Optimizing intracellular antibodies (intrabodies/nanobodies) to treat neurodegenerative disorders.

Publication date: Feb 01, 2020

Intrabodies (both single-chain Fv and single-domain VH, VHH, and VL nanobodies) offer unique solutions to some of the challenges of delivery and target engagement posed by immunotherapeutics for the brain and other areas of the nervous system. The specificity, which includes the recognition of post-translational modifications, and capacity for engineering that characterize these antibody fragments can be especially well-focused when the genes encoding only the binding sites of the antibody are expressed intracellularly. Multifunctional constructs use fusions with peptides that can re-target antigen-antibody complexes to enhance both pharmacodynamic activity and intracellular solubility simultaneously. Fusions with proteolytic targeting signals, such as the PEST degron, greatly enhance potency in some cases. Stem cell transplants can be protected from exogenous misfolded proteins by stable transfection with intrabodies. Tandem expression to target two or more misfolding proteins in one treatment may be especially valuable for proteostatic disruptions due to genetic, aging, or toxic triggers. Advances in bioinformatics, screening protocols, and especially gene therapy are showing great promise for intrabody/ nanobody treatments of a full range of neurological disorders, including Alzheimer’s disease and related tau dementias, Parkinson’s disease and Lewy body diseases, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases, among others.

Messer, A. and Butler, D.C. Optimizing intracellular antibodies (intrabodies/nanobodies) to treat neurodegenerative disorders. 06910. 2020 Neurobiol Dis (134):

Concepts Keywords
Aging Neurological disorders
Alzheimer Immunotherapy
Amyotrophic Lateral Sclerosis Branches of biology
Antibodies Lewy body dementia
Antibody Psychiatric diagnosis
Antigen RTT
Bioinformatics Neurological disorders
Brain Antibodies
Engineering Intrabody
Exogenous Single-domain antibody
Genetic Neurodegeneration
Huntington Bioinformatics
Immunotherapeutics Alpha
Intracellular Antibodies
Misfolding Immunotherapeutics
Nervous System
Neurodegenerative Disorders
Neurological Disorders
Parkinson
Peptides
Pharmacodynamic
Prion
Proteolytic
Solubility
Transfection

Semantics

Type Source Name
disease MESH neurodegenerative disorders
disease MESH aging
disease MESH neurological disorders
disease MESH dementias
disease MESH amyotrophic lateral sclerosis
disease MESH prion diseases
pathway KEGG Prion diseases

Original Article

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