Adhesion molecule expression indicates a therapeutical effect of natatizumab despite the presence of neutralizing antibodies

Objective: We report on serial α4-integrin expression levels of a patient with neutralizing anti-Natalizumab-antibodies.

Background: Natalizumab is a humanized monoclonal antibody directed against the adhesion molecule α4-integrin. Neutralizing anti-natalizumab-antibodies have been found to reduce the beneficial effects of Natalizumab treatment in multiple sclerosis (MS). Moreover, detection of high-titred neutralizing antibodies is associated with a higher risk of allergic side effects.

Methods: We determined serially cell surface bound α4-integrin expression levels on peripheral blood mononuclear cells by the aid of two-color flow cytometry during Natalizumab treatment of 35 years old female MS patient on Natalizumab therapy.

Results: We routinely determined α 4 integrin expression right before the first infusion of natalizumab and then every three months. In contrast to all other Natalizumab treated patients, in whom we found a significant decrease, the levels of α4-integrin expression remained unchanged after three months in one patient. We consecutively determined serum neutralizing anti-Natalizumab-antibodies which were found to be high-titred positive.

However, the patient showed impressive clinical and neuroradiological benefits from Natalizumab treatment. Therefore we decided to continue Natalizumab therapy. Moreover, we measured α4-integrin expression levels serially on days 1, 2, 3, 7 and 11 after the following Natalizumab infusions. Interestingly, α4-integrin expression was decreased one day after infusion, comparable to patients without antibodies. A 4 integrin levels remained lowered for several days and then reached baseline levels again after about seven days.

Discussion: We were able to demonstrate a short-term effect of Natalizumab treatment on the molecular level lasting for a few days despite of high-titred neutralizing antibodies. We suggest that this short-term effect as determined by reduced α4-integrin levels was responsible for the beneficial effects of Natalizumab treatment in our patient. However, it remains open whether individual patients with neutralizing antibodies would benefit from a higher frequency of Natalizumab administration.

This study was supported by Biogen-Idec Austria