Targeted hydrolysis of beta-amyloid with engineered antibody fragments

S. Kasturirangan, Michael Sierks

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Accumulation and deposition of beta amyloid (Aβ) play a critical role in the pathogenesis of Alzheimer's Disease (AD), and numerous approaches to control Aβ aggregation are being actively pursued. Brain Aβ levels are controlled by the action of several proteolytic enzymes such as neprilysin (NEP), insulin degrading enzyme (IDE) and plasmin. While up-regulation of these enzymes increased clearance of Aβ in transgenic mouse models of AD, these enzymes have other natural substrates and multiple cleavage sites in Aβ complicating their use for treating AD. Alternatively, immunotherapeutic approaches to clear Aβ are gaining interest. Active and passive immunization studies with Aβ can reduce plaque burden and memory loss, but clinical trials were stopped due to meningioencephalitis in some patients. Naturally occurring proteolytic antibodies have been shown to cleave Aβ, and their serum titers are increased in patients with AD reflecting a protective autoimmune response. These antibodies however cannot cross the blood brain barrier and depend entirely on peripheral clearance to clear Aβ. A potentially non-inflammatory approach to facilitate Aβ clearance and reduce toxicity is to promote hydrolysis of Aβ at its α-secretase site using affinity matured single chain antibody fragments (scFvs). Bispecific antibodies consisting of a proteolytic scFv and a targeting scFv can be engineered to selectively supplement and target extracellular α-secretase activity and to target toxic Aβ forms facilitating their degradation and clearance without generating an immune response. This strategy represents a suitable paradigm for treating other neurological diseases such as Parkinson's Disease, Lou Gehrig's Disease, and spongiform encephalopathies.

Original languageEnglish (US)
Pages (from-to)214-222
Number of pages9
JournalCurrent Alzheimer Research
Volume7
Issue number3
DOIs
StatePublished - May 2010

Fingerprint

Immunoglobulin Fragments
Amyloid
Alzheimer Disease
Hydrolysis
Amyloid Precursor Protein Secretases
Insulysin
Bispecific Antibodies
Neprilysin
Single-Chain Antibodies
Passive Immunization
Antibodies
Poisons
Fibrinolysin
Memory Disorders
Amyotrophic Lateral Sclerosis
Brain Diseases
Enzymes
Blood-Brain Barrier
Autoimmunity
Transgenic Mice

Keywords

  • α-Secretase
  • Beta amyloid cleavage
  • Bispecific scFV
  • Proteolytic scfv
  • Serine protease

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Targeted hydrolysis of beta-amyloid with engineered antibody fragments. / Kasturirangan, S.; Sierks, Michael.

In: Current Alzheimer Research, Vol. 7, No. 3, 05.2010, p. 214-222.

Research output: Contribution to journalArticle

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