Article
Pharmacology & Pharmacy
Bing Wang, Jo Goodman, Lorin K. Roskos
Summary: Therapeutic IgG(4) antibodies undergo Fab-arm exchange with endogenous IgG(4) to form monovalent hybrid molecules. This exchange is observed with tralokinumab, a monoclonal antibody being developed to treat atopic dermatitis, in healthy volunteers. The formation of monovalent hybrids becomes the dominant form of tralokinumab in volunteers within 1 day postdose, but it does not affect the potency of neutralizing interleukin-13.
CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Ramakrishnan Natesan, Neeraj J. Agrawal
Summary: We investigated the dynamics of IgG1 and IgG4 using long all atom molecular dynamics simulations. Our results showed that the de novo structures of IgG1 and IgG4, predicted using AlphaFold, eventually relax to a state with persistent Fc-Fab interactions. The conformational space sampled by antibody trajectories is dependent on the initial crystal structure and isotype.
SCIENTIFIC REPORTS
(2023)
Article
Biotechnology & Applied Microbiology
Yuanli Song, Hui Cai, Zhijun Tan, Nesredin Mussa, Zheng-Jian Li
Summary: This study demonstrates that therapeutic IgG1 and IgG4 antibodies display different sensitivity to the reducing agent TCEP and follow different pathways to form low molecular weight (LMW) species. The findings provide mechanistic insights into LMW formation of IgG1 and IgG4, which have implications for the selection of IgG1 or IgG4 in bispecific antibodies and cysteine-based antibody-drug conjugates.
APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Salman Shahid, Mingming Gao, D. Travis Gallagher, Edwin Pozharski, Robert G. Brinson, Zhen-Yong Keck, Steven K. H. Foung, Thomas R. Fuerst, Roy A. Mariuzza
Summary: This study elucidated the crystal structure of a bivalent domain-swapped Fab dimer, which recognizes the E2 envelope glycoprotein of HCV. The dimerization is mediated by the deletion of a single residue, leading to a unique Fab structure that can be used as a fiducial marker for single-particle cryoEM analysis of HCV E2. Bivalent domain-swapped Fab dimers engineered based on this structure may also serve as a means of doubling the effective size of conventional Fab-protein complexes for cryoEM.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Endocrinology & Metabolism
Yuan Li, Chenxu Zhao, Keli Zhao, Nan Yu, Yan Li, Yang Yu, Yang Zhang, Zhijing Song, Youyuan Huang, Guizhi Lu, Ying Gao, Junqing Zhang, Xiaohui Guo
Summary: This study reveals distinct distributions of TgAb IgG1 glycosylation in various thyroid diseases. The abnormally elevated glycosylation levels of TgAb IgG1 observed in HT, PTC, and PTC-T may indicate immune disorders and involvement in the pathogenesis of these diseases.
EUROPEAN THYROID JOURNAL
(2021)
Article
Multidisciplinary Sciences
Maximilian Brinkhaus, Erwin Pannecoucke, Elvera J. van der Kooi, Arthur E. H. Bentlage, Ninotska I. L. Derksen, Julie Andries, Bianca Balbino, Magdalena Sips, Peter Ulrichts, Peter Verheesen, Hans de Haard, Theo Rispens, Savvas N. Savvides, Gestur Vidarsson
Summary: Disrupting the association between the Immunoglobulin G constant fragment (Fc) and the neonatal Fc receptor (FcRn) by engineered antibodies is a promising strategy to reduce autoantibody levels in autoimmune diseases. Here authors show that the variable fragment (Fab) of immunoglobulins could disturb the Fc-FcRn interaction, therefore the therapeutic effect of Fc-only fragments might surpass that of Fc-engineered antibodies with enhanced binding to FcRn.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Cheng Zhang, Nuria Codina, Jiazhi Tang, Haoran Yu, Nesrine Chakroun, Frank Kozielski, Paul A. Dalby
Summary: The research findings highlighted the different destabilizing pathways of protein structure under low pH and high temperature stress conditions, revealing the potential for stabilizing mutations in the CL domain and C-L-C(H)1 interface. The analysis also identified key salt bridge losses as a cause of conformational changes under different stresses, with implications for future engineering efforts to enhance stability.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Multidisciplinary Sciences
Joel S. Bloch, Somnath Mukherjee, Julia Kowal, Ekaterina Filippova, Martina Niederer, Els Pardon, Jan Steyaert, Anthony A. Kossiakoff, Kaspar P. Locher
Summary: The development of a synthetic Fab called NabFab enables specific binding with nanobodies for high-resolution cryo-EM structure determination. NabFab, of synthetic origin and humanized, can be expressed in large amounts in E. coli for potential biomedical applications.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Biochemistry & Molecular Biology
Anna M. Davies, Rebecca L. Beavil, Momchil Barbolov, Balraj S. Sandhar, Hannah J. Gould, Andrew J. Beavil, Brian J. Sutton, James M. McDonnell
Summary: This study reveals the three-dimensional structures of the Fab region of IgD, providing insights into the least well characterized mammalian immunoglobulin isotype. It identifies conformational diversity within the C81 domain and structural similarities between IgD and IgG, as well as differences with IgA and IgM, supporting predicted evolutionary relationships among mammalian antibody isotypes. The unique conformation of the upper hinge region in IgD Fab may contribute to the overall disposition of the long linker sequence between the Fab and Fc regions found in human IgD.
MOLECULAR IMMUNOLOGY
(2023)
Article
Pharmacology & Pharmacy
Yue Liu, Hao Li, Zhen Yan, Lianshan Zhang, Piaoyang Sun
Summary: This study explores the mechanism of CDR fragmentation in therapeutic antibodies and identifies excipients that can control fragmentation. Trp100 oxidation is found to be correlated with fragment formation, and adding Trp can reduce the level of fragmentation. Moreover, substituting polysorbate 80 (PS80) with other surfactants, using a combination of antioxidants, or combining EDTA with PS80 can maintain the stability of the antibody.
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
(2022)
Article
Immunology
Sander J. van Tilburg, Bart C. Jacobs, Pleuni Ooijevaar-de Heer, Willem-Jan R. Fokkink, Ruth Huizinga, Gestur Vidarsson, Theo Rispens
Summary: This study developed novel ELISAs to specifically monitor the pharmacokinetics of IVIg, utilizing polymorphic determinants G1m(a), G1m(x), and G1m(f). The assays can discriminate between endogenous IgG and therapeutic polyclonal IgG, providing insights into the variability of IVIg pharmacokinetics.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2022)
Article
Biology
Torleif Tollefsrud Gjolberg, Rahel Frick, Simone Mester, Stian Foss, Algirdas Grevys, Lene Stokken Hoydahl, Oystein Kalsnes Jorstad, Tilman Schlothauer, Inger Sandlie, Morten C. Moe, Jan Terje Andersen
Summary: The analysis of clinically approved antibody-based therapeutics reveals that different structural designs have distinct biophysical properties affecting FcRn binding, intracellular transport, and plasma half-life. Understanding the impact of different features of antibody-based therapeutics on FcRn binding and transport is crucial for optimizing cellular sorting and plasma half-life. This study compares the FcRn engagement of IgG1 Fc fragment to clinically relevant IgGs and receptor domain Fc fusions, binding to VEGF or TNF-alpha, and provides insights into their intracellular accumulation, plasma half-life, and cellular transportation.
COMMUNICATIONS BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Ramakrishnan Natesan, Neeraj J. Agrawal
Summary: In this study, long molecular simulations were used to investigate the interactions between Fab1, Fab2, and the Fc region in a human IgG1 crystal structure. The results revealed the importance of these interactions in determining the conformation and dynamics of the antibody. Specifically, the Fab2 arm was found to be non-covalently bound to the Fc region through long-lived hydrogen bonds, resulting in stable conformer states and influencing the dynamics of Fab1.
SCIENTIFIC REPORTS
(2022)
Article
Medicine, Research & Experimental
James T. T. Heads, Sebastian Kelm, Kerry Tyson, Alastair D. G. Lawson
Summary: The propensity for some monoclonal antibodies to aggregate at physiological and manufacturing pH values can hinder their use as therapeutic molecules or delay their market introduction. In this study, the researchers developed a computational method, called MAPT, to accurately predict the aggregation propensity of antibodies in common storage buffers. The method combines isotype-dependent, charge-based models with a hydrophobicity descriptor derived from a homology model, resulting in a robust indicator for antibody developability.
Article
Biophysics
Valentina A. Spiteri, James Doutch, Robert P. Rambo, Jayesh Gor, Paul A. Dalby, Stephen J. Perkins
Summary: A comparative structural study of glycosylated and deglycosylated monoclonal human IgG1 revealed perturbations in the Fab-Fc separation after deglycosylation, with a broader conformational spectrum observed in the Fc region of deglycosylated IgG1 compared to glycosylated IgG1. This variability in Fc conformations was found to account for the loss of binding to the Fc gamma receptor in deglycosylated IgG1.
BIOPHYSICAL JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Sarah Dimeloe, Louise V. Rice, Hebe Chen, Charlotte Cheadle, John Raynes, Paul Pfeffer, Paul Lavender, David F. Richards, Mun Peak Nyon, James M. McDonnell, Claudia Kemper, Bibek Gooptu, Catherine M. Hawrylowicz
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
(2019)
Article
Immunology
Gintare Bucaite, Tara Kang-Pettinger, Jorge Moreira, Hannah J. Gould, Louisa K. James, Brian J. Sutton, James M. McDonnell
JOURNAL OF IMMUNOLOGY
(2019)
Article
Biophysics
Stefi V. Benjamin, Paul I. Creeke, Alistair J. Henry, James M. McDonnell
BIOMOLECULAR NMR ASSIGNMENTS
(2020)
Article
Biochemical Research Methods
Alkistis N. Mitropoulou, Tom Ceska, James T. Heads, Andrew J. Beavil, Alistair J. Henry, James M. McDonnell, Brian J. Sutton, Anna M. Davies
ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS
(2020)
Article
Multidisciplinary Sciences
Ricarda M. Hoffmann, Silvia Mele, Anthony Cheung, Daniel Larcombe-Young, Gintare Bucaite, Eirini Sachouli, Iva Zlatareva, Hassan O. J. Morad, Rebecca Marlow, James M. McDonnell, Mariangela Figini, Katie E. Lacy, Andrew J. N. Tutt, James F. Spicer, David E. Thurston, Sophia N. Karagiannis, Silvia Crescioli
SCIENTIFIC REPORTS
(2020)
Review
Allergy
D. Ferastraoaru, H. J. Bax, C. Bergmann, M. Capron, M. Castells, D. Dombrowicz, E. Fiebiger, H. J. Gould, K. Hartmann, U. Jappe, G. Jordakieva, D. H. Josephs, F. Levi-Schaffer, V Mahler, A. Poli, D. Rosenstreich, F. Roth-Walter, M. Shamji, E. H. Steveling-Klein, M. C. Turner, E. Untersmayr, S. N. Karagiannis, E. Jensen-Jarolim
CLINICAL AND TRANSLATIONAL ALLERGY
(2020)
Article
Biochemistry & Molecular Biology
Susan K. Vester, Rebecca L. Beavil, Steven Lynham, Andrew J. Beavil, Deborah S. Cunninghame Graham, James M. McDonnell, Timothy J. Vyse
Summary: The study identified nucleolin as a cell surface receptor of C1QTNF4, with interaction mediated by the second C1q-like domain of C1QTNF4 and the C terminus of nucleolin. C1QTNF4 primarily targets monocytes and B cells, actively internalizing upon cell binding. The findings contribute to a better understanding of C1QTNF4's role in the healthy immune system and its association with the development of systemic lupus erythematosus.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Veronica F. Ilkow, Anna M. Davies, Balvinder Dhaliwal, Andrew J. Beavil, Brian J. Sutton, James M. McDonnell
Summary: This study provides insights into the evolutionary differences between murine and human CD23, as well as highlighting some of the functional variances between CD23 in different species.
Article
Biochemical Research Methods
Caroline Pollard, Mark Hudson, James M. McDonnell, Paul G. Royall, Kim Wolff
Summary: A specific POCT for detecting MDMA in latent fingerprints has not been explored. The study aimed to design a sensitive POCT using SPR and LFA technology. By identifying a high-affinity antibody binding pair and testing titrations of fluorescently labelled antibody and antigen concentrations to allow clear distinction between negative and positive outcomes, a sensitive LFA screening tool was successfully designed. The tool showed better performance compared to a lower threshold of 40 pg/10 mu l.
DRUG TESTING AND ANALYSIS
(2022)
Review
Immunology
J. M. McDonnell, B. Dhaliwal, B. J. Sutton, H. J. Gould
Summary: The evolution of IgE in mammals provided an additional layer of immune protection at body surfaces for rapid and local response against environmental antigens. The IgE immune response includes expulsive and inflammatory forces against local antigen stimulation, but it may also cause tissue damage and allergic disease. Two well-known IgE receptors, FceRI and CD23, mediate IgE activities. Unlike other antibody receptors, CD23 also regulates IgE expression to maintain IgE homeostasis. Recent research has revealed previously unknown mechanisms for regulation of IgE and IgE complexes, such as the dynamic structure of IgE and its allosteric modulation capacity.
ANNUAL REVIEW OF IMMUNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Anna M. Davies, Rebecca L. Beavil, Momchil Barbolov, Balraj S. Sandhar, Hannah J. Gould, Andrew J. Beavil, Brian J. Sutton, James M. McDonnell
Summary: This study reveals the three-dimensional structures of the Fab region of IgD, providing insights into the least well characterized mammalian immunoglobulin isotype. It identifies conformational diversity within the C81 domain and structural similarities between IgD and IgG, as well as differences with IgA and IgM, supporting predicted evolutionary relationships among mammalian antibody isotypes. The unique conformation of the upper hinge region in IgD Fab may contribute to the overall disposition of the long linker sequence between the Fab and Fc regions found in human IgD.
MOLECULAR IMMUNOLOGY
(2023)
Review
Immunology
Brian J. Sutton, Anna M. Davies, Heather J. Bax, Sophia N. Karagiannis