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Tria Bioscience Corporation | Date: 2015-04-24

The present disclosure relates to peptide monomers comprising an amphipathic ?-helical peptide, and optionally, at least one T cell epitope peptide; and to dimers and trimers comprising the peptide monomers. The monomeric, dimeric, and trimeric peptides may be conjugated to at least one hapten, wherein the hapten is linked to a lysine or aspartic acid residue of the peptide monomer. These peptide conjugates are useful as vaccine delivery vehicles.

Miller K.D.,Tria Bioscience Corporation | Miller K.D.,Affinogen Bioscience LLC | Roque R.,Tria Bioscience Corporation | Clegg C.H.,Tria Bioscience Corporation
PLoS ONE | Year: 2014

Tobacco addiction represents one of the largest public health problems in the world and is the leading cause of cancer and heart disease, resulting in millions of deaths a year. Vaccines for smoking cessation have shown considerable promise in preclinical models, although functional antibody responses induced in humans are only modestly effective in preventing nicotine entry into the brain. The challenge in generating serum antibodies with a large nicotine binding capacity is made difficult by the fact that this drug is non-immunogenic and must be conjugated as a hapten to a protein carrier. To circumvent the limitations of traditional carriers like keyhole limpet hemocyanin (KLH), we have synthesized a short trimeric coiled-coil peptide (TCC) that creates a series of B and T cell epitopes with uniform stoichiometry and high density. Here we compared the relative activities of a TCC-nic vaccine and two control KLH-nic vaccines using Alum as an adjuvant or GLA-SE, which contains a synthetic TLR4 agonist formulated in a stable oil-in-water emulsion. The results showed that the TCC's high hapten density correlated with a better immune response in mice as measured by anti-nicotine Ab titer, affinity, and specificity, and was responsible for a reduction in anti-carrier immunogenicity. The Ab responses achieved with this synthetic vaccine resulted in a nicotine binding capacity in serum that could prevent >90% of a nicotine dose equivalent to three smoked cigarettes (0.05 mg/kg) from reaching the brain. © 2014 Miller et al.

Tareen S.U.,Immune Design | Kelley-Clarke B.,Immune Design | Nicolai C.J.,Immune Design | Cassiano L.A.,Immune Design | And 10 more authors.
Molecular Therapy | Year: 2014

As sentinels of the immune system, dendritic cells (DCs) play an essential role in regulating cellular immune responses. One of the main challenges of developing DC-targeted therapies includes the delivery of antigen to DCs in order to promote the activation of antigen-specific effector CD8 T cells. With the goal of creating antigen-directed immunotherapeutics that can be safely administered directly to patients, Immune Design has developed a platform of novel integration-deficient lentiviral vectors that target and deliver antigen-encoding nucleic acids to human DCs. This platform, termed ID-VP02, utilizes a novel genetic variant of a Sindbis virus envelope glycoprotein with posttranslational carbohydrate modifications in combination with Vpx, a SIVmac viral accessory protein, to achieve efficient targeting and transduction of human DCs. In addition, ID-VP02 incorporates safety features in its design that include two redundant mechanisms to render ID-VP02 integration-deficient. Here, we describe the characteristics that allow ID-VP02 to specifically transduce human DCs, and the advances that ID-VP02 brings to conventional third-generation lentiviral vector design as well as demonstrate upstream production yields that will enable manufacturing feasibility studies to be conducted. © The American Society of Gene & Cell Therapy.

Clegg C.H.,Tria Bioscience Corporation | Rininger J.A.,CaroGen Corporation | Baldwin S.L.,Infectious Disease Research Institute
Expert Review of Vaccines | Year: 2013

H5N1 is a highly pathogenic avian influenza virus that can cause severe disease and death in humans. H5N1 is spreading rapidly in bird populations and there is great concern that this virus will begin to transmit between people and cause a global crisis. Vaccines are the cornerstone strategy for combating avian influenza but there are complex challenges for pandemic preparedness including the unpredictability of the vaccine target and the manufacturing requirement for rapid deployment. The less-than-optimal response against the 2009 H1N1 pandemic unmasked the limitations associated with influenza vaccine production and in 2010, the President's Council of Advisors on Science and Technology re-emphasized the need for new recombinant-based vaccines and adjuvants that can shorten production cycles, maximize immunogenicity and satisfy global demand. In this article, the authors review the efforts spent in developing an effective vaccine for H5N1 influenza and summarize clinical studies that highlight the progress made to date. © 2013 Informa UK Ltd.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 579.38K | Year: 2013

DESCRIPTION (provided by applicant): Allergy is a major cause of illness and disability with an estimated 40-50 million people afflicted in the US alone. AIT provides long-term benefits for the patient and its need for optimization creates a compelling business opportunity. There is a very strong rationale to develop GLA for allergy based on its superior drug profile to MPL, a related TLR4 agonist that accelerates desensitization in people. Our preclinical development plan is easy to execute given the vaccines simple design, and it is very low risk given GLA's safety record in toxicology studies and current clinical programs. This Phase I SBIR will clarify the pharmacology and product profile for the IND. The goal is to confirm that GLA will augment the immunogenicity of multiple allergens and verify that it can accelerate desensitization in a compelling manner. The intention is to generate three potential vaccine candidates for evaluation by an external advisory board. In addition to new innovative allergy products, this work will help us understand the mechanisms of IgE-mediated disease and how to effectively cure allergy through tolerance induction. TRIA has the resources and experience to complete the task. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Allergy is a major cause of illness and disability with an estimated 40-50 million people afflicted in the US alone. Allergy immunotherapy cures some patients although it is underutilized and suffers from poor compliance. Adjuvants can be mixed with allergy vaccines to accelerate tolerance with fewer injections and no adverse reactions.

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

DESCRIPTION (provided by applicant): Influenza is a highly contagious respiratory disease that causes substantial mortality world-wide. There is great international concern that the Avian Influenza virus H5N1 will acquire the ability to transmit between humans and cause a global catastrophe. Consequently, the World Health Organization and the US National Strategy for Pandemic Influenza have delineated goals for stockpiling drugs that can protect against influenza infection. However, currently available H5N1 vaccines are poorly immunogenic and fail to induce broad cross-protective antibody responses to drifted viruses. Therefore, there is an urgent need for alternative treatments that provide potent and broadly cross-protective host immunity that can rapidly neutralize and control dissemination of H5N1 virus in humans. This Phase I SBIR proposal outlines a novel strategy that will simplify and accelerate monoclonal antibody (MAb) drug discovery for Flu. Our methodologies are designed to (1) augment induction of cross-reactive neutralizing antibodies in vivo and (2) permit rational selection of anti-hemagluttinin immunoglobulin (Ig) variable domains for building therapeutic monoclonal antibodies. Our novel approach combines an immunization protocol that dramatically increases antibody diversity in mice with DNA sequencing tools that provide a deep survey of the resulting Ig variable domain repertoire. We propose the following aims: (1) Select and characterize heterosubtypic neutralizing anti-H5 antibodies,and (2) Identify a lead antibody that is cross-protective in animal models of influenza infection. This Phase I SBIR proposal will establish proof of concept that cross-reactive anti-HA MAbs can be selected from immunized animals using a sequence-first screening strategy and that they are effective in advanced animal models of H5N1 infection. Successful completion of this project will result in a small set of therapeutic chimeric antibodies and will provide a strong rationale for conducting thenecessary IND-enabling studies in a subsequent Phase II proposal. Clinically, these antibodies will impact the treatment and prevention of pandemic flu. Scientifically, the availability of these antibodies will clarify HA structure-function relationships,lead to the identification of new epitopes for vaccine development, and guide the regulation of adaptive B cell responses, possibly in humans. We also believe that the concepts, methods and technologies described in this proposal will be broadly applicable for developing therapeutic antibodies to a variety of infectious diseases. PUBLIC HEALTH RELEVANCE: H5N1 viruses have caused over 400 human deaths with a 60% case fatality rate. There is a clear need for improved therapeutics to neutralize and control the spread of H5N1 virus in humans. Our goal is to produce novel therapeutic antibodies that can be used to treat people prior to pandemic flu exposure or during the early stages of infection, thereby reducing the risk of H5N1 infection for millions ofpeople throughout the world.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 352.84K | Year: 2012

DESCRIPTION (provided by applicant): Tobacco smoke is the primary cause of lung cancer, cardiovascular disease and premature death, with nearly 5 million people dying each year. Treatments that prevent smoking will have a major impact on global health andare attractive products for commercial development. Nicotine vaccines and antibodies represent an important strategy for preventing nicotine from reaching the brain, although current clinical-stage vaccines are ineffective and for most people the antibodyresponse is weak and short-lived. The challenge of inducing long- lasting antibodies titers requires a better method for presenting nicotine to the immune system. We hypothesize that targeted nicotine delivery to dendritic cells using agonistic mAbs to CD40 combined with a TLR4-based adjuvant will stimulate a superior antibody response. We will modify the rat anti-mouse CD40 mAb 1C10 for studies in mice and optimize its conjugation with derivatized nicotine. Mice will be vaccinated with ?CD40nic formulatedwith the TLR4-activating adjuvant GLA-SE. Anti-nicotine antibody titers will be benchmarked against mice vaccinated with a traditional vaccine, nicotine-KLH + alum. Vaccine potency will be determined using quantitative measures of antibody function including nicotine sequestration in blood and prevention of a nicotine abstinence response. Phase I SBIR funding will establish proof-of-concept in a relevant model and provide the justification for subsequent IND-enabling studies that will bring an innovative vaccine for smoking cessation into the clinic. PUBLIC HEALTH RELEVANCE: Tobacco smoke is the primary cause of lung cancer, cardiovascular disease and premature death. There is a strong unmet need for an effective aid to smoking cessation. To halt the addictive effects of nicotine and increase the success rate for smoking cessation, we have designed a novel vaccine that will prevent nicotine from crossing the blood-brain barrier.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 3.00M | Year: 2011

DESCRIPTION (provided by applicant): H5N1 is a highly pathogenic avian influenza virus that can cause severe disease and death in humans. H5N1 is spreading rapidly in bird populations world-wide and there is great concern that this virus will begin to transmit between people and cause a global pandemic catastrophe. Vaccines are the cornerstone strategy for combating avian flu but there are complex challenges facing us today including, (1) the inability to manufacture the vast numbers of safe and effective doses needed to prevent infection on a world-wide scale; (2) the fact that the current vaccines are ineffective and require large doses, and (3), virus strains are continually changing, which complicates vaccine strain selection. TRIA Bioscience Corp. is developing a novel adjuvanted vaccine for pandemic H5N1 Flu that should solve many of the scientific and technological barriers confronting this field. The vaccine antigen is recombinant H5 haemagglutinin (rH5), which uses a production process that simplifies many of the manufacturing issues associated with conventional vaccines, and the adjuvant (GLA-SE) that combines two clinically-validated strategies for augmenting vaccine performance, a synthetic Toll-Like Receptor-4 agonist, GLA, and an oil-in-water emulsion, SE. We are building on our compelling Phase I SBIR data by proposing activities leading up through an IND. First, we will compare GLA-SE activity against two simpler GLA-formulations designed to streamline adjuvant development and regulatory approval. Second, we will establish vaccine protection in ferret challenge models and establish safety and immunogenicity end-points in non-human primates. Third, we will manufacture and release cGMP-grade H5 protein and adjuvant, and obtain FDA clearance for a Phase I clinical trial. The results from this study will provide a relevant measure of dose sparing for vaccine manufacturers and inform clinicians about a new tool for inducing broad immunity against drifted strains of H5N1 virus. The US and world governments are investing billions of dollars in pandemic preparedness measures and TRIA will be well-positioned to participate in this market. This vaccine's design is broadly applicable to other infectious diseases, which increases its commercial potential evenfurther. PUBLIC HEALTH RELEVANCE: There is great international concern that the highly pathogenic H5N1 avian influenza virus will cause a pandemic infection resulting in millions of deaths. We are developing an adjuvanted vaccine with new technologies that will streamline manufacturing constraints and prevent H5N1 infection on a global scale.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2010

DESCRIPTION (provided by applicant): Despite two decades of persistent research on prophylactic and therapeutic immunization against HIV, an effective vaccine-based solution to the HIV pandemic has remained elusive. However, the last few years have provided important insights into the type of immune response that would be required for an effective HIV vaccine. For instance, in studies of natural HIV infection, T cell responses to the Gag protein are associated with lower viral load, and nonhuman primates (NHP) that mount robust Gag-specific T cell responses after immunization are more likely to survive after challenge with SIV. Immune Design Corp (IDC) is developing a vaccine platform around a novel DC-targeting non-integrating lentivector (DC-NILV). Using this delivery system, one can efficiently express antigens in DCs and elicit unprecedented CD8 T cell immune responses after a single administration. The ultimate goal of this project proposal is to establish a foundation for a DC-NILV-based HIV vaccine by developing and testing a DC-NILV SIV vaccine analogue for use in future NHP-SIV challenge studies. To accomplish this goal, we have chosen SIVMAC251-Gag and -Nef antigens encoded and delivered by our DC-NILV platform as vaccine candidates. To initiate this work, we will first develop a mid-scale DC-NILV production process based on the small-scale process currently in place, while establishing product release assays to assess vector quality and safety. Once these processes are established, we will optimize vaccine delivery for maximal immunogenicity in mice using assays that measure CD8 and CD4 T cell responses against SIV-Gag and -Nef. Finally, we will test the immunogenicity of SIV-Gag and -Nef when delivered via our vaccine platform in rhesus monkeys. During the course of the study, significant emphasis will be placed on the magnitude, breadth, and polyfunctionality of the ensuing immune responses as these characteristics are currently perceived to be the best correlates for long-term protective T cell-mediated immunity. The overall success of the study will primarily be measured using the following criteria: 1) The delivery of SIV antigens via DC-NILV provides and effective mechanism to generate CD8 T cell responses in NHP; 2) There is value in homologous DC-NILV prime-boost vaccine regimens for the generation of protective T cell-mediated immunity; and 3) The inclusion of multiple antigens within a single DC-NILV is able to expand the diversity of the ensuing immune response without compromising the response against individual protein antigens. PUBLIC HEALTH RELEVANCE: There is an unmet medical need for an effective vaccine against HIV as previous attempts have failed, most likely due to their inability to induce protective T cell responses. We are developing a novel vaccine vector that leads to robust T cell activation by delivering antigens directly to dendritic cells, the key cell type for initiation of adaptive immunity and memory. This vaccine vector has the potential to have great protective efficacy against HIV infection in humans.

PubMed | Imdaptive Inc., Infectious Disease Research Institute, Tria Bioscience Corporation and Colorado State University
Type: | Journal: Antiviral research | Year: 2016

The rapid rate of influenza virus mutation drives the emergence of new strains that inflict serious seasonal epidemics and less frequent, but more deadly, pandemics. While vaccination provides the best protection against influenza, its utility is often diminished by the unpredictability of new pathogenic strains. Consequently, efforts are underway to identify new antiviral drugs and monoclonal antibodies that can be used to treat recently infected individuals and prevent disease in vulnerable populations. Next Generation Sequencing (NGS) and the analysis of antibody gene repertoires is a valuable tool for Ab discovery. Here, we describe a technology platform for isolating therapeutic monoclonal antibodies (MAbs) by analyzing the IgVH repertoires of mice immunized with recombinant H5N1 hemagglutinin (rH5). As an initial proof of concept, 35 IgVH genes were selected using a CDRH3 search algorithm and co-expressed in a murine IgG2a expression vector with a panel of germline murine kappa genes. Culture supernatants were then screened for antigen binding. Seventeen of the 35 IgVH MAbs (49%) bound rH5VN1203 in preliminary screens and 8 of 9 purified MAbs inhibited 3 heterosubtypic strains of H5N1 virus when assayed by HI. Two of these MAbs demonstrated prophylactic and therapeutic activity in virus-challenged mice. This is the first example in which an NGS discovery platform has been used to isolate anti-influenza MAbs with relevant therapeutic activity.

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