Antitumor efficacy of a combination of CMC-544 (inotuzumab ozogamicin), a CD22-targeted cytotoxic immunoconjugate of calicheamicin, and rituximab against non-Hodgkin's B-cell lymphoma
Antitumor efficacy of a combination of CMC-544 (inotuzumab ozogamicin), a CD22-targeted cytotoxic immunoconjugate of calicheamicin, and rituximab against non-Hodgkin's B-cell lymphoma
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DOI：
10.1158/1078-0432.ccr-05-1905
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发表时间：
2006-01-01
影响因子：
11.5
通讯作者：
Damle, NK
中科院分区：
文献类型：
--
作者：
DiJoseph, JF;Dougher, MM;Damle, NK
目的：CMC-544是一种针对CD22的细胞毒性免疫结合物，目前正在B细胞性非霍奇金淋巴瘤(B-NHL)患者中进行评估。利妥昔单抗是一种CD20靶向抗体，通常用于B-NHL治疗。在此，我们描述了CMC-544和利妥昔单抗联合在临床前模型中对B细胞淋巴瘤(BCL)的抗肿瘤效果。实验设计：BCL与CMC-544、利妥昔单抗或它们的组合在体外培养。皮下注射BCL或皮下注射。或者静脉注射。建立本地化的S.C.BCL在裸鼠体内，播散性BCL在重度联合免疫缺陷小鼠体内。用CMC-544或利妥昔单抗在不同时间开始单独或联合应用对S.C.的影响。结果：CMC-544联合利妥昔单抗的体外生长抑制活性是相加的。利妥昔单抗而不是CMC-544具有效应性功能，如抗体依赖的细胞毒性和补体依赖的细胞毒性。利妥昔单抗在抑制已建立的bCL异种移植物生长方面不如发展中的异种移植物有效。相反，CMC-544对发展中的和已建立的BCL异种移植同样有效。虽然CMC-544和利妥昔单抗单独导致部分抑制BCL异种移植瘤的生长，但它们的联合应用抑制了异种移植瘤的生长达90%。在播散性bcl模型中，60%的CMC-544治疗的小鼠和20%的利妥昔单抗治疗的小鼠存活125天。相比之下，CMC-544联合利妥昔单抗治疗的小鼠存活时间超过125天。结论：CMC-544联合利妥昔单抗具有良好的抗肿瘤活性，为其作为B-NHL治疗方案的临床前评估提供了基础。
Purpose: CMC-544 is a CD22-targeted cytotoxic immunoconjugate, currently being evaluated in B-cell non-Hodgkin's lymphoma (B-NHL) patients. Rituximab is a CD20-targeted antibody commonly used in B-NHL therapy. Here, we describe antitumor efficacy of a combination of CMC-544 and rituximab against B-cell lymphoma (BCL) in preclinical models.Experimental Design: BCLs were cultured in vitro with CMC-544, rituximab, or their combination. BCLs were injected either s.c. or i.v. to establish localized s.c. BCL in nude mice or disseminated BCL in severe combined immunodeficient mice, respectively. I. p. treatment with CMC-544 or rituximab was initiated at various times either alone or in combination and its effect on s.c. BCL growth or survival of mice with disseminated BCL was monitored.Results: In vitro growth-inhibitory activity of CMC-544 combined with rituximab was additive. Rituximab but not CMC-544 exhibited effector functions, such as antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Rituximab was less effective in inhibiting growth of established BCL xenografts than developing xenografts. In contrast, CMC-544 was equally effective against both developing and established BCL xenografts. Although CMC-544 and rituximab individually caused partial inhibition of the growth of BCL xenografts at suboptimal doses examined, their combination suppressed xenograft growth by > 90%. In a disseminated BCL model, 60% of CMC-544-treated mice and 20% of rituximab-treated mice survived for 125 days. In contrast, 90% of mice treated with the combination of CMC-544 and rituximab survived for longer than 125 days.Conclusion: The demonstration of superior antitumor activity of a combination of CMC-544 and rituximab described here provides the preclinical basis for its clinical evaluation as a treatment option for B-NHL.