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Relationship Between Therapeutic Activity and Preferential Targeting of Toxic Soluble Aggregates by Amyloid-Beta-Directed Antibodies
Kaplan JM, Gibbs E, Coutts J, Zhao B, Mackenzie I, Cashman NR.. bioRxiv, 2024-04-25
Topic: Amyloid, tau and blood-test diagnosis
ABSTRACT Background Amyloid-beta (Aβ)-directed antibodies tested clinically for therapeutic activity against Alzheimer’s disease (AD) have shown varying degrees of efficacy. Although all of these antibodies target the Aβ peptide, their binding profile to different molecular species of Aβ differs and may underlie the observed variability in clinical outcomes. Objective Explore the relationship between targeting of soluble toxic Aβ species and therapeutic efficacy. Methods Surface plasmon resonance (SPR) was used to conduct a side-by-side comparison of the binding of various Aβ-directed antibodies to monomers and soluble Aβ oligomers from AD brains. Immunohistochemistry was performed to assess reactivity with plaque. Preclinical activity was assessed in human amyloid precursor protein (APP) transgenic mouse models of AD. Results Non-selective, pan-Aβ reactive antibodies such as crenezumab and gantenerumab, which have failed to produce a clinical benefit, bound all forms of Aβ tested. In a competition assay, these antibodies lost the ability to bind toxic AD brain oligomers when exposed to monomers. Aggregate-selective antibodies such as aducanumab, lecanemab and donanemab, showed reduced monomer binding and a greater ability to withstand monomer competition which correlated with their reported inhibition of cognitive decline. Of the antibodies in earlier stages of clinical testing, ACU193 and PMN310 displayed the greatest ability to retain binding to toxic AD brain oligomers while PRX h2731 was highly susceptible to monomer competition. Plaque binding was observed with all aggregate-reactive antibodies with the exception of PMN310, which was strictly selective for soluble oligomers. Targeting of oligomers by PMN310 protected cognition and was not associated with microhemorrhages in mouse models of AD. Conclusions Overall, these results suggest that selectivity for soluble toxic Aβ oligomers may be a driver of clinical efficacy, with a potentially reduced risk of ARIA if engagement with plaque is minimized.
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APA 7th
Kaplan, J. M., Gibbs, E., Coutts, J., Zhao, B., Mackenzie, I., & Cashman, N. R. (2024). Relationship Between Therapeutic Activity and Preferential Targeting of Toxic Soluble Aggregates by Amyloid-Beta-Directed Antibodies. bioRxiv. https://doi.org/10.1101/2024.04.20.590412
Vancouver
Kaplan JM, Gibbs E, Coutts J, Zhao B, Mackenzie I, Cashman NR. Relationship Between Therapeutic Activity and Preferential Targeting of Toxic Soluble Aggregates by Amyloid-Beta-Directed Antibodies. bioRxiv. 2024. doi:10.1101/2024.04.20.590412.
BibTeX
@article{kaplan2024-49f0b338,
author = {Kaplan, J. M. and Gibbs, E. and Coutts, J. and Zhao, B. and Mackenzie, I. and Cashman, N. R.},
title = {{Relationship Between Therapeutic Activity and Preferential Targeting of Toxic Soluble Aggregates by Amyloid-Beta-Directed Antibodies}},
journal = {bioRxiv},
year = {2024},
doi = {10.1101/2024.04.20.590412},
url = {https://doi.org/10.1101/2024.04.20.590412}
}
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Key findings
- Results Non-selective, pan-Aβ reactive antibodies such as crenezumab and gantenerumab, which have failed to produce a clinical benefit, bound all forms of Aβ tested.
- Targeting of oligomers by PMN310 protected cognition and was not associated with microhemorrhages in mouse models of AD.
- Conclusions Overall, these results suggest that selectivity for soluble toxic Aβ oligomers may be a driver of clinical efficacy, with a potentially reduced risk of ARIA if engagement with plaque is minimized.
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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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