HLA-DR is a member of the MHC class II antigen family expressed on hematologic and solid tumors. Antibodies directed against HLA-DR have demonstrated some clinical success, but toxicities limited development. IMMU-140 is an anti–HLA-DR antibody–drug conjugate composed of the active metabolite of irinotecan, SN-38, conjugated to a humanized anti–HLA-DR IgG4 antibody (IMMU-114); the IgG4 naked antibody is devoid of immune functions. Our aim was to determine if SN-38, the metabolite of a drug not commonly used in hematopoietic cancers, would be effective and safe when targeted to HLA-DR–expressing tumors. IMMU-140 had dual-therapeutic mechanisms, as evidenced by its retention of nonoverlapping anti–HLA-DR nonclassical apoptotic signaling and classical apoptosis mediated by its SN-38 payload. In seven human disease models [acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), acute myeloid leukemia (AML), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and melanoma], IMMU-140 provided significant therapeutic efficacy compared with controls, in vitro, in 3D spheroid models, and in vivo. Except for MM and HL, IMMU-140 imparted significantly improved antitumor effects compared with parental IMMU-114. Even in intractable AML and ALL, where IMMU-114 only had modest antitumor effects, IMMU-140 therapy mediated >80% improvement in survival. Therapy was well tolerated, as demonstrated by no marked loss in body weight. Combined with doxorubicin, IMMU-140 produced significantly greater antitumor effects in HL than with monotherapy and without any added toxicity. The dual-therapeutic action of IMMU-140 resulted in promising therapeutic activity in a range of hematopoietic tumors and melanoma, and therefore warrants clinical development. Mol Cancer Ther; 17(1); 150–60. ©2017 AACR.

中文翻译：

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IMMU-140，一种靶向 HLA-DR 的新型 SN-38-抗体-药物偶联物，介导血液癌症和恶性黑色素瘤的双重细胞毒性作用

HLA-DR 是在血液学和实体瘤上表达的 MHC II 类抗原家族的成员。针对 HLA-DR 的抗体已显示出一些临床成功，但毒性限制了发展。IMMU-140 是一种抗 HLA-DR 抗体药物偶联物，由伊立替康的活性代谢物 SN-38 与人源化抗 HLA-DR IgG4 抗体 (IMMU-114) 偶联而成；IgG4裸抗体没有免疫功能。我们的目标是确定 SN-38（一种不常用于造血系统癌症的药物的代谢物）在靶向表达 HLA-DR 的肿瘤时是否有效和安全。IMMU-140 具有双重治疗机制，其保留不重叠的抗 HLA-DR 非经典凋亡信号传导和由其 SN-38 有效载荷介导的经典凋亡证明了这一点。在七种人类疾病模型中[急性淋巴细胞白血病 (ALL)、慢性淋巴细胞白血病 (CLL)、多发性骨髓瘤 (MM)、急性髓性白血病 (AML)、弥漫性大 B 细胞淋巴瘤 (DLBCL)、霍奇金淋巴瘤 (HL) 和黑色素瘤]，与对照、体外、3D 球体模型和体内相比，IMMU-140 提供了显着的治疗效果。除了 MM 和 HL，与亲本 IMMU-114 相比，IMMU-140 具有显着改善的抗肿瘤作用。即使在顽固性 AML 和 ALL 中，IMMU-114 仅具有适度的抗肿瘤作用，IMMU-140 治疗也介导了 80% 以上的存活率提高。治疗耐受性良好，体重没有明显减轻就证明了这一点。与阿霉素联合使用时，IMMU-140 对 HL 的抗肿瘤作用明显高于单药治疗，并且没有任何额外的毒性。IMMU-140 的双重治疗作用在一系列造血肿瘤和黑色素瘤中产生了有希望的治疗活性，因此值得临床开发。摩尔癌症治疗; 17(1); 150-60。©2017 AACR。