A5045878198- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- T-cell and B-cell Immunology
- Protein purification and stability
- Immunotherapy and Immune Responses
- Immune Cell Function and Interaction
- Blood groups and transfusion
- Immunodeficiency and Autoimmune Disorders
- Complement system in diseases
- Transgenic Plants and Applications
- CAR-T cell therapy research
- vaccines and immunoinformatics approaches
- Bacteriophages and microbial interactions
- Celiac Disease Research and Management
- Advanced Biosensing Techniques and Applications
- interferon and immune responses
- Protein Interaction Studies and Fluorescence Analysis
- Viral Infectious Diseases and Gene Expression in Insects
- Cytomegalovirus and herpesvirus research
- Virus-based gene therapy research
- Galectins and Cancer Biology
- Receptor Mechanisms and Signaling
- DNA and Nucleic Acid Chemistry
- Synthesis and Biological Evaluation
- Acute Lymphoblastic Leukemia research
University of Oslo
2016-2025
Oslo University Hospital
2014-2025
657 Oslo
2023-2025
Copenhagen University Hospital
2007
Rigshospitalet
2007
Norwegian Institute of Public Health
2007
Norwegian Cancer Society
1991
University of Bergen
1980-1983
Human IgG3 displays the strongest effector functions of all IgG subclasses but has a short half-life for unresolved reasons. Here we show that binds to IgG-salvage receptor (FcRn), FcRn-mediated transport and rescue is inhibited in presence IgG1 due intracellular competition between IgG3. We reveal this occurs because single amino acid difference at position 435, where an arginine instead histidine found other subclasses. While R435 increases binding FcRn neutral pH, it decreases acidic...
Cross-presentation of IgG-containing immune complexes (ICs) is an important means by which dendritic cells (DCs) activate CD8 + T cells, yet it proceeds incompletely understood mechanism. We show that monocyte-derived − CD11b DCs require the neonatal Fc receptor for IgG (FcRn) to conduct cross-presentation ICs. Consequently, in absence FcRn, Fcγ (FcγR)-mediated antigen uptake fails initiate cross-presentation. FcRn shown regulate intracellular sorting ICs proper destination such occur....
Albumin is the most abundant protein in blood where it has a pivotal role as transporter of fatty acids and drugs. Like IgG, albumin long serum half-life, protected from degradation by pH-dependent recycling mediated interaction with neonatal Fc receptor, FcRn. Although FcRn IgG well characterized at atomic level, its not. Here we present structure-based modelling FcRn–albumin complex, supported binding analysis site-specific mutants, providing mechanistic evidence for presence pH-sensitive...
The N-linked glycan of immunoglobulin G (IgG) is indispensable for the interaction Fc domain with Fcγ receptors on effector cells and clearance target via antibody dependent cell-mediated cytotoxicity (ADCC). Escherichia coli expressed, aglycosylated domains bind FcγRs poorly cannot elicit ADCC. Using a novel bacterial display/flow cytometric library screening system we isolated variants that to FcγRI (CD64) nanomolar affinity. Binding was critically amino acid substitutions (E382V, lesser...
A major challenge for the therapeutic use of many peptides and proteins is their short circulatory half-life. Albumin has an extended serum half-life 3 weeks because its size FcRn-mediated recycling that prevents intracellular degradation, properties shared with IgG antibodies. Engineering strictly pH-dependent IgG-FcRn interaction known to extend However, this principle not been extensively explored albumin. We have engineered human albumin by introducing single point mutations in...
Eculizumab is a humanized IgG2/4 chimeric anti-complement C5 antibody used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) or atypical hemolytic uremic syndrome. The aim of this study was evaluate whether not the complement activity in newborns from pregnant women who receive eculizumab impaired. A novel eculizumab-C5 complex (E-C5) specific assay developed and revealed that two carried only 6-7% E-C5 detected their eculizumab-treated PNH mothers. Serum completely lacked...
The neonatal crystallizable fragment receptor (FcRn) is responsible for maintaining the long half-life and high levels of two most abundant circulating proteins, albumin IgG. In latter case, protective mechanism derives from FcRn binding to IgG in weakly acidic environment contained within endosomes hematopoietic parenchymal cells, whereupon diverted degradation lysosomes recycled. cellular location by which protects are partially understood. Here we demonstrate that mice with global or...
Monoclonal IgG antibodies are the fastest growing class of biologics, but large differences exist in their plasma half-life humans. Thus, to design with favorable pharmacokinetics, it is crucial identify determinants such differences. Here, we demonstrate that variable region sequences greatly affect cellular uptake and subsequent recycling rescue from intracellular degradation by endothelial cells. When masked cognate antigen, influences both transport behavior binding neonatal Fc receptor...
Monoclonal IgG antibodies constitute the fastest growing class of therapeutics. Thus, there is an intense interest to design more potent antibody formats, where long plasma half-life a commercially competitive differentiator affecting dosing, frequency administration and thereby potentially patient compliance. Here, we report on Fc-engineered variant with three amino acid substitutions Q311R/M428E/N434W (REW), that enhances mucosal distribution, as well allows for needle-free delivery across...
The MHC class I-related neonatal Fc receptor (FcRn) serves in the homeostatic regulation of IgG and albumin by increasing their half-lives. FcRn may bind simultaneously, a pH-dependent manner, with ligand binding at pH 6.0-6.5 release 7.0-7.4. FcRn-IgG interaction has been extensively characterized amino acid level shown to depend on conserved histidine residues IgG-Fc part that interact negatively charged alpha-2 domain FcRn. recently discovered FcRn-albumin remains be elucidated. Guided...
Posttranslational modification of Ag is implicated in several autoimmune diseases. In celiac disease, a cereal gluten-induced enteropathy with features, T cell recognition the gluten heavily dependent on posttranslational conversion Gln to Glu residues. Evidence suggests that enhanced deamidated peptides results from improved peptide binding MHC and TCR interaction peptide-MHC complex. this study, we report there biased usage Vβ6.7 chain among TCRs reactive immunodominant DQ2-α-II gliadin...
Albumin and IgG have remarkably long serum half-lives due to pH-dependent FcRn-mediated cellular recycling that rescues both ligands from intracellular degradation. Furthermore, increase in of albumin-based therapeutics has the potential improve their efficacies, but there is a great need for robust methods screening relative FcRn-dependent ability. Here, we report on novel human endothelial cell-based assay (HERA) can be used such pre-clinical screening. In HERA, rescue degradation depends...
Engineering of the constant Fc part monoclonal human IgG1 (hIgG1) Abs is an approach to improve effector functions and clinical efficacy next-generation IgG1-based therapeutics. A main focus in such development tailoring vivo half-life transport properties by engineering pH-dependent interaction between IgG neonatal receptor (FcRn), as FcRn homeostatic regulator hIgG1 half-life. However, whether affects binding other Fc-binding molecules, classical FcγRs complement factor C1q, has not been...
Albumin has a serum half-life of three weeks in humans and is utilized to extend the persistence drugs that are genetically fused or conjugated directly albumin albumin-binding molecules. Responsible for long FcRn protects from intracellular degradation. An in-depth understanding how binds across species importance design evaluation albumin-based therapeutics. consists homologous domains where domain I III human crucial binding FcRn. Here, we show swapping two loops whole with corresponding...