Sausville E A, Headlee D, Stetler-Stevenson M, Jaffe E S, Solomon D, Figg W D, Herdt J, Kopp W C, Rager H, Steinberg S M
Laboratory of Biological Chemistry, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Blood. 1995 Jun 15;85(12):3457-65.
IgG-RFB4-SMPT-dgA consists of deglycosylated ricin A chain (dgA) coupled to the monoclonal antihuman CD22 antibody, RFB4. This study determined the maximally tolerated dose (MTD) of this immunotoxin (IT) administered as a continuous 8-day infusion to 18 patients with B-cell lymphoma (30% CD22+ tumor cells) over 8 days. The MTD was 19.2 mg/m2/192 h (maximum toxicity grade 1), with vascular leak syndrome (VLS) as dose-limiting toxicity (DLT) at 28.8 mg/m2/192 h (grades 3 through 5 in 7 of 11 patients). Predictors of severe VLS included serum IT concentrations greater than 1,000 ng/mL and the absence of circulating tumor cells. Decreased urine sodium excreted in 24 hours provided evidence for mild VLS without notable changes in serum albumin. Four partial responses, 3 minor responses, 6 stable disease, and 3 progression of disease were observed. The mean maximal serum concentration (Cmax) in initial courses at the MTD (19.2 mg/m2) was 443 +/- 144 ng/mL (n = 3; range, 326 to 604). At 28.8 mg/m2/192 h, the Cmax was highly variable (n = 11; mean, 1,102 +/- 702; range, 9.6 to 2,032 ng/mL). Human antimouse or antiricin antibodies developed in 6 of 16 (37.5%) patients after one course of IT. However, 10 eligible patients received multiple courses of IT. Changes in serum cytokines and cytokine receptors did not correlate with toxicity but decreased soluble interleukin-2 receptor concentrations correlated with clinical response. Comparison to a prior study with the same IT administered by intermittent bolus infusions (Amlot et al, Blood 82:2624, 1993) suggests similar clinical response, toxicity, and immunogenicity.
IgG-RFB4-SMPT-dgA由去糖基化的蓖麻毒素A链（dgA）与单克隆抗人CD22抗体RFB4偶联而成。本研究确定了该免疫毒素（IT）以连续8天输注的方式给予18例B细胞淋巴瘤患者（30% CD22+肿瘤细胞）8天的最大耐受剂量（MTD）。MTD为19.2 mg/m²/192小时（最大毒性等级为1级），血管渗漏综合征（VLS）为剂量限制性毒性（DLT），在28.8 mg/m²/192小时时出现（11例患者中有7例为3至5级）。严重VLS的预测因素包括血清IT浓度大于1000 ng/mL以及无循环肿瘤细胞。24小时尿钠排泄减少为轻度VLS提供了证据，血清白蛋白无明显变化。观察到4例部分缓解、3例轻微缓解、6例病情稳定和3例病情进展。在初始疗程中，MTD（19.2 mg/m²）时的平均最大血清浓度（Cmax）为443±144 ng/mL（n = 3；范围为326至604）。在28.8 mg/m²/192小时时，Cmax高度可变（n = 11；平均值为1102±702；范围为9.6至2032 ng/mL）。16例患者中有6例（37.5%）在一个疗程的IT治疗后产生了人抗鼠或抗蓖麻毒素抗体。然而，10例符合条件的患者接受了多个疗程的IT治疗。血清细胞因子和细胞因子受体的变化与毒性无关，但可溶性白细胞介素-2受体浓度降低与临床反应相关。与先前一项关于以间歇性推注输注方式给予相同IT的研究（Amlot等人，《血液》82:2624，1993）相比，提示临床反应、毒性和免疫原性相似。
