Rahel Frick

• Frick, Rahel; Høydahl, Lene Støkken; Hodnebrug, Ina; Vik, Erik Sebastian; Dalhus, Bjørn & Sollid, Ludvig Magne [Vis alle 9 forfattere av denne artikkelen] (2022). Affinity maturation of TCR-like antibodies using phage display guided by structural modeling. Protein Engineering Design & Selection. ISSN 1741-0126. 35. doi: 10.1093/protein/gzac005. Fulltekst i vitenarkiv Vis sammendrag

  Abstract TCR-like antibodies represent a unique type of engineered antibodies with specificity toward pHLA, a ligand normally restricted to the sensitive recognition by T cells. Here, we report a phage display-based sequential development path of such antibodies. The strategy goes from initial lead identification through in silico informed CDR engineering in combination with framework engineering for affinity and thermostability optimization, respectively. The strategy allowed the identification of HLA-DQ2.5 gluten peptide-specific TCR-like antibodies with low picomolar affinity. Our method outlines an efficient and general method for development of this promising class of antibodies, which should facilitate their utility including translation to human therapy.

• Grevys, Algirdas; Frick, Rahel; Mester, Simone; Flem-Karlsen, Karine; Nilsen, Jeannette & Foss, Stian [Vis alle 13 forfattere av denne artikkelen] (2022). Antibody variable sequences have a pronounced effect on cellular transport and plasma half-life. iScience. 25:103746(2), s. 1–22. doi: 10.1016/j.isci.2022.103746. Fulltekst i vitenarkiv Vis sammendrag

  Monoclonal IgG antibodies are the fastest growing class of biologics, but large differences exist in their plasma half-life in humans. Thus, to design IgG antibodies with favorable pharmacokinetics, it is crucial to identify the determinants of such differences. Here, we demonstrate that the variable region sequences of IgG antibodies greatly affect cellular uptake and subsequent recycling and rescue from intracellular degradation by endothelial cells. When the variable sequences are masked by the cognate antigen, it influences both their transport behavior and binding to the neonatal Fc receptor (FcRn), a key regulator of IgG plasma half-life. Furthermore, we show how charge patch differences in the variable domains modulate both binding and transport properties and that a short plasma half-life, due to unfavorable charge patches, may partly be overcome by Fc-engineering for improved FcRn binding.

• Gjølberg, Torleif Tollefsrud; Frick, Rahel; Mester, Simone; Foss, Stian; Grevys, Algirdas & Høydahl, Lene Støkken [Vis alle 11 forfattere av denne artikkelen] (2022). Biophysical differences in IgG1 Fc-based therapeutics relate to their cellular handling, interaction with FcRn and plasma half-life. Communications Biology. 5(1), s. 1–17. doi: 10.1038/s42003-022-03787-x. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Antibody-based therapeutics (ABTs) are used to treat a range of diseases. Most ABTs are either full-length IgG1 antibodies or fusions between for instance antigen (Ag)-binding receptor domains and the IgG1 Fc fragment. Interestingly, their plasma half-life varies considerably, which may relate to how they engage the neonatal Fc receptor (FcRn). As such, there is a need for an in-depth understanding of how different features of ABTs affect FcRn-binding and transport behavior. Here, we report on how FcRn-engagement of the IgG1 Fc fragment compare to clinically relevant IgGs and receptor domain Fc fusions, binding to VEGF or TNF-α. The results reveal FcRn-dependent intracellular accumulation of the Fc, which is in line with shorter plasma half-life than that of full-length IgG1 in human FcRn-expressing mice. Receptor domain fusion to the Fc increases its half-life, but not to the extent of IgG1. This is mirrored by a reduced cellular recycling capacity of the Fc-fusions. In addition, binding of cognate Ag to ABTs show that complexes of similar size undergo cellular transport at different rates, which could be explained by the biophysical properties of each ABT. Thus, the study provides knowledge that should guide tailoring of ABTs regarding optimal cellular sorting and plasma half-life.

• Frick, Rahel; Høydahl, Lene Støkken; Petersen, Jan; Pré, Fleur du; Kumari, Shraddha & Berntsen, Grete [Vis alle 20 forfattere av denne artikkelen] (2021). A high-affinity human TCR-like antibody detects celiac disease gluten peptide-MHC complexes and inhibits T cell activation. Science immunology. 6:eabg4925(62), s. 1–16. doi: 10.1126/sciimmunol.abg4925. Fulltekst i vitenarkiv Vis sammendrag

  Antibodies specific for peptides bound to human leukocyte antigen (HLA) molecules are valuable tools for studies of antigen presentation and may have therapeutic potential. Here, we generated human T cell receptor (TCR)–like antibodies toward the immunodominant signature gluten epitope DQ2.5-glia-α2 in celiac disease (CeD). Phage display selection combined with secondary targeted engineering was used to obtain highly specific antibodies with picomolar affinity. The crystal structure of a Fab fragment of the lead antibody 3.C11 in complex with HLA-DQ2.5:DQ2.5-glia-α2 revealed a binding geometry and interaction mode highly similar to prototypic TCRs specific for the same complex. Assessment of CeD biopsy material confirmed disease specificity and reinforced the notion that abundant plasma cells present antigen in the inflamed CeD gut. Furthermore, 3.C11 specifically inhibited activation and proliferation of gluten-specific CD4+ T cells in vitro and in HLA-DQ2.5 humanized mice, suggesting a potential for targeted intervention without compromising systemic immunity.

• Høydahl, Lene Støkken; Frick, Rahel; Sandlie, Inger & Løset, Geir Åge (2019). Targeting the mhc ligandome by use of tcr-like antibodies. Antibodies. 8:32(2), s. 1–21. doi: 10.3390/antib8020032. Fulltekst i vitenarkiv Vis sammendrag

  Monoclonal antibodies (mAbs) are valuable as research reagents, in diagnosis and in therapy. Their high specificity, the ease in production, favorable biophysical properties and the opportunity to engineer different properties make mAbs a versatile class of biologics. mAbs targeting peptide–major histocompatibility molecule (pMHC) complexes are often referred to as “TCR-like” mAbs, as pMHC complexes are generally recognized by T-cell receptors (TCRs). Presentation of self- and non-self-derived peptide fragments on MHC molecules and subsequent activation of T cells dictate immune responses in health and disease. This includes responses to infectious agents or cancer but also aberrant responses against harmless self-peptides in autoimmune diseases. The ability of TCR-like mAbs to target specific peptides presented on MHC allows for their use to study peptide presentation or for diagnosis and therapy. This extends the scope of conventional mAbs, which are generally limited to cell-surface or soluble antigens. Herein, we review the strategies used to generate TCR-like mAbs and provide a structural comparison with the analogous TCR in pMHC binding. We further discuss their applications as research tools and therapeutic reagents in preclinical models as well as challenges and limitations associated with their use.

• Frick, Rahel; Gunnarsen, Kristin Støen; Dahal-Koirala, Shiva; Risnes, Louise Fremgaard; Sollid, Ludvig Magne & Sandlie, Inger [Vis alle 8 forfattere av denne artikkelen] (2019). A TRAV26-1-encoded recognition motif focuses the biased T cell response in celiac disease. European Journal of Immunology. ISSN 0014-2980. 50, s. 142–145. doi: 10.1002/eji.201948235. Fulltekst i vitenarkiv
• Høydahl, Lene Støkken; Richter, Lisa Maria; Frick, Rahel; Snir, Omri; Gunnarsen, Kristin Støen & Landsverk, Ole J. B. [Vis alle 18 forfattere av denne artikkelen] (2018). Plasma Cells Are the Most Abundant Gluten Peptide MHC-expressing Cells in Inflamed Intestinal Tissues From Patients With Celiac Disease. Gastroenterology. ISSN 0016-5085. 156(5), s. 1428–1439.e10. doi: 10.1053/j.gastro.2018.12.013. Fulltekst i vitenarkiv Vis sammendrag

  Background & Aims Development of celiac disease is believed to involve the transglutaminase-dependent response of CD4+ T cells toward deamidated gluten peptides in the intestinal mucosa of individuals with specific HLA-DQ haplotypes. We investigated the antigen presentation process during this mucosal immune response. Methods We generated monoclonal antibodies (mAbs) specific for the peptide–MHC (pMHC) complex of HLA-DQ2.5 and the immunodominant gluten epitope DQ2.5-glia-α1a using phage display. We used these mAbs to assess gluten peptide presentation and phenotypes of presenting cells by flow cytometry and enzyme-linked immune absorbent spot (ELISPOT) in freshly prepared single-cell suspensions from intestinal biopsies from 40 patients with celiac disease (35 untreated and 5 on a gluten-free diet) as well as 18 subjects with confirmed noninflamed gut mucosa (controls, 12 presumed healthy, 5 undergoing pancreatoduodenectomy, and 1 with potential celiac disease). Results Using the mAbs, we detected MHC complexes on cells from intestinal biopsies from patients with celiac disease who consume gluten, but not from patients on gluten-free diets. We found B cells and plasma cells to be the most abundant cells that present DQ2.5-glia-α1a in the inflamed mucosa. We identified a subset of plasma cells that expresses B-cell receptors (BCR) specific for gluten peptides or the autoantigen transglutaminase 2 (TG2). Expression of MHC class II (MHCII) was not restricted to these specific plasma cells in patients with celiac disease but was observed in an average 30% of gut plasma cells from patients and controls. Conclusions A population of plasma cells from intestinal biopsies of patients with celiac disease express MHCII; this is the most abundant cell type presenting the immunodominant gluten peptide DQ2.5-glia-α1a in the tissues from these patients. These results indicate that plasma cells in the gut can function as antigen-presenting cells and might promote and maintain intestinal inflammation in patients with celiac disease or other inflammatory disorders.

• Weitzner, Brian D.; Jeliazkov, Jeliazko R.; Lyskov, Sergey; Marze, Nicholas; Kuroda, Daisuke & Frick, Rahel [Vis alle 10 forfattere av denne artikkelen] (2017). Modeling and docking of antibody structures with Rosetta. Nature Protocols. ISSN 1754-2189. 12(2), s. 401–416. doi: 10.1038/nprot.2016.180. Fulltekst i vitenarkiv
• Gunnarsen, Kristin Støen; Høydahl, Lene Støkken; Risnes, Louise Fremgaard; Dahal-Koirala, Shiva; Neumann, Ralf Stefan & Bergseng, Elin [Vis alle 15 forfattere av denne artikkelen] (2017). A TCRα framework–centered codon shapes a biased T cell repertoire through direct MHC and CDR3β interactions. JCI Insight. 2(17). doi: 10.1172/jci.insight.95193. Fulltekst i vitenarkiv Vis sammendrag

  Selection of biased T cell receptor (TCR) repertoires across individuals is seen in both infectious diseases and autoimmunity, but the underlying molecular basis leading to these shared repertoires remains unclear. Celiac disease (CD) occurs primarily in HLA-DQ2.5+ individuals and is characterized by a CD4+ T cell response against gluten epitopes dominated by DQ2.5-glia-α1a and DQ2.5-glia-α2. The DQ2.5-glia-α2 response recruits a highly biased TCR repertoire composed of TRAV26-1 paired with TRBV7-2 harboring a semipublic CDR3β loop. We aimed to unravel the molecular basis for this signature. By variable gene segment exchange, directed mutagenesis, and cellular T cell activation studies, we found that TRBV7-3 can substitute for TRBV7-2, as both can contain the canonical CDR3β loop. Furthermore, we identified a pivotal germline-encoded MHC recognition motif centered on framework residue Y40 in TRAV26-1 engaging both DQB1*02 and the canonical CDR3β. This allowed prediction of expanded DQ2.5-glia-α2–reactive TCR repertoires, which were confirmed by single-cell sorting and TCR sequencing from CD patient samples. Our data refine our understanding of how HLA-dependent biased TCR repertoires are selected in the periphery due to germline-encoded residues. This research was originally published in JCI Insight. © 2018 American Society for Clinical Investigation

• Arntzen, Magnus Øverlie; Boddie, Paul; Frick, Rahel; Koehler, Christian & Thiede, Bernd (2015). Consolidation of proteomics data in the Cancer proteomics database. Proteomics. ISSN 1615-9853. 15(22), s. 3765–3771. doi: 10.1002/pmic.201500144. Fulltekst i vitenarkiv

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