title: AL amyloid imaging and therapy with a monoclonal antibody to a cryptic epitope on amyloid fibrils.
abstract: The monoclonal antibody 2A4 binds an epitope derived from a cleavage site of serum amyloid protein A (sAA) containing a -Glu-Asp- amino acid pairing. In addition to its reactivity with sAA amyloid deposits, the antibody was also found to bind amyloid fibrils composed of immunoglobulin light chains. The antibody binds to synthetic fibrils and human light chain (AL) amyloid extracts with high affinity even in the presence of soluble light chain proteins. Immunohistochemistry with biotinylated 2A4 demonstrated positive reaction with ALκ and ALλ human amyloid deposits in various organs. Surface plasmon resonance analyses using synthetic AL fibrils as a substrate revealed that 2A4 bound with a K(D) of ∼10 nM. Binding was inhibited in the presence of the -Glu-Asp- containing immunogen peptide. Radiolabeled 2A4 specifically localized with human AL amyloid extracts implanted in mice (amyloidomas) as evidenced by single photon emission (SPECT) imaging. Furthermore, co-localization of the radiolabeled mAb with amyloid was shown in biodistribution and micro-autoradiography studies. Treatment with 2A4 expedited regression of ALκ amyloidomas in mice, likely mediated by the action of macrophages and neutrophils, relative to animals that received a control antibody. These data indicate that the 2A4 mAb might be of interest for potential imaging and immunotherapy in patients with AL amyloidosis.
authors.affiliation: Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, United States of America. jwall@utmck.edu
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Wall
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kennel
authors.forename: Angela
authors.initials: A
authors.lastname: Williams
authors.forename: Tina
authors.initials: T
authors.lastname: Richey
authors.forename: Alan
authors.initials: A
authors.lastname: Stuckey
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Sallie
authors.initials: S
authors.lastname: Macy
authors.forename: Robert
authors.initials: R
authors.lastname: Donnell
authors.forename: Robin
authors.initials: R
authors.lastname: Barbour
authors.forename: Peter
authors.initials: P
authors.lastname: Seubert
authors.forename: Dale
authors.initials: D
authors.lastname: Schenk
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D000686:Amyloidosis / Q000000981:diagnostic imaging / Q000276:immunology / Q000628:therapy*; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000915:Antibody Affinity; D001536:Bence Jones Protein / Q000737:chemistry; D001667:Binding, Competitive; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009928:Organ Specificity; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon; D051598:Whole Body Imaging
chemical_list: D000682:Amyloid; D058846:Antibodies, Monoclonal, Murine-Derived; D000939:Epitopes; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; C518669:amyloid L, human; D001536:Bence Jones Protein