Brain uptake of multivalent and multi-specific DVD-Ig proteins after systemic administration

MAbs
Denise Karaoglu HanzatianAndrew Goodearl

Abstract

Therapeutic monoclonal antibodies and endogenous IgG antibodies show limited uptake into the central nervous system (CNS) due to the blood-brain barrier (BBB), which regulates and controls the selective and specific transport of both exogenous and endogenous materials to the brain. The use of natural transport mechanisms, such as receptor-mediated transcytosis (RMT), to deliver antibody therapeutics into the brain have been studied in rodents and monkeys. Recent successful examples include monovalent bispecific antibodies and mono- or bivalent fusion proteins; however, these formats do not have the capability to bind to both the CNS target and the BBB transport receptor in a bivalent fashion as a canonical antibody would. Dual-variable-domain immunoglobulin (DVD-Ig) proteins offer a bispecific format where monoclonal antibody-like bivalency to both the BBB receptor and the therapeutic target is preserved, enabling independent engineering of binding affinity, potency, valency, epitope and conformation, essential for successful generation of clinical candidates for CNS applications with desired drug-like properties. Each of these parameters can affect the binding and transcytosis ability mediated by different receptors on the bra...Continue Reading

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Citations

Jan 7, 2020·Médecine sciences : M/S·Pierre LafayeXavier Declèves
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Jan 19, 2022·Journal of Internal Medicine·Sneha RathiWilliam F Elmquist

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Methods Mentioned

BETA
Assay
ELISA
surface plasmon resonance
size-exclusion chromatography
protein assay

Software Mentioned

IDBS XLfit®
GraphPad Prism
GraphPad
SigmaPlot

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