A5015530713- SARS-CoV-2 and COVID-19 Research
- Monoclonal and Polyclonal Antibodies Research
- Immune Cell Function and Interaction
- Glycosylation and Glycoproteins Research
- Viral gastroenteritis research and epidemiology
- T-cell and B-cell Immunology
- SARS-CoV-2 detection and testing
- Viral Infections and Immunology Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Advanced Biosensing Techniques and Applications
- Alzheimer's disease research and treatments
- CAR-T cell therapy research
- Bacteriophages and microbial interactions
- vaccines and immunoinformatics approaches
- Prion Diseases and Protein Misfolding
- Nuclear Receptors and Signaling
- Animal Virus Infections Studies
- Biosensors and Analytical Detection
- Blood groups and transfusion
- DNA and Nucleic Acid Chemistry
- Multiple Sclerosis Research Studies
- Advanced biosensing and bioanalysis techniques
- COVID-19 Clinical Research Studies
- Immunotherapy and Immune Responses
- Parasites and Host Interactions
Garvan Institute of Medical Research
2016-2025
St Vincent's Clinic
2020-2025
UNSW Sydney
2020-2025
Wichita State University
2023
University of Kansas
2023
Plasma cells (PCs) derived from germinal centers (GCs) secrete the high-affinity antibodies required for long-term serological immunity. Nevertheless, process whereby GC B differentiate into PCs is uncharacterized, and mechanism underlying selective PC differentiation of only remains unknown. In this study, we show that induced among a discrete subset residing within light zone GC. Initiation signals delivered upon engagement with intact antigen. Signals by T follicular helper were not to...
Clonal anergy is an enigmatic self-tolerance mechanism because no apparent purpose served by retaining functionally silenced B cells bearing autoantibodies. Human autoantibodies with IGHV4-34*01 heavy chains bind to poly-N-acetyllactosamine carbohydrates (I/i antigen) on erythrocytes and lymphocytes, cause cold agglutinin disease, are carried 5% of naive that anergic. We analyzed the specificity three IgG antibodies isolated from healthy donors immunized against foreign rhesus D alloantigen...
Antibodies have the specificity to differentiate foreign antigens that mimic self antigens, but it remains unclear how such is acquired. In a mouse model, we generated B cells displaying an antibody cross-reacts with two related protein expressed on versus cells. cell anergy was imposed by antigen reversed upon challenge high-density antigen, leading germinal center recruitment and gene hypermutation. Single-cell analysis detected rapid selection for mutations decrease affinity slower...
Abstract Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. Over this time global vaccine programs introduced, contributing to lowered COVID-19 hospitalisation and mortality rates, particularly in the first world. In late 2021, Omicron (B.1.1.529) virus variant emerged, with significant genetic differences clinical effects from other concern (VOC). This demonstrated higher numbers polymorphisms gene...
Abstract Genetically distinct variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged since the start COVID-19 pandemic. Over this period, we developed a rapid platform (R-20) for viral isolation and characterization using primary remnant diagnostic swabs. This, combined with quarantine testing genomics surveillance, enabled all major SARS-CoV-2 circulating in Australia 2021. Our facilitated variant isolation, resolution fitness nasopharyngeal swabs ranking...
Abstract Emerging variants of concern (VOCs) are threatening to limit the effectiveness SARS-CoV-2 monoclonal antibodies and vaccines currently used in clinical practice; broadly neutralizing strategies for their identification therefore urgently required. Here we demonstrate that can be isolated from peripheral blood mononuclear cells convalescent patients using receptor binding domains carrying epitope-specific mutations. This is exemplified by two human antibodies, GAR05, epitope class 1,...
Abstract Interleukin-2 (IL-2) is an established therapeutic agent used for cancer immunotherapy. Since treatment efficacy mediated by CD8 + and NK cell activity at the tumour site, considerable efforts have focused on generating variants that expand these subsets systemically, as exemplified IL-2/antibody complexes ‘superkines’. Here we describe a novel determinant of antitumour using fusion proteins consisting IL-2 antibody fragment crystallizable (Fc) region. Generation long-lived IL-2-Fc...
Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Second-generation vaccines will need to elicit neutralizing antibodies against sites that evolutionarily conserved across the sarbecovirus subgenus. Here, we immunized mice containing a human antibody repertoire with diverse receptor-binding domains (RBDs) identify targeting of vulnerability. Antibodies broad reactivity clade B RBDs class 4 epitope, recurring IGHV/IGKV pairs, were readily elicited but...
Antibodies against coronavirus spike protein potently protect infection and disease, but whether such protection can be extended to variant coronaviruses is unclear. This exemplified by a set of iconic well-characterized monoclonal antibodies developed after the 2003 SARS outbreak, including mAbs m396, CR3022, CR3014 80R, which neutralize SARS-CoV-1, not SARS-CoV-2. Here, we explore antibody engineering strategies change broaden their specificity, enabling nanomolar binding potent...
The emergence of SARS-CoV-2 variants concern (VOCs) has greatly diminished the neutralizing activity previously FDA-approved monoclonal antibodies (mAbs), including that antibody cocktails and first-generation broadly such as S309 (Sotrovimab). In contrast, targeting cryptic conformational epitopes receptor binding domain (RBD) have demonstrated broad against emerging variants, but exert only moderate activity, which so far hindered clinical development. Here, we utilize in vitro display...
Significance Conformational diversity of foreign antigens and cross-reactivity with self are implicated in the failure to generate effective antibody responses against many challenging pathogens, but few studies directly address how these two factors affect formation. Here we this question from biophysical, structural, immunological perspectives using structurally related lysozyme proteins. The results show germinal centers have remarkable ability select producing cells along novel...
Abstract Genetically distinct viral variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recorded since January 2020. Over this time global vaccine programs introduced, contributing to lowered COVID-19 hospitalisation and mortality rates, particularly in the first world. In late 2021, Omicron (B.1.1.529) virus variant emerged, with significant genetic differences clinical effects from other concern (VOC). This a demonstrated higher number polymorphisms gene...
Humans lack the capacity to produce Galα1–3Galβ1–4GlcNAc (α-gal) glycan, and anti-α-gal antibodies upon exposure carbohydrate on a diverse set of immunogens, including commensal gut bacteria, malaria parasites, cetuximab, tick proteins. Here we use X-ray crystallographic analysis from α-gal knockout mice humans in complex with glycan reveal common binding motif, centered germline-encoded tryptophan residue at Kabat position 33 (W33) complementarity-determining region variable heavy chain...
Abstract Nucleic acids not only form the basis of heredity, but are increasingly a source novel nano-structures, -devices and drugs. This has spurred development chemically modified alternatives (xeno nucleic (XNAs)) comprising chemical configurations found in nature to extend their functional scope. XNAs can be evolved into ligands (XNA aptamers) that bind targets with high affinity specificity. However, detailed investigations structural aspects XNA aptamers have been limited. Here we...
We developed a repertoire approach to generate human antibody bispecifics. Using phage display selection of heavy chains in the presence competitor light chain and providing cognate with an affinity handle, we identified mutations that prevent heavy/light mispairing. The strategy allows for autonomously assemble into
ABSTRACT Antibodies against coronavirus spike protein potently protect infection and disease, however it remains unclear if such protection can be extended to variant coronaviruses. This is exemplified by a set of iconic well-characterized monoclonal antibodies developed after the 2003 SARS outbreak including mAbs m396, CR3022, CR3014 80R, which neutralize SARS-CoV-1, but not SARS-CoV-2. Here we explore antibody maturation strategies change broaden their specificity, enabling potent binding...
SUMMARY Emerging variants of concern (VOCs) are threatening to limit the effectiveness SARS-CoV-2 monoclonal antibodies and vaccines currently used in clinical practice; broadly neutralizing strategies for their identification therefore urgently required. Here we demonstrate that can be isolated from peripheral blood mononuclear cells (PBMCs) convalescent patients using receptor binding domains (RBDs) carrying epitope-specific mutations. This is exemplified by two human antibodies, GAR05,...