Interferon-Beta: Neutralizing Antibodies, Binding Antibodies, Pharmacokinetics and Pharmacodynamics, and Clinical Outcomes

Abstract

Antibodies to interferon-beta (IFNb) may occur during treatment with this drug and can be measured at several levels, the totality of antibodies referred to as antidrug antibodies (ADA) or binding antibodies, and in case of interference with the drug activity referred to as neutralizing antibodies (NAB). Antibodies can also interfere with the biological activity of IFNb as measured by pharmacodynamic markers. To get a complete picture of the interference between IFNb as a drug and the ADA, all the 3 above levels need to be considered. Furthermore, the interaction of these biomarkers changes over time with a shift of antibody properties with respect to immunoglobulin subtypes, affinity, and titers of antibodies. In case of persistent NAB, the clinical benefit of IFNb in the treatment of multiple sclerosis is abolished. In this report, the current knowledge on these issues will be reviewed. The data have been presented at a meeting in Coral Gables, Florida on April 18-21, 2012.

Unraveling the Effect of Immunogenicity on the PK/PD, Efficacy, and Safety of Therapeutic Proteins

“…Fortunately, this tolerance persisted even after termination of B cell recovery and immunosuppression. Dosing-through is another method that has also proven to be a successful strategy in overcoming the deleterious effects of ADA on efficacy [90]. For MS patients receiving long term IFN-s therapy, nADAs have also proven to be problematic.…”

Effect of HLA-DRB1 alleles and genetic variants on the development of neutralizing antibodies to interferon beta in the BEYOND and BENEFIT trials

“…Interferon β-preparations are widely used to treat multiple sclerosis (MS) or clinically isolated syndrome (CIS). Overall, up to 40% of patients will eventually develop antibodies against interferon β [6][7][8][9] , of which a significant proportion neutralize the biological activity of interferon β (neutralizing antibodies, NAbs) 10,11 . Several factors related to either the interferon β compound and administration or the individual patient influence immunogenicity 6,12-14 . In two previous studies on German MS patients, HLA class II alleles were found to influence the development of ADA against interferon β. HLA-DRB1*04:01 and HLA-DRB1*04:08 showed significant, HLA-DRB1*03:01, HLA-DRB1*04:04, HLA-DRB1*11:01, HLA-DRB1*11:04, and HLA-DRB1*16:01 nominal associations with ADA titer 15,16 .…”

“…4,5 Interferon β preparations are widely used to treat multiple sclerosis (MS) or clinically isolated syndrome (CIS). Overall, up to 40% of patients will eventually develop antibodies against interferon β, 6 –9 of which a significant proportion neutralize the biological activity of interferon β (neutralizing antibodies, NAbs). 10,11 Several factors related to either the interferon β compound and administration or the individual patient influence immunogenicity.…”

Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis

“…In particular, the occurrence of ADA may decrease the efficacy of BPs by neutralizing their activity or modifying their drug clearance and ADA may also be associated with BP-specific hypersensitivity reactions [4]. Clinically relevant neutralizing ADA (NAbs) against IFNβ usually develop between 9 and 18 months after start of therapy [5].…”