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In vivo targeting of antibody fragments to the nervous system for Alzheimer’s disease immunotherapy and molecular imaging of amyloid plaques
Author(s) -
Poduslo Joseph F.,
Ramakrishnan Muthu,
Holasek Silvina S.,
RamirezAlvarado Marina,
Kandimalla Karunya K.,
Gilles Emily J.,
Curran Geoffry L.,
Wengenack Thomas M.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04591.x
Subject(s) - in vivo , central nervous system , antibody , genetically modified mouse , blood–brain barrier , pathology , transgene , alzheimer's disease , amyloid (mycology) , monoclonal antibody , antigen , medicine , immunotherapy , immunology , chemistry , biology , disease , immune system , biochemistry , microbiology and biotechnology , gene
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 Aβ42 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.