In vivo imaging of alpha-synuclein with antibody-based PET

Roshanbin, Sahar; Xiong, Mengfei; Hultqvist, Greta; Söderberg, Linda; Zachrisson, Olof; Meier, Silvio R.; Ekmark‐Lewén, Sara; Bergström, Joakim; Ingelsson, Martin; Sehlin, Dag; Syvänen, Stina

doi:10.1016/j.neuropharm.2022.108985

Cited by 31 publications

(33 citation statements)

References 58 publications

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“…In addition to IDUA, eight other lysosomal enzymes have been re-engineered for BBB transport by enzyme fusion to the HIRMAb or the TfRMAb, as recently reviewed [709], and these are listed in Table 4. α-synuclein MAb PD [744] In the case of the nine IgG-lysosomal enzyme fusion proteins listed in Table 4, high affinity binding of the fusion protein to the insulin or transferrin receptor and high lysosomal enzyme activity was retained.…”

Section: Lysosomal Enzymesmentioning

confidence: 99%

“…This design placed the TfRMAb in a monovalent form and the AAA in a bivalent format. In a modified tetravalent BSA format, the 8D3 TfRMAb was engineered as a ScFv, which was then fused to the carboxyl terminus of each light chain (LC) of the AAA, mAb158 [796], or an α-synuclein MAb [744]. The mAb158 is the murine precursor to the BAN2401 AAA for AD [797].…”

Section: Bispecific Antibodiesmentioning

confidence: 99%

“…In summary, since the initial report of the engineering of a tetravalent BSA that targets either the insulin receptor [696] or transferrin receptor [794], at least eight different formats have been used for engineering a BBB-penetrating BSA [695,697,[740][741][742][743][744]796,798]. The antibodies range from monovalent for both arms of the BSA, to bivalent for both arms of the BSA, and to monovalent for one arm and bivalent for the other arm.…”

Section: Bispecific Antibodiesmentioning

confidence: 99%

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A Historical Review of Brain Drug Delivery

Pardridge

2022

Pharmaceutics

106

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The history of brain drug delivery is reviewed beginning with the first demonstration, in 1914, that a drug for syphilis, salvarsan, did not enter the brain, due to the presence of a blood–brain barrier (BBB). Owing to restricted transport across the BBB, FDA-approved drugs for the CNS have been generally limited to lipid-soluble small molecules. Drugs that do not cross the BBB can be re-engineered for transport on endogenous BBB carrier-mediated transport and receptor-mediated transport systems, which were identified during the 1970s–1980s. By the 1990s, a multitude of brain drug delivery technologies emerged, including trans-cranial delivery, CSF delivery, BBB disruption, lipid carriers, prodrugs, stem cells, exosomes, nanoparticles, gene therapy, and biologics. The advantages and limitations of each of these brain drug delivery technologies are critically reviewed.

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Section: Lysosomal Enzymesmentioning

confidence: 99%

Section: Bispecific Antibodiesmentioning

confidence: 99%

Section: Bispecific Antibodiesmentioning

confidence: 99%

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A Historical Review of Brain Drug Delivery

Pardridge

2022

Pharmaceutics

106

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“…We have previously expressed several αSYN antibodies in a bispecific format with a single chain variable fragment of the TfR1 antibody 8D3 [ 32 ] targeting the TfR as well as aggregated forms of αSYN, resulting in a dramatically increased brain uptake for in vivo αSYN detection in αSYN deposition model mice [ 33 ]. Here, we have used one of these antibodies, RmAbSynO2-scFv8D3, for targeting the extracellular pool of aggregated αSYN in a short-term treatment study in the L61 αSYN mouse model, following the characterization of biochemical and pharmacokinetic properties of the antibody.…”

Section: Introductionmentioning

confidence: 99%

Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody

et al. 2022

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Immunotherapy targeting aggregated alpha-synuclein (αSYN) is a promising approach for the treatment of Parkinson’s disease. However, brain penetration of antibodies is hampered by their large size. Here, RmAbSynO2-scFv8D3, a modified bispecific antibody that targets aggregated αSYN and binds to the transferrin receptor for facilitated brain uptake, was investigated to treat αSYN pathology in transgenic mice. Ex vivo analyses of the blood and brain distribution of RmAbSynO2-scFv8D3 and the unmodified variant RmAbSynO2, as well as in vivo analyses with microdialysis and PET, confirmed fast and efficient brain uptake of the bispecific format. In addition, intravenous administration was shown to be superior to intraperitoneal injections in terms of brain uptake and distribution. Next, aged female αSYN transgenic mice (L61) were administered either RmAbSynO2-scFv8D3, RmAbSynO2, or PBS intravenously three times over five days. Levels of TBS-T soluble aggregated αSYN in the brain following treatment with RmAbSynO2-scFv8D3 were decreased in the cortex and midbrain compared to RmAbSynO2 or PBS controls. Taken together, our results indicate that facilitated brain uptake of αSYN antibodies can improve treatment of αSYN pathology.

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“…Aβ is one such protein, but there are also many other proteins that form amyloid, and these proteins can therefore also be visualized by amyloid-radioligands. For example, alpha-synuclein that forms protein aggregates in the Parkinson's disease brain and transthyretin that causes amyloidosis in peripheral organs are detected by amyloid radioligands (70,71).…”

Section: Pet Imaging Of Aβ Pathology In Rodent Modelsmentioning

confidence: 99%

PET Imaging in Preclinical Anti-Aβ Drug Development

et al. 2022

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Positron emission tomography (PET), a medical imaging technique allowing for studies of the living human brain, has gained an important role in clinical trials of novel drugs against Alzheimer’s disease (AD). For example, PET data contributed to the conditional approval in 2021 of aducanumab, an antibody directed towards amyloid-beta (Aβ) aggregates, by showing a dose-dependent reduction in brain amyloid after treatment. In parallel to clinical studies, preclinical studies in animal models of Aβ pathology may also benefit from PET as a tool to detect target engagement and treatment effects of anti-Aβ drug candidates. PET is associated with a high level of translatability between species as similar, non-invasive protocols allow for longitudinal rather than cross-sectional studies and can be used both in a preclinical and clinical setting. This review focuses on the use of preclinical PET imaging in genetically modified animals that express human Aβ, and its present and potential future role in the development of drugs aimed at reducing brain Aβ levels as a therapeutic strategy to halt disease progression in AD.

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In vivo imaging of alpha-synuclein with antibody-based PET

Cited by 31 publications

References 58 publications

A Historical Review of Brain Drug Delivery

A Historical Review of Brain Drug Delivery

Reduction of αSYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody

PET Imaging in Preclinical Anti-Aβ Drug Development

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