title: Off-target activity of TNF-alpha inhibitors characterized by protein biochips.
abstract: Tumor necrosis factor-alpha inhibitors are widely and successfully used to treat rheumatic diseases. However, significant side effects have been reported. To detect the potential off-target activities of such inhibitors we characterized two therapeutic antibodies (adalimumab, infliximab) and one receptor fusion protein (etanercept) on protein biochips (UNIchip AV-400) containing a printed serial dilution of tumor necrosis factor-alpha and about 384 different human proteins. Etanercept binds to ten proteins (affinity: 20-33% of tumor necrosis factor-alpha recognition), and six of these proteins are related to ribosomal proteins. Interestingly, adalimumab binds to the same six proteins related to ribosomal proteins (affinity: 12-18%) as well as to four proteins crucially involved in ribosomal protein synthesis. Alignment of protein sequences indicates no significant sequence homology between these ten proteins bound by the biological drugs with the highest off-target activities. Taken together, our in vitro results demonstrate that a significant number of proteins are recognized by tumor necrosis factor-alpha inhibitors and are related to ribosome biogenesis.
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, Jeffrey Modell Immunodeficiency Center, University Children's Hospital Düsseldorf, 40225, Düsseldorf, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Feyen
authors.forename: Angelika
authors.initials: A
authors.lastname: Lueking
authors.forename: Axel
authors.initials: A
authors.lastname: Kowald
authors.forename: Christian
authors.initials: C
authors.lastname: Stephan
authors.forename: Helmut E
authors.initials: HE
authors.lastname: Meyer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Göbel
authors.forename: Tim
authors.initials: T
authors.lastname: Niehues
mesh_terms: D000068879:Adalimumab; D000595:Amino Acid Sequence; D000906:Antibodies / Q000276:immunology / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001171:Arthritis, Juvenile / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001665:Binding Sites; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology* / Q000627:therapeutic use; D000069285:Infliximab; D008969:Molecular Sequence Data; D040081:Protein Array Analysis / Q000379:methods*; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D012269:Ribosomal Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D012269:Ribosomal Proteins; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept