An EGP-2/Ep-CAM-expressing transgenic rat model to evaluate antibody-mediated immunotherapy.
The human pancarcinoma-associated epithelial glycoprotein-2 (EGP-2), also known as 17-1A or Ep-CAM, is a 38-kDa transmembrane antigen, commonly used for targeted immunotherapy of carcinomas. Although strongly expressed by most carcinomas, EGP-2 is also expressed in most simple epithelia. To evaluate treatment-associated effects and side-effects on tumor and normal tissue respectively, we generated an EGP-2-expressing transgenic Wistar rat. To express the cDNA of the EGP-2 in an epithelium-specific manner, the 5' and 3' distal flanking regions of the human keratin 18 (K18) gene were used. EGP-2 protein expression was observed in the liver and pancreas, whereas EGP-2 mRNA could also be detected in lung, intestine, stomach and kidney tissues. In this rat, EGP-2-positive tumors can be induced by injecting a rat-derived carcinoma cell line transfected with the GA733-2 cDNA encoding EGP-2. Transgenic rats were used to study specific in vivo localization of an i.v. anti-EGP-2 monoclonal antibody, MOC31, applied i.v. Immunohistochemical analyses showed the specific localization of MOC31 in s.c. induced EGP-2-positive tumors, as well as in the liver. In contrast, in EGP-2-transgenic rats, MOC31 did not bind to EGP-2-negative tumors, the pancreas, or other normal tissues in vivo. In conclusion, an EGP-2-transgenic rat model has been generated that serves as a model to evaluate the efficacy and safety of a variety of anti-EGP-2-based immunotherapeutic modalities.
McLaughlin
P M
PM
Immunology Branch, Division of Pathology and Laboratory Medicine, University Hospital of Groningen, 9713 GZ Groningen, The Netherlands.
Kroesen
B J
BJ
Dokter
W H
WH
van der Molen
H
H
de Groot
M
M
Brinker
M G
MG
Kok
K
K
Ruiters
M H
MH
Buys
C H
CH
de Leij
L F
LF
D000818:Animals; D030801:Animals, Genetically Modified; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D002277:Carcinoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D018076:DNA, Complementary / Q000235:genetics; D000071858:Epithelial Cell Adhesion Molecule; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007116:Immunization, Passive; D007124:Immunoenzyme Techniques; D007633:Keratins / Q000235:genetics; D008297:Male; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014781:Viscera / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D018076:DNA, Complementary; D000071858:Epithelial Cell Adhesion Molecule; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D007633:Keratins