“…While 28,29 Further, a number of studies have been published documenting anti-PEG antibodies in normal individuals who have never been exposed to PEGylated pharmaceutical agents, likely attributable to exposure to PEG-diols, which are increasingly present in processed foods and cosmetics. [29][30][31][32] However, the clinical significance of anti-PEG antibodies has been debated in the literature. In the Richter and Akerblom study, during hyposensitization with PEG-modified ragweed extract and honey bee venom, the patients showed an anti-PEG antibody response, however the responses were deemed of no clinical significance.…”