Evolution of a cytokine using DNA family shuffling

被引：105

作者：

Chang, CCJ ^{[1
]}

Chen, TT ^{[1
]}

Cox, BW ^{[1
]}

Dawes, GN ^{[1
]}

Stemmer, WPC ^{[1
]}

Punnonen, J ^{[1
]}

Patten, PA ^{[1
]}

机构：

[1] Maxygen Inc, Santa Clara, CA 95051 USA

来源：

NATURE BIOTECHNOLOGY | 1999年 / 17卷 / 08期

关键词：

DNA shuffling; cytokines; interferon; molecular breeding; pharmaceutical proteins;

D O I：

10.1038/11737

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

DNA shuffling of a family of over 20 human interferon-alpha (Hu-IFN-alpha) genes was used to derive variants with increased antiviral and antiproliferation activities in murine cells, A clone with 135,000-fold improved specific activity over Hu-IFN-alpha 2a was obtained in the first cycle of shuffling, After a second cycle of selective shuffling, the most active clone was improved 285,000-fold relative to Hu-IFN-alpha 2a and 185-fold relative to Hu-IFN-alpha 1, Remarkably, the three most active clones were more active than the native murine IFN-alpha s. These chimeras are derived from up to five parental genes but contained no random point mutations. These results demonstrate that diverse cytokine gene families can be used as starting material to rapidly evolve cytokines that are more active, or have superior selectivity profiles, than native cytokine genes.

引用

页码：793 / 797

页数：5

共 32 条

[1] THE DEVELOPMENT OF ANTI-INTERLEUKIN-2 ANTIBODIES IN PATIENTS TREATED WITH RECOMBINANT HUMAN INTERLEUKIN-2 (IL-2) [J].