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SEATTLE, WA, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 199.99K | Year: 2011

This Phase I, SBIR contract is for the development of a new vaccine targeting HER2/neu expressing breast cancers. The vaccine induces both cell-mediated and humoral immunity and the company is planning a first-in-man Phase I/Phase II clinical trial. It isanticipated that this new biotherapeutic product will complement and add to the armamentarium of existing therapies that treat HER2/new expressing breast cancers. In this SBIR Phase I study, the project will (1) manufacture the Ad5 [E1-, E2b]-HER2/new therapeutic product under cGLP, (2) perform toxicity evaluations of the therapeutic product, (3) collect and freeze organs/tissues for biodistribution studies. Etubics is developing a new vaccine targeting HER2/neu expressing breast cancers. The vaccine induces both cell-mediated and humoral immunity and we are planning a first-in-man Phase 1111 clinical trial. It is anticipated that this new biotherapeutic product will complement and add to the armamentarium of existing therapies that treat HER2/neu expressing breast cancers. The product consists of our novel Adenovirus serotype-5 vector platform (Ad5 [E1-, E2b-]-HER2/neu) that induces HER2/neu specific immunity in naIve and Ad5 immune pre-clinical animal models. Treatment with the product reduces tumorvolume in established HER2/neu positive tumors and prevents tumor implantation and progression. The product is manufactured in the Company's necessary and sufficient E.C? human cells. A Master Cell Bank has been produced under cGMP conditions. In SBIRPhase I studies, we will (1) manufacture the Ad5 [E1-, E2b]HER2/ neu therapeutic product under cGLP, (2) perform toxicity evaluations of the therapeutic product, and (3) collect and freeze organs/tissues for biodistribution studies. Upon completion of these studies, the Company will be prepared to cross-file with our FDA approved Ad5 [E1-, E2b-]-CEA IND and initiate manufacture of clinical grade material for a Phase 1111 clinical trial in breast cancer patients. Provide key


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 163.41K | Year: 2011

DESCRIPTION (provided by applicant): The objective of this project is to develop a therapeutic strategy for H V-associated malignancy based on the role of HPV in the pathogenesis. HPV related cancers express the E6/E7 oncoproteins of HPV that are ideal targets for immune inducing vaccines. We will develop a vaccine based upon a novel adenovirus serotype-S vector (Ads) platform with unique and additional deletions of the viral DNA polymerase and the pre- terminal protein in the early gene 2b (E2b) region (Ads [E1-, E2b-]). In studies employing HIV antigens, we reported that the new Ad5 [E1-, E2b-]-HlV vector vaccine was superior to a current Ads [E1-]-H V vector vaccine (containing deletion in the early gene 1 (E1) region) when used to induce CMI responses ina multiple immunization regimen. Significant antigen specific CMI responses were induced in mice and monkeys despite the presence of pre-existing AdS immunity. We will construct and produce an AdS [E1-, E2b-] vector vaccine that contains the HPV oncoproteins E6/E7 with non-oncogenic function. This new recombinant adenovirus will induce immune responses by expressing the modified HPV-E6/E7 antigens after direct transfection of antigen presenting cells. We will evaluate this in combination with a toll-like receptor agonist (TLRa) designed to enhance immune responses induced by the vaccine. Our pre-clinical data indicate that the AdS [E1-, E2b-] vec*or induces robust CMI responses against tumor associated antigen [fAA), even in the presence of pre- existing AdS immunity. In a murine cancer model employing the carcinoembryonic antigen (CEA) gene insert, tl.g -CEA immunogenicity and in vivo anti-tumor effects of repeated immunizations with i new AdS [E1-, E2b-l- GEA were compared to those observed with a currentgeneration Ads tE1-l-CEA. These AdS vectors were tested in a clinically relevant AdS immune setting. We observed that AdS immune mice immunized multiple times with AdS [E1-, E2b-]-CEA induced CEA-specific CMI responses that were significantly increased over those detected in AdS immune mice immunized multiple times with a current generation AdS tE1-l-CEA. Ads immune mice bearing CEA expressing tumors that were treated with AdS [E1-, E2b-J-CEA had an increased anti-tumor response as compared to AdS [E1-I-CEAtreated mice. These results demonstrate that AdS [E1-, Ezb-l-CEA can induce CMI immune responses that result in tumor growth inhibition despite the presence of pre-existing AdS immunity. We have also utilized the Ads [E1-, Ezb-] vector platform expressingthe TAA HER2lneu as a breast cancer immunotherapeutic agent. Ads [E1-, E2b-l-HERZlneu induced potent CMI against HER2/neu and significantly inhibited progression of established tumors in Ad5 immune mice. These data demonstrate that in vivo delivery of Ad5[E1-, E2b-] vectors expressing TM can induce anti-TAA immunity and inhibit progression of tumors in AdS immune animals. PUBLIC HEALTH RELEVANCE: In this study, we will develop a new adenoviral based drug (AdS [E1-, E2b-I-HPV-E6/7) to treat HtV+ patients with HPv-associated oropharyngeal and tonsillar ,ncers. The treatment platform is needed to overcome pre-existing AdS immunity that has prevented the widespread use of this type of technology.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 3.35M | Year: 2009

DESCRIPTION (provided by applicant): Current generation Adenovirus (Ad) vector vaccines deleted at the E1 or the E1, E3 regions have resulted in experimental potential to immunize against a variety of infectious diseases such as HIV. These Ad vectors permit the delivery of genes, which express proteins that stimulate the immune system. An advanced generation of Ad vectors with unique deletions of the E1 and E2b region (E2b encodes the viral DNA polymerase (pol) and the preterminal protein (pTP) has previously been described. The deletion of these genetic regions renders the Ad5 [E1-, E2b-] virus completely replication incompetent. The new human Ad5 [ E1-,E2b-] vectors have several advantages. Ad viral DNA replication is significantly diminished and the removal of the E2b region results in a 10,000-fold reduction in the production of Ad late gene products, further reducing the potential of Ad encoded viral proteins from impacting host immune responses. Moreover, use of Ad5 [E1-, E2b-] vectors have been shown to have decreased cytotoxicity. The Ad5 [E1-, E2b-] vectors can also lead to an increased quantity and sustained expression of inserted transgenes. These characteristics of Ad5 [E1-, E2b] vectors suggest that they are superior to Ad5 [ El-] vectors. In light of these advantages, our strategy is to employ the use of Ad5 [E1-, E2b-] vectors as a new platform for vaccine based vectors. Specifically, we chose to use this new Ad5 platform as a vaccine platform for HIV-1. Our Phase 1 goal to investigate Ad5 [E1-, E2b-] vectors was very successful. Multiple immunizations induced robust immunologic responses to transgene products. We observed that animals could be immunized with one antigen and then subsequently immunized with a second differing antigen in the presence of Ad5 immunity. In comparison with the current generation Ad5 [E1-] vector, our [E1-, E2b-] vector induced higher levels of interferon-? and lL-2 secreting lymphocytes both in Ad5 naive and Ad5 immune. Studies also demonstrate that animals could be immunized with a triad mixture of Ad5 [E1-, E2b-] gag, nef, pol. Our analysis of samples from our initial vaccine trial in NHPs suggest that they can be successfully immunized against the HIV gag protein in the presence of pre-existing Ad5 hyper immunity. In Phase II, studies will be performed in mice and NHPs to further develop the vaccination regimen. The Aims of the Phase II study are to (1) prepare SIV and human Ad5 [E1-, E2b-]-gag, pol, nef vaccine platforms. (2) determine the optimal frequency and optimal route of triad vaccination in mice by investigating immunizations on a weekly, bi-weekly and monthly schedule and also compare intradermal, intramuscular, intraperitoneal and intravenous routes of immunization with a triad mix of Ad5 [E1-, E2b-]-gag/pol/nef vectors. (3) determine the duration of transgene expression in vivo. (4) test safety and immunogenicity of the triad vaccine in Ad5 na ve and Ad5 immune NHP, and (5) perform SIV challenge studies of vaccinated NHPs. Etubics will perform these pre-clinical studies to advance this new vaccine platform into clinical trials. PUBLIC HEALTH RELEVANCE: With approximately 5,000 new HIV-1 infections occurring daily and the failure of the Merck 'STEP HIV vaccine trial, the need for a viable HIV-1 vaccine is urgent. During this study, we will further develop our advanced adenoviral vector delivery system for HIV vaccines. The system is needed to break through the barrier presented by vaccinees who have had prior adenovirus infections which includes many humans worldwide.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.47M | Year: 2009

DESCRIPTION (provided by applicant): The objective of this project is to continue to develop an adenoviral vector vaccine against CEA that is effective in stimulating cell-mediated immune responses in subjects previously immune to Adenovirus. The Ad-CEA vaccine endpoint is to treat patients with CEA bearing cancers. CEA is a tumor associated protein that has been reported to be useful as a vaccine treatmen target. Evidence indicates that a broad cell-mediate immune (CMl) response is needed to treat certain CEA bearing tumors. Adenovirus vector vaccines induce CMI responses and have emerged as a leading candidate to be used as a treatment vaccine delivery platform. First generation Adenovirus vaccines have proven less effective than anticipated and adverse reactions are in question. Furthermore pre-existing Adenovirus immunity of most humans causes decreased effectiveness. To address these issues, we have developed an advanced Adenovirus based vector that is devoid of early genes E1, E3,and E2b. These E2b deleted vectors, with deletions in the polymerase and preterminal protein genes, have an expanded cloning capacity and greatly reduced expression of viral late genes as compared to First Generation Adenoviral vectors. The reduced expression of multiple Adenoviral genes has been demonstrated to be advantageous for vaccine development for reasons such as reduced antigenic competition, greater longevity of expression which provides increased immunologic stimulus and reduced adverse effects. Such advantage are important in the presence of pre-existing Adenoviral immunity, and provide the E2b Adenoviral vectors with stealth like attributes. The Company has exclusive license for the new Adenoviral vector system and the E.C7 cell line that supports vector production. The proposed studies are designed to construct and further test the effectiveness of a CEA vaccine based on this new Adenoviral vector platform which will carry the CEA gene. Our Phase I studies tested this new vaccine for the potential to induce CEA memory CMI response as a prime and re-immunization (boost) potential in Ad-na ve and Ad-immune mice. Based upon our successful results observed in the Phase I studies, we propose to conduct human clinical Phase l/ll trials in our current project proposal. PUBLIC HEALTH RELEVANCE: This study will further develop pre-clinical information and lead to clinical trials of a new drug (Ads [E1-, E2b-]-CEA) to treat cancers which have carcinoembryonic antigen on their surface. The drug is needed to induce a greater immune response against certain cancers.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.50M | Year: 2011

Etubics Corporation is clinically testing a new vaccine targeting carcinoembryonic antigen (CEA) expressing cancers in a Phase I/II clinical trials under FDA IND14325. Many cancers express CEA, including colon, breast and pancreatic cancers. It is anticipated that this new biotherapeutic product will complement the armamentarium of existing therapies for the treatment of CEA expressing cancers. The product consists of the Company s novel Adenovirus serotype-5 platform expressing CEA (Ad5 [E1-, E2b-]-CEA) that induces antibodies and cell mediated immune responses that result in anti-tumor activity. The product is manufactured in the necessary and sufficient human E.C7 cell line. A Master Cell Bank has been produced under cGMP conditions. In this Phase II SBIRprogram, we will (1) evaluate the robustness of the manufacturing process, (2) perform an additional GMP manufacturing run to support the next phase clinical trials, (3) perform a product biodistribution study in animals, (4) develop functional assays using the therapeutic product, and (5) perform shelf-life studies of the product. It is expected that completion of these processes and studies will allow us to produce sufficient product to support large-scale clinical trials required to move toward approvalof this new biotherapeutic for active immunotherapy of CEA expressing cancers.

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