AL Amyloid Imaging and Therapy with a Monoclonal Antibody to a Cryptic Epitope on Amyloid Fibrils

Jonathan Wall, Stephen Kennel, Angela Williams, Tina Richey, Alan Stuckey, Ying Huang, Sallie Macy, Robert Donnell, Robin Barbour, Peter Seubert, Dale Schenk

Research output: Contribution to journalArticle

32 Citations (Scopus)

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 KD 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.

Original languageEnglish (US)
Article numbere52686
JournalPLoS ONE
Volume7
Issue number12
DOIs
StatePublished - Dec 29 2012
Externally publishedYes

Fingerprint

amyloid
Amyloid
epitopes
Epitopes
monoclonal antibodies
Monoclonal Antibodies
image analysis
Imaging techniques
Serum Amyloid A Protein
therapeutics
Amyloid Plaques
Antibodies
Immunoglobulin Light Chains
Light
Surface Plasmon Resonance
Amyloidosis
Therapeutics
Deposits
Single-Photon Emission-Computed Tomography
Autoradiography

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

AL Amyloid Imaging and Therapy with a Monoclonal Antibody to a Cryptic Epitope on Amyloid Fibrils. / Wall, Jonathan; Kennel, Stephen; Williams, Angela; Richey, Tina; Stuckey, Alan; Huang, Ying; Macy, Sallie; Donnell, Robert; Barbour, Robin; Seubert, Peter; Schenk, Dale.

In: PLoS ONE, Vol. 7, No. 12, e52686, 29.12.2012.

Research output: Contribution to journalArticle

Wall, J, Kennel, S, Williams, A, Richey, T, Stuckey, A, Huang, Y, Macy, S, Donnell, R, Barbour, R, Seubert, P & Schenk, D 2012, 'AL Amyloid Imaging and Therapy with a Monoclonal Antibody to a Cryptic Epitope on Amyloid Fibrils', PLoS ONE, vol. 7, no. 12, e52686. https://doi.org/10.1371/journal.pone.0052686
Wall, Jonathan ; Kennel, Stephen ; Williams, Angela ; Richey, Tina ; Stuckey, Alan ; Huang, Ying ; Macy, Sallie ; Donnell, Robert ; Barbour, Robin ; Seubert, Peter ; Schenk, Dale. / AL Amyloid Imaging and Therapy with a Monoclonal Antibody to a Cryptic Epitope on Amyloid Fibrils. In: PLoS ONE. 2012 ; Vol. 7, No. 12.
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