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, Parren Paul W H I
Genmab, Utrecht, The Netherlands.
Br J Haematol. 2008 Feb;140(3):303-12. doi: 10.1111/j.1365-2141.2007.06916.x. Epub 2007 Nov 27.
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.
我们评估了奥法木单抗（一种正在开发用于治疗B细胞介导疾病的人抗CD20抗体）体内持续活性所需的剂量。在小鼠异种移植模型中，单剂量给药使初始血浆抗体浓度达到5微克/毫升，预期可实现完全的靶点饱和，该剂量有效抑制了人B细胞肿瘤的发展。当血浆浓度降至预期导致半数最大饱和度的水平以下时，肿瘤生长恢复。值得注意的是，肿瘤负荷显著影响抗体的药代动力学。在猴子中，循环和组织中驻留的B细胞的初始清除需要相对高剂量水平。然而，只有当奥法木单抗水平降至10微克/毫升以下时，B细胞区室的重新填充才变得可检测到。我们得出结论，通过高初始剂量给药一旦实现全身CD20的饱和，维持循环细胞上靶点饱和的血浆浓度（5-10微克/毫升）可能足以维持生物活性。这些观察结果可能为在初始清除CD20阳性（肿瘤）细胞后建立维持免疫治疗的给药方案提供理论依据。
