title: Comparisons of affinities, avidities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor.
abstract: The TNF antagonists adalimumab, infliximab, and etanercept are effective treatments for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis, but only adalimumab and infliximab have been found to be efficacious in Crohn's disease. The present studies evaluated the TNF-binding and complement-activating properties of adalimumab, infliximab, and etanercept to determine whether these properties may explain differences in their clinical efficacy profiles. Association and dissociation rates of binding to soluble TNF were measured by surface plasmon resonance, and were found to be similar for adalimumab, infliximab, and etanercept, as were their calculated binding affinities. Avidity of binding to soluble TNF, measured by KinExA technology, was 10- to 20-fold greater for soluble etanercept (K(D)=0.4 picomolars [pM]) than for soluble adalimumab or infliximab (K(D)=8.6 and 4.2 pM, respectively). (125)I-adalimumab, -infliximab, and -etanercept bound to membrane TNF (mTNF) on mTNF-transfected cells with similar affinities (K(D)=483, 468, and 445 pM, respectively) that were each lower than for soluble TNF. Complement-dependent cytotoxicity (CDC) was induced in mTNF-transfected cells by adalimumab and infliximab, but was not induced in activated normal human PBMC by any of the 3 agents. In conclusion, the binding properties of adalimumab, infliximab, and etanercept were similar for soluble TNF, and very similar for mTNF, yet none of the 3 was able to induce CDC in activated PBMC. These results suggest that the different clinical efficacy profiles of these agents are not explained by differences in either TNF-intrinsic binding properties or complement lysis.
authors.affiliation: Department of Biologics, Abbott Bioresearch Center, Worcester, MA 01605, USA. Zehra.kaymakcalan@abbott.com
authors.forename: Zehra
authors.initials: Z
authors.lastname: Kaymakcalan
authors.forename: Paul
authors.initials: P
authors.lastname: Sakorafas
authors.forename: Sahana
authors.initials: S
authors.lastname: Bose
authors.forename: Susanne
authors.initials: S
authors.lastname: Scesney
authors.forename: Limin
authors.initials: L
authors.lastname: Xiong
authors.forename: Denise Karaoglu
authors.initials: DK
authors.lastname: Hanzatian
authors.forename: Jochen
authors.initials: J
authors.lastname: Salfeld
authors.forename: Eric H
authors.initials: EH
authors.lastname: Sasso
mesh_terms: D000068879:Adalimumab; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000915:Antibody Affinity / Q000187:drug effects*; D002462:Cell Membrane / Q000276:immunology*; D003167:Complement Activation / Q000187:drug effects*; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism / Q000494:pharmacology; D000069285:Infliximab; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D008565:Membrane Proteins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept