Llama single-domain antibodies directed against nonconventional epitopes of tumor-associated carcinoembryonic antigen absent from nonspecific cross-reacting antigen

被引:43
作者
Behar, Ghislaine [1 ,2 ]
Chames, Patrick [1 ,2 ]
Teulon, Isabelle [2 ,3 ]
Cornillon, Amelie [1 ,2 ]
Alshoukr, Faisal [2 ,4 ,5 ]
Roquet, Francoise [2 ,6 ]
Pugniere, Martine [2 ,6 ]
Teillaud, Jean-Luc [2 ,7 ,8 ,9 ]
Gruaz-Guyon, Anne [2 ,4 ,5 ]
Pelegrin, Andre [2 ,3 ]
Baty, Daniel [1 ,2 ]
机构
[1] CNRS, Lab Ingn Syst Macromol, Marseille, France
[2] CNRS, Grp Rech Immunociblage Tumeurs, Marseille, France
[3] Univ Montpellier, INSERM, Ctr Rech Cancerol Montpellier, Montpellier, France
[4] Ctr Rech Biomed Bichat Beaujon, INSERM, Paris, France
[5] Univ Paris 07, F-75221 Paris 05, France
[6] Univ Montpellier 1, CNRS, F-34006 Montpellier, France
[7] Ctr Rech Cordeliers, INSERM, Paris, France
[8] Univ Paris 06, F-75252 Paris 05, France
[9] Univ Paris 05, Paris, France
关键词
carcinoembryonic antigen; CEACAM5; nonspecific cross-reacting antigen; phage display; single domain antibodies; HEAVY-CHAIN ANTIBODIES; GAMMA-RIII CD16; LIGHT-CHAINS; FRAGMENTS; CELLS; PROTEINS; SEQUENCE; SECRETION; SELECTION; PEPTIDES;
D O I
10.1111/j.1742-4658.2009.07101.x
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
Single- domain antibodies ( sdAbs), which occur naturally in camelids, are endowed with many characteristics that make them attractive candidates as building blocks to create new antibody- related therapeutic molecules. In this study, we isolated from an immunized llama several high-affinity sdAbs directed against human carcinoembryonic antigen ( CEA), a heavily glycosylated tumor- associated molecule expressed in a variety of cancers. These llama sdAbs bind a different epitope from those defined by current murine mAbs, as shown by binding competition experiments using immuno. uorescence and surface plasmon resonance. Flow cytometry analysis shows that they bind strongly to CEA- positive tumor cells but show no cross- reaction toward nonspecific cross- reacting antigen, a highly CEA-related molecule expressed on human granulocytes. When injected into mice xenografted with a human CEA- positive tumor, up to 2% of the injected dose of one of these sdAbs was found in the tumor, despite rapid clearance of this 15 kDa protein, demonstrating its high potential as a targeting moiety. The single- domain nature of these new anti- CEA IgG fragments should facilitate the design of new molecules for immunotherapy or diagnosis of CEA- positive tumors.
引用
收藏
页码:4305 / 4317
页数:13
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