Providence, RI, United States
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Patent
Epivax Inc. | Date: 2012-05-09

The invention is directed to T cell epitopes wherein said epitopes comprises a peptide or polypeptide chain comprising at least a portion of an immunoglobulin constant or variable region. The invention also relates to methods of using and methods of making the epitopes of the invention.


Patent
Epivax Inc. | Date: 2012-02-29

The invention is directed to T cell epitopes wherein said epitopes comprises a peptide or polypeptide chain comprising at least a portion of an immunoglobulin constant or variable region. The invention also relates to methods of using and methods of making the epitopes of the invention.


Patent
Epivax Inc. | Date: 2015-07-22

The invention is directed to T cell epitopes wherein said epitopes comprises a peptide or polypeptide chain comprising at least a portion of an immunoglobulin constant region. The invention also relates to methods of using and methods of making the epitopes of the invention.


Patent
Epivax Inc. | Date: 2012-05-09

The invention is directed to T cell epitopes wherein said epitopes comprises a peptide or polypeptide chain comprising at least a portion of an immunoglobulin constant or variable region. The invention also relates to methods of using and methods of making the epitopes of the invention.


Patent
Epivax Inc. | Date: 2012-05-09

The invention is directed to T cell epitopes wherein said epitopes comprises a peptide or polypeptide chain comprising at least a portion of an immunoglobulin constant or variable region. The invention also relates to methods of using and methods of making the epitopes of the invention.


Patent
Epivax Inc. | Date: 2012-02-29

The invention is directed to T cell epitopes wherein said epitopes comprises a peptide or polypeptide chain comprising at least a portion of an immunoglobulin constant or variable region. The invention also relates to methods of using and methods of making the epitopes of the invention.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2012

DESCRIPTION (provided by applicant): Inducing Tolerance to Enzyme Replacement Therapy for Pompe Disease Pompe disease is a lysosomal storage disorder caused by defects in the enzyme acid alpha-glucosidase (GAA) that leads to glycogen accumulation affectingheart and skeletal muscle. Enzyme-replacement therapy with recombinant human (rh)GAA saves the lives of children with Pompe disease. The prognosis for patients who have no circulating endogenous GAA (CRIM-negative Pompe disease) is markedly worse. The development of high titers of anti-rhGAA antibody and decreased effectiveness of replacement therapy often result in the death of CRIM-negative Pompe infants in the first year of life. We propose to evaluate the effect of natural tolerance-inducing peptides,Tregitopes, in a murine model of CRIM-negative Pompe disease. Tregitopes cause the expansion and activation of regulatory T cells, suppress inflammatory T cell responses and reduce humoral immune responses to co-administered proteins. In the plan outlinedhere, we will test Tregitopes co-delivered with GAA epitopes, as a tolerance-inducing (1) Prophylactic therapy or (2) Therapeutic treatment of ongoing anti-GAA immune responses. We will evaluate an AAV-vector for Tregitope-GAA epitope delivery. The programwill establish proof-of-principle that will lead to further studies in Phase II. Even a moderate degree of success with the protocol developed here may improve the lives of CRIM-negative babies and could be applied to other enzyme replacement therapies towhich ADA have been induced. An experienced team will carry out the program, including Richard Garman who has extensive experience with the Pompe mouse model, Annie De Groot, a well-established T cell immunologist, Leslie Cousens, Ph.D. expert in Tregitope immunomodulation studies, Tim Messitt, Ph.D. molecular biologist and Federico Mingozzi Ph.D., AAV expert, who will co-develop the Tregitope-GAA AAV vector. PUBLIC HEALTH RELEVANCE: We propose to evaluate the effect of natural tolerance-inducing peptides, Tregitopes (T regulatory cell epitopes), to induce long-lasting and specific tolerance to enzyme replacement therapy in a murine model of Pompe disease. Proof of principle for Tregitopes in treating anti-drug antibody responses in the context of Pompedisease will have immediate impact on the field of enzyme replacement therapy and could lead to accelerated adaptation of Tregitope therapy in the treatment of these children.


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.


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


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.47M | Year: 2012

DESCRIPTION (provided by applicant): The goal of this Phase II project is to advance the development of novel tolerance-inducing peptides (Tregitopes) to prevent and/or treat Type 1 diabetes (T1D) by optimizing the clinical delivery vehicle and treatment protocol, and by identifying correlates of efficacy in preparation for Phase 1 clinical trials. More than 13,000 children in the U.S. are diagnosed with Type 1 Diabetes (T1D) each year. T1D results from destruction of insulin-producing pancreatic islet cells by auto-reactive T cells, eventually leading to glucose intolerance. Induction of antigen (Ag)-specific tolerance is the key to effective immunotherapy for T1D. EpiVax discovered a new biologic intervention for T1D called Tregitopes, which are administered along with insulin peptides in order to reprogram the autoimmune responses and induce islet cell Ag-specific tolerance. On the basis of excellent Phase I results, and parallel collaborative studies demonstrating the induction of Ag- specific tolerance in gene therapy and transplant models, this Phase II project will advance a form of Tregitope therapy called T1D-Ag-Specific Adaptive Tolerance Induction (T1D-ASATI) toward preclinical development. Successful translation of T1D-ASATI to the clinic will havea radical impact on the field of diabetes therapy, potentially abrogating the need for insulin therapy in T1D. Studies in Phase I of this project demonstrated that Tregitopes can both prevent and successfully treat diabetes in NOD mice, when delivered prior to, or at the onset of diabetes, however, the delivery vehicles tested in Phase I are not FDA-approvable. The primary objective of this Phase II project is, therefore, to select a clinically feasible delivery vehicle and regimen; the secondary objective is to define biomarkers or correlates of Tregitope efficacy to support clinical development. Aim 1 will identify a suitable delivery vehicle therapeutic administration route, administration frequency protocol, and dose range for Tregitope therapy in the genetically susceptible non-obese diabetic (NOD) mouse model of T1D. Delivery of either peptides or concatamers composed of the Tregitope and PPI epitopes will be tested in clinically proven vehicles: liposomes, glucan particles, and as a conjugate withrecombinant human albumin. Pharmacokinetic and toxicity testing of the final formulation have been included in this revised application, per the review. Aim 2 is devoted to defining key correlates of efficacy associated with the induction of tolerance byTregitopes in NOD mice, and adaptive tolerance induction in NOD GFP and DO11.10 FoxP3:knock-in mice. Induction of Ag-specific aTregs is an innovative feature of this approach. The long-term goal of this research program is to develop, define, validateand commercialize a novel, first-in-class, safe and effective biological therapy to prevent or treat T1D. We have secured the enthusiastic participation of a regulatory expert (Cavagnaro) and two experienced drug developers (CardioVax, Novozyme) that willsupport our program. Upon successful completion of the Phase II project, we will be well equipped to enter into pre-INDA discussions with the FDA in preparation for T1D-ASATI Phase I clinical trials. PUBLIC HEALTH RELEVANCE: Preserving islet cell function is believed to be a cure for Type 1 Diabetes. EpiVax is developing a novel approach to diabetes based on Tregitopes, small peptides derived from the natural plasma protein, immunoglobulin. Tregitopes prevent or reduce autoimmune destruction of cellsin the pancreas that produce insulin. Successful development of Tregitope therapy would have a radical impact on the field of diabetes therapy and could eliminate the need for insulin therapy in T1D.

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