The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants
Open accessAbstract
Antibodies to transferrin receptor (TfR) have potential use for therapeutic entry into the brain. We have shown that bispecific antibodies against TfR and β-secretase (BACE1 [β-amyloid cleaving enzyme-1]) traverse the blood–brain barrier (BBB) and effectively reduce brain amyloid β levels. We found that optimizing anti-TfR affinity improves brain exposure and BACE1 inhibition. Here we probe the cellular basis of this improvement and explore whether TfR antibody affinity alters the intracellular trafficking of TfR. Comparing high- and low-affinity TfR bispecific antibodies in vivo, we found that high-affinity binding to TfR caused a dose-dependent reduction of brain TfR levels. In vitro live imaging and colocalization experiments revealed that high-affinity TfR bispecific antibodies facilitated the trafficking of TfR to lysosomes and thus induced the degradation of TfR, an observation which was further confirmed in vivo. Importantly, high-affinity anti-TfR dosing induced reductions in brain TfR levels, which significantly decreased brain exposure to a second dose of low-affinity anti-TfR bispecific. Thus, high-affinity anti-TfR alters TfR trafficking, which dramatically impacts the capacity for TfR to mediate BBB transcytosis.
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Cites
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Self-citationA Therapeutic Antibody Targeting BACE1 Inhibits Amyloid-β Production in Vivo
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Terstappen, G. C., Meyer, A. H., Bell, R. D., & Zhang, W. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00139-y · Cited by 1,138
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The role of interleukin-6 signaling in nervous tissue
Rothaug, M., Becker-Pauly, C., & Rose-John, S. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.03.018 · Cited by 491
Metadata
- Authors
- Bien-Ly, N., Yu, Y. J., Bumbaca, D., Elstrott, J., Boswell, C. A., Zhang, Y., Luk, W., Lu, Y., Dennis, M. S., Weimer, R. M., Chung, I., & Watts, R. J.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2014-01-27
- Volume
- 211
- Issue
- 2
- Pages
- 233-244
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- OpenAlex
- W2100276489
- Cited by
- 353
- References
- 25
- FWCI
- 10.81
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Bien-Ly, N., Yu, Y. J., Bumbaca, D., Elstrott, J., Boswell, C. A., Zhang, Y., Luk, W., Lu, Y., Dennis, M. S., Weimer, R. M., Chung, I., & Watts, R. J. (2014). Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants. Journal of Experimental Medicine. https://doi.org/10.1084/jem.20131660
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