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Novel antibodies detect additional α-synuclein pathology in synucleinopathies: potential development for immunotherapy.
Alzheimers Res Ther. 2020 11 30; 12(1):159.AR

Abstract

BACKGROUND

Alpha-synuclein (α-Syn) aggregation is the primary characteristic of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Immunotherapy targeting α-Syn has shown promising results in animal models of the disease. This study investigates the target specificity of three different active vaccines for pathological α-Syn aggregates found in human brain tissue from synucleinopathies.

METHODS

Guinea pigs were immunised with 3 vaccines developed by United Neuroscience, and IgG fractions purified from the resulting immune sera (IGG-1, IGG-2 or IGG-3) were used to perform immunohistochemical staining of human cases of PD, DLB and MSA. The resulting immunoreactivity was compared to a commercially available α-Syn antibody from Novacastra (NOV) commonly used for diagnostic purposes. Images were captured from the substantia nigra (SN), temporal lobe, internal capsule, insular cortex and putamen and quantified for the percentage area with α-Syn immunoreactivity. Lewy bodies (LB) and Lewy neurites (LN) were further analysed in PD and DLB cases.

RESULTS

Vaccine-generated antibodies detected more α-Syn pathology compared to NOV. The levels of α-Syn immunoreactivity varied between brain region and disease type with IGG-3 recognising the highest levels of α-Syn in most cases and in all brain regions that are affected early in disease progression. IGG-3 had a high recognition for glial inclusions found in MSA which are known to have a more compact conformation. Slot blot analysis confirmed the specificity of IGG-3 for native oligomers and fibrillar α-Syn. Higher levels of α-Syn were recognised by IGG-2 in cortical regions, and by IGG-3 in SN of PD and DLB cases. This was due to increased immunolabelling of LNs in these brain regions suggesting that IGG-2 and IGG-3 recognised additional α-Syn pathology compared to IGG-1 and NOV. Whether the unique binding properties of the antibodies produced in guinea pigs will translate in the clinic remains to be addressed, which is the main limitation of this study.

CONCLUSIONS

These vaccines induce antibodies that bind α-Syn oligomers and aggregates in the human brain and specifically support the choice of the vaccine generating IGG-3 (i.e. UB-312) as a candidate for clinical trials for synucleinopathies.

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Authors+Show Affiliations

Nimmo JT
Clinical Neurosciences. Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
Verma A
United Neuroscience, Dublin, Republic of Ireland.
Dodart JC
United Neuroscience, Dublin, Republic of Ireland.
Wang CY
United Neuroscience, Dublin, Republic of Ireland.
Savistchenko J
Institute Francois Jacob (MIRCen), CEA and Laboratory of Neurodegenerative Diseases, CNRS, Paris, France.
Melki R
Institute Francois Jacob (MIRCen), CEA and Laboratory of Neurodegenerative Diseases, CNRS, Paris, France.
Carare RO
Clinical Neurosciences. Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
Nicoll JAR
Clinical Neurosciences. Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK. J.Nicoll@soton.ac.uk.

MeSH

AnimalsBrainGuinea PigsImmunotherapyLewy Body DiseaseMultiple System AtrophyParkinson DiseaseSynucleinopathiesalpha-Synuclein

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33256825

Citation

Nimmo, Jacqui T., et al. "Novel Antibodies Detect Additional Α-synuclein Pathology in Synucleinopathies: Potential Development for Immunotherapy." Alzheimer's Research & Therapy, vol. 12, no. 1, 2020, p. 159.
Nimmo JT, Verma A, Dodart JC, et al. Novel antibodies detect additional α-synuclein pathology in synucleinopathies: potential development for immunotherapy. Alzheimers Res Ther. 2020;12(1):159.
Nimmo, J. T., Verma, A., Dodart, J. C., Wang, C. Y., Savistchenko, J., Melki, R., Carare, R. O., & Nicoll, J. A. R. (2020). Novel antibodies detect additional α-synuclein pathology in synucleinopathies: potential development for immunotherapy. Alzheimer's Research & Therapy, 12(1), 159. https://doi.org/10.1186/s13195-020-00727-x
Nimmo JT, et al. Novel Antibodies Detect Additional Α-synuclein Pathology in Synucleinopathies: Potential Development for Immunotherapy. Alzheimers Res Ther. 2020 11 30;12(1):159. PubMed PMID: 33256825.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel antibodies detect additional α-synuclein pathology in synucleinopathies: potential development for immunotherapy. AU - Nimmo,Jacqui T, AU - Verma,Ajay, AU - Dodart,Jean-Cosme, AU - Wang,Chang Yi, AU - Savistchenko,Jimmy, AU - Melki,Ronald, AU - Carare,Roxana O, AU - Nicoll,James A R, Y1 - 2020/11/30/ PY - 2020/07/30/received PY - 2020/11/13/accepted PY - 2020/12/1/entrez PY - 2020/12/2/pubmed PY - 2021/6/25/medline KW - Dementia with Lewy bodies KW - Immunotherapy KW - Multiple system atrophy KW - Parkinson’s disease KW - Pathology KW - Synucleinopathies SP - 159 EP - 159 JF - Alzheimer's research & therapy JO - Alzheimers Res Ther VL - 12 IS - 1 N2 - BACKGROUND: Alpha-synuclein (α-Syn) aggregation is the primary characteristic of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Immunotherapy targeting α-Syn has shown promising results in animal models of the disease. This study investigates the target specificity of three different active vaccines for pathological α-Syn aggregates found in human brain tissue from synucleinopathies. METHODS: Guinea pigs were immunised with 3 vaccines developed by United Neuroscience, and IgG fractions purified from the resulting immune sera (IGG-1, IGG-2 or IGG-3) were used to perform immunohistochemical staining of human cases of PD, DLB and MSA. The resulting immunoreactivity was compared to a commercially available α-Syn antibody from Novacastra (NOV) commonly used for diagnostic purposes. Images were captured from the substantia nigra (SN), temporal lobe, internal capsule, insular cortex and putamen and quantified for the percentage area with α-Syn immunoreactivity. Lewy bodies (LB) and Lewy neurites (LN) were further analysed in PD and DLB cases. RESULTS: Vaccine-generated antibodies detected more α-Syn pathology compared to NOV. The levels of α-Syn immunoreactivity varied between brain region and disease type with IGG-3 recognising the highest levels of α-Syn in most cases and in all brain regions that are affected early in disease progression. IGG-3 had a high recognition for glial inclusions found in MSA which are known to have a more compact conformation. Slot blot analysis confirmed the specificity of IGG-3 for native oligomers and fibrillar α-Syn. Higher levels of α-Syn were recognised by IGG-2 in cortical regions, and by IGG-3 in SN of PD and DLB cases. This was due to increased immunolabelling of LNs in these brain regions suggesting that IGG-2 and IGG-3 recognised additional α-Syn pathology compared to IGG-1 and NOV. Whether the unique binding properties of the antibodies produced in guinea pigs will translate in the clinic remains to be addressed, which is the main limitation of this study. CONCLUSIONS: These vaccines induce antibodies that bind α-Syn oligomers and aggregates in the human brain and specifically support the choice of the vaccine generating IGG-3 (i.e. UB-312) as a candidate for clinical trials for synucleinopathies. SN - 1758-9193 UR - https://www.unboundmedicine.com/medline/citation/33256825/Novel_antibodies_detect_additional_α_synuclein_pathology_in_synucleinopathies:_potential_development_for_immunotherapy_ DB - PRIME DP - Unbound Medicine ER -