| 1. |
- Batist, Zachary, et al.
(författare)
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Figurations of Digital Practice, Craft, and Agency in Two Mediterranean Fieldwork Projects
- 2021
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Ingår i: Open Archaeology. - : Walter de Gruyter. - 2300-6560. ; 7:1, s. 1731-1755
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Tidskriftsartikel (refereegranskat)abstract
- Archaeological practice is increasingly enacted within pervasive and invisible digital infrastructures, tools, and services that affect how participants engage in learning and fieldwork, and how evidence, knowledge, and expertise are produced. This article discusses the collective imaginings regarding the present and future of digital archaeological practice held by researchers working in two archaeological projects in the Eastern Mediterranean, who have normalized the use of digital tools and the adoption of digital processes in their studies. It is a part of E-CURATORS, a research project investigating how archaeologists in multiple contexts and settings incorporate pervasive digital technologies in their studies. Based on an analysis of qualitative interviews, we interpret the arguments advanced by study participants on aspects of digital work, learning, and expertise. We find that, in their sayings, participants not only characterize digital tools and workflows as having positive instrumental value, but also recognize that they may severely constrain the autonomy and agency of researchers as knowledge workers through the hyper-granularization of data, the erosion of expertise, and the mechanization of work. Participants advance a notion of digital archaeology based on do-it-yourself (DIY) practice and craft to reclaim agency from the algorithmic power of digital technology and to establish fluid, positional distribution of roles and agency, and mutual validation of expertise. Operating within discourses of labour vs efficiency, and technocracy vs agency, sayings, elicited within the archaeological situated practice in the wild, become doings, echoing archaeology's anxiety in the face of pervasive digital technology.
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| 2. |
- Bonvicini, Gillian, et al.
(författare)
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Stronger affinity to Transferrin receptor enhances detection of amyloid-β pathology with bispecific antibody radioligands at a tracer dose
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- A popular method for delivering biologic therapeutics and diagnostics to the brain is by hijacking transferrin receptor (TfR)-mediated transcytosis. Moderate affinity towards TfR is beneficial for TfR-mediated brain delivery at therapeutic doses while a few studies have indicated that high TfR affinity may be more beneficial at tracer doses. With the development of antibody-based PET radioligands for neurodegenerative diseases, such as Alzheimer’s disease, a better understanding of the pharmacokinetics of TfR-binders at tracer dose is essential. Thus the aim of this study was to evaluate the effect of TfR affinity on brain uptake at a tracer dose in both wild-type (WT) mice and in a mouse model of Aβ pathology.Three different affinity variants of 8D3, produced by alanine point mutations, were selected. Bispecific antibodies were designed with knob-into-hole technology where one arm was the anti-mouse TfR antibody, 8D3, and the other arm was the anti-human Aβ antibody, bapineuzumab (Bapi). Antibody affinities were measured in an in vitro cell assay. In vivo pharmacokinetic analyses of radioiodinated bispecific antibodies and Bapi in brain, blood and peripheral organs were performed over 7 days post-injection in WT and Aβ mice.The affinities of the three bispecific antibodies to TfR were 10 nM, 20 nM and 240 nM. Independent of genotype, stronger TfR-affinity resulted in higher brain uptake. The two bispecific antibodies with stronger affinity behaved similarly and differentiated between WT and Aβ model mice at an earlier time point than the low affinity variant.This study supports the hypothesis that stronger TfR affinity yields better brain uptake at a tracer dose. With the better detection of Aβ pathology, stronger affinity to TfR is a critical feature for the design of future bispecific immunoPET radioligands for intrabrain targets using TfR-mediated transcytosis.
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| 3. |
- Schlein, Eva, et al.
(författare)
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Aβ targeting ImmunoPET : Brain pharmacokinetics comparison between a brain penetrating and a regular antibody
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Bispecific antibodies utilizing the transferrin receptor (TfR) for transport into the brain are being developed for both therapeutic and diagnostic applications. Compared with regular monospecific antibodies, the brain uptake of TfR-binding bispecific antibodies is rapid and efficient. However, due to differences in pharmacokinetic properties, it has been challenging to directly compare their brain uptake in vivo. In this study, we have studied the amyloid-β (Aβ) antibody Bapineuzumab (Bapi) and its bispecific variant Bapi-Fab8D3, which contains a fragment of the TfR-binding antibody 8D3. Both antibodies were recombinantly engineered to harbour a mutation that reduces binding to the neonatal Fc receptor (FcRn) and thus contributes to an increased clearance rate from blood.The antibodies were labelled with fluorine-18 (18F) and administered to wildtype (WT) mice, which were PET scanned for 2 h in an alternating manner to cover a period of 9 h, followed by ex vivo analyses. Next, the bispecific antibody [18F]Bapi-Fab8D3 was used for PET imaging if Aβ pathology in the AD mouse model AppNL-G-F compared with WT mice at 12 h after antibody administration. [18F]Bapi and [18F]Bapi-Fab8D3 had identical blood elimination curves in WT mice and PET data quantification demonstrated that [18F]Bapi brain concentration declined from the start and throughout the 9 h time period, while [18F]Bapi-Fab8D3 displayed a higher brain concentration, indicative of its active transport into the brain.[18F]Bapi-Fab PET imaging discriminated AppNL-G-F from WT mice already at 12 h after administration, suggesting that this novel antibody-based ligand could be used for same-day PET imaging.
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| 4. |
- Schlein, Eva, et al.
(författare)
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Reduced neonatal Fc receptor binding increases clearance and brain-to-blood ratio of a brain penetrating amyloid-β antibody
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Recent advances in the development of amyloid-β (Aβ) targeted immunotherapies for Alzheimer’s disease (AD) has highlighted the need for accurate diagnostic methods. Antibody-based positron emission tomography (PET) ligands are well suited for this purpose as they can be directed towards the same target as the therapeutic antibody. Bispecific brain penetrating antibodies are interesting for this purpose, but the slow clearance of antibodies remains a challenge for their use PET radioligands since antibody in the circulation as well as unbound antibody in the brain contribute to a non-specific background signal. Thus, a substantial time between the injection and the time of PET scanning is required to achieve an acceptable specific-to-nonspecific signal in PET. In this study, two antibody pairs were designed based on the Aβ antibody Bapineuzumab (Bapi), one regular IgG (Bapi) and one bispecific antibody with a Fab fragment of the transferrin receptor (TfR) antibody 8D3 fused to one of the heavy chains (Bapi-Fab8D3), for active TfR-mediated transport into the brain. One of the pairs was engineered to harbor a mutation in the Fc domain which reduced its binding to the neonatal Fc receptor (FcRn) and thereby increased the clearance of the antibody. Blood and brain pharmacokinetics of the antibody pairs were studied in WT mice and in the AD mouse model AppNL-G-F. The FcRn mutation substantially reduced blood half-life of both Bapi and Bapi-Fab8D3. With the high brain uptake of Bapi-Fab8D3, the brain-to-blood ratio of its FcRn mutated form was significantly higher in AppNL-G-F than WT mice already 12 h after injection and this difference increased further up to 24 h after antibody injection. Ex vivo autoradiography, used to visualize antibody distribution in the brain, showed specific antibody retention in areas with high amounts of Aβ pathology. Taken together, these results suggest that reducing FcRn binding of a full-sized bispecific antibody could drastically reduce the time from injection to imaging.
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| 5. |
- Schlein, Eva, et al.
(författare)
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Reducing neonatal Fc receptor binding enhances clearance and brain-to-blood ratio of TfR-delivered bispecific amyloid-β antibody
- 2024
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Ingår i: mAbs. - : Taylor & Francis. - 1942-0862 .- 1942-0870. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Recent development of amyloid-β (Aβ)-targeted immunotherapies for Alzheimer’s disease (AD) have highlighted the need for accurate diagnostic methods. Antibody-based positron emission tomography (PET) ligands are well suited for this purpose as they can be directed toward the same target as the therapeutic antibody. Bispecific, brain-penetrating antibodies can achieve sufficient brain concentrations, but their slow blood clearance remains a challenge, since it prolongs the time required to achieve a target-specific PET signal. Here, two antibodies were designed based on the Aβ antibody bapineuzumab (Bapi) – one monospecific IgG (Bapi) and one bispecific antibody with an antigen binding fragment (Fab) of the transferrin receptor (TfR) antibody 8D3 fused to one of the heavy chains (Bapi-Fab8D3) for active, TfR-mediated transport into the brain. A variant of each antibody was designed to harbor a mutation to the neonatal Fc receptor (FcRn) binding domain, to increase clearance. Blood and brain pharmacokinetics of radiolabeled antibodies were studied in wildtype (WT) and AD mice (AppNL-G-F). The FcRn mutation substantially reduced blood half-life of both Bapi and Bapi-Fab8D3. Bapi-Fab8D3 showed high brain uptake and the brain-to-blood ratio of its FcRn mutated form was significantly higher in AppNL-G-F mice than in WT mice 12 h after injection and increased further up to 168 h. Ex vivo autoradiography showed specific antibody retention in areas with abundant Aβ pathology. Taken together, these results suggest that reducing FcRn binding of a full-sized bispecific antibody increases the systemic elimination and could thereby drastically reduce the time from injection to in vivo imaging.
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