AMES, IA, United States
AMES, IA, United States

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Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 322.95K | Year: 2015

DESCRIPTION provided by applicant The knockdown of targeted genes by anti sense oligonucleotides ODNS and genetic medicines collectively G MEDS holds promise for a variety of therapies The delivery of effective quantities of ODNS to specific cells however has proved to be challenging We propose here a novel approach to ODN delivery that involves enveloped virus like particles EVLPs These delivery agents are prepared by the in vitro self assembly of pure G MEDS and pure viral capsid protein CP into virus like nanoparticles particles VLPs The capsid protects the contents yet as we have demonstrated is capable of giving up its contents in the cytoplasm of mammalian cells The particles which are highly mono disperse are then enveloped by lipid bilayers that can suppress the immunogenicity of the VLPs and are capable of being functionalized for targeting and uptake by mammalian cells of interest In preliminary experiments we have demonstrated our ability to prepare EVLPs using the CP of the cowpea chlorotic mottle virus and a model antisense ODN for vascular endothelial growth factor VEGF a protein over expressed in many cancer cells to stimulate angiogenesis a facilitate tumor survival under low oxygen conditions We propose to optimize the assembly and to functionalize the lipid bilayers with epidermal growth factor EGF which binds the EGF receptor that is over expressed on cancer cells especially those of breast cancer The effectiveness of the EVLP will be demonstrated by assaying the reduction in the secretion of VEGF in cultured breast cancer cells PUBLIC HEALTH RELEVANCE The development of the proposed system for delivering genetic medicines such as genes and oligonucleotides would be an important medical advance Its development would facilitate the targeted delivery of genetic medicines to specific cells tissues and organs thus enabling the development of healthcare products which will exert a significant impact on the practice of medicine


Patent
Molecular Express, Inc. and The Regents Of The University Of California | Date: 2014-06-30

The present invention relates to liposomal vaccine compositions, methods for the manufacture thereof, and methods for the use thereof to stimulate an immune response in an animal. These compositions comprise dimyristoylphosphatidylcholine (DMPC); either dimyristoylphosphatidylglycerol (DMPG) or dimyristoyltrimethylammonium propane (DMTAP) or both DMPC and DMTAP; and at least one sterol derivative providing a covalent anchor for one or more immunogenic polypeptide(s) or carbohydrate(s).


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase II | Award Amount: 320.18K | Year: 2015

DESCRIPTION provided by applicant Heroin and related opioids are highly addictive drugs known for their analgesic properties Since the number of heroin users in the United States has skyrocketed reaching epidemic levels Abuse of prescription opioid pain relievers oxycodone Oxycotin and hydrocodone Vicodin which are known gateway drugs to heroin has also increased dramatically Because opioids present a significant abuse liability new therapies are needed to combat the rapid rise in opioid dependence especially since traditional pharmacological treatments such as methadone fall short at preventing relapse Immunotherapy in the form of a conjugate vaccine is a promising new therapy for opioid addiction In previous work we demonstrated that a heroin keyhole limpet hemocyanin KLH conjugate formulated with alum adjuvant generated a high titer antibody response against heroin in mice and rats Moreover in rodents we showed that anti opioid antibodies elicited by this vaccine bound heroin and its metabolites in the blood with high specificity and affinity thus safely mitigating the psychoactive effects of heroin without binding to endogenous receptors As a result our heroin vaccine was able to block heroin self administration of dependent rats in many addiction models including conditioned place preference reinstatement and reacquisition Dose response heroin analgesia testing in mice revealed that this vaccine was able to shift EC of heroin fold however we have since improved our vaccine to produce a massive andgt fold heroin EC shift Furthermore we tested the long term performance of our optimized vaccine showing that it retains heroin immunoantagonism up to months post vaccination Our studies have indicated that this heroin vaccine is safe effective and long lasting The highly promising nature of our vaccine for treating heroin addiction warrants further preclinical development In this STTR Fast Track application we propose to select a lead heroin vaccine candidate for advancement to clinical evaluation and conduct the IND enabling activities necessary to initiate clinical studies PUBLIC HEALTH RELEVANCE Drug abuse is the leading preventable cause of death in the United States and despite the overwhelming body of knowledge that links drug abuse with numerous diseases crime statistics and medical costs existing cessation therapies are largely unsuccessful A new type of therapy in the form of a vaccine appears to be on the horizon but existing clinical candidates have so far failed to offer broad protection This application propose to use to develop a vaccine for treatment of heroin dependence and to prevent death from heroin overdose Successful achievement of the proposed studies would thus be of significant benefit to public health


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 245.94K | Year: 2014

DESCRIPTION (provided by applicant): For many years, the use of protein and peptide antigens to induce specific immune responses has been an area of intense effort with the goal of developing improved vaccines. In principle, this approach is attractive because it has the potential to provide immunological specificity, tighter control of manufacturing processes, and elimination of most of the secondary sources of materials or contaminants associated with the production of the immunogen. However, proteins andpeptides are typically ineffective at stimulating host immune responses when used as soluble antigens. Co-administration with immunostimulatory adjuvant molecules (IAMs) can significantly improve the immune response against protein and peptide antigens, but differences in their physicochemical properties often makes their delivery together to the cells of the immune system inefficient. Since protein and peptide antigens generally require administration with a strong adjuvant to induce potent immune re


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 762.25K | Year: 2016

DESCRIPTION provided by applicant We have demonstrated in our SBIR Phase I activities that the VesiVax r CALV vaccine and adjuvant platform technology can be successfully used to generate formulations containing Toll like Receptor TLR and agonists that elicit strong protective immunostimulatory responses in a murine pulmonary influenza challenge model With the aid of many collaborators and support from the NIAID we have demonstrated the ability of the VesiVax r system to stimulate protective immune responses in a variety of animal models and a range of antigens using our standard TLR agaonist Monophosphoryl Lipid A Currently there is an unmet need for novel potent immunostimulatory adjuvant molecule IAM formulations and the VesiVax r technology platform is designed as a highly flexible vaccine and adjuvant development system In this revised SBIR Phase II proposal we intend to expand our VesiVax r product portfolio by formulating several other IAMs and focus on further developing the VesiVax r formulations for commercial applications The Specific Aims proposed in this revised SBIR Phase II application include preparation of new VesiVax r IAM formulations and engineering scaffold proteins for less immunogenic antigens We will be testing these formulations in association with various types of antigens such as protein haptens and VLPs in the murine genital herpes simplex virus challenge model the murine nicotine addiction model the murine Chagas disease model the murine pancreatic cancer model and the guinea pig genital herpes model PUBLIC HEALTH RELEVANCE The execution of the studies proposed in this revised SBIR Phase II application formerly the SHIFT SBIR program PA is expected to lead to several significant outcomes that may potentially be of great benefit to public health First thes studies will essentially complete the development of the VesiVax r technology platform as a highly flexible vaccine and adjuvant development system that can be easily engineered to combine multiple antigens and immunostimulatory adjuvant molecules together thus maximizing the immune response to a particular pathogen Second we anticipate that several viable vaccine candidates may possibly be identified that are suitable for advancement to clinical evaluation


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2013

DESCRIPTION (provided by applicant): Molecular Express specializes in the design and engineering of functionalized liposomes for drug delivery and vaccine development. In previous studies, an extensive set of liposome formulations were screened to establish the optimal lipid combination that meets certain physicochemical parameters and provides strong immune responses in animals. These unilamellar vesicles have diameters of approximately 100 nm, are stable (i.e., no aggregation, precipitation or degradationof the components for over a year) in biological buffer solutions, and are commercially scalable. The immunogenic liposome compositions form the basis of a vaccine platform technology called the VesiVax(r) system. The VesiVax(r) system was designed to beeasily manipulated, so that target antigens could be displayed from the surface of the immunogenic liposomes for subsequent use in immunization studies. Vaccines based on the VesiVax(r) system can be engineered using two formats: i) target antigens or adjuvant proteins can be engineered to be expressed as a fusion protein with a hydrophobic domain (HD), which facilitates its incorporation into the liposomes or; ii) target antigens or adjuvants in the form of proteins, peptides or carbohydrates can be attached via conjugation to the surface of the liposomes (i.e., conjugatable adjuvant lipid vesicles; CALVs). The flexibility of the VesiVax(r) platform allows both antigens and adjuvants to be formulated together into the liposomes thus maximizing the immune response. In this SBIR AT Phase I proposal, we intend to establish the utility of the VesiVax(r) CALV platform as an effective adjuvant for virus-like particles (VLPs). To demonstrate this concept, we propose to prepare VesiVax(r) CALV formulations containing different Toll-like Receptor (TLR) agonists and then conjugating them to VLPs that have been designed to express HIV antigens (HIV-VLPs) (Specific Aim 1). The VesiVax(r) CALV HIV-VLPs will then be tested in mouse and rabbit models (Specific Aim 2). These studies are potentially of high impact because demonstration that: I) the VesiVax(r) CALVs can adjuvant VLPs would have an immediate impact through increasing sales of the CALV line of research kits; II) the sublingual route of administration stimulatespotent immune responses would be another useful application of the VesiVax(r) technology and; III) one or more VesiVax(r) CALV HIV-VLP formulations stimulate potent HIV antibody neutralization activity in the in vitro assays will set the stage for the selection of one or more of these candidates to undergo further testing in non-human primates prior to final selection of a VesiVax(r) CALV HIV-VLP candidate that will be advanced to clinical testing. Such a vaccine will provide the basis for a cost effectiveHIV immunization strategy that could be implemented on a global scale. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Since its discovery in the early 1980's, the Human Immunodeficiency Virus (HIV), the etiologic agent of the Acquired Immunodeficiency Syndrome (AIDS), has caused the deaths of millions of humans and continues to be a significant health problem throughout the world, especially in third world countries. Although anti-HIV drugs have had a positive impact on reducing the threat ofAIDS, the HIV infection rate is still at alarming levels and hence, it is now more apparent than ever that the development of an effective HIV vaccine will be the only cost effective strategy that will bring AIDS under control. While immunization has generally been a successful approach for controlling many infectious diseases, the development of a vaccine that provides broad protective immunity against infection by HIV has proven to be problematic. The application of new immunization techniques to developaffordable, advanced prophylactic HIV vaccines that provide broad protection is now a high priority for the global research community. In this SBIR AT proposal, we intend to establish the utility of the VesiVax(r) CALV platform as an effective adjuvant for virus-like particles (VLPs). To demonstrate this concept, we propose to prepare VesiVax(r) CALV formulations containing different Toll-like Receptor (TLR) agonists and then conjugating them to VLPs that have been designed to express HIV antigens (HIV-VLPs). We will also establish that the VesiVax(r) CALV HIV-VLPs can be administered by the more convenient sublingual route of immunization. Successful demonstration that one or more VesiVax(r) CALV HIV-VLP formulations stimulate potent HIV antibody neutralization activity in the in vitro assays will set the stage for the selection of one or more of these candidates to undergo further testing in non-human primates prior to final selection of a VesiVax(r) CALV HIV-VLP candidate that will be advanced to clinicaltesting. Such a vaccine will provide the basis for a cost effective HIV immunization strategy that could be implemented on a global scale and hence, would be of great benefit to the public.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 290.26K | Year: 2015

DESCRIPTION provided by applicant We have noticed anecdotally that in several of our vaccination studies certain of our andquot negativeandquot animal control groups often showed protective efficacy above what we would have expected to observe In particular andquot negative controlandquot groups of animals that contained an immunostimulatory adjuvant molecule IAM without the target antigen provided modest protection against challenge with lethal doses of viral e g influenza virus or fungal e g Aspergillus fumigatus pathogens Further the protective effect appeared to be enhanced by the presence of the cholesterol maleimide CMI moiety that is incorporated into the VesiVax r CALV conjugatable adjuvant lipid vesicles formulation to facilitate conjugation of the target antigen to the liposomes in this test group the target antigen has not been conjugated to the VesiVax r CALVs There also seemed to be a time dependence for the protective effect i e we observed that challenge with the pathogen one week after the last vaccination resulted in more effective protection than challenge three weeks or more after the last vaccination Based on these observations we designed and executed a more controlled vaccination study to examine whether or not the protective effect was real and to demonstrate that the addition of the CMI ligand enhances this effect The most thoroughly studied IAM we have tested in the VesiVax r CALV platform is monophosphoryl lipid A MPL a Toll like Receptor TLR agonist We thus used MPL as a model IAM in our preliminary studies Our results suggest that indeed significant protection from pathogen challenge can be achieved without having a target antigen present in the vaccine and that the CMI does improve the protective immune response We hypothesize that the CMI is facilitating the stimulation of protective immunity via the innate immune response Thus we propose in this SBIR Phase I application to examine the potential commercial utility of this discovery in greater detail with a goal of demonstrating that unconjugated VesiVax r CALVs have the potential to be used as a andquot universalandquot vaccine against different pathogens To maximize the impact of these studies we will test this concept in an outbred mouse model of lethal influenza challenge PUBLIC HEALTH RELEVANCE The anticipated significant outcome that will be achieved through execution of the proposed studies will be the demonstration that a VesiVax r CMI IAM formulation without a pathogen specific target antigen can stimulate potent protective immune responses against different pathogens This would be of high impact since the ability to harness the innate immune response to provide cross protection against different strains of pathogens such as influenza virus would be of great benefit to public health


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 329.91K | Year: 2015

DESCRIPTION provided by applicant The principal objective of this proposal is to develop an Aspergillus fumigatus VesiVax r vaccine The studies proposed in this Phase I Application will specifically address refining a liposomal based vaccine using the defined candidate antigens i e Aspf Aspf and AspfHemolysin that will provide protective immune responses against aspergillosis Our central hypothesis is that a highly immunogenic liposome delivery system developed by Molecular Express VesiVax r can be used to rapidly design and engineer candidate vaccines against A fumigatus The liposomal Aspergillus vaccine candidates will be tested in a relevant immunocompromised mouse model for their ability to protect against a pulmonary Aspergillus challenge Preliminary data using Aspf Aspf and Aspf Hemolysin are very encouraging Here we intend to follow up those studies by determining the minimum number of Aspf proteins needed for the vaccine and the dosage of vaccine that is optimal We will also determine whether the Aspf vaccine will provide additional protection to animals requiring antifungal therapy It is conceivable that A fumigatus may break through the host immunity in vaccinated patients that are also immunocompromised e g patients on chemotherapy We will test whether the Aspf vaccination prior to infection can ameliorate the fungal infection when antifungal therapy is used post infection We will determine the colony forming units in the lungs bronchial alveolar lavage BAL and kidneys to assess the extent of Aspergillus fungal infection In addition to survival and signs of disease we will measure cytokine levels in the BAL and lungs to determine if there is a decrease of inflammatory cytokines in the BAL and lung tissue in infected mice Histopathological analysis will be done on the lungs to determine the level of fungal infection and the type and extent of the immune response in these tissues From these studies described in this SBIR Phase I application the most effective candidate Aspergillus vaccine candidate will be used for advancement to clinical evaluation and development of a commercial product Commercialization will be done with the intent of using our Aspf vaccine to prevent or ameliorate disease in the primary patient population the immunocompromised hosts such as those individuals undergoing a solid organ transplant bone marrow transplant or cancer chemotherapy In these patients the opportunity exists to immunize the patient prior to the onset of the most severe immunosuppression with the goal that the acquired resistance from the vaccine can carry over through the course of the immunosuppression thus reducing patient mortality and infection with Aspergillus PUBLIC HEALTH RELEVANCE The principal objective of this proposal is to develop an Aspergillus fumigatus vaccine We have previously published data showing that our liposomal based vaccines can stimulate a strong protective immune response against influenza and Herpes Simplex Virus We have preliminary data showing that the use of three Aspergillus proteins incorporated into the VesiVax r liposome formulation also stimulates a protective immune response in both a systemic and pulmonary A fumigatus mouse model Here we propose to further evaluate these A fumigatus protein vaccines to identify the best combination and dose We will further evaluate the added value of this Aspergillus vaccine in conjunction with antifungal therapy in an immunocompromised pulmonary aspergillosis mouse model From these studies we will identify a candidate A fumigatus vaccine that will be further evaluated for efficacy against other Aspergillus species and to develop this into a commercial vaccine product


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 225.03K | Year: 2015

DESCRIPTION provided by applicant Heroin and related opioids are highly addictive drugs known for their analgesic properties Since the number of heroin users in the United States has skyrocketed reaching epidemic levels Abuse of prescription opioid pain relievers oxycodone Oxycotin and hydrocodone Vicodin which are known gateway drugs to heroin has also increased dramatically Because opioids present a significant abuse liability new therapies are needed to combat the rapid rise in opioid dependence especially since traditional pharmacological treatments such as methadone fall short at preventing relapse Immunotherapy in the form of a conjugate vaccine is a promising new therapy for opioid addiction In previous work we demonstrated that a heroin keyhole limpet hemocyanin KLH conjugate formulated with alum adjuvant generated a high titer antibody response against heroin in mice and rats Moreover in rodents we showed that anti opioid antibodies elicited by this vaccine bound heroin and its metabolites in the blood with high specificity and affinity thus safely mitigating the psychoactive effects of heroin without binding to endogenous receptors As a result our heroin vaccine was able to block heroin self administration of dependent rats in many addiction models including conditioned place preference reinstatement and reacquisition Dose response heroin analgesia testing in mice revealed that this vaccine was able to shift EC of heroin fold however we have since improved our vaccine to produce a massive andgt fold heroin EC shift Furthermore we tested the long term performance of our optimized vaccine showing that it retains heroin immunoantagonism up to months post vaccination Our studies have indicated that this heroin vaccine is safe effective and long lasting The highly promising nature of our vaccine for treating heroin addiction warrants further preclinical development In this STTR Fast Track application we propose to select a lead heroin vaccine candidate for advancement to clinical evaluation and conduct the IND enabling activities necessary to initiate clinical studies PUBLIC HEALTH RELEVANCE Drug abuse is the leading preventable cause of death in the United States and despite the overwhelming body of knowledge that links drug abuse with numerous diseases crime statistics and medical costs existing cessation therapies are largely unsuccessful A new type of therapy in the form of a vaccine appears to be on the horizon but existing clinical candidates have so far failed to offer broad protection This application propose to use to develop a vaccine for treatment of heroin dependence and to prevent death from heroin overdose Successful achievement of the proposed studies would thus be of significant benefit to public health


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2016

DESCRIPTION provided by applicant There is a significant interest and need for developing new immunostimulatory adjuvant molecules that stimulate potent immune responses To date the only immunostimulatory adjuvant molecule that has been approved for human use is the Toll like Receptor TLR agonist monophosphoryl lipid A MPL Other immunostimulatory adjuvant molecules such as poly I C a synthetic double stranded RNA mimic TLR resiquimod a synthetic single stranded RNA mimic TLR or CpG a DNA oligonucleotide TLR have been in clinical development for a number of disease indications A new class of immunostimulatory adjuvant molecules cyclic dinucleotides CDNs have recently been shown to exert potent immunostimulatory properties through activation of an internal receptor called the STimulator of INterferon Genes STING In this project we propose to optimize a small molecule immunostimulatory adjuvant tucaresol which we have synthesized with a andquot lipid tailandquot to facilitate formulation in the VesiVax r vaccine and adjuvant platform technology We will synthesize lipidated tucaresol LT derivatives and prepare VesiVax r LT formulations with a model recombinant protein antigen i e gD PEPcD HD which we have shown to provide protective immune responses in our well characterized mouse model of intravaginal HSV challenge PUBLIC HEALTH RELEVANCE This project could exert a significant impact on the field of vaccine and adjuvant research by identifying an optimal lipid derivative of tucaresol LT This would be highly valuable since the ability to match a particular protein or peptide antigen with an appropriate adjuvant molecule to generate an optimal immune response represents an advance over current strategies for protein or peptide vaccine development In addition the fine control o the concentrations of the lipids and LT molecules to be synthesized in this project combined with the ability to manipulate the ratio of these components with a target protein antigen to maximize the immune response cannot be easily achieved with any other adjuvant system The development of new LT formulations using the VesiVax technology platform is intended to make the development of potent subunit vaccines much easier and hence will be of great benefit to public health

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