In vivo targeting of antibody fragments to the nervous system for Alzheimer's disease immunotherapy and molecular imaging of amyloid plaques.
Targeting therapeutic or diagnostic proteins to the nervous system is limited by the presence of the blood-brain barrier. We report that a F(ab')(2) fragment of a monoclonal antibody against fibrillar human Abeta42 that is polyamine (p)-modified has increased permeability at the blood-brain barrier, comparable binding to the antigen, and comparable in vitro binding to amyloid plaques in Alzheimer's disease (AD) transgenic mouse brain sections. Intravenous injection of the pF(ab')(2)4.1 in the AD transgenic mouse demonstrated efficient targeting to amyloid plaques throughout the brain, whereas the unmodified fragment did not. Removal of the Fc portion of this antibody derivative will minimize the inflammatory response and cerebral hemorrhaging associated with passive immunization and provide increased therapeutic potential for treating AD. Coupling contrast agents/radioisotopes might facilitate the molecular imaging of amyloid plaques with magnetic resonance imaging/positron emission tomography. The efficient delivery of immunoglobulin G fragments may also have important applications to other neurodegenerative disorders or for the generalized targeting of nervous system antigens.
Poduslo
Joseph F
JF
Molecular Neurobiology Laboratory, Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. poduslo.joseph@mayo.edu
Ramakrishnan
Muthu
M
Holasek
Silvina S
SS
Ramirez-Alvarado
Marina
M
Kandimalla
Karunya K
KK
Gilles
Emily J
EJ
Curran
Geoffry L
GL
Wengenack
Thomas M
TM
D000544:Alzheimer Disease / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D001667:Binding, Competitive / Q000276:immunology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology* / Q000378:metabolism* / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods* / Q000639:trends; D007275:Injections, Intravenous; D007525:Isoelectric Focusing; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000276:immunology*; D010447:Peptide Hydrolases / Q000737:chemistry; D058225:Plaque, Amyloid / Q000187:drug effects / Q000276:immunology*; D011485:Protein Binding / Q000276:immunology; D021381:Protein Transport / Q000276:immunology; D011869:Radioligand Assay; D011971:Receptors, Immunologic / Q000187:drug effects / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; C052643:F(ab')2 receptor; D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D010446:Peptide Fragments; D011971:Receptors, Immunologic; C075222:amyloid beta-protein (1-42); D010447:Peptide Hydrolases