The objective of this NIAID Advanced STTR Phase I proposal is to combine the strengths of academic investigators from the fields of immunology and animal disease modeling with the resources of ApoImmune Inc. to develop a novel vaccine, ApoVax104-TB"""""""" targeting both active and latent Tuberculosis (TB) infections. ApoVax104-TB"""""""" uses a novel proprietary vaccine based on ApoImmune's chimeric protein consisting of streptavidin and the costimulatory ligand, 4-1BBL, conjugated with known Mycobacterium tuberculosis T-cell antigens. This vaccine concept bears significant potential as a preventive and therapeutic vaccine against TB since the 4-1BBL component of the vaccine has been shown to induce adaptive (CD4+ and CD8+ T cell responses) and innate (dendritic cells, macrophages, and NK cells) immunity and overcome various immune evasion mechanisms (CD4+CD25+FoxP3+ Treg cells and clonal anergy). This application proposes to develop a subunit vaccine against TB based on a triple antigen strategy consisting of recombinant Ag85B, ESAT-6, and Mpt83 TB proteins. Ag85B and ESAT-6 are expressed by actively growing bacteria, and Mpt83 is expressed in non-dividing bacteria, thereby targeting both subpopulations in the lung. These antigens will be biotinylated and conjugated to chimeric 4-1BBL via biotin- streptavidin interaction and delivered in vivo specifically to dendritic cells constitutively expressing the 4-1BB receptor. The underlying hypothesis is that 4-1BBL interaction with 4-1BB on dendritic cells will activate these cells for antigen uptake, processing, and presentation to T cells, thereby generating potent adaptive immunity. At a second stage, 4-1BBL may directly work on activated CD4+ and CD8+ T cells with upregulated 4-1BB receptor to expand these cells and augment the memory response. At a third stage, 4-1BBL may overcome various immune evasion mechanisms, such as clonal anergy and CD4+CD25+FoxP3+ Treg cells, implicated in persistent TB. These combined effects are expected to result in protective as well as therapeutic effects against TB. This hypothesis is supported by our strong preliminary data demonstrating better efficacy of ApoVax104 than two bench-mark adjuvants, Monophosphoryl Lipid A and CpG, as components of a therapeutic vaccine against cervical cancer. The efficacy of ApoVax104-TBTM will be tested in preventive and therapeutic settings of TB in an animal model. If proven effective, these studies will be followed by a Phase II STTR application to further develop the vaccine for testing in a Phase I clinical trail. The development of a vaccine against TB will have tremendous societal benefits as well as target a global market in the billions of dollars.

Public Health Relevance

This project will establish the necessary fundamental parameters to develop a novel vaccine against tuberculosis (TB). Using ApoImmune's lead vaccine, ApoVax104"""""""", we will develop a vaccine that will suppress the spread of TB by acting as a preventative as well as a therapeutic vaccine. ApoImmune's novel immunotherapy, ApoVax104 TM vaccine, is a new innovative approach to treating infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
5R43AI074176-02
Application #
7679538
Study Section
Special Emphasis Panel (ZRG1-IMM-K (12))
Program Officer
Jacobs, Gail G
Project Start
2008-09-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$429,811
Indirect Cost
Name
Apovax, Inc.
Department
Type
DUNS #
140646345
City
Louisville
State
KY
Country
United States
Zip Code
40202
Srivastava, Abhishek K; Dinc, Gunes; Sharma, Rajesh K et al. (2014) SA-4-1BBL and monophosphoryl lipid A constitute an efficacious combination adjuvant for cancer vaccines. Cancer Res 74:6441-51
Srivastava, Abhishek K; Sharma, Rajesh K; Yolcu, Esma S et al. (2012) Prime-boost vaccination with SA-4-1BBL costimulatory molecule and survivin eradicates lung carcinoma in CD8+ T and NK cell dependent manner. PLoS One 7:e48463
Madireddi, Shravan; Schabowsky, Rich-Henry; Srivastava, Abhishek K et al. (2012) SA-4-1BBL costimulation inhibits conversion of conventional CD4+ T cells into CD4+ FoxP3+ T regulatory cells by production of IFN-?. PLoS One 7:e42459
Sharma, Rajesh K; Srivastava, Abhishek K; Yolcu, Esma S et al. (2010) SA-4-1BBL as the immunomodulatory component of a HPV-16 E7 protein based vaccine shows robust therapeutic efficacy in a mouse cervical cancer model. Vaccine 28:5794-802
Sharma, Rajesh K; Schabowsky, Rich-Henry; Srivastava, Abhishek K et al. (2010) 4-1BB ligand as an effective multifunctional immunomodulator and antigen delivery vehicle for the development of therapeutic cancer vaccines. Cancer Res 70:3945-54
Sharma, R K; Yolcu, E S; Elpek, K G et al. (2010) Tumor cells engineered to codisplay on their surface 4-1BBL and LIGHT costimulatory proteins as a novel vaccine approach for cancer immunotherapy. Cancer Gene Ther 17:730-41
Schabowsky, Rich-Henry; Elpek, Kutlu G; Madireddi, Shravan et al. (2009) A novel form of 4-1BBL has better immunomodulatory activity than an agonistic anti-4-1BB Ab without Ab-associated severe toxicity. Vaccine 28:512-22