Sapra Puja, Stein Rhona, Pickett Jennifer, Qu Zhengxing, Govindan Serengulam V, Cardillo Thomas M, Hansen Hans J, Horak Ivan D, Griffiths Gary L, Goldenberg David M
Immunomedics, Inc., Morris Plains, New Jersey 07950, USA.
Clin Cancer Res. 2005 Jul 15;11(14):5257-64. doi: 10.1158/1078-0432.CCR-05-0204.
IMMU-110 is a drug immunoconjugate composed of doxorubicin conjugated to the humanized anti-CD74 monoclonal antibody, hLL1, at a doxorubicin/monoclonal antibody ratio of approximately 8:1 (mol/mol). CD74 is a rapidly internalizing molecule associated with HLA-DR, which has high expression by several tumor types. Here, we describe safety evaluations of IMMU-110 in mice and monkeys as well as efficacy studies in a xenograft model of the human multiple myeloma cell line, MC/CAR.
In vitro binding of IMMU-110 was determined by a cell-based ELISA and cytotoxicity of IMMU-110 assayed with a tetrazolium assay. Pharmacokinetics and biodistribution of radiolabeled IMMU-110 were examined in tumor-free BALB/c mice, and the therapeutic effectiveness was evaluated in severe combined immunodeficient mice bearing MC/CAR cells. Acute toxicity of IMMU-110 was studied in CD74-positive cynomolgus monkeys (Macaca fascicularis).
In vitro, IMMU-110 specifically binds to CD74 and is cytotoxic against MC/CAR cells. In vivo, IMMU-110 displayed a pharmacokinetic and biodistribution profile identical to that of unconjugated hLL1 monoclonal antibody, except for higher kidney uptake. Treatment with a single dose of IMMU-110 as low as 50 microg antibody/mouse (or 1.4 microg doxorubicin/mouse), 5 days postinjection of the multiple myeloma cells, resulted in cure of most mice. In mice, no host toxicity of IMMU-110 was observed at the highest protein dose tested (125 mg/kg). In cynomolgus monkeys, bone marrow toxicity was observed at 30 and 90 mg/kg doses.
The excellent safety and efficacy profile of IMMU-110 supports clinical testing of this immunoconjugate in the treatment of CD74-positive B-cell malignancies.
IMMU-110是一种药物免疫偶联物，由阿霉素与人源化抗CD74单克隆抗体hLL1偶联而成，阿霉素与单克隆抗体的比例约为8:1（摩尔/摩尔）。CD74是一种与HLA-DR相关的快速内化分子，在多种肿瘤类型中高表达。在此，我们描述了IMMU-110在小鼠和猴子中的安全性评估以及在人多发性骨髓瘤细胞系MC/CAR异种移植模型中的疗效研究。
通过基于细胞的ELISA测定IMMU-110的体外结合，并采用四唑盐测定法检测IMMU-110的细胞毒性。在无肿瘤的BALB/c小鼠中检测放射性标记的IMMU-110的药代动力学和生物分布，并在携带MC/CAR细胞的严重联合免疫缺陷小鼠中评估其治疗效果。在CD74阳性食蟹猴（食蟹猴）中研究IMMU-110的急性毒性。
在体外，IMMU-110特异性结合CD74并对MC/CAR细胞具有细胞毒性。在体内，IMMU-110的药代动力学和生物分布特征与未偶联的hLL1单克隆抗体相同，只是肾脏摄取较高。在注射多发性骨髓瘤细胞5天后，用低至50μg抗体/小鼠（或相当于1.4μg阿霉素/小鼠）的单剂量IMMU-110治疗，可治愈大多数小鼠。在小鼠中，在测试的最高蛋白剂量（125mg/kg）下未观察到IMMU-110对宿主的毒性。在食蟹猴中，在30mg/kg和90mg/kg剂量下观察到骨髓毒性。
IMMU-110优异的安全性和疗效特征支持对这种免疫偶联物进行治疗CD74阳性B细胞恶性肿瘤的临床试验。
