THE X-RAY STRUCTURE OF AN ANTITUMOR ANTIBODY IN COMPLEX WITH ANTIGEN

被引:88
作者
JEFFREY, PD
BAJORATH, J
CHANG, CY
YELTON, D
HELLSTROM, I
HELLSTROM, KE
SHERIFF, S
机构
[1] BRISTOL MYERS SQUIBB CO, PHARMACEUT RES INST, PRINCETON, NJ 08543 USA
[2] BRISTOL MYERS SQUIBB CO, PHARMACEUT RES INST, SEATTLE, WA 98121 USA
来源
NATURE STRUCTURAL BIOLOGY | 1995年 / 2卷 / 06期
关键词
D O I
10.1038/nsb0695-466
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The crystal structures of the murine BR96 Fab and its human chimera have been determined in complex with the nonoate methyl ester derivative of Lewis Y (nLe(Y)) at 2.8 Angstrom and 2.5 Angstrom resolution, respectively. BR96 binds the carbohydrate in a large pocket which is formed by residues of all CDR loops except L2. The binding of the carbohydrate is mediated predominantly by aromatic residues in BR96. Analysis of the structure suggests that BR96 is capable of recognizing a structure larger than the Le(Y) tetrasaccharide, providing a possible explanation for its high tumour selectivity. The structure provides a rationale for mutagenesis experiments that have resulted in BR96 CDR loop mutants with increased affinity for nLe(Y) and/or tumour cells.
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收藏
页码:466 / 471
页数:6
相关论文
共 40 条
[1]  
Hellstrom K.E., Hellstrom I., Principles of tumour immunity: Tumour antigens, Biologic Therapy of Cancer, pp. 35-52, (1991)
[2]  
Trail P.A., Et al., Cure of xenografted human carcinomas by BR96- doxorublcin immunoconjugates, Science, 261, pp. 212-215, (1993)
[3]  
Hellstrom I., Garrigues H.J., Garrigues U., Hellstrom K.E., Highly tumour-reactive, internalizing, mouse monoclonal antibodies to Ler- related cell surface antigens, Cancer Res, 50, pp. 2183-2190, (1990)
[4]  
Hakomorl S., Aberrant glycosylation In tumours and tumour- associated carbohydrate antigens, Advan. Cancer Res, 52, pp. 257-331, (1989)
[5]  
Garrigues J., Erson J., Hellstrom K.E., Hellstrom I., Antitumour Mab BR96 blocks cell migration and binds to lysosomal membrane glycoprotein on cell surface mlcrosplkes and ruffled membranes, J. Cell. Biol, 125, pp. 129-142, (1994)
[6]  
Garrigues J., Garrigues U., Hellstrom I., Hellstrom K.E., Le' specific antibody with potent anti-tumour activity Is internalized and degraded in lysosomes, Am. J. Pathol, 142, pp. 607-622, (1993)
[7]  
Willner D.E., (6-Maleimidocaproyl)hydrazone of doxorublcln- a new derivative for the preparation of immunoconjugates of doxorubicin, Bioconjugate Chem, 4, pp. 521-527, (1993)
[8]  
Yelton D.E., Affinity maturation of the BR96 anticarcinoma antibody in vitro by codon-based mutagenesis, J. Immunol
[9]  
Bajorath J., Three-dimensional model of the BR96 monoclonal antibody variable fragment, Bioconjugate Chem, 5, pp. 213-219, (1994)
[10]  
Chang C.Y., Jeffrey P.D., Bajorath J., Hellstrom I., Hellstrom K.E., Sheriff S., Crystallization and preliminary X-ray analysis of the monoclonal anti-tumour antibody BR96 and its complex with the Lewis Y determinant, J. Molec. Biol, 235, pp. 372-376, (1994)