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P4–285: SAR228810: An antiprotofibrillar beta‐amyloid antibody designed to reduce risk of amyloid‐related imaging abnormalities (ARIA)
Laurent Pradier, Caroline Cohen, Veronique Blanchard, Thomas Debeir, Pascal Barnéoud, Thierry Canton, Jean Ménager, Andrees Bohme et al.. Alzheimer s & Dementia, 2013-07-01
Topic: Inflammation, microglia and astrocytes
SAR228810 is a humanized monoclonal antibody (mAb) binding specifically to soluble protofibrillar and fibrillar forms of Aβ peptide. Compared to other anti-A β mAb, SAR228810 does not neutralize soluble Aβ monomers or low molecular weight Aβ complexes. Accordingly, SAR228810 binds to congophilic amyloid plaques (present only in Alzheimer's Disease (AD) patients) and not to Aβ diffuse deposits (present in most aged cases). SAR228810 was designed with an engineered immunoglobulin G4 framework that reduces risk of ARIA. The IgG1 framework of other anti-amyloid mAb carries the risk of Fc g receptor-mediated overactivation of microglial cells, which may contribute to an inappropriate proinflammatory response leading to vasogenic edema and cerebral microhemorrhage. Proinflammatory effects might also compromise any potential clinical improvements that these drugs could bring. SAR228810 has very low binding affinity to human activating FcγRs and no binding to C1q, demonstrating very low effector functions. SAR228810 derives from a parent murine mAb, SAR255952, with very low effector functions. SAR255952 and SAR228810 were administered weekly intraperitoneally inAPP transgenic mice (APP SL line). SAR255952 dose-dependently reduced brain Aβ accumulation and amyloid plaque formation as well as plaque-related inflammation in hippocampus. The effects of SAR255952 translated into synaptic functional improvement in ex-vivo hippocampal slices. SAR255952 showed activity from the dose of 3 mg/kg after dosing over 4 months. In agreement with its lack of binding to monomeric Aβ, SAR255952 does not lead to increase in plasma or CSF Aβ, further suggesting that SAR255952 remains unbound until it reaches its antigen in the brain (stealth antibody). The effect of the clinical candidate, SAR228810, was evaluated in the same model after induction of immunotolerance by transient depletion of CD4+ T lymphocytes. SAR228810 at 10 mg/kg/week showed the same level of efficacy as the murineSAR255952. SAR255952 (up to 50 mg/kg/week IV) did not increase brain microhemorrhages and/or microscopic changes in meningeal and cerebral arteries in old APPSL mice. Conversely, brain cortical microhemorrhages or degeneration/necrosis in meningeal and/or cerebral arteries was noted with 3D6, the murine antibody of bapineuzumab. Based on SAR228810 improved efficay/safety profile, a phase1 single and multiple dose administration clinical study in AD patientshas been initiated.
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APA 7th
Pradier, L., Cohen, C., Blanchard, V., Debeir, T., Barnéoud, P., Canton, T., et al. (2013). P4–285: SAR228810: An antiprotofibrillar beta‐amyloid antibody designed to reduce risk of amyloid‐related imaging abnormalities (ARIA). Alzheimer s & Dementia. https://doi.org/10.1016/j.jalz.2013.05.1678
Vancouver
Pradier L, Cohen C, Blanchard V, Debeir T, Barnéoud P, Canton T, et al. P4–285: SAR228810: An antiprotofibrillar beta‐amyloid antibody designed to reduce risk of amyloid‐related imaging abnormalities (ARIA). Alzheimer s & Dementia. 2013. doi:10.1016/j.jalz.2013.05.1678.
BibTeX
@article{pradier2013-c5f3311d,
author = {Pradier, Laurent and Cohen, Caroline and Blanchard, Veronique and Debeir, Thomas and Barnéoud, Pascal and Canton, Thierry and Ménager, Jean and Bohme, Andrees and others},
title = {{P4–285: SAR228810: An antiprotofibrillar beta‐amyloid antibody designed to reduce risk of amyloid‐related imaging abnormalities (ARIA)}},
journal = {Alzheimer s \& Dementia},
year = {2013},
doi = {10.1016/j.jalz.2013.05.1678},
url = {https://doi.org/10.1016/j.jalz.2013.05.1678}
}
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Key findings
- Compared to other anti-A β mAb, SAR228810 does not neutralize soluble Aβ monomers or low molecular weight Aβ complexes.
- In agreement with its lack of binding to monomeric Aβ, SAR255952 does not lead to increase in plasma or CSF Aβ, further suggesting that SAR255952 remains unbound until it reaches its antigen in the brain (stealth antibody).
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Study details
- Evidence strengthLow
How this study scored 34/100
Published in a peer-reviewed journal. 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 journal's citation record, 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 20 of the 58 points we could judge it on, which is 34 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Alzheimer s & Dementia) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 1 / 5 | 2013 — within 20 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 | 20 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 20 of the 58 points we could judge it on is 34 out of 100. |
| Total | 34 / 100 | — |
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