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Engineering anti-amyloid antibodies with transferrin receptor targeting improves brain biodistribution and mitigates ARIA
Pizzo ME, Plowey ED, Khoury N, Kwan W, Abettan J, DeVos SL, Discenza CB, Earr T et al.. bioRxiv, 2024-07-26
Topic: Amyloid, tau and blood-test diagnosis
Although the first generation of immunotherapies for Alzheimer’s disease (AD) are now clinically approved, amyloid-related imaging abnormalities (ARIA) remain a major safety problem for this class of drugs. Here, we report an antibody transport vehicle (ATV) targeting the transferrin receptor (TfR) for brain delivery of amyloid beta (Aý) antibodies that significantly reduced ARIA-like lesions and improved plaque target engagement in a mouse model of amyloid deposition. Asymmetrical Fc mutations (ATV cisLALA ) allowed the molecule to selectively retain effector function only when bound to Aý while mitigating TfR-related hematology liabilities. Mice treated with ATV cisLALA :Aý exhibited broad brain parenchymal antibody distribution; in contrast, anti-Aý IgG was highly enriched at arterial perivascular spaces where vascular Aý localizes and likely plays a role in induction of ARIA. Importantly, ATV cisLALA : Aý almost completely eliminated ARIA-like lesions and vascular inflammation associated with anti-Aý treatment. Taken together, ATV cisLALA has the potential to significantly improve both safety and efficacy of Aý immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.
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APA 7th
Pizzo, M. E., Plowey, E. D., Khoury, N., Kwan, W., Abettan, J., DeVos, S. L., et al. (2024). Engineering anti-amyloid antibodies with transferrin receptor targeting improves brain biodistribution and mitigates ARIA. bioRxiv. https://doi.org/10.1101/2024.07.26.604664
Vancouver
Pizzo ME, Plowey ED, Khoury N, Kwan W, Abettan J, DeVos SL, et al. Engineering anti-amyloid antibodies with transferrin receptor targeting improves brain biodistribution and mitigates ARIA. bioRxiv. 2024. doi:10.1101/2024.07.26.604664.
BibTeX
@article{pizzo2024-32f7f831,
author = {Pizzo, M. E. and Plowey, E. D. and Khoury, N. and Kwan, W. and Abettan, J. and DeVos, S. L. and Discenza, C. B. and Earr, T. and others},
title = {{Engineering anti-amyloid antibodies with transferrin receptor targeting improves brain biodistribution and mitigates ARIA}},
journal = {bioRxiv},
year = {2024},
doi = {10.1101/2024.07.26.604664},
url = {https://doi.org/10.1101/2024.07.26.604664}
}
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Key findings
- Here, we report an antibody transport vehicle (ATV) targeting the transferrin receptor (TfR) for brain delivery of amyloid beta (Aý) antibodies that significantly reduced ARIA-like lesions and improved plaque target engagement in a mouse model of amyloid deposition.
- Importantly, ATV cisLALA : Aý almost completely eliminated ARIA-like lesions and vascular inflammation associated with anti-Aý treatment.
- Taken together, ATV cisLALA has the potential to significantly improve both safety and efficacy of Aý immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 19 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 12 of the 62 points we could judge it on, which is 19 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 4 / 5 | 2024 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 12 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 12 of the 62 points we could judge it on is 19 out of 100. |
| Total | 19 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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