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.

L1CAM–integrin interaction induces constitutive NF-κB activation in pancreatic adenocarcinoma cells by enhancing IL-1β expression

“…MAbs that bind to the first Ig domain (L1-9.3), the sixth Ig domain (L1-35.9) or the FNIII repeats (L1-11A) of L1CAM were selected. (Wolterink et al, 2010). A significant effect on IL-1b production was only observed with mAb L1-39.5 to the sixth Ig domain (Figure 7a).…”

“…The detailed procedure has been described before (Wolterink et al, 2010). Two independent biological replicates were analysed.…”

L1CAM in the Early Enteric and Urogenital System

“…Apart from the fact that L1CAM is a significant prognostic marker for tumors, it has been considered a possible target for an antibody-based therapy, [32][33][34] and current studies aim at the implementation of L1CAM in daily clinical use. Before that, however, can be achieved, the basic mechanism of L1CAM has to be thoroughly elucidated, including the exact role of L1CAM in the human organogenesis.…”

The Adhesion Molecule L1CAM as a Novel Therapeutic Target for Treatment of Pancreatic Cancer Patients?

“…Biweekly treatment with the anti-L1CAM antibody L1-11A dose-dependently inhibited tumor growth of intraperitoneally inoculated SKOV3ip ovarian carcinoma cells and ascites formation by up to 75 % in nude mice (Arlt et al, 2006). In the same tumor model system, therapeutic efficacy of L1CAM antibodies with different isotypes has been evaluated demonstrating that therapy with the L1-9.3/IgG2a antibody results in the best anti-tumor response in terms of reduced tumor burden and prolonged survival (Wolterink et al, 2010). Expression profiling of mRNA isolated from tumors www.intechopen.com…”

“…337 revealed an altered gene expression after L1CAM antibody treatment including genes involved in apoptosis, chemotaxis, angiogenesis and inflammatory responses. Moreover, antibody-treatment caused a massive infiltration of macrophages into the tumor suggesting that efficacy of anti-L1CAM antibody therapy is based on immunologically and nonimmunologically mediated mechanisms (Wolterink et al, 2010). Therapeutic efficacy of radiolabeled anti-L1CAM antibodies has been proven in nude mice orthotopically inoculated with SKOV3ip ovarian carcinoma cells or with neuroblastoma xenografts (Hoefnagel et al 2001;Knogler et al, 2007).…”