A5040796674- Monoclonal and Polyclonal Antibodies Research
- Immune Cell Function and Interaction
- Chronic Lymphocytic Leukemia Research
- Peptidase Inhibition and Analysis
- T-cell and B-cell Immunology
- Cancer Immunotherapy and Biomarkers
- Glycosylation and Glycoproteins Research
- CAR-T cell therapy research
- Immune cells in cancer
- Pancreatic and Hepatic Oncology Research
- interferon and immune responses
- IgG4-Related and Inflammatory Diseases
- Immunotherapy and Immune Responses
- Lymphoma Diagnosis and Treatment
- PI3K/AKT/mTOR signaling in cancer
- Cancer, Hypoxia, and Metabolism
- Immunodeficiency and Autoimmune Disorders
- Protein Degradation and Inhibitors
- Viral Infections and Vectors
- Congenital Diaphragmatic Hernia Studies
- Chronic Myeloid Leukemia Treatments
- Neuroblastoma Research and Treatments
- Neuroendocrine Tumor Research Advances
- Lung Cancer Research Studies
- Ubiquitin and proteasome pathways
University of Southampton
2015-2025
Southampton General Hospital
2009-2018
Cancer Research UK
2017
Tenovus Cancer Care
2010-2011
King's College London
2004-2005
St George's Hospital
2004
St George's, University of London
2004
mAbs are becoming increasingly utilized in the treatment of lymphoid disorders. Although Fc-FcgammaR interactions thought to account for much their therapeutic effect, this does not explain why certain mAb specificities more potent than others. An additional effector mechanism underlying action some is direct induction cell death. Previously, we demonstrated that CD20-specific (which termed type II mAbs) evoke a nonapoptotic mode death appears be linked with homotypic adhesion. Here, reveal...
Antibiotic prescribing by general practitioners (GPs) increased in the 1980s and peaked 1995. Prescribing volumes subsequently fell over a quarter between 1995 2000, mostly accounted for reduced antibiotic acute respiratory illnesses. We aimed to investigate changes consultation rates proportion of consultations with antibiotics prescribed different types tract infections.Data were derived from 108 UK practices, covering mean 642,685 patients, reporting data General Practice Research...
Following the success of rituximab, 2 other anti-CD20 monoclonal antibodies (mAbs), ofatumumab and obinutuzumab, have entered clinical use. Ofatumumab has enhanced capacity for complement-dependent cytotoxicity, whereas a type II mAb, lacks ability to redistribute into lipid rafts is glycoengineered augmented antibody-dependent cellular cytotoxicity (ADCC). We previously showed that I mAbs such as rituximab propensity undergo antigenic modulation compared with II. Here we assessed key...
Abstract Tumors routinely attract and co-opt macrophages to promote their growth, angiogenesis, metastasis. Macrophages are also the key effector cell for mAb therapies. Here we report that tumor microenvironment creates an immunosuppressive signature on tumor-associated (TAM), which favors expression of inhibitory rather than activating Fcγ receptors (FcγR), thereby limiting efficacy immunotherapy. We assessed a panel TLR STING agonists (a) ability reprogram state optimal Both STINGa TLRa...
Monoclonal antibodies (mAbs) can destroy tumors by recruiting effectors such as myeloid cells, or targeting immunomodulatory receptors to promote cytotoxic T cell responses. Here, we examined the therapeutic potential of combining a direct tumor-targeting mAb, anti-CD20, with an extended panel mAbs. Only anti-CD27/CD20 combination provided cures. This was apparent in multiple lymphoma models, including huCD27 transgenic mice using anti-huCD27, varlilumab. Detailed mechanistic analysis...
CD134 (OX40) is a member of the tumour necrosis factor receptor superfamily (TNFRSF). It acts as costimulatory on T cells, but its role NK cells poorly understood. CD137, another TNFRSF has been shown to enhance anti-tumour activity in various malignancies. Here, we examine expression and function human mouse B-cell lymphoma. was transiently upregulated upon activation both species. In contrast induction dependent close proximity to, or cell-to-cell contact with, monocytes cells. Stimulation...
Abstract Although the MYC oncogenic network represents an attractive therapeutic target for lymphoma, inhibitors have been difficult to develop. Alternatively, of epigenetic/ transcriptional regulators, particularly bromodomain and extraterminal (BET) family, used modulate MYC. However, current benzodiazepine-derivative BET (BETi) elicit disappointing responses dose-limiting toxicity in relapsed/refractory potentially because enrichment high-risk molecular features chemical...
Abstract Myofibroblastic cancer-associated fibroblast (myoCAF)–rich tumors generally contain few T cells and respond poorly to immune-checkpoint blockade. Although myoCAFs are associated with poor outcome in most solid tumors, the molecular mechanisms regulating myoCAF accumulation remain unclear, limiting potential for therapeutic intervention. Here, we identify ataxia-telangiectasia mutated (ATM) as a central regulator of phenotype. Differentiating myofibroblasts vitro cultured ex vivo...
Abstract FcγRs are key regulators of the immune response, capable binding to Fc portion IgG Abs and manipulating behavior numerous cell types. Through a variety receptors, isoforms, cellular expression patterns, they able fine-tune direct appropriate responses. Furthermore, determinants mAb immunotherapy, with isotype FcγR interaction governing therapeutic efficacy. Critical understanding biology this complex family receptors reagents that robust highly specific for each receptor. In study,...
F c receptors ( R s) play a key role in regulating and coordinating responses from both innate adaptive arms of the immune system. The inhibitory gamma receptor II cγ RIIB ; CD 32) is central to this regulation with −/− mice demonstrating augmented m A b immunotherapy, elevated incidence severity auto‐immunity, increased response b‐mediated cancer therapy. To date, these observations have remained unexploited therapeutically, partly through lack specific reagents capable exclusively binding...
Abstract Fc receptors (FcR) play a key role in coordinating responses from both the innate and adaptive immune system. The inhibitory gamma receptor (FcγRIIB/CD32B; referred to as FcγRII mice) restrains response, specifically through regulating immunoglobulin G (IgG) effector functions. FcγRII-deficient mice demonstrate elevated incidence severity of autoimmunity increased immunization infections. To explore potential FcγRIIB target for augmenting vaccines, we tested ability monoclonal...
Abstract Genetic deficiency of the inhibitory Fc receptor, FcγRIIB (CD32b), has been shown to augment activity activatory FcγR and promote mAb immunotherapy. To investigate whether mAbs capable blocking have similar capacity, we recently generated a panel specific anti-mouse that do not cross-react with other FcRs, allowing us study potential as therapeutic target. Previous work revealed number these eliciting programmed cell death targets, in present demonstrated their ability target...
Somatic hypermutation (SHM) is a pivotal process in adaptive immunity that occurs the germinal centre and allows B cells to change their primary DNA sequence diversify antigen receptors. Here, we report genome binding of Lamin B1, component nuclear envelope involved epigenetic chromatin regulation, reduced during B-cell activation formation lymphoid centres. Chromatin immunoprecipitation-Seq analysis showed kappa heavy variable immunoglobulin domains were released from B1 suppressive...
FcgRIIB controls antibody
Background Previous data suggests that anti-OX40 mAb can elicit anti-tumor effects in mice through deletion of Tregs. However, OX40 also has powerful costimulatory on T cells which could evoke therapeutic responses. Human trials with antibodies have shown these entities are well tolerated but to date delivered disappointing clinical responses, indicating the rules for optimal use anti-human (hOX40) is not yet fully understood. Changes timing and dosages may lead improved outcomes; however,...
Approximately 800,000 leukemia and lymphoma cases are diagnosed worldwide each year. Burkitt's (BL) chronic lymphocytic (CLL) examples of contrasting B-cell cancers; BL is a highly aggressive lymphoid tumor, frequently affecting children, whereas CLL typically presents as an indolent, slow-progressing the elderly. The B-cell-specific overexpression myc TCL1 oncogenes in mice induce spontaneous malignancies modeling CLL, respectively. Quantitative mass spectrometry proteomics isobaric...
Abstract Idelalisib is a highly selective oral inhibitor of PI3Kδ indicated for the treatment patients with relapsed chronic lymphocytic leukemia in combination rituximab. Despite additive clinical effects, previous studies have paradoxically demonstrated that targeted therapies potentially negatively affect anti-CD20 mAb effector mechanisms. To address these potential we investigated impact inhibition by idelalisib on mechanisms rituximab and obinutuzumab. At clinically relevant...
PI3Kδ plays pivotal roles in the maintenance, proliferation and survival of malignant B-lymphocytes. Although not curative, inhibitors (PI3Kδi) demonstrate impressive clinical efficacy and, alongside other signaling inhibitors, are revolutionizing treatment hematological malignancies. However, only limited vivo data available regarding their mechanism action. With rising number novel treatments, challenge is to identify combinations that deliver curative regimes. A deeper understanding...
Background Immune compromised mice are increasingly used for the preclinical development of monoclonal antibodies (mAb). Most common non-obese diabetic (NOD) severe combined immunodeficient (SCID) and their derivatives such as NOD SCID interleukin-2 γ-/- (NSG), which attractive hosts patient-derived xenografts. Despite widespread use, relative biological performance mAb in these strains has not been extensively studied. Methods Clinically relevant various isotypes were administered to tumor...