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Engineered antibodies: new possibilities for brain PET?

Engineered antibodies: new possibilities for brain PET?
Engineered antibodies: new possibilities for brain PET?

Almost 50 million people worldwide are affected by Alzheimer’s disease (AD), the most common neurodegenerative disorder. Development of disease-modifying therapies would benefit from reliable, non-invasive positron emission tomography (PET) biomarkers for early diagnosis, monitoring of disease progression, and assessment of therapeutic effects. Traditionally, PET ligands have been based on small molecules that, with the right properties, can penetrate the blood–brain barrier (BBB) and visualize targets in the brain. Recently a new class of PET ligands based on antibodies have emerged, mainly in applications related to cancer. While antibodies have advantages such as high specificity and affinity, their passage across the BBB is limited. Thus, to be used as brain PET ligands, antibodies need to be modified for active transport into the brain. Here, we review the development of radioligands based on antibodies for visualization of intrabrain targets. We focus on antibodies modified into a bispecific format, with the capacity to undergo transferrin receptor 1 (TfR1)-mediated transcytosis to enter the brain and access pathological proteins, e.g. amyloid-beta. A number of such antibody ligands have been developed, displaying differences in brain uptake, pharmacokinetics, and ability to bind and visualize the target in the brain of transgenic mice. Potential pathological changes related to neurodegeneration, e.g. misfolded proteins and neuroinflammation, are suggested as future targets for this novel type of radioligand. Challenges are also discussed, such as the temporal match of radionuclide half-life with the ligand’s pharmacokinetic profile and translation to human use. In conclusion, brain PET imaging using bispecific antibodies, modified for receptor-mediated transcytosis across the BBB, is a promising method for specifically visualizing molecules in the brain that are difficult to target with traditional small molecule ligands.

Alzheimer’s disease (AD), Amyloid-β (Aβ), Antibody, Blood–brain barrier (BBB), Positron emission tomography (PET), Transferrin receptor 1 (TfR1)-mediated transcytosis
1619-7070
2848-2858
Sehlin, Dag
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Syvänen, Stina
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Ballanger, Bénédicte
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Barthel, Henryk
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Bischof, Gérard N.
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Boche, Delphine
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Boecker, Hennig
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Bohn, Karl Peter
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Borghammer, Per
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Cross, Donna
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Di Monte, Donato
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Drzezga, Alexander
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Endepols, Heike
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Giehl, Kathrin
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Goedert, Michel
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Hammes, Jochen
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Herholz, Karl
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Höglinger, Günter
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Hönig, Merle
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Jessen, Frank
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Klockgether, Thomas
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Mandelkow, Eva Maria
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Maurer, Andreas
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Sabri, Osama
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Schneider, Anja
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Syvänen, Stina
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van Eimeren, Thilo
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Vasdev, Neil
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Villemagne, Victor
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Willbold, Dieter
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on behalf of the MINC faculty
Sehlin, Dag
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Syvänen, Stina
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Ballanger, Bénédicte
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Barthel, Henryk
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Bischof, Gérard N.
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Boche, Delphine
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Boecker, Hennig
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Bohn, Karl Peter
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Borghammer, Per
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Cross, Donna
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Di Monte, Donato
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Drzezga, Alexander
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Endepols, Heike
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Giehl, Kathrin
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Goedert, Michel
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Hammes, Jochen
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Hansson, Oskar
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Herholz, Karl
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Höglinger, Günter
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Hönig, Merle
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Jessen, Frank
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Klockgether, Thomas
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Lafaye, Pierre
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Lammerstma, Adriaan
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Mandelkow, Eckhard
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Mandelkow, Eva Maria
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Maurer, Andreas
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Neumaier, Bernd
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Nordberg, Agneta
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Onur, Özgur
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Reetz, Kathrin
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Rodriguez-Vietez, Elena
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Rowe, James
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Sabri, Osama
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Schneider, Anja
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Strafella, Antonio
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Syvänen, Stina
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van Eimeren, Thilo
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Vasdev, Neil
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Villemagne, Victor
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Willbold, Dieter
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Sehlin, Dag and Syvänen, Stina , on behalf of the MINC faculty (2019) Engineered antibodies: new possibilities for brain PET? European Journal of Nuclear Medicine and Molecular Imaging, 46 (13), 2848-2858. (doi:10.1007/s00259-019-04426-0).

Record type: Review

Abstract

Almost 50 million people worldwide are affected by Alzheimer’s disease (AD), the most common neurodegenerative disorder. Development of disease-modifying therapies would benefit from reliable, non-invasive positron emission tomography (PET) biomarkers for early diagnosis, monitoring of disease progression, and assessment of therapeutic effects. Traditionally, PET ligands have been based on small molecules that, with the right properties, can penetrate the blood–brain barrier (BBB) and visualize targets in the brain. Recently a new class of PET ligands based on antibodies have emerged, mainly in applications related to cancer. While antibodies have advantages such as high specificity and affinity, their passage across the BBB is limited. Thus, to be used as brain PET ligands, antibodies need to be modified for active transport into the brain. Here, we review the development of radioligands based on antibodies for visualization of intrabrain targets. We focus on antibodies modified into a bispecific format, with the capacity to undergo transferrin receptor 1 (TfR1)-mediated transcytosis to enter the brain and access pathological proteins, e.g. amyloid-beta. A number of such antibody ligands have been developed, displaying differences in brain uptake, pharmacokinetics, and ability to bind and visualize the target in the brain of transgenic mice. Potential pathological changes related to neurodegeneration, e.g. misfolded proteins and neuroinflammation, are suggested as future targets for this novel type of radioligand. Challenges are also discussed, such as the temporal match of radionuclide half-life with the ligand’s pharmacokinetic profile and translation to human use. In conclusion, brain PET imaging using bispecific antibodies, modified for receptor-mediated transcytosis across the BBB, is a promising method for specifically visualizing molecules in the brain that are difficult to target with traditional small molecule ligands.

Text
Sehlin-Syvänen2019_Article_EngineeredAntibodiesNewPossibi - Version of Record
Available under License Creative Commons Attribution.
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More information

Accepted/In Press date: 3 July 2019
e-pub ahead of print date: 24 July 2019
Published date: 1 December 2019
Keywords: Alzheimer’s disease (AD), Amyloid-β (Aβ), Antibody, Blood–brain barrier (BBB), Positron emission tomography (PET), Transferrin receptor 1 (TfR1)-mediated transcytosis

Identifiers

Local EPrints ID: 438508
URI: http://eprints.soton.ac.uk/id/eprint/438508
ISSN: 1619-7070
PURE UUID: a7aff956-c76a-403b-bbff-1d97f26b4000
ORCID for Delphine Boche: ORCID iD orcid.org/0000-0002-5884-130X

Catalogue record

Date deposited: 11 Mar 2020 17:33
Last modified: 26 Nov 2021 02:43

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Contributors

Author: Dag Sehlin
Author: Stina Syvänen
Author: Bénédicte Ballanger
Author: Henryk Barthel
Author: Gérard N. Bischof
Author: Delphine Boche ORCID iD
Author: Hennig Boecker
Author: Karl Peter Bohn
Author: Per Borghammer
Author: Donna Cross
Author: Donato Di Monte
Author: Alexander Drzezga
Author: Heike Endepols
Author: Kathrin Giehl
Author: Michel Goedert
Author: Jochen Hammes
Author: Oskar Hansson
Author: Karl Herholz
Author: Günter Höglinger
Author: Merle Hönig
Author: Frank Jessen
Author: Thomas Klockgether
Author: Pierre Lafaye
Author: Adriaan Lammerstma
Author: Eckhard Mandelkow
Author: Eva Maria Mandelkow
Author: Andreas Maurer
Author: Brit Mollenhauer
Author: Bernd Neumaier
Author: Agneta Nordberg
Author: Özgur Onur
Author: Kathrin Reetz
Author: Elena Rodriguez-Vietez
Author: Axel Rominger
Author: James Rowe
Author: Osama Sabri
Author: Anja Schneider
Author: Antonio Strafella
Author: Stina Syvänen
Author: Thilo van Eimeren
Author: Neil Vasdev
Author: Victor Villemagne
Author: Dieter Willbold
Corporate Author: on behalf of the MINC faculty

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