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Providence, RI, United States

Su Y.,Uniformed Services University of the Health Sciences | Su Y.,University of Maryland Baltimore County | Rossi R.,Uniformed Services University of the Health Sciences | Rossi R.,University of Maryland Baltimore County | And 4 more authors.
Journal of Leukocyte Biology | Year: 2013

Tregitopes are a set of epitopes, derived from IgG, that bind to MHCII, activate nTregs, and promote tolerance. We have now confirmed that coadministration of Tregi-topes with a range of proteins (autoantigens and nominal antigens, such as OVA) in vitro and in vivo leads to suppression of T cell and antibody responses to the test antigens. In this study, we demonstrate that Tregi-topes are not immunogenic in vivo even when emulsified with strong adjuvants, such as IFA or CFA. Moreover, in vivo administration of Tregitopes with IFA or CFA does not induce Th1 or Th2 cytokine expression under restimulation conditions in vitro. We investigated tolerance induction by codelivering Tregitopes with OVA using B cells. When B cells were pulsed with OVA plus Tregitopes and transferred into naïve mice, we found that cellular and humoral immune responses to the OVA were suppressed. As a result of their ability to induce Tregs and the absence of immunogenicity in the context of strong adjuvants, Tregitopes might be considered a novel immunomodulatory approach for the suppression of immune responses to protein therapeutics (such as FVIII and mAb), as well as for treatment of autoimmune diseases. © Society for Leukocyte Biology. Source


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2016

DESCRIPTION provided by applicant The avian origin H N influenza virus that emerged in humans in China in presents a unique challenge to vaccine development because it is poorly immunogenic Neutralizing antibodies are not detected in acute phase infection Anti H antibody responses are significantly delayed and exhibit low avidity in comparison with antibodies generated following seasonal influenza vaccination and infection Furthermore unadjuvanted H N vaccines developed using conventional approaches elicit weak hemagglutinin inhibition HAI antibody titers in clinical trials Adjuvanted formulations may overcome this limitation but present significant regulatory challenges because adverse effects have recently been associated with adjuvanted influenza vaccines Alternative vaccine approaches are needed to redress the low immunogenicity of H N and circumvent safety risks Because HAI titers are directly related to effector CD T cell frequencies induced by vaccination we hypothesize that a vaccine strategy that enhances effector CD T cell activation will improve H N vaccine efficacy without requiring adjuvant formulation In published studies we observed that the T cell epitope content of H N virus differs significantly from more immunogenic influenza subtypes H N contains fewer T cell epitopes and some epitopes stimulate regulatory T cells Tregs that may help the virus evade effector responses needed for protection These findings suggest that H N vaccine design that carefully addresses the T cell subsets primed by immunization will overcome limitations of conventional vaccine approaches The goal of this research program is to produce an unadjuvanted influenza H N virus like particle VLP vaccine that augments effector CD T cell responses and diminishes Treg effects for enhanced protection against disease This new SBIR program will apply cutting edge computational and experimental methods that EpiVax has successfully applied against influenza and other viral and bacterial pathogens as well as deep experience in influenza VLP production and vaccine testing in collaboration with Dr Ted Ross at the University of Georgia Two different engineered VLP strategies will be tested i addition of effector epitopes and ii removal of Treg epitopes Using these prototype effector T cell epitope enhanced VLP vaccines in the proof of concept program described here we will evaluate the vaccines for immunogenicity and efficacy and move forward in a Phase II program to further optimize efficacy and complete safety toxicity studies in the run up to clinical trial PUBLIC HEALTH RELEVANCE The avian origin H N influenza virus that emerged in humans in China in presents a unique challenge to vaccine development because it is poorly immunogenic Neutralizing antibodies are not detected in acute phase infection Anti H antibody responses are significantly delayed and exhibit low avidity in comparison with antibodies generated following seasonal influenza vaccination and infection Furthermore unadjuvanted H N vaccines developed using conventional approaches elicit weak hemagglutinin inhibition HAI antibody titers in clinical trials Adjuvanted formulations may overcome this limitation but present significant regulatory challenges because adverse effects have recently been associated with adjuvanted influenza vaccines Alternative vaccine approaches are needed to redress the low immunogenicity of H N and circumvent safety risks Because HAI titers are directly related to effector CD T cell frequencies induced by vaccination we hypothesize that a vaccine strategy that enhances effector CD T cell activation will improve H N vaccine efficacy without requiring adjuvant formulation In published studies we observed that the T cell epitope content of H N virus differs significantly from more immunogenic influenza subtypes H N contains fewer T cell epitopes and some epitopes stimulate regulatory T cells Tregs that may help the virus evade effector responses needed for protection These findings suggest that H N vaccine design that carefully addresses the T cell subsets primed by immunization will overcome limitations of conventional vaccine approaches The goal of this research program is to produce an unadjuvanted influenza H N virus like particle VLP vaccine that augments effector CD T cell responses and diminishes Treg effects for enhanced protection against disease This new SBIR program will apply cutting edge computational and experimental methods that EpiVax has successfully applied against influenza and other viral and bacterial pathogens as well as deep experience in influenza VLP production and vaccine testing in collaboration with Dr Ted Ross at the University of Georgia Two different engineered VLP strategies will be tested i addition of effector epitopes and ii removal of Treg epitopes Using these prototype effector T cell epitope enhanced VLP vaccines in the proof of concept program described here we will evaluate the vaccines for immunogenicity and efficacy and move forward in a Phase II program to further optimize efficacy and complete safety toxicity studies in the run up to clinical trial


Two major obstacles confronting HIV vaccine design have been the extensive viral diversity of HIV-1 globally and viral evolution driven by escape from CD8(+) cytotoxic T-cell lymphocyte (CTL)-mediated immune pressure. Regions of the viral genome that are not able to escape immune response and that are conserved in sequence and across time may represent the "Achilles' heel" of HIV and would be excellent candidates for vaccine development. In this study, T-cell epitopes were selected using immunoinformatics tools, combining HLA-A3 binding predictions with relative sequence conservation in the context of global HIV evolution. Twenty-seven HLA-A3 epitopes were chosen from an analysis performed in 2003 on 10,803 HIV-1 sequences, and additional sequences were selected in 2009 based on an expanded set of 43,822 sequences. These epitopes were tested in vitro for HLA binding and for immunogenicity with PBMCs of HIV-infected donors from Providence, Rhode Island. Validation of these HLA-A3 epitopes conserved across time, clades, and geography supports the hypothesis that epitopes such as these would be candidates for inclusion in our globally relevant GAIA HIV vaccine constructs. Source


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 757.71K | Year: 2012

DESCRIPTION (provided by applicant): The goal of this new SBIR program is to produce a combined clotting Factor VIII replacement and immunomodulatory therapy that will provide FVIII-specific tolerance induction at therapeutic doses for Hemophilia A patients. Hemophiliacs with lt 1% functional FVIII are classified as severe and must receive regular doses of replacement factor. A major issue with successful FVIII replacement therapy for Hemophilia A is overcoming the neutralizing antibody response against FVIII that is seen in up to 30% of hemophiliacs and 50% of patients with severe disease. These inhibitors delay or inhibit clotting by interfering with FVIII binding to its ligands. A number of treatments for inhibitors exist but these approaches are either not fully successful or still experimental and present a large health risk for the patient. There is an urgent need for a safe, biologically rational and cost effective approach to induce long-term immune tolerance to FVIII. Tregitopes are immunoglobulin-derived natural regulatory T-cell (nTreg) epitopes that expand a subset of circulating nTregs, leading to suppression of inflammation and, when administered with a target antigen, adaptive tolerance. Since publication of this discovery in 2008, we have shown that presentation of Tregitopes at the surface of antigen presentation cells (APCs) to nTregs drives tolerogenic pathways in both APCs and nTregs, and induces target-antigen specific adaptive Tregs that interface with the same APC. Thus, as a natural immune system 'off switch,' Tregitopes have great potential as therapeutics to induce immunological tolerance to co-administered proteins. We therefore propose to couple Tregitopes to FVIII to produce a novel combined replacement and tolerance induction therapy. In this Phase I proof-of concept application, we propose to (i) demonstrate that FVIII-Tregitope modulates human T cell responses and establish correlates of tolerance induction that may be used in clinical trial design and (ii) demonstrate FVIII-Tregitope-mediated tolerance induction in an in vivo hemophilia model, which enables evaluation of Tregitope efficacy on the key outcome - elimination of inhibitors. In future Phase II studies, we will transition to recombinant production of FVIII-Tregitope, a process too complex and costly for proof-of-concept studies. ProBioGen, our Phase II collaborator, is a leading company with expertise in activities central to the manufacture of recombinant human FVIII, including cell line engineering, upstream fermentation, downstream purification, liquid pre-formulation of bulk drug substance and in-process analytics including titer determination and chromogenic determination of FVIII bioactivity. In addition, we have established a strong collaboration with a large Pharma that has experience in the regulatory and clinical trial aspects of FVIII drug development and anticipate that FVIII-Tregitope will move into clinical studies once we achieve the goals of the SBIR program. PUBLIC HEALTH RELEVANCE: Hemophilia A patients do not develop immune tolerance to the very treatment they require, replacement clotting Factor VIII. This research program aims to demonstrate that Factor VIII, when linked to immunosuppressive segments of immunoglobulin, is tolerogenic atnormal therapeutic dosing levels.


Cousens L.P.,Epivax Inc. | Tassone R.,Epivax Inc. | Mazer B.D.,McGill University | Ramachandiran V.,Emory University | And 3 more authors.
Autoimmunity Reviews | Year: 2013

In the course of screening immunoglobulin G (IgG) sequences for T cell epitopes, we identified novel Treg epitope peptides, now called Tregitopes, contained in the highly conserved framework regions of Fab and Fc. Tregitopes may provide one explanation for the expansion and stimulation of Treg cells following intravenous immunoglobulin (IVIg) therapy. Their distinguishing characteristics include in silico signatures that suggest high-affinity binding to multiple human HLA class II DR and conservation across IgG isotypes and mammalian species with only minor amino acid modifications. Tregitopes induce expansion of CD4+/CD25hi/FoxP3+ T cells and suppress immune responses to co-incubated antigens in vitro. By comparing the human IgG Tregitopes (hTregitopes 167 and 289, located in the IgG CH1 and CH2 domains) and Fab to murine sequences, we identified class II-restricted murine Tregitope homologs (mTregitopes). In vivo, mTregitopes suppress inflammation and reproducibly induce Tregs to expand. In vitro studies suggest that the Tregitope mechanism of action is to induce Tregs to respond, leading to production of regulatory signals, followed by modulation of dendritic cell phenotype. The identification of Treg epitopes in IgG suggests that additional Tregitopes may also be present in other autologous proteins; methods for identifying and validating such peptides are described here. The discovery of Tregitopes in IgG and other autologous proteins may lead to the development of new insights as to the role of Tregs in autoimmune diseases. © 2012 Elsevier B.V. Source

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