Incidence and Clinical Significance of Therapy-Induced Neutralizing Antibodies Against Interferon-β

Abstract

In A 6-month open adjuvant trial, we treated 21 patients with melanoma with natural interferon-ß (IFN-ß) (Fiblaferon, Rentschier, Laupheim, Germany), and a further 7 patients with recombinant (r)IFN-ß (Betaferon, Rentschier, Laupheim, Germany). With both IFN-ß preparations, the course consisted of three subcutaneous injections of 3 million IU per week given each week for a total of 24 weeks. All patients had stage II malignant melanoma (UICC 1979), and had had all detectable metastases removed surgically before enrollment in the trial.Patients were monitored for neutralizing antibodies against IFN-ß at the beginning of the study, and then every 4 weeks for the next 24 weeks, as well as at 24 and 48 weeks after the end of the treatment period. Neutralizing antibody formation was detected by a cytopathic effect reduction assay. The levels of ß2microglobulin, 2',5'-oligoadenylate synthetase and neopterin were also monitored before and during the treatment.Of the 21 patients treated with natural IFN-ß, 20 (95%) had developed significant levels of anti-IFN-ß antibodies after the 24-week treatment period, which contrasts with only 2 of the 7 patients (29%) treated with recombinant IFN-ß (Table 1 ). These antibodies persisted for a considerable time; 24 weeks and 48 weeks after the cessation of therapy, respectively, 80% and 60% of patients still had neutralizing antibodies. In some patients, the titers increased after cessation of therapy. There was no apparent correlation between the maximum antibody titer and the persistence of antibodies (Table 2). 2,',5'-OHgoadenylate synthetase, ß2-microglobulin, and neopterin levels increased greatly in all the patients when treatment with IFN-ß was initiated. In the patients treated with natural IFN-ß, these levels fell back to pretreatment levels after 8-12 weeks. This was not the case in the patients treated with recombinant IFN-ß, in whom the levels remained markedly elevated throughout the whole treatment period, and returned to normal levels only after treatment was discontinued. We saw a clear correlation between the formation of neutralizing antibodies and the decrease in ß2 microglobulin, 2',5'-oligoadenylate synthetase and neopterin levels, which shows that there was a drop in the biological activity of the injected IFN-ß in the presence of the antibodies. We found complete cross-reactivity between the antibodies formed against the natural IFN-ß and those against Betaferon (which is a glycosylated recombinant IFN-ß, produced in Chinese hamster ovary cells), perhaps because both are glycosylated at identical sites, even though with a different pattern of sugars. Thus, we cannot advocate a switch from treatment with natural IFN-ß to recombinant IFN-ß if antibodies are detected.However, it remains to be determined whether Betaser, a nonglycosylated IFN-ß preparation produced in Escherichia coli, might still be effective.Neutralizing antibodies against IFNs have previously been found to have clinical significance mainly in patients with hematological disorders and in those...

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