Trop-2-targeting tetrakis-ranpirnase has potent antitumor activity against triple-negative breast cancer.
Trop-2-targeting tetrakis-ranpirnase has potent antitumor activity against triple-negative breast cancer.
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DOI：
10.1186/1476-4598-13-53
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发表时间：
2014-03-10
期刊：
影响因子：
37.3
通讯作者：
Chang CH
中科院分区：
文献类型：
--
作者：
Liu D;Cardillo TM;Wang Y;Rossi EA;Goldenberg DM;Chang CH
豹蛙酶（Rap）是一种两栖动物核糖核酸酶，在临床研究中报道具有抗肿瘤活性、毒性极小且免疫原性可忽略不计，但不利的药代动力学和次优功效阻碍了其进一步的临床开发。为了提高基于Rap的治疗剂的潜力，我们已经使用DOCK-AND-Rap ™（DNL™）方法来构建一类新的IgG-Rap免疫RNA酶。在本研究中，评价了一对这些构建体（Rap）2-E1-（Rap）2和（Rap）2-E1*-（Rap）2作为三阴性乳腺癌（TNBC）的潜在治疗剂，所述构建体分别包含连接至hRS 7（人源化抗Trop-2）的CH 3和CK末端的Rap的四个拷贝。对基于DNL的免疫RNA酶（Rap）2-E1-（Rap）2和（Rap）2-E1*-（Rap）2进行了表征，并在一组乳腺癌细胞系上体外和在MDA-MB-468异种移植模型中体内测试了生物活性。（Rap）2-E1-（Rap）2高度纯化（>95%），在表达Trop-2的TNBC细胞系MDA-MB-468中表现出特异性细胞结合和快速内化，并对Trop-2中高表达的多种乳腺癌细胞系（包括MDA-MB-468、BT-20、HCC 1806、SKBR-3和MCF-7）表现出有效的体外细胞毒性（EC 50 ≤ 1 nM）。相比之下，在MDA-MB-468和BT-20细胞中，通过用选择性非Trop-2结合抗体如依帕珠单抗（抗CD 22）取代hRS 7产生的（Rap）2-E1-（Rap）2的结构对应物的效力比（Rap）2-E1-（Rap）2低至少50倍，两者都缺乏同源抗原的表达。此外，（Rap）2-E1-（Rap）2在MDA-MB-231（低Trop-2）或HCC 1395（无Trop-2）中的有效性较低（EC 50> 50 nM），并且对人外周血单核细胞没有显示出任何毒性。在小鼠TNBC模型中，当给予最大耐受剂量时，用（Rap）2-E1*-（Rap）2实现了显著的存活益处。产生了一类新的免疫RNA酶，其具有增强的癌症靶向治疗效力。来自（Rap）2-E1-（Rap）2和（Rap）2-E1*-（Rap）2的有希望的结果支持它们作为TNBC和其他Trop-2表达癌症的潜在治疗选择的进一步研究。
Ranpirnase (Rap) is an amphibian ribonuclease with reported antitumor activity, minimal toxicity, and negligible immunogenicity in clinical studies, but the unfavorable pharmacokinetics and suboptimal efficacy hampered its further clinical development. To improve the potential of Rap-based therapeutics, we have used the DOCK-AND-LOCK™ (DNL™) method to construct a class of novel IgG-Rap immunoRNases. In the present study, a pair of these constructs, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, comprising four copies of Rap linked to the CH3 and CK termini of hRS7 (humanized anti-Trop-2), respectively, were evaluated as potential therapeutics for triple-negative breast cancer (TNBC). The DNL-based immunoRNases, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, were characterized and tested for biological activities in vitro on a panel of breast cancer cell lines and in vivo in a MDA-MB-468 xenograft model. (Rap)2-E1-(Rap)2 was highly purified (>95%), exhibited specific cell binding and rapid internalization in MDA-MB-468, a Trop-2-expressing TNBC line, and displayed potent in vitro cytotoxicity (EC50 ≤ 1 nM) against diverse breast cancer cell lines with moderate to high expression of Trop-2, including MDA-MB-468, BT-20, HCC1806, SKBR-3, and MCF-7. In comparison, structural counterparts of (Rap)2-E1-(Rap)2, generated by substituting hRS7 with selective non-Trop-2-binding antibodies, such as epratuzumab (anti-CD22), were at least 50-fold less potent than (Rap)2-E1-(Rap)2 in MDA-MB-468 and BT-20 cells, both lacking the expression of the cognate antigen. Moreover, (Rap)2-E1-(Rap)2 was less effective (EC50 > 50 nM) in MDA-MB-231 (low Trop-2) or HCC1395 (no Trop-2), and did not show any toxicity to human peripheral blood mononuclear cells. In a mouse TNBC model, a significant survival benefit was achieved with (Rap)2-E1*-(Rap)2 when given the maximal tolerated dose. A new class of immunoRNases was generated with enhanced potency for targeted therapy of cancer. The promising results from (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2 support their further investigation as a potential treatment option for TNBC and other Trop-2-expressing cancers.
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影响因子：
45.3
作者：
Mikulski, SM;Costanzi, JJ;Shogen, K
通讯作者：
Shogen, K
影响因子：
5.7
作者：
Chang, Chien-Hsing;Gupta, Pankaj;Goldenberg, David M.
通讯作者：
Goldenberg, David M.
影响因子：
11.5
作者：
Johnston, Stephen R. D.
通讯作者：
Johnston, Stephen R. D.
DOI：
10.1073/pnas.0600982103
发表时间：
2006-05-02
影响因子：
11.1
作者：
Rossi, EA;Goldenberg, DM;Chang, CH
通讯作者：
Chang, CH
DOI：
10.1111/j.1365-2184.1988.tb00855.x
发表时间：
1988-05-01
期刊：
CELL AND TISSUE KINETICS
影响因子：
--
作者：
DARZYNKIEWICZ, Z;CARTER, SP;SHOGEN, K
通讯作者：
SHOGEN, K