Tassone Pierfrancesco, Gozzini Antonella, Goldmacher Victor, Shammas Masood A, Whiteman Kathleen R, Carrasco Daniel R, Li Cheng, Allam Charles K, Venuta Salvatore, Anderson Kenneth C, Munshi Nikhil C
Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, VA Boston Healthcare System, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cancer Res. 2004 Jul 1;64(13):4629-36. doi: 10.1158/0008-5472.CAN-04-0142.
HuN901 is a humanized monoclonal antibody that binds with high affinity to CD56, the neuronal cell adhesion molecule. HuN901 conjugated with the maytansinoid N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), a potent antimicrotubular cytotoxic agent, may provide targeted delivery of the drug to CD56 expressing tumors. Based on gene expression profiles of primary multiple myeloma (MM) cells showing expression of CD56 in 10 out of 15 patients (66.6%) and flow cytometric profiles of MM (CD38(bright)CD45(lo)) cells showing CD56 expression in 22 out of 28 patients (79%), we assessed the efficacy of huN901-DM1 for the treatment of MM. We first examined the in vitro cytotoxicity and specificity of huN901-DM1 on a panel of CD56(+) and CD56(-) MM cell lines, as well as a CD56(-) Waldenstrom's macroglobulinemia cell line. HuN901-DM1 treatment selectively decreased survival of CD56(+) MM cell lines and depleted CD56(+) MM cells from mixed cultures with a CD56(-) cell line or adherent bone marrow stromal cells. In vivo antitumor activity of huN901-DM1 was then studied in a tumor xenograft model using a CD56(+) OPM2 human MM cell line in SCID mice. We observed inhibition of serum paraprotein secretion, inhibition of tumor growth, and increase in survival of mice treated with huN901-DM1. Our data therefore demonstrate that huN901-DM1 has significant in vitro and in vivo antimyeloma activity at doses that are well tolerated in a murine model. Taken together, these data provide the framework for clinical trials of this agent to improve patient outcome in MM.
HuN901是一种人源化单克隆抗体,它能与神经元细胞粘附分子CD56高亲和力结合。HuN901与美登素类化合物N(2')-脱乙酰基-N(2')-(3-巯基-1-氧代丙基)-美登素(DM1,一种强效抗微管细胞毒性剂)偶联,可将药物靶向递送至表达CD56的肿瘤细胞。基于原发性多发性骨髓瘤(MM)细胞的基因表达谱显示15例患者中有10例(66.6%)表达CD56,以及MM(CD38(明亮)CD45(低))细胞的流式细胞术分析显示28例患者中有22例(79%)表达CD56,我们评估了huN901-DM1治疗MM的疗效。我们首先检测了huN901-DM1对一组CD56(+)和CD56(-) MM细胞系以及一个CD56(-) 华氏巨球蛋白血症细胞系的体外细胞毒性和特异性。HuN901-DM1处理选择性地降低了CD56(+) MM细胞系的存活率,并从与CD56(-) 细胞系或贴壁骨髓基质细胞的混合培养物中清除了CD56(+) MM细胞。然后在SCID小鼠中使用CD56(+) OPM2人MM细胞系的肿瘤异种移植模型研究了huN901-DM1的体内抗肿瘤活性。我们观察到接受huN901-DM1治疗的小鼠血清副蛋白分泌受到抑制、肿瘤生长受到抑制且存活率提高。因此,我们的数据表明,huN901-DM1在小鼠模型中耐受性良好的剂量下具有显著的体外和体内抗骨髓瘤活性。综上所述,这些数据为该药物进行临床试验以改善MM患者的预后提供了框架。