In vivo targeting of antibody fragments to the nervous system for Alzheimer's disease immunotherapy and molecular imaging of amyloid plaques

Joseph F. Poduslo, Muthu Ramakrishnan, Silvina S. Holasek, Marina Ramirez-Alvarado, Karunya K. Kandimalla, Emily J. Gilles, Geoffry L. Curran, Thomas M. Wengenack

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

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′)24.1 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.

Original languageEnglish (US)
Pages (from-to)420-433
Number of pages14
JournalJournal of Neurochemistry
Volume102
Issue number2
DOIs
StatePublished - Jul 2007

Keywords

  • Alzheimer's disease
  • Amyloid plaques
  • Antibody fragments
  • Contrast agent
  • Molecular imaging
  • Passive immunization

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