Transcytosis of payloads that are non-covalently complexed to bispecific antibodies across the hCMEC/D3 blood-brain barrier model
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Daniela Schmid
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.
Acknowledgements
We thank Heike Seul and Martina Wagner for excellent support and contributions. D.S. and A.B. are supported by the Roche Postdoc Fund (RPF)/Targeted Therapies.
Conflict of interest statement: The authors are employees of Roche Pharma Research and Early Development. Roche is interested in targeted therapies.
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Supplemental Material:
The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2017-0311).
©2018 Walter de Gruyter GmbH, Berlin/Boston
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Articles in the same Issue
- Frontmatter
- Highlight Issue ‘Molecular Basis of Life 2017’
- HIGHLIGHT: GBM Fall Meeting “Molecular Basis of Life 2017”
- Neuronal RNP granules: from physiological to pathological assemblies
- Regulation of LRRK2: insights from structural and biochemical analysis
- The role of (auto)-phosphorylation in the complex activation mechanism of LRRK2
- Oncogenic BRAFV600E drives expression of MGL ligands in the colorectal cancer cell line HT29 through N-acetylgalactosamine-transferase 3
- Hypoxia and serum deprivation induces glycan alterations in triple negative breast cancer cells
- Targeting autophagy for the treatment of cancer
- From molecules to patients: exploring the therapeutic role of soluble guanylate cyclase stimulators
- DNA-encoded libraries – an efficient small molecule discovery technology for the biomedical sciences
- Transcytosis of payloads that are non-covalently complexed to bispecific antibodies across the hCMEC/D3 blood-brain barrier model
- Mitochondrial contributions to neuronal development and function
- Intracellular communication between lipid droplets and peroxisomes: the Janus face of PEX19
- Protein crystallization in living cells
- Synthetic DNA filaments: from design to applications
- Spectroscopic characterization of the Co-substituted C-terminal domain of rubredoxin-2
- Twitch or swim: towards the understanding of prokaryotic motion based on the type IV pilus blueprint
