A5087407738- HIV Research and Treatment
- Immunotherapy and Immune Responses
- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- CAR-T cell therapy research
- HER2/EGFR in Cancer Research
- Immune Response and Inflammation
- Cell Adhesion Molecules Research
- Complementary and Alternative Medicine Studies
- Signaling Pathways in Disease
- Advanced Fluorescence Microscopy Techniques
- Glycosylation and Glycoproteins Research
- Advanced Biosensing Techniques and Applications
- Immune responses and vaccinations
- Acupuncture Treatment Research Studies
- HIV/AIDS drug development and treatment
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Complement system in diseases
- Neuroinflammation and Neurodegeneration Mechanisms
- Phytochemicals and Medicinal Plants
- Lymphoma Diagnosis and Treatment
- interferon and immune responses
- RNA modifications and cancer
- Mosquito-borne diseases and control
University of British Columbia
2015-2025
Neoleukin Therapeutics (United States)
2024
Institute of Applied Mathematics
2019
Heidelberg University
2009-2017
University Hospital Heidelberg
2010-2017
Abstract Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast gastric/gastric esophageal junction cancers resistance remains problem. Here, we engineer IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique enhanced functionalities compared to both trastuzumab combination plus pertuzumab (tras + pert)....
Nef, an accessory protein of the Human Immunodeficiency Virus type 1 (HIV-1), is dispensable for viral replication in cell culture, but promotes virus and pathogenesis infected host. Acting as protein-interaction adaptor, HIV-1 Nef modulates numerous target activities including surface receptor expression, cytoskeletal remodeling, vesicular transport, signal transduction. In T-lymphocytes, altering T-cell antigen (TCR) signaling has long been recognized one key function protein. However,...
Abstract Integrating signals from multiple receptors allows cells to interpret the physiological context in which a signal is received. Here we describe mechanism for receptor crosstalk receptor-induced increases actin dynamics lower threshold signalling by another receptor. We show that Toll-like ligands lipopolysaccharide and CpG DNA, are conserved microbial molecules, enhance B-cell antigen (BCR) activating actin-severing protein cofilin. Single-particle tracking reveals increased...
Significance Nanoclustering has emerged as an organization principle of membrane proteins. This form compartmentalization been observed in eukaryotes and, to a lesser extent, bacteria. Bacterial proteins secretion systems often play central roles during host invasion. Here we reveal that ABC transporter from Mycobacterium tuberculosis ( Mtb ), which is important for its growth mice, compartmentalizes the bacterial membrane. We demonstrate cytoplasmic region this intrinsic ability...
When B cells encounter antigens on the surface of an antigen-presenting cell (APC), receptors (BCRs) are gathered into microclusters that recruit signaling enzymes. These then move centripetally and coalesce central supramolecular activation cluster immune synapse. The mechanisms controlling BCR organization during synapse formation, how this impacts signaling, not fully understood. We show coalescence depends actin-related protein 2/3 (Arp2/3) complex, which nucleates branched actin...
Significance HIV infection can be restricted by different host cell proteins. One such restriction factor is SAM domain and HD domain-containing protein 1 (SAMHD1), a triphosphohydrolase that cleaves dNTPs, which are required for reverse transcription. The accessory lentiviral X (Vpx) from simian immunodeficiency viruses (SIV) of sooty mangabeys rhesus macaques or HIV-2 degrade SAMHD1. Here we show Vpx proteins SIVs red-capped mandrills enhance resting CD4 T cells, but not macrophages,...
Nef is an accessory protein and pathogenicity factor of human immunodeficiency virus (HIV) simian (SIV) which elevates replication in vivo. We recently described for HIV type 1(SF2) (HIV-1(SF2)) the potent interference with T-lymphocyte chemotaxis via its association cellular kinase PAK2. Mechanistic analysis revealed that this interaction results deregulation actin-severing cofilin thus blocks chemokine-mediated actin remodeling required cell motility. However, efficiency PAK2 highly...
Single-particle tracking (SPT) is a powerful method for exploring single-molecule dynamics in living cells with nanoscale spatiotemporal resolution. Photostability and bright fluorescence make quantum dots (Qdots) popular choice SPT. However, their large size could potentially alter the mobility of molecule interest. To test this, we labelled B cell receptors on surface B-lymphocytes monovalent Fab fragments antibodies that were either linked to Qdots via streptavidin or directly conjugated...
Abstract Signal initiation by engagement of the TCR triggers actin rearrangements, receptor clustering, and dynamic organization signaling complexes to elicit sustain downstream signaling. Nef, a pathogenicity factor HIV, disrupts early in target T cells. To define mechanism underlying this Nef-mediated signal disruption, we employed quantitative single-cell microscopy following surface-mediated stimulation that allows for visualization distinct as microclusters (MCs). Despite marked...
ABSTRACT Human immunodeficiency virus type 1 (HIV-1) Nef enhances replication and contributes to immune evasion in vivo , but the underlying molecular mechanisms remain incompletely defined. interferes with host cell actin dynamics restrict T lymphocyte responses chemokine stimulation receptor engagement. This relies on assembly of a labile multiprotein complex including kinase PAK2 that usurps phosphorylate inactivate actin-severing factor cofilin. Components exocyst (EXOC), an octameric...
Abstract HER2-directed therapies have improved clinical outcomes for many patients with HER2-positive breast and gastric cancer. Despite these successes, there remains a need to develop HER2-targeted other HER2-expressing tumors, particularly in the setting of recurrent or metastatic disease. Zanidatamab (ZW25) is humanized, bispecific, immunoglobulin (Ig) G1-like antibody directed against juxtamembrane extracellular domain (ECD4) dimerization (ECD2) human epidermal growth factor receptor 2...
There is great potential for engineering cellular therapeutics by repurposing biological systems. Here, we report utilization of the granzyme-perforin pathway cytotoxic lymphocytes as a cell-to-cell protein delivery module. We designed and constructed granzyme B-derived chaperone molecules fused to fluorescent payload expressed these constructs in natural killer (NK) cells. Using confocal microscopy flow cytometry, investigated co-localization chaperones with lytic granules...
Single-molecule localization microscopy (SMLM) has become an essential tool for examining a wide variety of biological structures and processes. However, the relatively long acquisition time makes SMLM prone to drift-induced artifacts. Here we report optical design with electrically tunable lens (ETL) that actively stabilizes in three dimensions nearly eliminates mechanical drift (RMS ~0.7 nm lateral ~2.7 axial). The bifocal employed fiducial markers on coverslip was able stabilize sample...
Nuclear factor kappa B (NF-κB) is a critical transcription involved in regulating cell activation, inflammation, and survival. The linear ubiquitin chain assembly complex (LUBAC) which consists of HOIL1, HOIP, SHARPIN, catalyzes the ubiquitination target proteins-a post-translational modification that essential for NF-κB activation. Human germline pathogenic variants dysregulate signaling are associated with immunodeficiency and/or autoinflammation including dermatitis, recurrent fevers,...
The vague, generalized term "immuno-booster" has become a common household usage during the current novel coronavirus disease (COVID-19) pandemic. It been used to label products and practices that supposedly improve general immunity, thereby preventing contagion. use of immuno-boosting or immunomodulating capacity complementary alternative medicine (CAM) limited data in animal models lacks prospective long-term trials humans establish efficacy safety.1Cassa Macedo A. Oliveira Vilela de Faria...
Abstract When B cells encounter antigens on the surface of an antigen-presenting cell (APC), receptors (BCRs) are gathered into microclusters that recruit signaling enzymes. These then move centripetally and coalesce central supramolecular activation cluster immune synapse. The mechanisms controlling BCR organization during synapse formation, how this impacts signaling, not fully understood. We show coalescence depends actin-related protein 2/3 (Arp2/3) complex, which nucleates branched...
Abstract Zanidatamab (ZW25) is a biparatopic antibody that simultaneously binds two distinct epitopes of the oncogenic cell surface receptor HER2. currently being evaluated in global Phase 1, 2 and registration-enabling clinical trials as potential new treatment for patients with HER2-expressing cancers, including biliary tract, gastroesophageal adenocarcinomas, breast, other tumor types. The extracellular domain HER2 comprises four domains zanidatamab binding to on membrane proximal 4....