Neuwelt E A, Barnett P A, Hellström I, Hellström K E, Beaumier P, McCormick C I, Weigel R M
Oregon Health Sciences University, Division of Neurosurgery, Portland 97201.
Cancer Res. 1988 Sep 1;48(17):4725-9.
Iodinated monoclonal antibodies (IgG 96.5 and two monomeric Fab fragments 96.5 and 48.7) to melanoma-associated antigens were administered after osmotic blood-brain barrier (BBB) opening in normal rats. Osmotic BBB disruption significantly (P less than 0.0001) increased monoclonal antibody delivery to the brain. Following BBB opening and intracarotid administration, there was no difference in the disrupted brain concentration integral area under the curve between Fab and IgG over the 72-h experimental period. However, Fab concentration in the disrupted brain was initially higher than IgG, and the clearance was more rapid (P less than 0.0001), decreasing 50% by approximately 4.5 h compared to 25.5 h for IgG. Plasma clearance was also more rapid for the Fab than IgG. The levels decreased 50% by 1.5 h for Fab and 15 h for IgG. The route and timing of antibody infusion had a significant effect on delivery to the disrupted brain with the Fab fragments but not with the intact IgG. Antibody recovered from disrupted brain retained its immunological reactivity as measured by a cell binding assay for at least 24 h. IgG and Fab delivery to the ipsilateral brain after BBB disruption increased (P less than 0.001) with increasing dose over a more than 3-log dose range. These data provide information applicable to the therapeutic use of monoclonal antibodies in brain tumor treatment.
在正常大鼠经渗透性血脑屏障（BBB）开放后，给予针对黑色素瘤相关抗原的碘化单克隆抗体（IgG 96.5以及两个单体Fab片段96.5和48.7）。渗透性血脑屏障破坏显著（P小于0.0001）增加了单克隆抗体向脑内的递送。在血脑屏障开放并经颈内动脉给药后，在72小时的实验期内，Fab和IgG在破坏脑内的浓度曲线下积分面积无差异。然而，破坏脑内的Fab浓度最初高于IgG，且清除更快（P小于0.0001），与IgG的25.5小时相比，Fab约4.5小时降低50%。Fab的血浆清除也比IgG更快。Fab在1.5小时降低50%，IgG在15小时降低50%。抗体输注的途径和时间对Fab片段向破坏脑内的递送有显著影响，而对完整IgG则无影响。通过细胞结合试验测定，从破坏脑内回收的抗体至少24小时内保留其免疫反应性。在超过3个对数剂量范围内，随着剂量增加，血脑屏障破坏后IgG和Fab向同侧脑内的递送增加（P小于0.001）。这些数据为单克隆抗体在脑肿瘤治疗中的治疗应用提供了适用信息。
