Interferon-beta (IFN-β) antibodies in interferon-β1a-and interferon-β1b-treated multiple sclerosis patients.: Prevalence, kinetics, cross-reactivity, and factors enhancing interferon-β immunogenicity in vivo

We analysed the role of dosage, route and frequency of administration of clinical grade interferon-beta (IFN-beta) preparations in inducing anti-IFN-beta antibodies (IFN-beta -Abs) in 5 groups of relapsing-remitting multiple sclerosis (RRMS) patients who were respectively treated as follows: 1) weekly intramuscular (i.m.) injections of 30 mug of recombinant IFN-beta 1a (Avonex (TM)), 2) subcutis (s.c.) injections of 250 mug IFN-beta 1b (Betaferon (R)) every other day, 3) weekly i.m. injections of 250 mug IFN-beta 1b (Betaferon (R)), 4) s.c. injections of 22 mug of IFN-beta 1a (Rebif (R)) three times a week, and 5) i.m. injections of 22 mug of IFN-beta 1a (Rebif (R) ) twice a week. IFN-beta -Abs were determined by ELISA, IFN-beta 1b was more immunogenic than IFN-beta 1a not only when administered s.c. every other day, but also when administered i.m. at a lower weekly dose; i.m. injection, however, significantly delayed the appearance, and induced lower serum levels of IFN-beta -Abs. In patients treated with s.c. IFN-beta 1b, Ab levels peaked 3 to 9 months after therapy initiation, and then slowly, But progressively, declined to pre-therapy levels that in some patients were reached after three years. Patients treated with i.m. or s.c. IFN-beta 1a only rarely developed IFN-beta -Abs, and then at very low titers, Overall, the i.m. weekly administration of IFN-beta 1a was the less immunogenic treatment. In IFN-beta 1b-treated patients, a wash-out period of two/three months was sufficient to bring the IFN-beta -Ab levels below the cut-off. Our findings suggest that the immunogenicity of IFN-beta 1a is low, regardless of the route of administration and the dosage, while that of IFN-beta 1b is high, and is significantly, but not completely reduced by i.m. administration. As IFN-beta -Abs are cross-reactive, a wash-out period is suggested when the preparation is changed from IFN-beta 1b to IFN-beta 1a in order to maintain the clinical benefits of the therapy.