Search results for: Per-Ola Freskgård

Items from 1 to 15 out of 15 results

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First Infusion Reactions are Mediated by FcγRIIIb and Neutrophils

Felix Weber, Daniel Breustedt, Sonja Schlicht, Claas A. Meyer, more

Pharmaceutical Research > 2018 > 35 > 9 > 1-11

Purpose Administration of therapeutic monoclonal antibodies (mAbs) is frequently accompanied by severe first infusion reactions (FIR). The mechanism driving FIR is still unclear. This study aimed to investigate the cellular and molecular mechanisms causing FIR in humanized mouse models and their potential for evaluating FIR risk in patients. Methods Mice humanized for Fc gamma receptors (FcγRs)...

article

Brain Shuttle Antibody for Alzheimer’s Disease with Attenuated Peripheral Effector Function due to an Inverted Binding Mode

Felix Weber, Bernd Bohrmann, Jens Niewoehner, Jens A.A. Fischer, more

Cell Reports > 2018 > 22 > 1 > 149-162

Receptors show promise for the transport of monoclonal antibodies (mAbs) across the blood-brain barrier. However, safety liabilities associated with peripheral receptor binding and Fc effector function have been reported. We present the Brain Shuttle-mAb (BS-mAb) technology, and we investigate the role of Fc effector function in vitro and in an Fcγ receptor (FcγR)-humanized mouse model. Strong first...

article

Antibody therapies in CNS diseases

Per-Ola Freskgård, Eduard Urich

Neuropharmacology > 2017 > 120 > C > 38-55

Therapeutic antibodies have essentially been banned from the central nervous system, and are so far limited to use mainly in multiple sclerosis. This is primarily due to the fact that antibody penetration across the blood–brain barrier is very limited, with about only 0.1% of circulating antibodies estimated to reach the brain at steady-state concentration. Nonetheless, advances are being made with...

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Increased Brain Penetration and Potency of a Therapeutic Antibody Using a Monovalent Molecular Shuttle

Jens Niewoehner, Bernd Bohrmann, Ludovic Collin, Eduard Urich, more

Neuron > 2014 > 81 > 1 > 49-60

Although biotherapeutics have vast potential for treating brain disorders, their use has been limited due to low exposure across the blood-brain barrier (BBB). We report that by manipulating the binding mode of an antibody fragment to the transferrin receptor (TfR), we have developed a Brain Shuttle module, which can be engineered into a standard therapeutic antibody for successful BBB transcytosis...

article

New configuration of an in vitro blood–brain barrier model

Eduard Urich, Per-Ola Freskgard

Drug Discovery Today > 2010 > 15 > 23-24 > 1109-1110

article

Sequential coagulation factor VIIa domain binding to tissue factor

Maria Österlund, Egon Persson, Uno Carlsson, Per-Ola Freskgård, more

Biochemical and Biophysical Research Communications > 2005 > 337 > 4 > 1276-1282

Vessel wall tissue factor (TF) is exposed to blood upon vascular damage which enables association with factor VIIa (FVIIa). This leads to initiation of the blood coagulation cascade through localization and allosteric induction of FVIIa procoagulant activity. To examine the docking pathway of the FVIIa–TF complex, various residues in the extracellular part of TF (sTF) that are known to interact with...

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Transition state analysis of the complex between coagulation factor VIIa and tissue factor: suggesting a sequential domain-binding pathway

Maria Österlund, Egon Persson, Magdalena Svensson, Uno Carlsson, more

Biochemical and Biophysical Research Communications > 2005 > 327 > 3 > 789-793

Injury of a blood vessel exposes membrane-bound tissue factor (TF) to blood, which allows binding of coagulation factor VIIa (FVIIa). This initiation of the coagulation cascade is dictated by a specific multi-domain interaction between FVIIa and TF. To examine the energies involved in the transition state of the FVIIa:TF complex, various residues in the extracellular part of TF (sTF) that are known...

article

Spin and Fluorescent Probing of the Binding Interface between Tissue Factor and Factor VIIa at Multiple Sites

Rikard Owenius, Maria Österlund, Magdalena Svensson, Mikael Lindgren, more

Biophysical Journal > 2001 > 81 > 4 > 2357-2369

The specific complex between the extracellular part of tissue factor (sTF) and factor VIIa (FVIIa) was chosen as a model for studies of the binding interface between two interacting proteins. Six surface-exposed positions in sTF, residues known to contribute to the sTF-FVIIa interaction, were selected for cysteine mutation and site-directed labeling with spin and fluorescent probes. The binding interface...

article

Probing Inhibitor-Induced Conformational Changes along the Interface between Tissue Factor and Factor VIIa

Maria Österlund, Rikard Owenius, Karin Carlsson, Uno Carlsson, more

Biochemistry > 2001 > 40 > 31 > 9324 - 9328

article

Tissue Factor-dependent Factor VIIa Signaling

Lars C. Petersen, Per-Ola Freskgård, Mirella Ezban

Trends in Cardiovascular Medicine > 2000 > 10 > 2 > 47-52

Tissue factor (TF) is known primary as a cofactor for factor VIIa-mediated triggering of blood coagulation, which proceeds in a cascade of extracellular reactions. Recent investigations have, however, revealed that intracellular activities can also be induced by the proteolytic activity of factor VIIa bound to cell surface TF. Factor VIIa signal transduction has thus been reported to induce mobilization...

article

Properties of Spin and Fluorescent Labels at a Receptor-Ligand Interface

Rikard Owenius, Maria Österlund, Mikael Lindgren, Magdalena Svensson, more

Biophysical Journal > 1999 > 77 > 4 > 2237-2250

Site-directed labeling was used to obtain local information on the binding interface in a receptor-ligand complex. As a model we have chosen the specific association of the extracellular part of tissue factor (sTF) and factor VIIa (FVIIa), the primary initiator of the blood coagulation cascade. Different spectroscopic labels were covalently attached to an engineered cysteine in position 140 in sTF,...

article

Adsorption to silica nanoparticles of human carbonic anhydrase II and truncated forms induce a molten-globule-like structure

Peter Billsten, Per-Ola Freskgård, Uno Carlsson, Bengt-Harald Jonsson, more

FEBS Letters > 1997 > 402 > 1 > 67-72

Human carbonic anhydrase II pseudo-wild type (HCAII _pwt ) and two truncated variants were adsorbed to ≈9 nm silica nanoparticles. Ellipsometry was used as an indirect measure of protein adsorption. The structural changes of adsorbed proteins were investigated with the use of circular dichroism (CD), intrinsic fluorescence, ANS binding ability and inhibitor binding capacity. It was found that...

article

GroEL/ES-mediated refolding of human carbonic anhydrase II: role of N-terminal helices as recognition motifs for GroEL

Malin Persson, Göran Aronsson, Nils Bergenhem, Per-Ola Freskgård, more

Biochimica et Biophysica Acta (BBA)/Protein Structure and Molecular Enzymology > 1995 > 1247 > 2 > 195-200

The presence of GroEL/ES during the refolding of human carbonic anhydrase II (pseudo-wild type) was found to increase the yield of active enzyme from 65 to 100%. This chaperone action on the enzyme could be obtained by adding GroEL alone, and the time-course in that case was only moderately slower than the spontaneous process. Truncated forms of carbonic anhydrase, in which N-terminal helices were...

article

Cis-trans isomerization is rate-determining in the reactivation of denatured human carbonic anhydrase II as evidenced by proline isomerase

Cecilia Fransson, Per-Ola Freskgård, Helena Herbertsson, Åsa Johansson, more

FEBS Letters > 1992 > 296 > 1 > 90-94

The refolding of human carbonic anhydrase II is a sequential process. The slowest step involved is the recovery of enzymic activity (t ₁ ₂ =9 min). Kinetic data from 'double-jump' measurements indicate that proline isomerization might be rate determining, in the reactivation of the denatured enzyme. Proof of this is provided by the effect of proline isomerase on the reactivation kinetics;...

article

Folding around the C-terminus of human carbonic anhydrase II Kinetic characterization by use of a chemically reactive SH-group introduced by protein engineering

Per-Ola Freskgård, Uno Carlsson, Lars-Göran Mårtensson, Bengt-Harald Jonsson

FEBS Letters > 1991 > 289 > 1 > 117-122

We are characterizing the process of refolding of the enzyme human carbonic anhydrase II from the denatured state in guanidine hydrochloride. To describe the folding in defined parts of the protein we use protein engineering to introduce cysteine residues as unique chemically reactive probes. The accessibility of the cysteine SH-group to the alkylating reagent iodoacetate, at different stages during...

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