High detection sensitivity with antibody-based PET radioligand for amyloid beta in brain

Fang, Xiaotian T.; Hultqvist, Greta; Meier, Silvio R.; Antoni, Gunnar; Sehlin, Dag; Syvänen, Stina

doi:10.1016/j.neuroimage.2018.10.011

Cited by 59 publications

(70 citation statements)

References 26 publications

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“…Whether this difference is dependent of the fusion protein formats or the size of the cargo was not studied here, but other TfR1 binders, such as the well-studied mTfR1 antibody 8D3, do not seem to be much affected by cargo size; we have previously shown that 8D3 can efficiently shuttle both a full size IgG 9 and a 28 kDa single chain antibody fragment (scFv). 29 Additional factors, such as orientation of the VNAR on IgG, valency of TfR1 binding as well as IgG glycosylation may also play an important role.…”

Section: Discussionmentioning

confidence: 99%

Brain delivery of biologics using a cross‐species reactive transferrin receptor 1 VNAR shuttle

Sehlin

Stocki²,

Gustavsson

et al. 2020

FASEB j.

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Transferrin receptor 1 (TfR1) mediated transcytosis is an attractive strategy to enhance brain uptake of protein drugs, but translation remains a challenge. Here, a single domain shark antibody VNAR fragment (TXB2) with similar affinity to murine and human TfR1 was used to shuttle protein cargo into the brain. TXB2 was fused to a human IgG1 Fc domain (hFc) or to the amyloid‐β (Aβ) antibody bapineuzumab (Bapi). TXB2‐hFc displayed 20‐fold higher brain concentrations compared with a control VNAR‐hFc at 18 hours post‐injection in wt mice. At the same time point, brain concentrations of Bapi‐TXB2 was threefold higher than Bapi. In transgenic mice overexpressing human Aβ, the brain‐to‐blood concentration ratio increased with time due to interaction with intracerebral Aβ deposits. The relatively stable threefold difference between Bapi‐TXB2 and Bapi was observed for up to 6 days after injection. PET imaging and ex vivo autoradiography revealed more parenchymal distribution of Bapi‐TXB2 compared with Bapi. In conclusion, the TXB2 VNAR shuttle markedly increased brain uptake of protein cargo and increased brain concentrations of the Aβ binding antibody Bapi.

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Section: Discussionmentioning

confidence: 99%

Brain delivery of biologics using a cross‐species reactive transferrin receptor 1 VNAR shuttle

Sehlin

Stocki²,

Gustavsson

et al. 2020

FASEB j.

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“…These studies showed that a tribody, based on two scFv158 and a Fab-8D3 [40], with a size of approximately 110 kDa (Fig. 5c), and a tandem-scFv based on an scFv3D6 fused to an scFv8D3 [41], with a size of approximately 58 kDa (Fig. 5d), were more rapidly cleared from blood than the larger 210 kDa [ 124 I]RmAb158-scfv8D3, and allowed for imaging of Aβ pathology at an earlier time point after administration (Fig.…”

Section: Antibody-based Radioligands For Imaging Of Aβmentioning

confidence: 99%

“…PET imaging with bispecific antibodies has been performed primarily in two AD mouse models, tg-ArcSwe and tg-Swe [37, 38, 41], expressing human APP with both the Arctic (E693G) and Swedish (KM670/671NL) amyloid precursor protein (APP) mutations or the Swedish mutation alone. Tg-ArcSwe is characterized by early formation of soluble Aβ aggregates and subsequent formation of dense core plaques, closely mimicking plaques formed in the human brain, while tg-Swe has a late-onset pathology, rapid progression, and less dense plaques [42].…”

Section: Antibody-based Radioligands For Imaging Of Aβmentioning

confidence: 99%

“…When quantified as standardized uptake value ratio (SUVR), using cerebellum as reference region, [ 124 I]8D3-F(ab’) 2 -h158 showed earlier and better discrimination between transgenic and WT mice compared with [ 11 C]PIB (Fig. 6b) [37, 41]. Interestingly, tg-ArcSwe mice, showing more dense plaque pathology, had higher [ 11 C]PIB retention than Swe mice, which instead gave a higher signal with the antibody ligand.…”

Section: Antibody-based Radioligands For Imaging Of Aβmentioning

confidence: 99%

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Engineered antibodies: new possibilities for brain PET?

Sehlin

Syvänen

Ballanger³

et al. 2019

Eur J Nucl Med Mol Imaging

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Almost 50 million people worldwide are affected by Alzheimer's disease (AD), the most common neurodegenerative disorder. Development of disease-modifying therapies would benefit from reliable, non-invasive positron emission tomography (PET) biomarkers for early diagnosis, monitoring of disease progression, and assessment of therapeutic effects. Traditionally, PET ligands have been based on small molecules that, with the right properties, can penetrate the blood-brain barrier (BBB) and visualize targets in the brain. Recently a new class of PET ligands based on antibodies have emerged, mainly in applications related to cancer. While antibodies have advantages such as high specificity and affinity, their passage across the BBB is limited. Thus, to be used as brain PET ligands, antibodies need to be modified for active transport into the brain. Here, we review the development of radioligands based on antibodies for visualization of intrabrain targets. We focus on antibodies modified into a bispecific format, with the capacity to undergo transferrin receptor 1 (TfR1)-mediated transcytosis to enter the brain and access pathological proteins, e.g. amyloid-beta. A number of such antibody ligands have been developed, displaying differences in brain uptake, pharmacokinetics, and ability to bind and visualize the target in the brain of transgenic mice. Potential pathological changes related to neurodegeneration, e.g. misfolded proteins and neuroinflammation, are suggested as future targets for this novel type of radioligand. Challenges are also discussed, such as the temporal match of radionuclide half-life with the ligand's pharmacokinetic profile and translation to human use. In conclusion, brain PET imaging using bispecific antibodies, modified for receptor-mediated transcytosis across the BBB, is a promising method for specifically visualizing molecules in the brain that are difficult to target with traditional small molecule ligands.

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“…Taken together, our findings suggest scFvs may be a viable therapeutic option for the treatment of synucleinopathies. By linking to tracer compounds scFvs can also be developed as attractive target to be used in in vivo imaging applications as diagnostic tool towards synucleinopathies 23,63,67,68 . Future studies should aim to analyze the effect of the scFvs in other in vivo and animal models of synucleinopathies, which will provide important insights into safety and tolerability in intact organisms, in addition to the α-syn aggregation blocking properties of this class of scFv.…”

Section: Discussionmentioning

confidence: 99%

Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity

Gupta

Salim

Hmila

et al. 2020

Sci Rep

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Synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are characterized by pathological accumulation of α-synuclein (α-syn). Amongst the various approaches attempting to tackle the pathological features of synucleinopathies, antibodybased immunotherapy holds much promise. However, the large size of antibodies and corresponding difficulty in crossing the blood-brain barrier has limited development in this area. To overcome this issue, we engineered single-chain variable fragments (scFvs) against fibrillar α-syn, a putative diseaserelevant form of α-syn. The purified scFvs showed specific activity towards α-syn fibrils and oligomers in comparison to monomers and recognized intracellular inclusions in human post-mortem brain tissue of Lewy body disease cases, but not aged controls. In vitro studies indicated scFvs inhibit the seeding of α-syn aggregation in a time-dependent manner, decreased α-syn seed-induced toxicity in a cell model of PD, and reduced the production of insoluble α-syn phosphorylated at Ser-129 (pS129-α-syn). These results suggest that our α-syn fibril-specific scFvs recognize α-syn pathology and can inhibit the aggregation of α-syn in vitro and prevent seeding-dependent toxicity. Therefore, the scFvs described here have considerable potential to be utilized towards immunotherapy in synucleinopathies and may also have applications in ante-mortem imaging modalities. Synucleinopathies are a group of neurodegenerative disorders comprising Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) 1. PD is clinically characterized by motor symptoms of bradykinesia, unsteady gait and resting tremor that precedes cognitive impairment whilst, in contrast, DLB manifests as a cognitive disorder that often leads to motor features 2. However, despite differences in the sequence of clinical symptomatology, PD and DLB are both neuropathologically characterized by accumulations of the protein α-synuclein (α-syn) in vulnerable neurons as Lewy bodies (LBs) and in neuronal processes as Lewy neurites 3. MSA is characterized by α-syn aggregates in oligodendroglia as Papp-Lantos bodies/glial cytoplasmic inclusions 4 , though neuronal accumulations of α-syn are also observed 5. Several lines of evidence indicate that α-syn aggregation is a critical pathogenic event in the natural history of Lewy body diseases. α-Syn is the major protein component of LBs, various point mutations and/or multiplications in the α-syn gene have been described in familial PD, exogenous expression of α-syn in Drosophila and transgenic mice induce the formation of PD-like pathological phenotypes and behavior, and down-regulation of the α-syn protein reduces risk of developing PD 6-13. Although α-syn is implicated in PD risk, it is also thought to have important neuronal functions as it is a relatively abundant protein, comprising 0.5-1% of the total protein in soluble cytosolic brain fractions 14,15. Although α-syn is a soluble, monomeric, unfo...

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High detection sensitivity with antibody-based PET radioligand for amyloid beta in brain

Cited by 59 publications

References 26 publications

Brain delivery of biologics using a cross‐species reactive transferrin receptor 1 VNAR shuttle

Brain delivery of biologics using a cross‐species reactive transferrin receptor 1 VNAR shuttle

Engineered antibodies: new possibilities for brain PET?

Fibrillar form of α-synuclein-specific scFv antibody inhibits α-synuclein seeds induced aggregation and toxicity

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