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Bethesda, MD, United States

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 158.85K | Year: 2009

DESCRIPTION (provided by applicant): The present proposal seeks to develop a novel anti-prostate specific antigen (PSA) IgE antibody for the treatment of prostate cancer (PCA) with the goal to induce a hypersensitivity reaction to the tumor. The objective of this proposal is to generate the anti-PSA IgE and to demonstrate that this anti-PSA IgE will target the tumor by two parallel pathways: a) by mediating bystander antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADCP) effects in the tumor microenvironment and b) by activating PSA- specific T and B cells due to uptake of immune complexes (IC) composed of anti-PSA IgE and soluble PSA antigen by antigen-presenting cells (APCs). Together, these mechanisms can result in an acute inflammation of the tumor microenvironment with subsequent tumor destruction. This will initially be investigated in in vitro systems, followed by studies in relevant animal models and clinical trials in hormone refractory PCA. Specific Aims: To accomplish our goal we propose three specific aims: 1) to construct, test and produce at small-scale the human/mouse chimeric anti-PSA IgE antibody, 2) to biochemically and biologically characterize the anti-PSA IgE in vitro, and 3) to assess the direct anti-tumor effector mechanisms of the anti-PSA IgE. Study Design: The anti-PSA IgE will be constructed by genetically fusing the cDNA encoding the variable regions of the anti-PSA MAb-AR47.47 to the DNA encoding the human kappa and epsilon constant regions and transfecting the construct into murine myeloma cells. To evaluate the properties of the anti-PSA IgE in vitro, we will evaluate the antibody's ability to bind antigen of different sources. Binding to human Fc receptor will be studied by flow cytometry, using cell lines, isolated human DCs and monocytes. Antigen-presentation studies with PSA and PSA-anti-PSA-IgE IC pulsed human DCs will be used to detect T helper CTL responses by intracellular cytokine staining for IL-4 and IL-5 vs. interferon- by CD8+ and CD4+ T cells and by confocal microscopy. Finally, we will evaluate the ability of the IgE to mediate ADCC of LNCaP tumor cells by eosinophils and test for mast cell degranulation. More elaborate in vivo studies are planned for Phase II using a human IgE/human Fc receptor transgenic mouse model. The anti-tumor activity will then be studied in this model crossed to PSA-transgenic mice bearing syngeneic human PSA expressing tumor cells. Relevance: The relevance of this project relates to the limitations of current treatment options for metastatic, hormone-refractory prostate cancer and prostate cancer in African-American men. The anti-PSA IgE will be a novel molecule capable of a two-pronged attack against cancer cells, through direct elimination of tumor cells by mast cells and eosinophils and through an adaptive anti-tumor immune response. The proposed approach is expected to significantly contribute to a decrease in the human and economic cost associated with prostate cancer and to address an unmet medical need for treatment of hormone-refractory cancer. PUBLIC HEALTH RELEVANCE: With an estimated 186,320 new cases in the US for 2008, Prostate Cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths in American men. Incidence rates and death rates are significantly higher in African American men than in white men. Although the 5-year survival rate for all stages combined has increased due to earlier diagnosis, patients with metastatic disease, which account for approximately 15% of patients, often cannot be cured by chemotherapy and palliative radiotherapies once patients become refractory to androgen ablation, thus the need to develop innovative modalities of treatment.

Linssen M.M.L.,Leiden University | van Raalte D.H.,VU University Amsterdam | Toonen E.J.M.,Immune Therapeutics | Alkema W.,Merck And Co. | And 6 more authors.
Cellular Signalling | Year: 2011

Glucocorticoids (GCs), such as prednisolone (PRED), are widely prescribed anti-inflammatory drugs, but their use may induce glucose intolerance and diabetes. GC-induced beta cell dysfunction contributes to these diabetogenic effects through mechanisms that remain to be elucidated. In this study, we hypothesized that activation of the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress could be one of the underlying mechanisms involved in GC-induced beta cell dysfunction. We report here that PRED did not affect basal insulin release but time-dependently inhibited glucose-stimulated insulin secretion in INS-1E cells. PRED treatment also decreased both PDX1 and insulin expression, leading to a marked reduction in cellular insulin content. These PRED-induced detrimental effects were found to be prevented by prior treatment with the glucocorticoid receptor (GR) antagonist RU486 and associated with activation of two of the three branches of the UPR. Indeed, PRED induced a GR-mediated activation of both ATF6 and IRE1/XBP1 pathways but was found to reduce the phosphorylation of PERK and its downstream substrate eIF2α. These modulations of ER stress pathways were accompanied by upregulation of calpain 10 and increased cleaved caspase 3, indicating that long term exposure to PRED ultimately promotes apoptosis. Taken together, our data suggest that the inhibition of insulin biosynthesis by PRED in the insulin-secreting INS-1E cells results, at least in part, from a GR-mediated impairment in ER homeostasis which may lead to apoptotic cell death. © 2011 Elsevier Inc. Source

Frijters R.,Radboud University Nijmegen | van Vugt M.,Immune Therapeutics | Smeets R.,Immune Therapeutics | van Schaik R.,Schering | And 3 more authors.
PLoS Computational Biology | Year: 2010

The scientific literature represents a rich source for retrieval of knowledge on associations between biomedical concepts such as genes, diseases and cellular processes. A commonly used method to establish relationships between biomedical concepts from literature is co-occurrence. Apart from its use in knowledge retrieval, the co-occurrence method is also wellsuited to discover new, hidden relationships between biomedical concepts following a simple ABC-principle, in which A and C have no direct relationship, but are connected via shared B-intermediates. In this paper we describe CoPub Discovery, a tool that mines the literature for new relationships between biomedical concepts. Statistical analysis using ROC curves showed that CoPub Discovery performed well over a wide range of settings and keyword thesauri. We subsequently used CoPub Discovery to search for new relationships between genes, drugs, pathways and diseases. Several of the newly found relationships were validated using independent literature sources. In addition, new predicted relationships between compounds and cell proliferation were validated and confirmed experimentally in an in vitro cell proliferation assay. The results show that CoPub Discovery is able to identify novel associations between genes, drugs, pathways and diseases that have a high probability of being biologically valid. This makes CoPub Discovery a useful tool to unravel the mechanisms behind disease, to find novel drug targets, or to find novel applications for existing drugs. © 2010 Frijters et al. Source

Zhao D.,Liaoning Medical University | Plotnikoff N.,Immune Therapeutics | Griffin N.,Immune Therapeutics | Song T.,China Medical University at Heping | Shan F.,Liaoning Medical University
International Immunopharmacology | Year: 2016

Methionine enkephalin (MENK), an endogenous neuropeptide has a crucial role in both neuroendocrine and immune systems. MENK is believed to have an immunoregulatory activity to have cancer biotherapy activity by binding to the opioid receptors on immune and cancer cells. Clinical trial studies in cancer patients have shown that MENK activates immune cells directly and by inhibiting regulatory T-cells (Tregs). MENK may also change the tumor microenvironment by binding to opioid receptor on or in cancer cells. All of these mechanisms of action have biologic significance and potential for use in cancer immunotherapy. Furthermore, they reveal a relationship between the endocrine and immune systems. Due to the apparent role of MENK in cancer therapy we reviewed herein, the research undertaken with MENK in recent years; which has advanced our understanding of the role MENK has in cancer progression and its relationship to immunity, supporting MENK as a new strategy for cancer immunotherapy. © 2016 Elsevier B.V. All rights reserved. Source

Daniels T.R.,University of California at Los Angeles | Leuchter R.K.,University of California at Los Angeles | Quintero R.,University of California at Los Angeles | Helguera G.,University of California at Los Angeles | And 7 more authors.
Cancer Immunology, Immunotherapy | Year: 2012

Breast and ovarian cancer are two of the leading causes of cancer deaths among women in the United States. Overexpression of the HER2/neu oncoprotein has been reported in patients affected with breast and ovarian cancers, and is associated with poor prognosis. To develop a novel targeted therapy for HER2/neu expressing tumors, we have constructed a fully human IgE with the variable regions of the scFv C6MH3-B1 specific for HER2/neu. This antibody was expressed in murine myeloma cells and was properly assembled and secreted. The Fc region of this antibody triggers in vitro degranulation of rat basophilic cells expressing human FcεRI (RBL SX-38) in the presence of murine mammary carcinoma cells that express human HER2/neu (D2F2/E2), but not the shed (soluble) antigen (ECDHER2) alone. This IgE is also capable of inducing passive cutaneous anaphylaxis in a human FcεRIα transgenic mouse model, in the presence of a cross-linking antibody, but not in the presence of soluble ECDHER2. Additionally, IgE enhances antigen presentation in human dendritic cells and facilitates cross-priming, suggesting that the antibody is able to stimulate a secondary T-cell anti-tumor response. Furthermore, we show that this IgE significantly prolongs survival of human FcεRIα transgenic mice bearing D2F2/E2 tumors. We also report that the anti-HER2/neu IgE is well tolerated in a preliminary study conducted in Macaca fascicularis (cynomolgus) monkeys. In summary, our results suggest that this IgE should be further explored as a potential therapeutic against HER2/neu overexpressing tumors, such as breast and ovarian cancers. © 2011 Springer-Verlag. Source

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