The structure of an antitumor C(H)2-domain-deleted humanized antibody.
The structure of an antitumor C(H)2-domain-deleted humanized antibody.
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抗肿瘤 C(H)2 结构域缺失的人源化抗体的结构。
DOI：
10.1016/j.jmb.2005.03.036
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
McPherson,Alexander
中科院分区：
文献类型：
--
作者：
Larson,StevenB;Day,JohnS;Glaser,Scott;Braslawsky,Gary;McPherson,Alexander
CH 2结构域缺失的CC 49（HuCC 49 Δ CH 2）是一种重组人源化抗体，可识别多种人癌细胞上表达的TAG-72抗原，从培养细胞中分泌，为两种同型二聚体亚型的混合物。亚型A在重链位置239和242处含有两个共价链间二硫键，而亚型B未能形成任何链间二硫键，而是具有239-242个链内二硫键。形式A目前处于临床前开发中，作为治疗结肠直肠癌的治疗剂，尽管形式B显示出相同的功效。HuCC 49 Δ CH 2晶型B仅在存在去污剂的情况下才能从甲酸钠中结晶。X射线衍射数据收集与Triton X-100生长的一个单一的低温冷却的晶体和结构，解决了分子置换。对于2.8 μ m的数据，该模型已精确到R=0.246（Rfree=0.297）。抗体围绕晶体学2重轴以大约222对称性的四聚体形式聚集在晶体中。原子力显微镜的研究表明，这种四聚体结构是晶体结构单元，也存在于母液中。四聚体由两个环组成，背靠背，厚度为1.83 μ m。每个环由两个抗体组成，其中一个抗体的两个Fab的互补决定区（CDR）以头对头方式与第二个抗体的CDR区相互作用。这些环长约167厘米，宽约112厘米。当与常规抗体中发现的通常取向相比时，CH 3结构域相对于Fab反转。没有看到将CH 3结构域连接到抗体Fab部分的多肽，并且几乎可以肯定是无序的。HuCC 49 Δ CH 2的抗原结合位点在拓扑结构和电荷分布上与抗体B72.3的抗原结合位点非常相似，但不相同，抗体B72.3结合TAG-72上的相似表位。结合位点由一个深裂缝组成，该裂缝与芳香族氨基酸侧链紧密相连，但由许多带电基团限制。
CH2-domain-deleted CC49 (HuCC49ΔCH2), a recombinant humanized antibody that recognizes the TAG-72 antigen expressed on a variety of human carcinomas, is secreted from cultured cells as a mixture of two homodimeric isoforms. Isoform A contains two covalent interchain disulfide bonds at heavy chain positions 239 and 242, while isoform B fails to develop any interchain disulfide bonds but has 239–242 intrachain disulfide bonds instead. Form A is currently in preclinical development as a therapeutic agent for treating colorectal carcinoma, though form B shows equal efficacy. HuCC49ΔCH2 form B can be crystallized from sodium formate only in the presence of detergents. X-ray diffraction data were collected on a single cryo-cooled crystal grown with Triton X-100 and the structure was solved by molecular replacement. The model has refined to R=0.246 (Rfree=0.297) for 2.8Å data. The antibodies pack in the crystal around crystallographic 2-fold axes as tetramers with approximate 222 symmetry. Atomic force microscopy studies show that this tetrameric structure is the crystal building block and also exists free in the mother liquor. The tetramer is composed of two rings, back-to-back, with a thickness of ∼83Å. Each ring is composed of two antibodies with the complementarity-determining regions (CDR) of the two Fabs of one antibody interacting with the CDR regions of the second antibody in a head-to-head fashion. These rings are approximately 167Å long and 112Å wide. The CH3 domain is inverted with respect to the Fabs when compared to the usual orientation found in conventional antibodies. The polypeptides joining the CH3 domains to the Fab portions of the antibody are not seen and are almost certainly disordered. The antigen combining site of HuCC49ΔCH2 is very similar, but not identical, in topology and charge distribution to that of antibody B72.3, which binds a similar epitope on TAG-72. The combining site consists of a deep cleft, heavily lined with aromatic amino acid side-chains but bounded by numerous charged groups.
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完整抗体结构的比较及其对效应器功能的影响。
影响因子：
--
作者：
L. J. Harris;S. Larson;A. McPherson
通讯作者：
A. McPherson
结合使用 AFM 和 X 射线衍射来分析工程化、结构域缺失的抗体的晶体。
DOI：
10.1107/s0907444905001216
发表时间：
2005
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Larson,StevenB;Kuznetsov,YuG;Day,John;Zhou,Jiashu;Glaser,Scott;Braslawsky,Gary;McPherson,Alexander
通讯作者：
McPherson,Alexander
与肿瘤相关糖蛋白 72 抗原发生反应的 B72.3 第二代单克隆抗体的生成和表征。
影响因子：
11.2
作者：
R. Muraro;M. Kuroki;D. Wunderlich;D. Poole;D. Colcher;A. Thor;J. Greiner;J. Simpson;A. Molinolo;P. Noguchi;J. Schlom;R M Nih
通讯作者：
R M Nih
免疫血清
DOI：
10.1038/077411a0
发表时间：
1919
期刊：
The Indian Medical Gazette
影响因子：
--
作者：
J. Koop
通讯作者：
J. Koop
一种 CDR 移植（人源化）结构域缺失的抗肿瘤抗体。
影响因子：
3.4
作者：
D. C. Slavin;S. Kashmiri;Hyun;D. Milenic;D. Poole;Eric Bernon;J. Schlom;P. Hand
通讯作者：
P. Hand