已入深夜,您辛苦了!由于当前在线用户较少,发布求助请尽量完整的填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!祝你早点完成任务,早点休息,好梦!

In vitro affinity maturation of human GM-CSF antibodies by targeted CDR-diversification

抗体 亲和力成熟 细胞因子 生物 受体 体外 体细胞突变 免疫系统 免疫学 分子生物学 细胞生物学 B细胞 生物化学
作者
Stefan Steidl,Olaf Ratsch,Bodo Brocks,Manuela Dürr,Elisabeth Thomassen-Wolf
出处
期刊:Molecular Immunology [Elsevier]
卷期号:46 (1): 135-144 被引量:85
标识
DOI:10.1016/j.molimm.2008.07.013
摘要

The mammalian immune system applies somatic hypermutation to select for antibodies with improved dissociation rates in vivo up to an intrinsic limit, previously termed as affinity ceiling. However, for certain therapeutic applications it may be desirable to further improve antibody affinities beyond that limit. In this study the selection of antibodies specific for the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) from the HuCAL GOLD human antibody library is described. In order to increase affinity and also functional activity, in vitro affinity maturation of a pool of lead Fab candidates was carried out. CDR-L3 and parallel CDR-H2 diversification using trinucleotide consensus cassettes were followed by the combination of optimized CDR-L3 and CDR-H2 leading to a 5000-fold improved affinity finally reaching a KD of 400 fM. Cytokine neutralizing potential of MOR04357 was evaluated in a TF-1 proliferation assay. Along with affinity optimization a 2000-fold increase in potency was observed compared to the parental antibody. Due to species cross-reactivity MOR04357 also blocks rat GM-CSF induced proliferation of FDCP-1 cells. Receptor inhibition studies showed that MOR04357 prevents the interaction of GM-CSF with the GM-CSF receptor alpha chain. As a consequence this leads to a blockade in signal transduction as measured by abolished STAT5 phosphorylation in the presence of GM-CSF and antibody. Due to its pro-inflammatory role GM-CSF has been implicated in the pathophysiology of inflammatory diseases like rheumatoid arthritis or asthma. Based on the mode of action described herein MOR04357 shows favourable antibody features as a potential drug candidate.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
1秒前
2秒前
如初完成签到 ,获得积分10
4秒前
5秒前
JamesPei应助香妃采纳,获得10
6秒前
抹茶拿铁加奶砖完成签到 ,获得积分10
6秒前
7秒前
xaill完成签到,获得积分10
8秒前
8秒前
Shirley发布了新的文献求助10
8秒前
Jack完成签到 ,获得积分0
9秒前
JamesPei应助曲奇喵采纳,获得30
9秒前
行者发布了新的文献求助10
11秒前
努力毕业ing完成签到,获得积分10
13秒前
赵晶晶给赵晶晶的求助进行了留言
16秒前
17秒前
科研冰山完成签到 ,获得积分10
18秒前
英俊智宸完成签到,获得积分10
21秒前
ganzhongxin完成签到,获得积分10
22秒前
聪明的语蓉完成签到 ,获得积分10
24秒前
大爷醒醒啊完成签到,获得积分10
25秒前
26秒前
Shirley关注了科研通微信公众号
27秒前
勤奋鞋子完成签到,获得积分10
30秒前
文明8完成签到,获得积分10
30秒前
人群是那么像羊群完成签到 ,获得积分10
30秒前
32秒前
35秒前
光亮寻绿发布了新的文献求助10
36秒前
HEIKU应助香妃采纳,获得10
37秒前
皮蛋robin汤完成签到 ,获得积分10
38秒前
大徐1175发布了新的文献求助10
39秒前
li完成签到 ,获得积分10
44秒前
44秒前
46秒前
Owen应助缓慢的藏鸟采纳,获得10
47秒前
梵高完成签到,获得积分10
50秒前
不发SCI不罢休的小菜完成签到 ,获得积分10
51秒前
52秒前
mx完成签到,获得积分10
53秒前
高分求助中
Spray / Wall-interaction Modelling by Dimensionless Data Analysis 2000
Mathematics and Finite Element Discretizations of Incompressible Navier—Stokes Flows 500
A new species of Coccus (Homoptera: Coccoidea) from Malawi 500
2-Acetyl-1-pyrroline: an important aroma component of cooked rice 500
A real-time energy management strategy based on fuzzy control and ECMS for PHEVs 400
Handbook on People's China (1957) 400
2024 Medicinal Chemistry Reviews 400
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3189847
求助须知:如何正确求助?哪些是违规求助? 2839133
关于积分的说明 8023024
捐赠科研通 2502062
什么是DOI,文献DOI怎么找? 1336196
科研通“疑难数据库(出版商)”最低求助积分说明 637804
邀请新用户注册赠送积分活动 605852