Treating Multiple Sclerosis with Monoclonal Antibodies: A 2010 Update

Mathias Buttmann

Disclosures

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

In This Article

Ofatumumab

Ofatumumab (Arzerra®) is a fully human IgG1 mAb against CD20.[94,97,98] In contrast to RTX and OCRE it is directed against the small 7-mer loop of CD20 and binds in close proximity to the plasma membrane.[93] OFA is being developed by Genmab (Copenhagen, Denmark) and GlaxoSmithKline (London, UK).

Indications

Based on a pivotal study, OFA received accelerated FDA-approval for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and ALEM in October 2009.[99,100] Furthermore, OFA was successfully tested in Phase I/II trials for relapsing or refractory follicular lymphoma[101] and RA,[102,103] and it is currently being studied in Phase III trials for these three conditions. In 2009, the first placebo-controlled Phase III RA trial was announced to have met its primary end point, with an efficacy approximately comparable to both RTX and OCRE.[214] Among other Phase II trials, OFA is currently being investigated in a Phase I/II trial in patients with RRMS.[215] In contrast to OCRE, OFA has not been associated with an increased rate of serious and/or opportunistic infections in patients with RA until December 2009, which had put part of the OCRE trial program on hold.

Modes of Action

In contrast to OCRE, OFA is a weak inducer of ADCC and a strong inducer of CDC.[104–106] Stronger CDC activity was attributed to a higher avidity of complement C1q binding to OFA than to RTX, and to the fact that OFA binds to CD20 in closer proximity to the plasma membrane than OCRE and RTX, thereby effectively concentrating activated components of the complement system close to the cell membrane and possibly shielding activated complement components from inactivation.[105,106] The importance of C1q was questioned by another study, suggesting that CDC activity of an anti-CD20 mAb mainly depends on its influence on CD20 mobility to detergent-resistant membrane fractions called lipid rafts.[107] Translocation of CD20 to lipid rafts is required for effective CDC upon mAb binding.[108] Strong CDC activity might indicate that OFA could induce more infusion-related adverse events than RTX or OCRE;[96] however, a direct comparison between OFA and other anti-CD20 mAbs has not been published to date. On the other hand, in vitro and ex vivostudies demonstrated that OFA shows a stronger cytolytic potential than RTX,[105,109] which might be more relevant for the treatment of RTX-refractory hematological disorders[107,108] than for MS therapy, where effective B-cell depletion can be achieved with RTX in all patients.[81,110]

Pharmacology

Rapid and sustained CD19+ B-cell depletion was observed in all OFA-treated patients included in the Phase I/II RA trial, receiving two doses of either 300, 700 or 1000 mg OFA 2 weeks apart, and signs of gradual B-cell recovery were observed from week 20.[104,105] Pharmacological preclinical data and clinical results in patients with hematological disorders including pharmacokinetic data were recently summarized by Robak.[98]

Ofatumumab for MS

A European multicenter, randomized, placebo-controlled Phase I/II study investigating OFA in 324 patients with RRMS started in June 2008 (NCT00640328).[215] The safety of three different OFA dosages (100, 300 or 700 mg) in comparison to placebo over 4 weeks was first evaluated in 36 patients in part A of the study. In part B, another cohort of approximately 288 patients is being treated with one of three different OFA doses (100, 300 or 700 mg) or placebo. After week 24, verum patients are retreated with the same dose OFA or with placebo while patients on placebo receive OFA at the highest tolerated dose determined in part A. Safety over 6 months and cumulative number of new Gd-enhancing MRI lesions from week 8 to 24 are defined as co-primary end points. As of December 2009, September 2010 was the expected final data collection date for primary outcome measures and the estimated study completion date was September 2012.

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