Enhanced delivery of antibodies across the blood-brain barrier via TEMs with inherent receptor-mediated phagocytosis.
Alzheimer's disease
CD98
Pre-clinical research
TfR
antibody exposure in brain
blood-brain barrier
brain metastasis
her2
phagocytosis
receptor-mediated transcytosis
tau
Journal
Med (New York, N.Y.)
ISSN: 2666-6340
Titre abrégé: Med
Pays: United States
ID NLM: 101769215
Informations de publication
Date de publication:
09 Dec 2022
09 Dec 2022
Historique:
received:
28
10
2021
revised:
28
06
2022
accepted:
22
09
2022
pubmed:
19
10
2022
medline:
15
12
2022
entrez:
18
10
2022
Statut:
ppublish
Résumé
The near impermeability of the blood-brain barrier (BBB) and the unique neuroimmune environment of the CNS prevents the effective use of antibodies in neurological diseases. Delivery of biotherapeutics to the brain can be enabled through receptor-mediated transcytosis via proteins such as the transferrin receptor, although limitations such as the ability to use Fc-mediated effector function to clear pathogenic targets can introduce safety liabilities. Hence, novel delivery approaches with alternative clearance mechanisms are warranted. Binders that optimized transport across the BBB, known as transcytosis-enabling modules (TEMs), were identified using a combination of antibody discovery techniques and pharmacokinetic analyses. Functional activity of TEMs were subsequently evaluated by imaging for the ability of myeloid cells to phagocytose target proteins and cells. We demonstrated significantly enhanced brain exposure of therapeutic antibodies using optimal transferrin receptor or CD98 TEMs. We found that these modules also mediated efficient clearance of tau aggregates and HER2+ tumor cells via a non-classical phagocytosis mechanism through direct engagement of myeloid cells. This mode of clearance potentially avoids the known drawbacks of FcγR-mediated antibody mechanisms in the brain such as the neurotoxic release of proinflammatory cytokines and immune cell exhaustion. Our study reports a new brain delivery platform that harnesses receptor-mediated transcytosis to maximize brain uptake and uses a non-classical phagocytosis mechanism to efficiently clear pathologic proteins and cells. We believe these findings will transform therapeutic approaches to treat CNS diseases. This research was funded by Janssen, Pharmaceutical Companies of Johnson & Johnson.
Sections du résumé
BACKGROUND
BACKGROUND
The near impermeability of the blood-brain barrier (BBB) and the unique neuroimmune environment of the CNS prevents the effective use of antibodies in neurological diseases. Delivery of biotherapeutics to the brain can be enabled through receptor-mediated transcytosis via proteins such as the transferrin receptor, although limitations such as the ability to use Fc-mediated effector function to clear pathogenic targets can introduce safety liabilities. Hence, novel delivery approaches with alternative clearance mechanisms are warranted.
METHODS
METHODS
Binders that optimized transport across the BBB, known as transcytosis-enabling modules (TEMs), were identified using a combination of antibody discovery techniques and pharmacokinetic analyses. Functional activity of TEMs were subsequently evaluated by imaging for the ability of myeloid cells to phagocytose target proteins and cells.
FINDINGS
RESULTS
We demonstrated significantly enhanced brain exposure of therapeutic antibodies using optimal transferrin receptor or CD98 TEMs. We found that these modules also mediated efficient clearance of tau aggregates and HER2+ tumor cells via a non-classical phagocytosis mechanism through direct engagement of myeloid cells. This mode of clearance potentially avoids the known drawbacks of FcγR-mediated antibody mechanisms in the brain such as the neurotoxic release of proinflammatory cytokines and immune cell exhaustion.
CONCLUSIONS
CONCLUSIONS
Our study reports a new brain delivery platform that harnesses receptor-mediated transcytosis to maximize brain uptake and uses a non-classical phagocytosis mechanism to efficiently clear pathologic proteins and cells. We believe these findings will transform therapeutic approaches to treat CNS diseases.
FUNDING
BACKGROUND
This research was funded by Janssen, Pharmaceutical Companies of Johnson & Johnson.
Identifiants
pubmed: 36257298
pii: S2666-6340(22)00408-1
doi: 10.1016/j.medj.2022.09.007
pii:
doi:
Substances chimiques
Receptors, Transferrin
0
Antibodies
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
860-882.e15Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests All authors are employees of and have a financial interest in Johnson & Johnson, the parent company of Janssen Pharmaceuticals LLC.