Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy.

Abstract

Amyloidosis is a malignant pathology associated with the formation of proteinaceous amyloid fibrils that deposit in organs and tissues, leading to dysfunction and severe morbidity. More than 25 proteins have been identified as components of amyloid, but the most common form of systemic amyloidosis is associated with the deposition of amyloid composed of Ig light chains (AL). Clinical management of amyloidosis focuses on reducing synthesis of the amyloid precursor protein. However, recently, passive immunotherapy using amyloid fibril-reactive antibodies, such as 11-1F4, to remove amyloid from organs has been shown to be effective at restoring organ function in patients with AL amyloidosis. However, 11-1F4 does not bind amyloid in all AL patients, as evidenced by PET/CT imaging, nor does it efficiently bind the many other forms of amyloid. To enhance the reactivity and expand the utility of the 11-1F4 mAb as an amyloid immunotherapeutic, we have developed a pretargeting "peptope" comprising a multiamyloid-reactive peptide, p5+14, fused to a high-affinity peptide epitope recognized by 11-1F4. The peptope, known as p66, bound the 11-1F4 mAb in vitro with subnanomolar efficiency, exhibited multiamyloid reactivity in vitro and, using tissue biodistribution and SPECT imaging, colocalized with amyloid deposits in a mouse model of systemic serum amyloid A amyloidosis. Pretreatment with the peptope induced 11-1F4 mAb accumulation in serum amyloid A deposits in vivo and enhanced 11-1F4-mediated dissolution of a human AL amyloid extract implanted in mice.

• Authors: Jonathan S Wall, Angela D Williams, James S Foster, Tina Richey, Alan Stuckey, Sallie Macy, Craig Wooliver, Shawn R Campagna, Eric D Tague, Abigail T Farmer, Ronald H Lands, Emily B Martin, R Eric Heidel, Stephen J Kennel
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 46 Pg. E10839-E10848 (11 13 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 30377267 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid
• Amyloidogenic Proteins
• Antibodies, Bispecific
• Antibodies, Monoclonal
• Epitopes
• Immunoglobulin Light Chains
• Peptides
• Serum Amyloid A Protein
• monoclonal antibody 11-1f4

Topics

• Amyloid (metabolism)
• Amyloidogenic Proteins (metabolism)
• Amyloidosis (metabolism, therapy)
• Animals
• Antibodies, Bispecific (immunology)
• Antibodies, Monoclonal (immunology, physiology)
• Cadaver
• Epitopes (metabolism)
• Humans
• Immunoglobulin Light Chains (immunology)
• Mice
• Peptides (metabolism)
• Positron Emission Tomography Computed Tomography
• Protein Binding
• Serum Amyloid A Protein (metabolism)
• Tissue Distribution
• Treatment Outcome