Transcytosis of payloads that are non-covalently complexed to bispecific antibodies across the hCMEC/D3 blood-brain barrier model.

Biological Chemistry
Daniela SchmidUlrich Brinkmann

Abstract

A transcellular shuttle system was generated for the delivery of non-covalently linked payloads across blood-brain barrier (BBB) endothelial cells. Transcytosis-enabling shuttles are composed of bispecific antibodies (bsAbs) that simultaneously bind transferrin receptor (TfR) and haptens such as digoxigenin or biocytinamide. Haptenylated payloads are attached to these vehicles via non-covalent hapten-antibody complexation. This enables targeting to and internalization into human BBB-derived microvascular endothelial hCMEC/D3 cells. In contrast to other shuttles, this system does not require special affinities or formats of their TfR-binding moieties for transcytosis and subsequent release. Non-covalent payload complexation to bsAb is flexible and robust, works for a multitude of payloads and enables separation of payloads from shuttles during transcytosis. Released payloads can enter the brain without connected bsAb entities, minimizing potential interference with distribution or functionality. Intracellular separation of shuttle and payload and recycling to cell surfaces may also enable recharging of the cell-bound BBB shuttle with payload for subsequent (merry-go-round) transport cycles.

References

Aug 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·U BrinkmannI Pastan
Aug 12, 1998·Journal of Molecular Biology·T K BeraI Pastan
Sep 6, 2005·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·B B WekslerP O Couraud
May 4, 2011·Proceedings of the National Academy of Sciences of the United States of America·Silke MetzUlrich Brinkmann
May 27, 2011·Science Translational Medicine·Y Joy YuMark S Dennis
Jan 11, 2012·Methods in Enzymology·William M Pardridge, Ruben J Boado
Jun 23, 2012·Methods in Molecular Biology·Michael GroteUlrich Brinkmann
Jan 25, 2013·Molecular Therapy. Nucleic Acids·Britta SchneiderUlrjch Brinkmann
Mar 28, 2013·Fluids and Barriers of the CNS·Babette WekslerPierre-Olivier Couraud
Jun 27, 2013·Journal of Controlled Release : Official Journal of the Controlled Release Society·Eike HoffmannUlrich Brinkmann
Nov 8, 2014·Science Translational Medicine·Y Joy YuRyan J Watts
Feb 12, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Stefan DenglUlrich Brinkmann
Mar 3, 2015·Drug Discovery Today·Roland E Kontermann, Ulrich Brinkmann
Mar 24, 2015·Advanced Drug Delivery Reviews·Melvin M EversWilleke M C van Roon-Mom
Oct 17, 2015·Methods in Molecular Biology·Irmgard S ThoreyUlrich Brinkmann
Jan 23, 2016·Nature Reviews. Drug Discovery·William A Banks
Jan 11, 2017·MAbs·Ulrich Brinkmann, Roland E Kontermann
Oct 27, 2017·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·William M Pardridge

❮ Previous
Next ❯

Citations

Dec 14, 2018·Cellular and Molecular Life Sciences : CMLS·Roberto VillaseñorLudovic Collin
Jan 25, 2021·Advanced Drug Delivery Reviews·Pere MongeAlexander N Zelikin

❮ Previous
Next ❯

Methods Mentioned

BETA
FACS
size exclusion chromatography
enzyme-linked immunosorbent assay
ELISA
confocal microscopy
PCR

Software Mentioned

FlowJo
ImageJ
Huygens

Related Concepts

Related Feeds

Blood Brain Barrier

The blood brain barrier is a border that separates blood from cerebrospinal fluid. Discover the latest search on this highly selective semipermeable membrane here.

Antibody Engineering

Antibody engineering technologies are constantly advancing to improve the clinical effectiveness of monoclonal and bispecific antibodies. Discover the latest research on Antibody Engineering here.

Blood Brain Barrier Regulation in Health & Disease

The blood brain barrier is essential in regulating the movement of molecules and substances in and out of the brain. Disruption to the blood brain barrier and changes in permeability allow pathogens and inflammatory molecules to cross the barrier and may play a part in the pathogenesis of neurodegenerative disorders. Here is the latest research in this field.

Blood Brain Barrier Chips

The blood brain barrier (BBB) is comprised of endothelial cells that regulate the influx and outflux of plasma concentrations. Lab-on-a-chip devices allow scientists to model diseases and mechanisms such as the passage of therapeutic antibodies across the BBB. Discover the latest research on BBB chips here.

Related Papers

Proceedings of the National Academy of Sciences of the United States of America
Silke MetzUlrich Brinkmann
European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V
Kapil GadkarSaroja Ramanujan
© 2022 Meta ULC. All rights reserved