CCR4-IL2 bispecific immunotoxin is more effective than brentuximab for targeted therapy of cutaneous T-cell lymphoma in a mouse CTCL model.
CCR4-IL2 bispecific immunotoxin is more effective than brentuximab for targeted therapy of cutaneous T-cell lymphoma in a mouse CTCL model.
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DOI：
10.1002/2211-5463.13625
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发表时间：
2023-07
期刊：
影响因子：
2.6
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中科院分区：
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皮肤T细胞淋巴瘤(CTCL)包括两个主要亚型：真菌样肉芽肿和Sezary综合征。真菌样肉芽肿和Sezary综合征的系统治疗的全球有效率约为30%，这些治疗方法被认为都不是治愈的。C-C趋化因子受体4(CCR4)和CD25是治疗CTCL的令人鼓舞的靶点，分别是莫伽珠单抗和地氟平的靶点。我们开发了一种针对CCR4和CD25的新型CCR4-IL2双特异性免疫毒素(CCR4-IL2IT)。CCR4-IL2IT在免疫缺陷的NSG小鼠肿瘤模型中显示出对CCR4+CD25+CD30+CTCL的优越疗效。CCR4-IL2 IT的调查性新药使能研究正在进行中，包括良好的制造规范生产和毒理学研究。在这项研究中，我们使用免疫缺陷的小鼠CTCL模型，比较了CCR4-IL2IT和美国食品和药物管理局批准的药物布妥昔单抗在 体内的疗效。在免疫缺陷的NSG小鼠CTCL模型中，CCR4-IL2 IT明显比Brentuximab更有效，CCR4-IL2 IT和Brentuximab联合治疗比单独使用Brentuximab或CCR4-IL2 IT更有效。因此，CCR4-IL2IT是一种很有前途的治疗CTCL的候选药物。我们比较了CCR4-IL2双特异性免疫毒素(CCR4-IL2IT)和FDA批准的布妥昔单抗在免疫缺陷小鼠CTCL模型中的体内疗效。我们发现CCR4-IL2IT在延长生存期方面明显优于Brentuximab，并且CCR4-IL2IT与Brentuximab联合治疗比单独使用Brentuximab或CCR4-IL2IT更有效。
Cutaneous T‐cell lymphoma (CTCL) encompasses two main subtypes: mycosis fungoides and Sezary syndrome. Global response rates for the systemic treatment of mycosis fungoides and Sezary syndrome are approximately 30%, and none of these treatments are thought to be curative. C–C chemokine receptor type 4 (CCR4) and CD25 are encouraging targets for the treatment of CTCL and are individually targeted by mogamulizumab and denileukin diftitox, respectively. We developed a novel CCR4‐IL2 bispecific immunotoxin (CCR4‐IL2 IT) targeting both CCR4 and CD25. CCR4‐IL2 IT demonstrated superior efficacy against CCR4+CD25+CD30+ CTCL in an immunodeficient NSG mouse tumor model. Investigative New Drug‐enabling studies of CCR4–IL2 IT are ongoing, including Good Manufacturing Practice production and toxicology studies. In this study, we compared the in vivo efficacy of CCR4‐IL2 IT versus the US Food and Drug Administration–approved drug, brentuximab, using an immunodeficient mouse CTCL model. We demonstrated that CCR4–IL2 IT was significantly more effective in prolonging survival than brentuximab, and combination treatment of CCR4–IL2 IT and brentuximab was more effective than brentuximab or CCR4–IL2 IT alone in an immunodeficient NSG mouse CTCL model. Thus, CCR4–IL2 IT is a promising novel therapeutic drug candidate for CTCL treatment. We have compared the in vivo efficacy of CCR4‐IL2 bispecific immunotoxin (CCR4‐IL2 IT) versus the FDA‐approved brentuximab in an immunodeficient mouse CTCL model. We demonstrated that CCR4–IL2 IT was significantly more effective in prolonging survival than brentuximab, and combination treatment of CCR4–IL2 IT and brentuximab was more effective than brentuximab or CCR4–IL2 IT alone.