title: Antibody therapy to human L1CAM in a transgenic mouse model blocks local tumor growth but induces EMT.
abstract: L1 cell adhesion molecule (L1CAM) is overexpressed in many human cancers, confers bad prognosis and augments cell motility, invasion and metastasis. Results from xenograft mouse models suggested that L1CAM antibodies might be promising tools for cancer therapy. Here, we generated human L1CAM-transgenic mice to study therapeutic efficacy and putative side effects in a model system. We established three transgenic lines (M2, M3 and F4) expressing the human L1CAM transgene in brain, kidney and colon with decreasing intensity (M2, M3 > F4). The expression pattern was similar to that of L1CAM in humans. No interference of the transgene with the expression of endogenous L1CAM was observed. Immunohistochemical analysis revealed correct expression of the transgene in mouse cortex and collective duct of the kidney. Injection of (125)I-labeled L1CAM antibodies resulted in specific enrichment in the kidney but not in the brain. The injection of the therapeutic anti-human L1CAM mAb L1-9.3/2a into transgenic mice even at high doses did not cause behavioral changes or other side effects. Similar results were obtained using a mouse specific L1CAM mAb in normal mice. Tumor therapy experiments were performed using syngeneic mouse tumor cells (RET melanoma and Panc02 pancreatic adenocarcinoma) transduced with human L1CAM. MAb L1-9.3/2a efficiently and specifically attenuated local tumor growth in both model systems without apparent side effects. The therapeutic effect was dependent on immune effector mechanisms. Analysis of Panc02-huL1CAM tumors after therapy showed elevated levels of EGF and evidence of immune-induced epithelial-mesenchymal transition. The results suggest that our transgenic mice are valuable tools to study L1CAM-based antibody therapy.
authors.affiliation: Translational Immunology, D015, Tumor Immunology Programme German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Doberstein
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.forename: Uwe
authors.initials: U
authors.lastname: Haberkorn
authors.forename: Niko P
authors.initials: NP
authors.lastname: Bretz
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.forename: Rafael
authors.initials: R
authors.lastname: Carretero
authors.forename: Gerhard
authors.initials: G
authors.lastname: Moldenhauer
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Peter
authors.initials: P
authors.lastname: Altevogt
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007457:Iodine Radioisotopes / Q000627:therapeutic use; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D039842:Neural Cell Adhesion Molecule L1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D016499:Radioimmunotherapy; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D007457:Iodine Radioisotopes; D039842:Neural Cell Adhesion Molecule L1; D012333:RNA, Messenger
keywords: EMT; L1CAM; immunotherapy; transgenic mice