In the United States, two types of recombinant human interferon beta (IFNß) therapy are approved for the treatment of relapsing-remitting multiple sclerosis (MS): IFNß-1b (Betaseron®) and IFNß-1a (Avonex®). IFNß-1b, a nonglycosylated molecule, reduces the frequency of relapses by 34%. IFNß-1a, a glycosylated molecule, reduces the relapse rate by 32% and, in addition, slows disease progression.1 Rebif®, another IFNß-1a therapy, is not approved for use in the U.S.
These treatments may fail, however, because of non-compliance with therapy, intolerable adverse effects, non-responsive disease, or the development of neutralizing antibodies (NABs). NABs are formed in up to a third of patients and are capable of reducing or abrogating the normal biological and treatment effects of interferons.6 Khan and Dhib-Jalbut suggest the mechanism by which NABs affect interferon therapies: "NABs are believed to bind directly to that epitope of the IFNß molecule that binds to the IFNß receptor, and are likely to neutralize the effect of IFNß on target cells."1
Thus, in patients identified by a biological viral cytopathic effect assay as NAB positive, physicians may see reduced clinical efficacy of the interferon therapy, as well as cross-reactivity with other interferon drugs. Cross-reactivity refers to the phenomenon of the immune system developing antibodies to one agent (i.e., an interferon drug) and then recognizing and developing antibodies to another similar agent (i.e., another interferon drug). Several studies document that NAB cross-reactivity does exist and can influence the bioavailabilty and efficacy of IFNß therapy in MS patients.3
Identifying patients who exhibit reduced responsiveness or non-responsiveness to interferon therapies as being NAB positive may be clinically significant when weighing treatment options for such patients. Instead of switching NAB positive patients to another interferon therapy, physicians may want to consider non-interferon therapies, such as Copaxone (glatiramer acetate, GA), because of the cross-reactive characteristic of NABs.2
NAB positivity in patients undergoing interferon therapy has been documented for all three drugs, albeit at differing incidences. The IFNß Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group (British Columbia study) define NAB positivity as at least two consecutive titers of 20 neutralizing units or greater, as determined by a biological viral cytopathic effect assay (which is recommended by the World Health Organization).3
Approximately 40% of patients treated with Betaseron® IFNß-1b developed NABs and reduced clinical efficacy appeared in association with NABs, according to the British Columbia study.4 Rudick et al. found NABs in 17% of patients treated with Avonex® IFNß-1a.2, 4 Similarly, a study noted that NABs developed in 23.7% of patients undergoing Rebif® IFNß-1a therapy, with an identifiable reduction in clinical and MRI efficacy.7
NAB positive patients in the British Columbia Study appeared the same as placebo patients on MRI between the first and second year of IFNß-1b treatment.6 "[T]here was...a significant loss of treatment effect on enlarging MRI lesions in NAB [positive] patients compared with NAB [negative] patients, and a trend toward increased new lesion formation."6
The cause of increased incidence of NAB formation (and the correlating reduction in clinical efficacy) in patients receiving IFNß-1b when compared to patients receiving either of the IFNß-1a therapies has not yet been determined. Rudick et al. postulates three possible causes:
- the route and frequency of drug administration
Studies have found lower immunogenicity with intramuscular versus subcutaneous injections and with once a week versus three times a week injections. - the absence of glycosylation in IFNß-1b, leading to the formation of aggregates
The formation of aggregates is probably due to the absence of glycosylation. Aggregates are known to increase immunogenicity. - the differences in amino acid sequences
The amino acid sequences that comprise IFNß-1a and IFNß-1b are different, which can produce differences in immunogenicity.4
In addition to decreased clinical efficacy, NABs have been identified as a factor in cross-reactivity between IFNß-1b and IFNß-1a. Patients who develop NABs to IFNß-1b therapy tend to develop NABs to IFNß-1a therapy, and vice versa.1,2 Cohen et al. found that NABs reacted with IFNß-1a 23% of the time in patients who had previously received IFNß-1b for 12 to 18 months. Moreover, NABs reacted with IFNß-1a 26% of the time in patients who had previously received IFNß-1b for more than 18 months.2
Data suggests that the titer of NABs present can assist in making the medical decision of which MS therapy may be most appropriate. For example, in a 26-month study of 101 patients by Bethoux and Rudick at the Cleveland Clinic, patients were tested for NABs based on disease activity, such as continued relapses during therapy (39%), disability progression (55%), or MRI disease activity (6%).5
The study found that a positive NAB test resulted in a treatment change in every case.5 Most of the patients switched to another disease-modifying therapy. Treatment decisions in patients with a negative or borderline NABs titer consisted of the following: 61% continued the same treatment regimen; 28% continued IFNß with the addition of another medication, such as pulse IV methylprednisone or azathioprine; and 10% switched to another disease-modifying therapy.3
NAB positivity does not equate with non-responsiveness to therapy in every instance. However, upon therapeutic failure due to lack of IFNß benefit, the presence of NABs can help determine which therapy would be most appropriate for the MS patient. A persistent high titer of NABs to one IFNß drug suggests that the patient is unlikely to benefit from another IFNß drug, and the alternative therapy should probably not include IFNß.2 However, if NABs are not detected and a patient is doing poorly on IFNß therapy, the addition of another drug to the current treatment regimen is an option. Khan and Dhib-Jalbut summarize the impact of NABs on interferon therapies and how it can affect therapeutic decisions in MS:
"[I]t is recommended that patients who continue to have relapses despite several months of treatment with either IFNß preparation and are being considered for alternate IFNß therapy be tested for NABs. The presence of NABs to either IFNß preparation in such patients, particularly high titers, would tend to suggest that switching to alternate IFNß preparation may not be clinically beneficial because NABs to one IFNß molecule may neutralize the efficacy of alternate IFNß molecules."1
