ABSTRACT
Epithelial cell adhesion molecule EpCAM is a transmembrane glycoprotein that is frequently overexpressed in a variety of carcinomas. This pan-carcinoma antigen has served as the target for a plethora of immunotherapies. Innovative therapeutic approaches include the use of trifunctional antibodies (trAbs) that recruit and activate different types of immune effector cells at the tumour site. The trAb catumaxomab has dual specificity for EpCAM and CD3. In patients with malignant ascites, catumaxomab significantly increased the paracentesis-free interval, corroborating the high efficacy of this therapeutic antibody. Here, we characterised the monoclonal antibody (mAb) HO-3, that is, the EpCAM-binding arm of catumaxomab. Peptide mapping indicated that HO-3 recognises a discontinuous epitope, having three binding sites in the extracellular region of EpCAM. Studies with glycosylation-deficient mutants showed that mAb HO-3 recognised EpCAM independently of its glycosylation status. High-affinity binding was not only detected for mAb HO-3, but also for the monovalent EpCAM-binding arm of catumaxomab with an excellent K(D) of 5.6 x 10(-10) M. Furthermore, trAb catumaxomab was at least a 1000-fold more effective in eliciting the eradication of tumour cells by effector peripheral blood mononuclear cells compared with mAb HO-3. These findings suggest the great therapeutic potential of trAbs and clearly speak in favour of EpCAM-directed cancer immunotherapies.
Subject(s)
Antigens, Neoplasm/therapeutic use , Cell Adhesion Molecules/therapeutic use , Immunotherapy , Neoplasms/therapy , Amino Acid Sequence , Antibodies, Bispecific/metabolism , Antigens, Neoplasm/chemistry , Antigens, Neoplasm/immunology , Antigens, Neoplasm/metabolism , Base Sequence , Cell Adhesion Molecules/chemistry , Cell Adhesion Molecules/immunology , Cell Adhesion Molecules/metabolism , Cell Line, Tumor , DNA Primers , Epidermal Growth Factor/chemistry , Epidermal Growth Factor/metabolism , Epithelial Cell Adhesion Molecule , Epitopes/chemistry , Glycosylation , Humans , Molecular Sequence DataSubject(s)
Alleles , Drosophila melanogaster/genetics , Mosaicism , Animals , Eye Color , Female , Homozygote , Male , Phenotype , Y ChromosomeABSTRACT
The possibilities of medicamental antirheumatic treatment, are reviewed. Drugs are divided in nonsteroidal antirheumatic drugs, corticoids and combined drugs, so called basic treatment, and locally administered drugs. Mechanisms of action, indication, and effects of those groups are discussed and literature is briefly reviewed.