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
ff完成签到,获得积分10
1秒前
不安的凡梦完成签到,获得积分20
1秒前
JL完成签到,获得积分10
2秒前
图图完成签到 ,获得积分10
4秒前
爆米花应助ageaaa采纳,获得10
4秒前
小羊完成签到 ,获得积分10
7秒前
搜集达人应助敏静采纳,获得10
9秒前
14秒前
缓慢珠完成签到,获得积分10
15秒前
NSS完成签到,获得积分10
16秒前
17秒前
lylyx发布了新的文献求助10
19秒前
20秒前
田様应助ylq采纳,获得10
24秒前
吕半鬼完成签到,获得积分0
24秒前
24秒前
楠茸完成签到 ,获得积分10
27秒前
FashionBoy应助大半个菜鸟采纳,获得10
29秒前
深情安青应助大半个菜鸟采纳,获得10
29秒前
32秒前
君无名发布了新的文献求助10
35秒前
asdfqaz完成签到 ,获得积分10
36秒前
快乐排骨汤完成签到 ,获得积分10
41秒前
B612小行星完成签到 ,获得积分10
43秒前
jianning完成签到,获得积分10
46秒前
大个应助科研通管家采纳,获得10
48秒前
爆米花应助科研通管家采纳,获得10
48秒前
爱静静应助科研通管家采纳,获得10
48秒前
浅尝离白应助科研通管家采纳,获得30
48秒前
JamesPei应助科研通管家采纳,获得10
48秒前
科研通AI2S应助科研通管家采纳,获得10
48秒前
英姑应助科研通管家采纳,获得10
48秒前
杳鸢应助科研通管家采纳,获得30
48秒前
爱静静应助科研通管家采纳,获得10
48秒前
48秒前
lzxbarry完成签到,获得积分0
50秒前
51秒前
我睡觉的时候不困完成签到 ,获得积分10
53秒前
无花果应助冯吒采纳,获得10
53秒前
53秒前
高分求助中
Spray / Wall-interaction Modelling by Dimensionless Data Analysis 2000
Evolution 3rd edition 1500
保险藏宝图 1000
Lire en communiste 1000
Mantiden: Faszinierende Lauerjäger Faszinierende Lauerjäger 700
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 700
Mathematics and Finite Element Discretizations of Incompressible Navier—Stokes Flows 500
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 3186596
求助须知:如何正确求助?哪些是违规求助? 2836848
关于积分的说明 8011698
捐赠科研通 2499227
什么是DOI,文献DOI怎么找? 1334156
科研通“疑难数据库(出版商)”最低求助积分说明 637071
邀请新用户注册赠送积分活动 605030