Superior Antitumor Activity of SAR3419 to Rituximab in Xenograft Models for Non-Hodgkin's Lymphoma
Superior Antitumor Activity of SAR3419 to Rituximab in Xenograft Models for Non-Hodgkin's Lymphoma
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DOI：
10.1158/1078-0432.ccr-08-2808
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发表时间：
2009-06-15
影响因子：
11.5
通讯作者：
Zuany-Amorim, Claudia
中科院分区：
文献类型：
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作者：
Al-Katib, Ayad M.;Aboukameel, Amro;Zuany-Amorim, Claudia
目的：为了研究与细胞毒性美登素衍生物N-2 '-脱乙酰基-N-2'-偶联的SAR 3419（一种新型人源化抗CD 19抗体（huB 4））的活性，（4-巯基-4-甲基-1-氧代戊基）美登素在非霍奇金淋巴瘤的临床前异种移植模型中的应用。使用弥漫性大B细胞淋巴瘤皮下模型评估了SAR 3419单药治疗的抗肿瘤活性，并与常规治疗进行了比较结果：SAR 3419对严重联合免疫缺陷小鼠滤泡性小裂细胞淋巴瘤（WSU-FSCCL）的治疗效果优于CHOP（环磷酰胺-阿霉素-长春新碱-泼尼松）方案和利妥昔单抗。在两种模型中，仅SAR 3419给药导致整组动物存活至实验结束（150-155天）。较高剂量的SAR 3419（15和30 mg/kg）比较低剂量的7.5 mg/kg更有效。免疫缀合是必要的，因为单独的huB 4或DM 4都不具有显著活性。在两种模型中，利妥昔单抗治疗产生的抗肿瘤活性与低剂量SAR 3419相当。环磷酰胺-阿霉素-长春新碱-泼尼松单独在两种模型中均显示出适度的活性。WSU-FSCCL全身模型中的尸检和组织染色显示，对照组和给药组的所有死亡均为软脑膜淋巴瘤。有趣的是，一些动物存活到实验结束时，似乎健康的时候安乐死没有显示lymphoma.Conclusions显微镜证据：总体而言，SAR 3419是一个非常活跃的免疫毒素在临床前模型的人类B细胞淋巴瘤，并持有作为一种新的和良好的耐受性治疗B细胞非霍奇金淋巴瘤的承诺。
Purpose: To investigate the activity of SAR3419, a novel humanized anti-CD19 antibody (huB4), conjugated to a cytotoxic maytansine derivative N-2'-deacetyI-N-2'-(4-mercapto4-methyl-1-oxopentyl) maytansine, in preclinical xenograft models for non-Hodgkin's lymphoma.Experimental Design: Antitumor activity of SAR3419 was assessed as a single agent and in comparison with conventional therapies using a subcutaneous model for diffuse large B-cell lymphoma (WSU-DLCL2) and a systemic model for follicular small cleaved cell lymphoma (WSU-FSCCL) in mice with severe combined immune deficiency.Results: Our results showed that in these chemotherapy-resistant models, SAR3419 was more effective than CHOP (cyclophosphamide-Adriamycin-vincristine-prednisone) regimen or rituximab. Only treatment with SAR3419 led to survival of the whole group of animals to the end of the experiment (150-155 days) in both models. Higher doses of SAR3419 (15 and 30 mg/kg) were more effective than lower dose of 7.5 mg/kg. The immunoconjugation was necessary because neither huB4 nor DM4 alone had significant activity. Treatment with rituximab resulted in antitumor activity in both models comparable with the low dose of SAR3419. Cyclophosphamide-Adriamycin-vincristine-prednisone alone showed modest activity in both models. Necropsy and tissue staining in the WSU-FSCCL systemic model revealed that all deaths featured leptomeningeal lymphoma in the control and treated groups. Interestingly, some of the animals that survived to the end of the experiment and seemed healthy at time of euthanasia did show microscopic evidence of lymphoma.Conclusions: Overall, SAR3419 is a very active immunotoxin in preclinical models for human B-cell lymphoma and holds promise as a novel and well-tolerated therapy in B-cell non-Hodgkin's lymphoma.