Schroff R W, Morgan A C, Woodhouse C S, Abrams P G, Farrell M M, Carpenter B E, Oldham R K, Foon K A
J Biol Response Mod. 1987 Aug;6(4):457-72.
Thirteen patients with metastatic malignant melanoma received intravenous therapy with the murine antimelanoma monoclonal antibody 9.2.27. Five patients were entered on a dose escalation protocol with twice weekly escalating doses of 10-500 mg, in an extension of a previously reported trial. These patients demonstrated near saturation of available antibody binding sites in vivo following the 500 mg dose, with minimal toxicity. The remaining patients were entered onto a dose schedule comparison study, with a 500 mg dose administered either in a single 2 h infusion or as five daily 2 h infusions of 100 mg to examine the effects of different dose schedules and of an interrupted schedule on subsequent therapy with the same antibody. Intratumor localization of the monoclonal antibody did not appear to vary with respect to the dose schedule; however, interruption in therapy for 4 weeks was accompanied by somewhat poorer localization of antibody. This effect appeared to be primarily attributable to development of human antimurine antiglobulin in 25-30% of patients with resultant decrease in intratumor localization of antibody and more rapid clearance of the 9.2.27 antibody from the circulation. Earlier reports with other antibodies notwithstanding, initial infusions of 500 mg of 9.2.27 did not induce tolerance to the murine immunoglobulin. This study confirms and extends the findings of our initial trial of the 9.2.27 antibody by demonstrating that, although clinical responses were not observed, the antibody can be safely administered at doses up to 500 mg, with good intratumor localization of antibody. The diminished localization of antibody associated with antiglobulin responses indicates the importance of monitoring antiglobulin levels during therapy, and the necessity of controlling or preventing this phenomenon when monoclonal antibodies are administered in multiple doses as drug, toxin, or radionuclide immunoconjugates.
13例转移性恶性黑色素瘤患者接受了鼠抗黑色素瘤单克隆抗体9.2.27的静脉治疗。在一项先前报道试验的扩展研究中，5例患者进入剂量递增方案，每周两次递增剂量为10 - 500 mg。这些患者在500 mg剂量后体内可用抗体结合位点接近饱和，毒性极小。其余患者进入剂量方案比较研究，500 mg剂量以单次2小时输注或每日5次每次100 mg共2小时输注的方式给药，以研究不同剂量方案以及中断方案对后续使用相同抗体治疗的影响。单克隆抗体在肿瘤内的定位似乎不因剂量方案而异；然而，治疗中断4周会伴随抗体定位稍差。这种效应似乎主要归因于25% - 30%的患者产生人抗鼠抗球蛋白，导致肿瘤内抗体定位减少以及9.2.27抗体从循环中清除加快。尽管有关于其他抗体的早期报道，但最初输注500 mg的9.2.27并未诱导对鼠免疫球蛋白的耐受性。本研究通过证明尽管未观察到临床反应，但抗体可安全地以高达500 mg的剂量给药，且抗体在肿瘤内定位良好，从而证实并扩展了我们最初对9.2.27抗体试验的结果。与抗球蛋白反应相关的抗体定位减少表明在治疗期间监测抗球蛋白水平的重要性，以及当单克隆抗体作为药物、毒素或放射性核素免疫缀合物以多剂量给药时控制或预防这种现象的必要性。
