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Anti-pyroglutamate-3 Aβ immunotherapy engages microglia and inhibits amyloid accumulation in transgenic mouse models of Aβ amyloidosis
Fan Liao, María Calvo-Rodríguez, Meha Chhaya, Julian P. Sefrin, Erik I. Charych, Mario Mezler, Diana Clausznitzer, Emily J. McGlame et al.. Acta Neuropathologica, 2025-06-02
Topic: Brain proteins, microglia and lab models
Alzheimer disease (AD) is the most common form of dementia affecting more than 6 million people in the United States. Currently, 3 monospecific antibodies targeting different Amyloid β (Aβ) species have been approved by the US FDA as disease modifying therapeutics for treatment in early AD patients with amyloid pathology. ABBV-916 is a clinical stage human IgG1 monoclonal antibody which binds to N-terminal truncated, pyroglutamate-modified at amino acid position 3, Aβ (Aβ pE3 ). The current study characterized ABBV-916 using human tissue samples and amyloid precursor protein (APP) transgenic mice. ABBV-916 selectively bound to recombinant Aβ pE3-42 fibrils and native amyloid plaques in unfixed AD brain tissue but did not bind targets in human CSF. ABBV-916 significantly reduced dense plaques from brain tissue that were co-cultured with hiPSC-derived phagocytes. In APPPS1-21 mice, ABBV‑916 bound plaques in a dose-dependent manner after a single intravenous injection. In addition, three months of weekly administration of ABBV-916 murine surrogate antibody significantly decreased amyloid plaques in APPPS1-21 mice. In vivo two-photon imaging revealed that the murine version of ABBV-916 inhibited the growth of the plaques in APPPS1-21 mice. ABBV-916 murine surrogate antibody recruited microglia to plaques within 24-48 hours after a single intraperitoneal injection in Cx3cr1-tdTomato/APPPS1-21 mice. Importantly, in contrast to a positive control antibody, ABBV‑916 murine precursor antibody did not cause microhemorrhage in aged APPPS1-21 mice. Taken together, our results suggest that ABBV-916 is a promising drug candidate. Clinical testing is on-going to evaluate the plaque removal and safety profiles of ABBV-916 in AD patients.
Key findings
- ABBV-916 significantly reduced dense plaques from brain tissue that were co-cultured with hiPSC-derived phagocytes.
- In addition, three months of weekly administration of ABBV-916 murine surrogate antibody significantly decreased amyloid plaques in APPPS1-21 mice.
- In vivo two-photon imaging revealed that the murine version of ABBV-916 inhibited the growth of the plaques in APPPS1-21 mice.
- Taken together, our results suggest that ABBV-916 is a promising drug candidate.
Why it matters
In human tissue samples and APP transgenic mice, the antibody ABBV-916 bound to a specific form of amyloid beta, reduced dense plaques, decreased amyloid plaques after three months of weekly administration, and inhibited plaque growth. These results are from laboratory and animal work, and the authors describe ABBV-916 as a promising drug candidate rather than a proven treatment.
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Study details
- Evidence strengthLow
How this study scored 41/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Acta Neuropathologica) |
| Journal's citation record | 3 / 4 | Acta Neuropathologica: journal h-index 287 (OpenAlex, 2026-10-29) |
| 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 | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — 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 | Laboratory or animal study (title names “transgenic”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 6 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 3.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 6 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Eric H. Karran: h-index 41 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | AbbVie (United States): institution h-index 443 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 2 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40455292) |
| Free to read | 2 / 2 | Free to read |
| Total | 41 / 100 | — |
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Read the original
- DOI: 10.1007/s00401-025-02892-5
- PubMed: 40455292
- Original source →
- Free full text: Acta Neuropathologica →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Liao, F., Calvo-Rodríguez, M., Chhaya, M., Sefrin, J. P., Charych, E. I., Mezler, M., et al. (2025). Anti-pyroglutamate-3 Aβ immunotherapy engages microglia and inhibits amyloid accumulation in transgenic mouse models of Aβ amyloidosis. Acta Neuropathologica. https://doi.org/10.1007/s00401-025-02892-5
Vancouver
Liao F, Calvo-Rodríguez M, Chhaya M, Sefrin JP, Charych EI, Mezler M, et al. Anti-pyroglutamate-3 Aβ immunotherapy engages microglia and inhibits amyloid accumulation in transgenic mouse models of Aβ amyloidosis. Acta Neuropathologica. 2025. doi:10.1007/s00401-025-02892-5. PMID: 40455292.
BibTeX
@article{liao2025-40455292,
author = {Liao, Fan and Calvo-Rodríguez, María and Chhaya, Meha and Sefrin, Julian P. and Charych, Erik I. and Mezler, Mario and Clausznitzer, Diana and McGlame, Emily J. and others},
title = {{Anti-pyroglutamate-3 Aβ immunotherapy engages microglia and inhibits amyloid accumulation in transgenic mouse models of Aβ amyloidosis}},
journal = {Acta Neuropathologica},
year = {2025},
doi = {10.1007/s00401-025-02892-5},
pmid = {40455292},
url = {https://doi.org/10.1007/s00401-025-02892-5}
}
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