title: Therapeutic antibodies to human L1CAM: functional characterization and application in a mouse model for ovarian carcinoma.
abstract: Recent work has identified L1CAM (CD171) as a novel marker for human carcinoma progression. Functionally, L1CAM promotes tumor cell invasion and motility, augments tumor growth in nude mice, and facilitates experimental tumor metastasis. These functional features qualify L1 as an interesting target molecule for tumor therapy. Here, we generated a series of novel monoclonal antibodies (mAb) to the L1CAM ectodomain that were characterized by biochemical and functional means. All novel mAbs reacted specifically with L1CAM and not with the closely related molecule CHL1, whereas antibodies to the COOH terminal part of L1CAM (mAb2C2, mAb745H7, pcytL1) showed cross-reactivity. Among the novel mAbs, L1-9.3 was selected and its therapeutic potential was analyzed in various isotype variants in a model of SKOV3ip cells growing i.p. in CD1 nude mice. Only therapy with the IgG2a variant efficiently prolonged survival and reduced tumor burden. This was accompanied by an increased infiltration of F4/80-positive monocytic cells. Clodronate pretreatment of tumor-bearing animals led to the depletion of monocytes and abolished the therapeutic effect of L1-9.3/IgG2a. Expression profiling of tumor-derived mRNA revealed that L1-9.3/IgG2a therapy induced altered expression of cellular genes associated with apoptosis and tumor growth. Our results establish that anti-L1 mAb therapy acts via immunologic and nonimmunologic effector mechanism to block tumor growth. The novel antibodies to L1CAM could become helpful tools for the therapy of L1-positive human carcinomas.
authors.affiliation: Tumor Immunology Program, Translational Immunology Unit (D015), German Cancer Research Center, Heidelberg, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Wolterink
authors.forename: Gerhard
authors.initials: G
authors.lastname: Moldenhauer
authors.forename: Mina
authors.initials: M
authors.lastname: Fogel
authors.forename: Helena
authors.initials: H
authors.lastname: Kiefel
authors.forename: Marco
authors.initials: M
authors.lastname: Pfeifer
authors.forename: Sandra
authors.initials: S
authors.lastname: Lüttgau
authors.forename: Ricardo
authors.initials: R
authors.lastname: Gouveia
authors.forename: Julia
authors.initials: J
authors.lastname: Costa
authors.forename: Jan
authors.initials: J
authors.lastname: Endell
authors.forename: Ulrich
authors.initials: U
authors.lastname: Moebius
authors.forename: Peter
authors.initials: P
authors.lastname: Altevogt
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D003429:Cross Reactions; D000939:Epitopes / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D039842:Neural Cell Adhesion Molecule L1 / Q000037:antagonists & inhibitors / Q000276:immunology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D007074:Immunoglobulin G; D039842:Neural Cell Adhesion Molecule L1