Treating Multiple Sclerosis with Monoclonal Antibodies: A 2010 Update

Mathias Buttmann

Disclosures

Expert Rev Neurother. 2010;10(5):791-809. 

In This Article

LY2127399

LY2127399 (Eli Lilly, IN, USA) is a fully human IgG4 mAb directed against BAFF[134,135] that neutralizes both soluble and membrane-bound forms of BAFF.[136] First results from a Phase II trial in patients with RA, where the agent was well tolerated and effective, were recently presented.[137] Several further Phase II trials in patients with RA are currently running. In addition, a multicenter, placebo-controlled, safety and efficacy dose-finding Phase II trial in 245 patients with RRMS, testing LY2127399 as a formulation for subcutaneous injection every 4 or 12 weeks, started in April 2009 (NCT00882999). A reduction in cumulative total Gd-enhancing MRI lesions over 24 weeks will be the primary end point. As of February 2010, March 2011 was the estimated final data collection date for the primary outcome measure, and September 2011 the estimated study completion date.

In experimental autoimmune encephalomyelitis models, BAFF overexpression was found in diseased brain[138] and simultaneous neutralization of BAFF and APRIL, which only partially share the same receptors and show different serum kinetics,[134] suppressed disease activity and modulated humoral but also T-cell immune responses.[139] BAFF overexpression was also reported in MS brain lesions.[140] While BAFF blood levels were found to be elevated in a number of human autoimmune diseases, including RA and systemic lupus erythematosus, where BAFF is thought to trigger disease activity (reviewed in[141]), they were found to be normal in MS patients in comparison to controls at the protein level.[142,143] Moreover, both IFN-β and ALEM treatment were shown to increase BAFF serum levels in MS patients.[62,144] Due to the proven therapeutic effects of these two drugs, and taking into account a failed trial program investigating the BAFF/APRIL blocker atacicept (EMD Serono, Geneva, Switzerland) in MS patients, where the drug increased disease activity, it seems conceivable that in contrast to patients with other autoimmune diseases, increased BAFF levels might be beneficial or at least not harmful in MS patients. However, it is tempting to speculate that BAFF induction might be involved in thyroid autoimmunity in MS patients, as both IFN-β and ALEM were associated with thyroid autoimmunity in MS patients.[145,146] Of special note, atacicept, a recombinant immunoglobulin fusion protein with one of the BAFF/APRIL receptors (TACI), blocks both BAFF and APRIL, while LY2127399 only neutralizes BAFF. Therefore, it can not be excluded that BAFF blockade alone, without blocking APRIL, might reduce MS disease activity.

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