Newton D L, Hansen H J, Mikulski S M, Goldenberg D M, Rybak S M
SAIC Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702-1201, USA.
Blood. 2001 Jan 15;97(2):528-35. doi: 10.1182/blood.v97.2.528.
LL2, an anti-CD22 monoclonal antibody against B-cell lymphoma, was covalently linked to the amphibian ribonuclease, onconase, a member of the pancreatic RNase A superfamily. LL2 increased in vitro potency (10 000-fold) and specificity against human Daudi Burkitt lymphoma cells while decreasing systemic toxicity of onconase. Monensin further increased potency of LL2-onconase on Daudi cells (IC(50), 20 and 1.5 pM, absence and presence of monensin, respectively). A 1-hour exposure to LL2-onconase was sufficient to kill Daudi cells in culture. These favorable in vitro properties translated to significant antitumor activity against disseminated Daudi lymphoma in mice with severe combined immunodeficiency disease. In mice inoculated with tumor cells intraperitoneally (ip), LL2-onconase (100 microg 5 times ip every day) increased the life span of animals with minimal disease 200%. The life span of mice with advanced disseminated Daudi lymphoma (tumor cells inoculated intravenously) was increased 135%. Mice injected with LL2-onconase tolerated a dose as high as 300 mg/kg. Because both onconase and LL2 are in clinical trials as cancer therapeutics, the covalently linked agents should be considered for treatment of non-Hodgkin lymphoma.
LL2是一种针对B细胞淋巴瘤的抗CD22单克隆抗体，它与两栖类核糖核酸酶——癌胚核糖核酸酶（一种胰腺核糖核酸酶A超家族成员）共价连接。LL2提高了对人Daudi伯基特淋巴瘤细胞的体外效力（10000倍）和特异性，同时降低了癌胚核糖核酸酶的全身毒性。莫能菌素进一步提高了LL2-癌胚核糖核酸酶对Daudi细胞的效力（IC(50)分别为20和1.5 pM，不存在和存在莫能菌素时）。暴露于LL2-癌胚核糖核酸酶1小时足以杀死培养中的Daudi细胞。这些良好的体外特性转化为对严重联合免疫缺陷病小鼠播散性Daudi淋巴瘤的显著抗肿瘤活性。在腹腔内（ip）接种肿瘤细胞的小鼠中，LL2-癌胚核糖核酸酶（每天5次，每次100微克，ip）使病情轻微的动物寿命延长200%。患有晚期播散性Daudi淋巴瘤（静脉注射接种肿瘤细胞）的小鼠寿命延长135%。注射LL2-癌胚核糖核酸酶的小鼠能耐受高达300毫克/千克的剂量。由于癌胚核糖核酸酶和LL2都作为癌症治疗药物处于临床试验阶段，这种共价连接的药物应被考虑用于治疗非霍奇金淋巴瘤。
