CEACAM5-targeted therapy of human colonic and pancreatic cancer xenografts with potent labetuzumab-SN-38 immunoconjugates.
CEACAM5-targeted therapy of human colonic and pancreatic cancer xenografts with potent labetuzumab-SN-38 immunoconjugates.
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DOI：
10.1158/1078-0432.ccr-09-0586
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发表时间：
2009-10-01
期刊：
影响因子：
--
通讯作者：
Goldenberg DM
中科院分区：
文献类型：
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作者：
Govindan SV;Cardillo TM;Moon SJ;Hansen HJ;Goldenberg DM
为了提高癌症前药CPT-11的疗效并降低其胃肠道毒性，我们开发了其活性形式的免疫偶联物SN-38和抗ceacam5抗体，用于靶向化疗。抗ceacam5单抗的n -38偶联物，labetuzumab (hMN-14)，在药物20-羟基位置的交联剂附着性质不同，在体外，转移性和/或皮下（sc）人结肠癌和胰腺癌移植裸鼠中使用适当的对照，以及在ceacam5阴性肿瘤模型中进行了评估。一项在人结肠癌sc LS174T模型中的初步研究证实了不同缀合物的相对有效性。在裸鼠GW-39人结肠癌肺转移模型中，使用两种特异性的labetuzumab-SN-38偶联物（0.25 mg SN-38当量/kg， q4d×8）治疗，与对照组相比，显著延长了中位生存时间（MST） （P <0.002）。在sc LS174T异种移植模型的扩展评估中，特异性SN-38偶联物产生了显著的肿瘤生长控制和MST的增加，与其他对照组相比，包括CPT-11，累积剂量高出33倍（P <0.01）。在人类胰腺肿瘤异种移植治疗中也观察到改善。在ceacam5阴性的系统性淋巴瘤异种移植中，一种labetuzumab- cn -38偶联物检测无效，而针对肿瘤模型的偶联物产生100%的存活率。开发的labetuzumab-SN-38偶联物在人类肿瘤模型中显示出选择性治疗效果，无毒剂量是CPT-11使用剂量的一小部分。
To improve the efficacy and reduce the gastrointestinal toxicity of the cancer prodrug, CPT-11, we have developed immunoconjugates of its active form, SN-38, and an anti-CEACAM5 antibody for targeted chemotherapy. SN-38 conjugates of the anti-CEACAM5 mAb, labetuzumab (hMN-14), varying in the nature of the cross-linker attachment at the drug’s 20-hydroxyl position, were evaluated in vitro, in metastatic and/or subcutaneous (sc) human colonic and pancreatic cancer xenografts in nude mice using appropriate controls, and in a CEACAM5-negative tumor model. A pilot study in a sc LS174T model of human colonic carcinoma established the relative effectiveness of different conjugates. In the lung metastatic model of GW-39 human colonic carcinoma in nude mice, therapy with two specific labetuzumab-SN-38 conjugates, using 0.25 mg SN-38 equivalent/kg, q4d×8, significantly extended median survival time (MST) versus controls (P <0.002). In an expanded evaluation in the sc LS174T xenograft model, specific SN-38 conjugates produced significant tumor growth control and increases in MST versus other controls, including CPT-11 at a 33-fold greater cumulative dose (P <0.01). An improvement was also observed in the therapy of a sc human pancreatic tumor xenograft. In a CEACAM5-negative systemic lymphoma xenograft, one labetuzumab-SN-38 conjugate examined was ineffective, while the conjugate specific for the tumor model produced 100% survival. The promising labetuzumab-SN-38 conjugates developed showed selective therapeutic efficacy in human tumor models at nontoxic doses that were a fraction of the CPT-11 doses used.