Estimation of dose requirements for sustained in vivo activity of a therapeutic human anti-CD20 antibody

Bleeker, Wim K., Munk, Martin E., Mackus, Wendy J.M., van den Brakel, Jeroen H.N., Pluyter, Marielle, Glennie, Martin J., van de Winkel, Jan G.J. and Parren, Paul W.H.L. (2008) Estimation of dose requirements for sustained in vivo activity of a therapeutic human anti-CD20 antibody. British Journal of Haematology, 140 (3), 303-312. (doi:10.1111/j.1365-2141.2007.06916.x).

Abstract

We evaluated the dose requirements for sustained in vivo activity of ofatumumab, a human anti-CD20 antibody under development for the treatment of B cell-mediated diseases. In a mouse xenograft model, a single dose, resulting in an initial plasma antibody concentration of 5 microg/ml, which was expected to result in full target saturation, effectively inhibited human B-cell tumour development. Tumour growth resumed when plasma concentrations dropped below levels that are expected to result in half-maximal saturation. Notably, tumour load significantly impacted antibody pharmacokinetics. In monkeys, initial depletion of circulating and tissue residing B cells required relatively high-dose levels. Re-population of B-cell compartments, however, only became detectable when ofatumumab levels dropped below 10 microg/ml. We conclude that, once saturation of CD20 throughout the body has been reached by high initial dosing, plasma concentrations that maintain target saturation on circulating cells (5-10 microg/ml) are probably sufficient for sustained biological activity. These observations may provide a rationale for establishing dosing schedules for maintenance immunotherapy following initial depletion of CD20 positive (tumour) cells.

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