Engineered antibodies with increased activity to recruit complement

被引:219
作者
Idusogie, EE
Wong, PY
Presta, LG
Gazzano-Santoro, H
Totpal, K
Ultsch, M
Mulkerrin, MG
机构
[1] Abgenix, Dept Bioanalyt Chem, Fremont, CA 94555 USA
[2] Genentech Inc, Dept Qual Control Clin Dev, S San Francisco, CA 94080 USA
[3] Genentech Inc, Dept Immunol, S San Francisco, CA 94080 USA
[4] Genentech Inc, Dept Bioanalyt Technol, S San Francisco, CA 94080 USA
[5] Genentech Inc, Dept Prod Engn, S San Francisco, CA 94080 USA
关键词
D O I
10.4049/jimmunol.166.4.2571
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
This manuscript describes two sites in a human IgG1 that, when mutated individually or in combination, result in a dramatic increase in Clq binding and complement-dependent cytotoxicity activity. These two residues, K326 and E333, are located at the extreme ends of the C1q binding epicenter in the C(H)2 domain of a human IgG. A mutation to tryptophan at K326 debilitates Ab-dependent cell-mediated cytotoxicity activity. In addition, substitutions of the residues E333 with serine and of K326 with tryptophan in a human IgG2 confer biological activity in the complement-dependent cytotoxicity assay in which the wild-type IG2 is inactive. This study reveals that the residues K326 and E333 play a significant role in the control of the biological activity of an IgG molecule and can rescue the activity of an inactive IgG isotype. The Journal of Immunology, 2001, 166: 2571-2575.
引用
收藏
页码:2571 / 2575
页数:5
相关论文
共 25 条
[1]   Targeted anti-cancer therapy using rituximab, a chimaeric anti-CD20 antibody (IDEC-C2B8) in the treatment of non-Hodgkin's B-cell lymphoma [J].
Anderson, DR ;
GrilloLopez, A ;
Varns, C ;
Chambers, KS ;
Hanna, N .
BIOCHEMICAL SOCIETY TRANSACTIONS, 1997, 25 (02) :705-708
[2]   HUMAN-ANTIBODY EFFECTOR FUNCTION [J].
BURTON, DR ;
WOOF, JM .
ADVANCES IN IMMUNOLOGY, 1992, 51 :1-+
[3]   IMMUNOGLOBULIN-G - FUNCTIONAL SITES [J].
BURTON, DR .
MOLECULAR IMMUNOLOGY, 1985, 22 (03) :161-206
[5]   THE BINDING-SITE FOR CLQ ON IGG [J].
DUNCAN, AR ;
WINTER, G .
NATURE, 1988, 332 (6166) :738-740
[6]   CONSTRUCTION AND CHARACTERIZATION OF AN ACTIVE FACTOR-VIII VARIANT LACKING THE CENTRAL 1/3 OF THE MOLECULE [J].
EATON, DL ;
WOOD, WI ;
EATON, D ;
HASS, PE ;
HOLLINGSHEAD, P ;
WION, K ;
MATHER, J ;
LAWN, RM ;
VEHAR, GA ;
GORMAN, C .
BIOCHEMISTRY, 1986, 25 (26) :8343-8347
[7]   A non-radioactive complement-dependent cytotoxicity assay for anti-CD20 monoclonal antibody [J].
GazzanoSantoro, H ;
Ralph, P ;
Ryskamp, TC ;
Chen, AB ;
Mukku, VR .
JOURNAL OF IMMUNOLOGICAL METHODS, 1997, 202 (02) :163-171
[8]  
Gorman C.M., 1990, DNA Prot. Eng. Tech, V2, P3
[9]   REACTION BETWEEN THE ISOLATION GLOBULAR SUBUNITS OF THE COMPLEMENT COMPONENT CLQ AND IGG-COMPLEXES [J].
HUGHESJONES, NC ;
GARDNER, B .
MOLECULAR IMMUNOLOGY, 1979, 16 (09) :697-701
[10]   Mapping of the C1q binding site on rituxan, a chimeric antibody with a human IgG1 Fc [J].
Idusogie, EE ;
Presta, LG ;
Gazzano-Santoro, H ;
Totpal, K ;
Wong, PY ;
Ultsch, M ;
Meng, YG ;
Mulkerrin, MG .
JOURNAL OF IMMUNOLOGY, 2000, 164 (08) :4178-4184