A5071903220- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Lung Cancer Treatments and Mutations
- Cancer Genomics and Diagnostics
- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- Advanced Breast Cancer Therapies
- CAR-T cell therapy research
- Cancer Treatment and Pharmacology
- Medical Imaging Techniques and Applications
- Breast Cancer Treatment Studies
- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Advanced Biosensing Techniques and Applications
- Chronic Lymphocytic Leukemia Research
- Single-cell and spatial transcriptomics
- Chemokine receptors and signaling
- Growth Hormone and Insulin-like Growth Factors
- Radiopharmaceutical Chemistry and Applications
- Peptidase Inhibition and Analysis
- Radiomics and Machine Learning in Medical Imaging
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Glycosylation and Glycoproteins Research
- Asthma and respiratory diseases
- Computational Drug Discovery Methods
King's College London
2016-2025
Guy's Hospital
2016-2025
Breast Cancer Now
2016-2025
Klogene (United States)
2024
St Thomas' Hospital
2016-2021
British Columbia Centre of Excellence for Women's Health
2013
King's College School
2011
Royal Cornwall Hospital
2011
Antibody-drug conjugates (ADCs) are emerging as effective tools in cancer therapy, combining the antibody's exquisite specificity for target antigen-expressing cell together with cytotoxic potency of payload. Much success stems from rational design "toxic warheads", chemically linked to antibodies, and fine-tuning intricate properties chemical linkers. Here, we focus on antibody moiety ADCs, dissecting impact Fab, linkers, isotype Fc structure anti-tumoral immune-activating functions ADCs....
The immunosuppressive transmembrane protein PD-L1 was shown to traffic via the multivesicular body (MVB) and be released on exosomes. A high-content siRNA screen identified endosomal sorting complexes required for transport (ESCRT)-associated ALIX as a regulator of both EGFR activity surface presentation in basal-like breast cancer (BLBC) cells. depletion results prolonged enhanced stimulation-induced well defective trafficking through MVB, reduced exosomal secretion, its redistribution cell...
Abstract Cancer cells tend to metastasize first tumor-draining lymph nodes, but the mechanisms mediating cancer cell invasion into lymphatic vasculature remain little understood. Here, we show that in human breast tumor microenvironment (TME), presence of increased numbers RORγt+ group 3 innate lymphoid (ILC3) correlates with an likelihood node metastasis. In a preclinical mouse model cancer, CCL21-mediated recruitment ILC3 tumors stimulated production CXCL13 by TME stromal cells, which turn...
Abstract In breast cancer, humoral immune responses may contribute to clinical outcomes, especially in more immunogenic subtypes. Here, we investigated B lymphocyte subsets, immunoglobulin expression, and clonal features tumors, focusing on aggressive triple-negative cancers (TNBC). samples from patients with TNBC healthy volunteers, circulating tumor-infiltrating lymphocytes (TIL-B) were evaluated. CD20+CD27+IgD− isotype-switched increased compared matched blood. TIL-B frequently formed...
Abstract Outcomes for half of patients with melanoma remain poor despite standard-of-care checkpoint inhibitor therapies. The prevalence the melanoma-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) expression is ~70%, therefore effective immunotherapies directed at CSPG4 could benefit many patients. Since IgE exerts potent immune-activating functions in tissues, we engineer a monoclonal antibody human constant domains recognizing to target melanoma. binds melanomas including...
Abstract Purpose: Anti-EGFR antibodies show limited response in breast cancer, partly due to activation of compensatory pathways. Furthermore, despite the clinical success cyclin-dependent kinase (CDK) 4/6 inhibitors hormone receptor–positive tumors, aggressive triple-negative cancers (TNBC) are largely resistant CDK2/cyclin E expression, whereas free CDK2 display normal tissue toxicity, limiting their therapeutic application. A cetuximab-based antibody drug conjugate (ADC) carrying a CDK...
Abstract Purpose: Highly aggressive triple-negative breast cancers (TNBCs) lack validated therapeutic targets and have high risk of metastatic disease. Folate receptor alpha (FRα) is a central mediator cell growth regulation that could serve as an important target for cancer therapy. Experimental Design: We evaluated FRα expression in by genomic (n = 3,414) IHC 323) analyses its association with clinical parameters outcomes. measured the functional contributions TNBC biology RNA interference...
IgE antibodies are key mediators of antiparasitic immune responses, but their potential for cancer treatment via antibody-dependent cell-mediated cytotoxicity (ADCC) has been little studied. Recently, tumor antigen-specific IgEs were reported to restrict cell growth by engaging high-affinity Fc receptors on monocytes and macrophages; however, the underlying therapeutic mechanisms undefined
The TSH receptor (TSHR) is the critical target for antibody production in Graves' disease (GD). Insulin-like growth factor 1 (IGF1R) has been proposed as a second autoantigen complications of GD such orbitopathy. We attempted to induce orbital tissue remodeling mice undergoing immunizations with plasmids encoding TSHR and IGF1R delivered by vivo skeletal muscle electroporation, procedure known give sustained, long-term response. Female BALB/c were challenged A-subunit or IGF1Rα subunit...
B cells participate in immune surveillance human circulation and tissues, including tumors such as melanoma. By contrast, the role of humoral responses cutaneous immunity is underappreciated. We report circulating skin-homing CD22+CLA+B healthy volunteers melanoma patients (n = 73) CD22+ normal skin samples 189). Normal malignant featured mature IgG CD22 mRNA, alongside mRNA for transiently-expressed enzyme Activation-induced cytidine Deaminase (AID). Gene expression analyses...
Highlights•β4 integrin-expressing macrophages release TGF-β1 near breast cancer lymphovasculature•TGF-β1 drives β4 integrin clustering on macrophages, enhancing macrophage adhesion•TGF-β1 signals through RhoA to drive lymphatic endothelial cell contraction•Lymphatic remodeling signaling cascade facilitates metastasisSummaryLymphatic vasculature is crucial for metastasis in triple-negative (TNBC); however, cellular and molecular drivers controlling lymphovascular are poorly understood. We...
B cells are known to contribute the anti-tumor immune response, especially in immunogenic tumors such as melanoma, yet humoral immunity has not been characterized these cancers detail. Here we show comprehensive phenotyping samples of circulating and tumor-resident well serum antibodies melanoma patients. Memory enriched compared blood paired feature distinct antibody repertoires, linked specific isotypes. Tumor-associated undergo clonal expansion, class switch recombination, somatic...
Artificial intelligence and machine learning models have been developed to engineer antibodies for specific recognition of antigens, however these approaches often focus on the antibody complementarity determining region (CDR) whilst ignoring immunoglobulin framework (FW) which provides structural rigidity support flexible CDR loops. Here we present an integrated computational-experimental workflow, combining static structure analyses, molecular dynamics simulations in vitro physicochemical...
B cells are emerging as key players of anti-tumor adaptive immune responses. We investigated regulatory and pro-inflammatory cytokine-expressing in patients with melanoma by flow cytometric intracellular cytokine, CyTOF, transcriptomic, immunofluorescence, single-cell RNA-seq, B:T cell co-culture analyses. found enhanced circulating (TGF-β+ PD-L1+) reduced TNF-α+ populations compared healthy volunteers (HVs), including lower IFN-γ+:IL-4+ higher TGF-β+:TNF-α+ ratios patients. TGF-β-expressing...
Despite emerging targeted and immunotherapy treatments, no monoclonal antibodies or antibody-drug conjugates (ADCs) directly targeting tumor cells are currently approved for melanoma therapy. The tumor-associated antigen chondroitin sulphate proteoglycan 4 (CSPG4), a neural crest glycoprotein over-expressed on 70% of melanomas, contributes to proliferative signaling pathways, but despite highly tumor-selective expression it has not yet been using ADCs. We developed novel ADC comprising an...
Abstract Background Prognostic stratification of breast cancers remains a challenge to improve clinical decision making. We employ machine learning on cancer transcriptomics from multiple studies link the expression specific genes histological grade and classify tumours into more or less aggressive prognostic type. Materials methods Microarray data 5031 untreated spanning 33 published datasets corresponding were integrated. A model based gradient boosted trees was trained grade-1 grade-3...
Cancer immunotherapy with monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapies can benefit from selection of new targets high levels tumor specificity early assessments efficacy safety to derisk potential therapies. Employing mass spectrometry, bioinformatics, immuno-mass spectrometry CRISPR/Cas9 we identified the target tumor-specific SF-25 antibody. We engineered IgE CAR immunotherapies derived clone evaluated for cancer therapy. as tumor-associated SLC3A2, a surface...
Despite decades of research in the epidermal growth factor receptor (EGFR) signalling field, and many targeted anti-cancer drugs that have been tested clinically, success rate for these agents clinic is low, particularly terms improvement overall survival. Intratumoral heterogeneity proposed as a major mechanism underlying treatment failure molecule-targeted agents. Here we highlight application fluorescence lifetime microscopy (FLIM)-based biosensing to demonstrate intratumoral EGFR...