A5021000758- Alzheimer's disease research and treatments
- Drug Transport and Resistance Mechanisms
- Radiopharmaceutical Chemistry and Applications
- Monoclonal and Polyclonal Antibodies Research
- Pharmacological Effects and Toxicity Studies
- Neuroscience and Neuropharmacology Research
- Epilepsy research and treatment
- Medical Imaging Techniques and Applications
- Click Chemistry and Applications
- Neuroinflammation and Neurodegeneration Mechanisms
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Prion Diseases and Protein Misfolding
- Computational Drug Discovery Methods
- Glycosylation and Glycoproteins Research
- Bioinformatics and Genomic Networks
- S100 Proteins and Annexins
- Advanced MRI Techniques and Applications
- RNA Interference and Gene Delivery
- Receptor Mechanisms and Signaling
- Chemical Reactions and Isotopes
- Neurotransmitter Receptor Influence on Behavior
- Metabolomics and Mass Spectrometry Studies
- Neuropeptides and Animal Physiology
- Protein Structure and Dynamics
- Barrier Structure and Function Studies
Uppsala University
2016-2025
Rockefeller University
2020
Brigham and Women's Hospital
2020
Cornell University
2020
Princeton University
2020
Federation of American Societies for Experimental Biology
2020
National Institutes of Health
2020
Yale University
2020
Harvard University
2020
Leiden University
2010-2018
Species differences occur in the brain concentrations of drugs, but reasons for these are not yet apparent. This study was designed to compare uptake three radiolabeled P-glycoprotein (P-gp) substrates across species using positron emission tomography. Brain and brain-to-plasma ratios were compared; [<sup>11</sup>C]verapamil rats, guinea pigs, monkeys; [<sup>11</sup>C](<i>S</i>)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethylamino)-2(<i>S</i>)-phenylpiperidine (GR205171) monkeys,...
Abstract Owing to their specificity and high-affinity binding, monoclonal antibodies have potential as positron emission tomography (PET) radioligands are currently used image various targets in peripheral organs. However, the central nervous system, antibody uptake is limited by blood–brain barrier (BBB). Here we present a PET ligand be for diagnosis evaluation of treatment effects Alzheimer’s disease. The amyloid β (Aβ) mAb158 radiolabelled conjugated transferrin receptor enable...
The blood-brain barrier (BBB) is an obstacle for antibody passage into the brain, impeding development of immunotherapy and antibody-based diagnostics brain disorders. In present study, we have developed a shuttle active transport antibodies across BBB by receptor-mediated transcytosis. We thus recombinantly fused two single-chain variable fragments (scFv) transferrin receptor (TfR) 8D3 to light chains mAb158, selectively binding Aβ protofibrils, which are involved in pathogenesis...
Immunotherapy is a very fast expanding field within drug discovery and, hence, rapid and inexpensive expression of antibodies would be extremely valuable. Antibodies are, however, difficult to express. Multifunctional with additional binding domains further complicate the expression. Only few protocols describe production tetravalent bispecific all limited levels. Here, we protocol that can produce functional tetravalent, at around 22 mg protein/l low cost. The system based on Expi293 cells,...
The major pathological hallmarks of Alzheimer's disease (AD) are the progressive aggregation and accumulation beta-amyloid (Aβ) hyperphosphorylated tau protein into neurotoxic deposits. Aβ has been suggested as critical early inducer, driving progression. However, factors that promote remain elusive. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate spatial distribution patterns lipids, peptides, proteins in biological tissue sections. In present study,...
Evidence suggests that amyloid-β (Aβ) protofibrils/oligomers are pathogenic agents in Alzheimer's disease (AD). Unfortunately, techniques enabling quantitative estimates of these species patients or patient samples still rather limited. Here w
PET imaging of amyloid-beta (Aβ) deposits in brain has become an important aid Alzheimer's disease diagnosis, and inclusion criterion for patient enrolment into clinical trials new anti-Aβ treatments. Available radioligands visualizing Aβ bind to insoluble fibrils, i.e. plaques. Levels prefibrillar forms, e.g. soluble oligomers protofibrils, correlate better than plaques with severity these species are the neurotoxic form leading neurodegeneration. The goal was create antibody-based...
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (Aβ) deposition, hyperphosphorylation of tau, and neuroinflammation. Astrocytes, the most abundant glial cell type in nervous system, respond to disorders through astrogliosis, i.e., converting reactive inflammatory state. The aim this study was investigate how vivo quantification astrogliosis using positron emission tomography (PET) radioligand deuterium-l-[11C]deprenyl ([11C]DED), binding enzyme...
Amyloid-β (Aβ) immunotherapy is one of the most promising disease-modifying strategies for Alzheimer's disease (AD). Despite recent progress targeting aggregated forms Aβ, low antibody brain penetrance remains a challenge. In present study, we used transferrin receptor (TfR)-mediated transcytosis to facilitate uptake our previously developed Aβ protofibril-selective mAb158, with aim increasing efficacy directed toward soluble protofibrils. protein precursor (AβPP)-transgenic mice (tg-ArcSwe)...
Transferrin receptor (TfR1) mediated enhanced brain delivery of antibodies have been studied extensively in preclinical settings. However, the pharmacokinetics, i.e. entry, distribution and elimination are still not fully understood for this class antibodies. The overall aim study was to compare pharmacokinetics two BBB-penetrating bispecific different size (210 vs 58 kDa). Specifically, we wanted investigate if faster systemic clearance smaller non-IgG antibody di-scFv3D6-8D3, comparison...
Abstract Background Alzheimer’s disease (AD) immunotherapy with antibodies targeting amyloid-β (Aβ) has been extensively explored in clinical trials. The aim of this study was to the long-term brain distribution two radiolabeled monoclonal Aβ antibody variants – RmAb158, recombinant murine version BAN2401, which recently demonstrated amyloid removal and reduced cognitive decline AD patients, bispecific RmAb158-scFv8D3, engineered for enhanced uptake via transferrin receptor-mediated...
The protein alpha-synuclein (αSYN) plays a central role in synucleinopathies such as Parkinsons's disease (PD) and multiple system atrophy (MSA). Presently, there are no selective αSYN positron emission tomography (PET) radioligands that do not also show affinity to amyloid-beta (Aβ). We have previously shown radiolabeled antibodies, engineered enter the brain via transferrin receptor (TfR), is promising approach for PET imaging of intrabrain targets. In this study, we used strategy...
The use of transgenic mice displaying amyloid-β (Aβ) brain pathology has been essential for the preclinical assessment new treatment strategies Alzheimer's disease. However, properties Aβ in such have not systematically compared to brains patients with Here, we determined structures nine ex vivo fibrils from six different mouse models by cryogenic-electron microscopy. We found novel fibril APP/PS1, ARTE10 and tg-SwDI models, whereas human type II filament fold was ARTE10, tg-APPSwe APP23...
Transferrin receptor 1 (TfR1) mediated transcytosis is an attractive strategy to enhance brain uptake of protein drugs, but translation remains a challenge. Here, single domain shark antibody VNAR fragment (TXB2) with similar affinity murine and human TfR1 was used shuttle cargo into the brain. TXB2 fused IgG1 Fc (hFc) or amyloid-β (Aβ) bapineuzumab (Bapi). TXB2-hFc displayed 20-fold higher concentrations compared control VNAR-hFc at 18 hours post-injection in wt mice. At same time point,...
Antibodies are highly specific for their target molecules, but poor brain penetrance has restricted use as PET ligands imaging of targets within the CNS. The aim this study was to develop an antibody-based radioligand, using TribodyTM format, soluble amyloid-beta (Aβ) protofibrils, which suggested cause neurodegeneration in Alzheimer's disease. Antibodies, even when expressed smaller engineered formats, large molecules that do not enter sufficient amounts purposes. Hence, transport across...
Amyloid-β (Aβ) oligomers and protofibrils are suggested to be the most neurotoxic Aβ species in Alzheimer's disease (AD). Hence, antibodies with strong selective binding these soluble aggregates of therapeutic potential. We have recently introduced HexaRmAb158, a multivalent antibody additional Aβ-binding sites form single-chain fragment variables (scFv) on N-terminal ends protofibril (RmAb158). Due short distance between them, HexaRmAb158 displayed slow dissociation from vitro. In current...
Transferrin receptor 1 (TfR1) mediated brain delivery of antibodies could become important for increasing the efficacy emerging immunotherapies in Alzheimer's disease (AD). However, age, dose, binding to TfR1 on blood cells, and pathology influence TfR1-mediated transcytosis TfR1-binders across blood-brain barrier (BBB). The aim study was, therefore, investigate impact these factors a bispecific TfR1-transported Aβ-antibody, mAb3D6-scFv8D3, comparison with conventional antibody mAb3D6.Young...
Recent development of amyloid-β (Aβ)-targeted immunotherapies for Alzheimer's disease (AD) have highlighted the need accurate diagnostic methods. Antibody-based positron emission tomography (PET) ligands are well suited this purpose as they can be directed toward same target therapeutic antibody. Bispecific, brain-penetrating antibodies achieve sufficient brain concentrations, but their slow blood clearance remains a challenge, since it prolongs time required to target-specific PET signal....
Multiomics analysis of single tissue sections using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) provides comprehensive molecular insights. However, optimizing sample preparation for MALDI-MSI to achieve high sensitivity and reproducibility various biomolecules, such as lipids, N-glycans, tryptic peptides, presents a significant challenge. This study introduces robust reproducible protocol the sequential latter molecules in fresh-frozen rodent brain...