Stone M J, Sausville E A, Fay J W, Headlee D, Collins R H, Figg W D, Stetler-Stevenson M, Jain V, Jaffe E S, Solomon D, Lush R M, Senderowicz A, Ghetie V, Schindler J, Uhr J W, Vitetta E S
Baylor University Medical Center, Charles A. Sammons Cancer Center, Dallas, TX 75235-8576, USA.
Blood. 1996 Aug 15;88(4):1188-97.
IgG-HD37-SMPT-dgA is a deglycosylated ricin A chain (dgA)-containing immunotoxin (IT) prepared by conjugating the monoclonal murine (MoAb) anti-CD19 antibody, HD37, to dgA using the heterobifunctional hindered disulfide linker, N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio) toluene (SMPT). In this report, we have used two regimens for the administration of IgG-HD37-SMPT-dgA to patients with non-Hodgkin's lymphoma (NHL) in two concomitant phase I trials. One trial examined four intermittent bolus infusions administered at 48-hour intervals. The other studied a continuous infusion (CI) administered over the same 8-day period. In the intermittent bolus regimen, the maximum tolerated dose (MTD) was 16 mg/m2/8 d and the dose-limiting toxicity (DLT) consisted of vascular leak syndrome (VLS), aphasia, and evidence of rhabdomyolysis encountered at 24 mg/m2/8 d. Using the CI regimen, the MTD was defined by VLS at 19.2 mg/m2/8 d. At the MTD of both regimens, a novel toxicity, consisting of acrocyanosis with reversible superficial distal digital skin necrosis in the absence of overt evidence of systemic vasculitis, occurred in 3 patients. Of 23 evaluable patients on the bolus schedule, there was 1 persisting complete response (CR; > 40 months) and 1 partial response (PR). Of 9 evaluable patients on the continuous infusion regimen, there was 1 PR. Pharmacokinetic parameters for the bolus regimen at the MTD showed a mean maximum serum concentration (Cmax) of 1,209 +/- 430 ng/mL, with a median T1/2 beta for all courses of 18.2 hours (range, 10.0 to 80.0 hours), a volume of distribution (Vd) of 10.9 L (range, 3.1 to 34.5 L), and a clearance (CL) of 0.45 L/h (range, 0.13 to 2.3 L/h). For the CI regimen at MTD, the mean Cmax was 963 +/- 473 ng/mL, with a median T1/2 beta for all courses of 22.8 hours (range, 24.1 to 30.6 hours), a Vd of 9.4 L (range, 4.4 to 19.5 L), and a CL of 0.32 L/h (range, 0.12 to 0.55 L/h). Twenty-five percent of the patients on the bolus infusion regimen and 30% on the CI regimen made antibody against mouse Ig (HAMA) and/or ricin A chain antibody (HARA). We conclude that this IT can be administered safely and that both regimens achieve comparable peak serum concentrations at the MTD; these concentrations are similar to those achieved previously using other regimens with IgG-dgA ITs at their respective MTDs. Thus, toxicity is related to the serum level of the IT and does not differ with different targeting MoAbs.
IgG-HD37-SMPT-dgA是一种去糖基化的含蓖麻毒素A链（dgA）的免疫毒素（IT），它是通过使用异双功能受阻二硫键连接剂N-琥珀酰亚胺基-氧羰基-α-甲基-α-（2-吡啶二硫基）甲苯（SMPT），将鼠单克隆（MoAb）抗CD19抗体HD37与dgA偶联而制备的。在本报告中，我们在两项同期的I期试验中，对非霍奇金淋巴瘤（NHL）患者使用了两种方案给予IgG-HD37-SMPT-dgA。一项试验研究了每48小时进行一次的四次间歇性大剂量输注。另一项研究了在相同的8天期间进行的持续输注（CI）。在间歇性大剂量方案中，最大耐受剂量（MTD）为16 mg/m²/8天，剂量限制性毒性（DLT）包括血管渗漏综合征（VLS）、失语症，以及在24 mg/m²/8天出现的横纹肌溶解证据。使用CI方案时，MTD由19.2 mg/m²/8天的VLS定义。在两种方案的MTD时，3例患者出现了一种新的毒性反应，表现为肢端发绀伴可逆性浅表性远端指皮肤坏死，且无明显的系统性血管炎证据。在大剂量方案的可评估的23例患者中，有1例持续完全缓解（CR；>40个月）和1例部分缓解（PR）。在持续输注方案的9例可评估患者中，有1例PR。大剂量方案在MTD时的药代动力学参数显示，平均最大血清浓度（Cmax）为1209±430 ng/mL，所有疗程的中位T1/2β为18.2小时（范围为10.0至80.0小时），分布容积（Vd）为10.9 L（范围为3.1至34.5 L），清除率（CL）为0.45 L/h（范围为0.13至2.3 L/h）。对于CI方案在MTD时，平均Cmax为963±473 ng/mL，所有疗程的中位T1/β为22.8小时（范围为24.1至30.6小时），Vd为9.4 L（范围为4.4至19.5 L），CL为0.32 L/h（范围为0.12至0.55 L/h）。大剂量输注方案的25%患者和CI方案的30%患者产生了抗小鼠Ig（HAMA）和/或蓖麻毒素A链抗体（HARA）。我们得出结论，这种IT可以安全给药，并且两种方案在MTD时达到了相当的血清峰值浓度；这些浓度与之前使用其他IgG-dgA IT方案在各自MTD时达到的浓度相似。因此，毒性与IT的血清水平相关，并且不因不同的靶向MoAb而有所不同。
