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Dive into the research topics where Amy E. Gilbert is active.

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Featured researches published by Amy E. Gilbert.


Journal of Clinical Investigation | 2013

IgG4 subclass antibodies impair antitumor immunity in melanoma

Panagiotis Karagiannis; Amy E. Gilbert; Debra H. Josephs; Niwa Ali; Tihomir Dodev; Louise Saul; Isabel Correa; Luke Roberts; Emma Beddowes; Alexander Koers; Carl Hobbs; Silvia Ferreira Rodrigues Mendes Ferreira; Jenny Geh; Ciaran Healy; Mark Harries; K. Acland; Philip J. Blower; Tracey J. Mitchell; David J. Fear; James Spicer; Katie E. Lacy; Frank O. Nestle; Sophia N. Karagiannis

Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10–driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4+-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell–mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcγRI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.


Scientific Reports | 2015

A tool kit for rapid cloning and expression of recombinant antibodies

Tihomir Dodev; Panagiotis Karagiannis; Amy E. Gilbert; Debra H. Josephs; Holly Bowen; Louisa K. James; Heather J. Bax; Rebecca L. Beavil; Marie O. Y. Pang; Hannah J. Gould; Sophia N. Karagiannis; Andrew J. Beavil

Over the last four decades, molecular cloning has evolved tremendously. Efficient products allowing assembly of multiple DNA fragments have become available. However, cost-effective tools for engineering antibodies of different specificities, isotypes and species are still needed for many research and clinical applications in academia. Here, we report a method for one-step assembly of antibody heavy- and light-chain DNAs into a single mammalian expression vector, starting from DNAs encoding the desired variable and constant regions, which allows antibodies of different isotypes and specificity to be rapidly generated. As a proof of principle we have cloned, expressed and characterized functional recombinant tumor-associated antigen-specific chimeric IgE/κ and IgG1/κ, as well as recombinant grass pollen allergen Phl p 7 specific fully human IgE/λ and IgG4/λ antibodies. This method utilizing the antibody expression vectors, available at Addgene, has many applications, including the potential to support simultaneous processing of antibody panels, to facilitate mechanistic studies of antigen-antibody interactions and to conduct early evaluations of antibody functions.


Cancer Immunology, Immunotherapy | 2012

Recombinant IgE antibodies for passive immunotherapy of solid tumours: from concept towards clinical application

Sophia N. Karagiannis; Debra H. Josephs; Panagiotis Karagiannis; Amy E. Gilbert; Louise Saul; Sarah Rudman; Tihomir Dodev; Alexander Koers; Philip J. Blower; Christopher Corrigan; Andrew J. Beavil; James Spicer; Frank O. Nestle; Hannah J. Gould

Therapeutic antibodies have revolutionised treatment of some cancers and improved prognosis for many patients. Over half of those available are approved for haematological malignancies, but efficacious antibodies for solid tumours are still urgently needed. Clinically available antibodies belong to the IgG class, the most prevalent antibody class in human blood, while other classes have not been extensively considered. We hypothesised that the unique properties of IgE, a class of tissue-resident antibodies commonly associated with allergies, which can trigger powerful immune responses through strong affinity for their particular receptors on effector cells, could be employed for passive immunotherapy of solid tumours such as ovarian and breast carcinomas. Our laboratory has examined this concept by evaluating two chimaeric antibodies of the same specificity (MOv18) but different isotype, an IgG1 and an IgE against the tumour antigen folate receptor α (FRα). The latter demonstrates the potency of IgE to mount superior immune responses against tumours in disease-relevant models. We identified Fcε receptor-expressing cells, monocytes/macrophages and eosinophils, activated by MOv18 IgE to kill tumour cells by mechanisms such as ADCC and ADCP. We also applied this notion to a marketed therapeutic, the humanised IgG1 antibody trastuzumab and engineered an IgE counterpart, which retained the functions of trastuzumab in restricting proliferation of HER2/neu-expressing tumour cells but also activated effector cells to kill tumour cells by different mechanisms. On-going efficacy, safety evaluations and future first-in-man clinical studies of IgE therapeutics constitute key metrics for this concept, providing new scope for antibody immunotherapies for solid tumours.


Clinical & Experimental Allergy | 2011

Harnessing engineered antibodies of the IgE class to combat malignancy: initial assessment of FcɛRI‐mediated basophil activation by a tumour‐specific IgE antibody to evaluate the risk of type I hypersensitivity

Sarah Rudman; Debra H. Josephs; H. Cambrook; Panagiotis Karagiannis; Amy E. Gilbert; Tihomir Dodev; John F. Hunt; Alexander Koers; Ana Montes; Leonie S. Taams; Silvana Canevari; Mariangela Figini; Philip J. Blower; Andrew J. Beavil; C. F. Nicodemus; Christopher Corrigan; Stan B. Kaye; Frank O. Nestle; Hannah J. Gould; James Spicer; Sophia N. Karagiannis

Background IgE antibodies, sequestered into tissues and retained locally by the high‐affinity IgE receptor, FcɛRI, on powerful effector cells such as mast cells, macrophages and eosinophils, may offer improvements in the therapy of solid tumours. The chimeric antibody, MOv18 IgE, against the human ovarian carcinoma antigen, folate receptor α (FRα), is more effective than its IgG1 counterpart in xenograft models of ovarian cancer. Although MOv18 IgE binds to a single epitope on FRα and cannot cross‐link IgE receptors on basophils, there remains a risk that components in the circulation of ovarian cancer patients might cross‐link FRα‐MOv18‐IgE‐receptor‐FcɛRI complexes on basophils to cause type I hypersensitivity.


PLOS ONE | 2011

Monitoring the Systemic Human Memory B Cell Compartment of Melanoma Patients for Anti-Tumor IgG Antibodies

Amy E. Gilbert; Panagiotis Karagiannis; Tihomir Dodev; Alexander Koers; Katie E. Lacy; Debra H. Josephs; Pooja Takhar; Jenny L. C. Geh; Ciaran Healy; Mark Harries; K. Acland; Sarah Rudman; Rebecca L. Beavil; Philip J. Blower; Andrew J. Beavil; Hannah J. Gould; James Spicer; Frank O. Nestle; Sophia N. Karagiannis

Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10) to primary and metastatic melanoma cells compared to healthy volunteers (n = 10) (P<0.0001). Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21) (P<0.0001). Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800) compared to 2% of cultures from healthy controls (n = 600) produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer.


OncoImmunology | 2013

IgG4 antibodies and cancer-associated inflammation Insights into a novel mechanism of immune escape

Panagiotis Karagiannis; Amy E. Gilbert; Frank O. Nestle; Sophia N. Karagiannis

The role of B cells and antibodies in cancer is insufficiently understood but is receiving increasing attention. We have recently identified IgG4 as an antibody subclass elicited by melanoma-associated interleukin-10-driven inflammation. In this setting, IgG4 exhibit inefficient immunostimulatory capacity and block the cytotoxic activities of other antibodies. These previously unappreciated mechanisms of immune escape may constitute promising targets for the development of novel anticancer immunotherapies.


Cancer Research | 2017

Anti-folate receptor-α IgE but not IgG recruits macrophages to attack tumors via TNFa/MCP-1 signaling

Debra H. Josephs; Heather J. Bax; Tihomir Dodev; Mirella Georgouli; Mano Nakamura; Giulia Pellizzari; Louise Saul; Panagiotis Karagiannis; Anthony Cheung; Cecilia Herraiz; Kristina M. Ilieva; Isabel Correa; Matthew Fittall; Silvia Crescioli; Patrycja Gazinska; Natalie Woodman; Silvia Mele; Giulia Chiaruttini; Amy E. Gilbert; Alexander Koers; Marguerite G. Bracher; Christopher Selkirk; Heike Lentfer; Claire Barton; Elliott Lever; Gareth Muirhead; Sophia Tsoka; Silvana Canevari; Mariangela Figini; Ana Montes

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 cancer cell growth by engaging high-affinity Fc receptors on monocytes and macrophages; however, the underlying therapeutic mechanisms were undefined and in vivo proof of concept was limited. Here, an immunocompetent rat model was designed to recapitulate the human IgE-Fcε receptor system for cancer studies. We also generated rat IgE and IgG mAbs specific for the folate receptor (FRα), which is expressed widely on human ovarian tumors, along with a syngeneic rat tumor model expressing human FRα. Compared with IgG, anti-FRα IgE reduced lung metastases. This effect was associated with increased intratumoral infiltration by TNFα+ and CD80+ macrophages plus elevated TNFα and the macrophage chemoattractant MCP-1 in lung bronchoalveolar lavage fluid. Increased levels of TNFα and MCP-1 correlated with IgE-mediated tumor cytotoxicity by human monocytes and with longer patient survival in clinical specimens of ovarian cancer. Monocytes responded to IgE but not IgG exposure by upregulating TNFα, which in turn induced MCP-1 production by monocytes and tumor cells to promote a monocyte chemotactic response. Conversely, blocking TNFα receptor signaling abrogated induction of MCP-1, implicating it in the antitumor effects of IgE. Overall, these findings show how antitumor IgE reprograms monocytes and macrophages in the tumor microenvironment, encouraging the clinical use of IgE antibody technology to attack cancer beyond the present exclusive reliance on IgG. Cancer Res; 77(5); 1127-41. ©2017 AACR.


Microbiology spectrum | 2013

Immunoglobulin E and Allergy: Antibodies in Immune Inflammation and Treatment.

Sophia N. Karagiannis; Panagiotis Karagiannis; Debra H. Josephs; Louise Saul; Amy E. Gilbert; Nadine Upton; Hannah J. Gould

The pathogenic role of immunoglobulin E (IgE) antibodies in triggering and maintaining allergic inflammation in response to allergens is due to the binding of multivalent allergens to allergen-specific IgEs on sensitized effector cells. These interactions trigger effector cell activation, resulting in release of potent inflammatory mediators, recruitment of inflammatory cells, antigen presentation, and production of allergen-specific antibody responses. Since its discovery in the 1960s, the central role of IgE in allergic disease has been intensively studied, placing IgE and its functions at the heart of therapeutic efforts for the treatment of allergies. Here, we provide an overview of the nature, roles, and significance of IgE antibodies in allergic diseases, infections, and inflammation and the utility of antibodies as therapies. We place special emphasis on allergen-IgE-Fcε receptor complexes in the context of allergic and inflammatory diseases and describe strategies, including monoclonal antibodies, aimed at interrupting these complexes. Of clinical significance, one antibody, omalizumab, is presently in clinical use and works by preventing formation of IgE-Fcε receptor interactions. Active immunotherapy approaches with allergens and allergen derivatives have also demonstrated clinical benefits for patients with allergic diseases. These treatments are strongly associated with serum increases of IgE-neutralizing antibodies and feature a notable redirection of humoral responses towards production of antibodies of the IgG4 subclass in patients receiving immunotherapies. Lastly, we provide a new perspective on the rise of recombinant antibodies of the IgE class recognizing tumor-associated antigens, and we discuss the potential utility of tumor antigen-specific IgE antibodies to direct potent IgE-driven immune responses against tumors.


British Journal of Dermatology | 2012

IgE antibodies targeting a major melanoma antigen are more effective than IgG antibodies for tumour protection in a humanized melanoma model

Panagiotis Karagiannis; Amy E. Gilbert; Tihomir Dodev; Debra H. Josephs; Nura Alkathiri; Dimitra Dafou; Chrysanthi Ainali; Alexander Koers; Louise Saul; Sophia Tsoka; James Spicer; Hannah J. Gould; Andrew J. Beavil; Frank O. Nestle; Sophia N. Karagiannis

Bioscience, University Sydney, AUPhotoaged skin is characterised by profound remodelling of the extracellular matrix (ECM). We have previously shown that UV chromophore (Cys, His, Phe, Trp and Tyr)-rich proteins are differentially degraded by UV radiation (UVR). We tested the hypothesises that; (i) UV-mediated ECM degradation occurs via reactive oxygen species (ROS), by exposing chromophore-rich fibronectin and chromophore-poor tropoelastin to UVR in depleted-O2 and D2O environments and (ii) exogenous ROS mediates differential degradation of the same proteins. As the photodynamic production of ROS can be inhibited in depleted-O2 environments we exposed purified fibronectin to a broadband UVB (TL-12: 50 and 500mJ/cm2) in ambient and depleted-O2 conditions by bubbling with N2. Solutions were analysed by reducing SDS-PAGE. Irradiation of fibronectin in ambient-O2 (50 and 500mJ/cm2) caused dose-dependent aggregation (5 and 83 fold changes in the optical density (OD) of the aggregate at 50 and 500mJ/cm2 respectively), fibronectin aggregation was abrogated (68 fold lower OD) in the depleted-O2 compared with ambient-O2. Conversely, fibronectin aggregation was increased 4 fold in D2O compared with H2O environments. UV-mediated changes to the molecular weight (Mw) of fibronectin were recapitulated by exposure to H2O2 (40mM for 2 hrs). In contrast, UVB irradiation in both H2O and D2O had no observable effect on the Mw of tropoelastin. Therefore, ROS may play an important role in the selective degradation of long-lived UV chromophore-rich ECM in both UV-exposed and protected ageing tissues. Research supported by Alliance Boots.


PLOS ONE | 2018

The influence of poverty and rabies knowledge on healthcare seeking behaviors and dog ownership, Cameroon

Galileu Barbosa Costa; Amy E. Gilbert; Benjamin P. Monroe; Jesse D. Blanton; Sali Ngam Ngam; Sergio Recuenco; Ryan M. Wallace

Background Rabies is a fatal encephalitis caused by lyssaviruses, with most human cases worldwide resulting from rabid dog bites. Although effective animal and human vaccines have been available for over 100 years, control efforts have not been adequately implemented on the global scale and rabies remains one of the greatest global zoonotic threats to human health. We conducted a knowledge, attitudes and practices survey in Northern Cameroon to describe dog ownership characteristics, rates of dog bites, and post-bite healthcare seeking behaviors. Methods The survey was performed in four rural Cameroonian communities. A structured community-based questionnaire was conducted over a 20-day period in April 2010, and focused on socio-economic factors correlated with gaps in rabies knowledge. Information pertaining to socio-demographics, as well as attitudes and practices with regard to animal bites and bite treatment practices were recorded. Characteristics of dog ownership such as dog confinement, resources provided to dogs, and dog vaccination status were examined. Human to dog ratios were compared on a linear scale to poverty scores by community. When applicable, 2-tailed Chi-square tests or Fisher’s exact tests were calculated to determine relationships between variables. We also used One-way Analysis of Variance (ANOVA) to identify associations between rabies knowledge and wealth with dog ownership, dog vaccination, and human healthcare seeking behaviors. Independent variables were evaluated using multivariate logistic regression analysis. Results A total of 208 households were enrolled. Respondents were predominantly male (68.3%), with a median age of 43.6 years. Eighty-four households (39.9%) reported owning a total of 141 dogs (human dog ratio 10.4:1). The majority of dogs (61%) were allowed to roam freely. A history of rabies vaccination was reported for 30.8% of owned dogs. Respondents reported 11 bites during the two years preceding the survey (annual bite incidence was 2.6% [95% CI 1.4%– 4.6%]). Only one person (9.1%) received rabies post-exposure prophylaxis (PEP), and none described symptoms of clinical illness consistent with rabies. Respondents who indicated that they would seek medical care and PEP after a dog bite had higher average wealth and rabies knowledge index scores (p = 0.01 and 0.04, respectively). Respondents who indicated that they would seek care from a traditional healer had significantly lower wealth scores, but not significantly different knowledge scores (p < 0.01 and p = 0.49, respectively). Conclusions In the communities evaluated, the majority of dogs were allowed to roam freely and had no history of rabies vaccination; factors that favor enzootic transmission of canine rabies virus. We also identified a strong relationship between poverty and dog ownership. Bite events were relatively common among respondents, and very few victims reported utilizing health services to treat wounds. Increased wealth and knowledge were significantly associated with increased likelihood that a respondent would seek medical care and post-exposure prophylaxis. These findings indicate the need for educational outreach to raise awareness of dog rabies and proper prevention measures.

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