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Anticytokine antibodies in beta‐interferon‐treated patients

using aliquots of the same serum specimens used to measure the neutralizing antibody by a viral cytopathic effect reduction biological assay employed during the Betaseron multicenter trial. The standard for measuring IFN antibodies used for many years has been the viral bioassay. This bioassay depends on infecting all cultures with live virus. Although the current MxA bioassay was developed by Berlex in full agreement with an FDA mandate for a new assay, multiple sclerosis (MS) patient sera are not currently being tested by Berlex Laboratories, contrary to Pachner’s assertion. Rather, the tests are being performed by independent laboratories; Immunodiagnostic Laboratories in the US (San Leandro, CA) and Rentschler in Europe (Laupheim, Germany). It is also not true that alternative bioassays from other laboratories are unavailable: Athena Diagnostics, Inc. offers a bioassay for IFN antibodies, and the test is also performed in the laboratory of Dr. Sidney Grossberg at the Medical College of Wisconsin (Milwaukee). As emphasized in the primary publication on the possible effects of neutralizing antibodies during the multicenter trial of Betaseron in MS patients: one must distinguish binding antibodies, measured by ELISA or Western blot, from neutralizing antibodies, measured by a bioassay. Pachner is correct that virtually all patients treated with IFN develop binding antibodies; in fact, even 75% of placebotreated patients have binding antibodies (Product Licensing Application, 1993; Berlex Laboratories). This relative nonspecificity of the ELISA and its “nearly always abnormal” aspect makes it essentially useless for following MS patients. If Pachner has data showing that one can distinguish lack of treatment efficacy by the exact titer of ELISA antibodies, he should present the data on which this opinion is based. Our studies show that there is no meaningful correlation between neutralizing antibodies and binding antibodies. Only antibodies neutralizing the biological activity of the IFN molecule may be correlated with clinical significance: the consensus view shared by experts in the field. These are the antibodies measured by both the viral and MXA bioassays. Pachner makes the point that there is little financial incentive for pharmaceutical companies that market IFNs to pursue neutralizing antibody studies. Nonetheless, in addition to developing and validating the new MxA bioassay, Berlex Laboratories has sponsored and continues to support much research in this area. Currently, two studies of the effects of Betaseron in secondary progressive MS are ongoing, involving over 1600 patients. More than 20,000 serum samples from these patients will be collected and analyzed for neutralizing antibody content. In May 1997, Berlex Laboratories and Schering AG in New York City jointly sponsored the International Workshop on ZFN Antibodies. This meeting, chaired by Drs. Ferdinand0 Dianzani and G. Barry Arnason, brought together international experts in the field of alphaand beta-IFN research. At this meeting, these experts presented new data on the relation between neutralizing antibodies and interferons and biologic response markers, magnetic resonance imaging parameters, and clinical outcome measures. The findings of this workshop will be the subject of a future publication.