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BIRMINGHAM, AL, United States

Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 100.00K | Year: 2006

DESCRIPTION (provided by applicant): Conditionally replicative adenoviruses (CRAds) represent an important novel approach for cancer therapy. CRAd agents are designed to specifically replicate in and kill tumor cells to yield an effective yet safe therapeutic outcome. Although their great potential has awarded them rapid translation into human clinical trials where the safety of CRAds have been clearly highlighted, little data have been obtained with regards to the critical functions of CRAds efficient infection of tumor cells, tumor-specific replication, and lateral spread. Without deeper understanding of the nature of these replicative agents especially in a patient context, further development of CRAds would be greatly hindered. The crux of a general dilemma in the virotherapy field is lack of a monitoring system compatible with replicative agents. Unfortunately, most gene therapy vector detection schemes have been specifically designed to assess gene expression. These modalities are unsuitable for monitoring of CRAds because their very nature is to kill infected tumor cells, a concept at odds with the notion of viable transgene expression. Furthermore, reporters by themselves cannot accurately depict the underlying level of replication as well as true physical distribution of viral progeny, two crucial functions of replicative agents. Clinical trials to date have had to rely on traditional histological analysis of biopsy specimens which are error-prone and cannot portray the multiplicative nature of CRAds. The ideal monitoring system for CRAds should embody the following features: (1) report the level of viral replication, (2) allow direct detection of viral spread, (3) permit dynamic detection of viral activity, (4) minimally perturb replication and spread efficiency of the virus, and (5) possess the power for noninvasive detection. To address this issue, we hypothesized that a genetic adenovirus labeling system using a structural reporter fusion protein would dynamically represent viral replication and spread. We propose adenovirus capsid labeling with pIX-HSV-tkto allow PET-based imaging. In addition, labeling with both EGFP and HSV-tk would allow imaging analysis by both optical and PET-based methods. It is evident that a monitoring system for CRAds is needed for advancing the field. A genetic structural labeling system for adenovirus would offer noninvasive dynamic detection of replication and spread. Not only would this system be indispensable in developing advanced CRAds, it would also be applicable for monitoring CRAd therapy in patients.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 100.00K | Year: 2006

DESCRIPTION (provided by applicant): Adenovirus vectors are employed in a wide range of gene therapy and vaccine applications due to several attractive features such as high titer attainment, structural stability, broad infectivity, established protocols for genetic manipulation and high levels of transgene expression with lack of host genome integration. However development of these vectors in the clinical context has highlighted that vector efficacy would be improved by cell specific targeting. Essentially this embodies the genetic modification of adenoviral capsid proteins to allow the incorporation of suitable targeting moieties to re-direct tropism. As a means to optimize Ad vector utility in this manner we have technology that allows radical genetic modification of fiber. Specifically we have the ability to genetically de-knob the fiber and re-trimerize with fibritin motifs. The removal of the constraining knob allows the chimeric fiber to incorporate complex ligands that can re-direct tropism of the Ad vector. Targeting motifs of interest include antibody-related molecules as they embody unparalleled affinity and specificity for recognition and binding to target cell surface markers as well as embracing a wide spectrum of characterized targets. In this regard, the emerging class of humanized single domain antibodies (dAbs), based on the variable regions of heavy or light chains of immunoglobulins, are of interest as they are small, robust and soluble, a factor which potentially overcomes cytosolic redox problems, i.e. misfolding of antibody fragments, that derive from being incorporated into fiber, a protein that is routed through the cytosol. The development of a tropism modified Ad vector will involve genetic incorporation of a dAb species into fibritin modified fibers, and demonstrate that the dAb retains the function of antigen recognition within the constraints of an Ad capsid protein. We will explore the capacity of the Ad vectors to target and deliver genes in a CAR-independent, receptor specifc manner in in vitro systems. Our studies will establish the employment of genetically incorporated dAbs into the fiber as a means to improve Ad vector capacity through cell specific targeting. We view the creation of our dAb targeted Ad vector as a major progression forward to furthering the utility of Ad in vivo for vaccine and gene therapy applications.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 100.00K | Year: 2002

Conditionally replicative adenoviruses (CRAds) propagate selectively in tumors and have been used to achieve extensive lysis and transduction of tumors. It is important for these replicative viruses to achieve tumor-selective replication to reduce their toxicity. Our group has developed methods of specific trans-complementation of replication-defective adenoviral vectors based on co-delivery of plasmids that enable replication. Using these methods, we have achieved replication of viruses defective in essential early regions E1 and E4. In addition, we have defined novel tumor-specific promoter (tsp) elements for achieving the desired tumor-selective replication of CRAd agents. It is our hypothesis that improving the infectivity and specificity of conditionally replicative vectors will improve their therapeutic efficacy. We intend to modify the fiber of a replicative adenovirus with an RGD motif that binds to integrins. This will provide an additional infectivity pathway different from the natural adenovirus receptor. In the second part of this project, we intend to combine this fiber modification with new methods to achieve tumor-selective replication based on the transcriptional control of E4 and/or E2 with the novel tsp elements.


Grant
Agency: Department of Defense | Branch: Office of the Secretary of Defense | Program: SBIR | Phase: Phase I | Award Amount: 0.00 | Year: 2002

Anti-cancer immunization is limited by the poor immunogenicity of tumor-associated antigens (TAAs) normally used for vaccination. This problem may be overcome by direct adenovirus-mediated delivery of TAAs to dendritic cells (DCs), which play a centralrole in the generation of the immune response. The specificity and efficiency of this vaccination strategy may be improved by specifically targeting the vectors to DCs. Therefore, we propose to develop an Ad vector targeted to CD40 molecules expressed onthe surface of DCs. In one approach, CD40-specific ligands, the natural CD40 ligand (CD40L) and an anti-CD40 single chain antibody, will be cross-linked to TAA-expressing Ad vectors by peptide zippers genetically incorporated into both the Ad capsid andthe ligand. In an alternative approach, the human immunoglobulin Fc domain and the Z domain of S. aureus protein A will be incorporated into the ligand and the Ad fiber protein, respectively. In both cases, the entire targeting complex is designed toself-assemble during the propagation of the Ad vector. We hypothesize that this vector design will result in more efficient antigen presentation by DCs, thereby leading to significant improvements in anti-cancer immunization-based treatment strategies.The prostate-specific membrane antigen will be employed as a model TAA.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 100.00K | Year: 2007

DESCRIPTION (provided by applicant): The emerging threat of bio-terrorism provides a major challenge to protect the civilian population through standard prophylactic vaccine means. The recent anthrax attacks highlighted the urgent need to develop vaccine strategies that act rapidly to the threat of the biological pathogen, and which can be produced in an economically effective manner. In the context of anthrax, the protective antigen (PA) of this pathogen elicits a strong immune response and is used in the current prophylactic vaccine. However, due to the protracted protocol of the current vaccine, an alternative delivery system of PA, one of which rapidly induces the immune system to produce antibodies, in a sustained manner is necessary. One such mechanism would be gene delivery of PA using adenovirus (Ad) gene delivery vectors, which provide an ideal platform to meet both economic and vaccination requirements. Ad vectors are employed in a wide range of gene therapy and vaccine applications and have an established broad safety record in humans, with attractive features such as high titer production, structural stability, broad infectivity, established protocols for genetic manipulation and high levels of transgene expression with lack of host genome integration. Importantly, these vectors are efficient at evoking immunity against the transgene they carry. However, development of these vectors in the clinical context has highlighted that vector efficacy may be limited by the host humoral responses due to pre-existing titers of neutralizing antibodies, in humans, against the vector itself. On the basis of this caveat we have a novel strategy, termed shielding, in which we have technology to genetically modify the virion capsid to provide an uniformly shielded Ad vector. We have identified the pIX capsid protein as an ideal locale for genetic incorporation of shielding ligands, in particular self-proteins such as albumin, to conceal the Ad vector from pre-existing neutralizing antibodies. In this SBIR proposal the basic feasibility of employing a shielding protein, albumin, in the Ad capsid in a defined manner utilizing a specific capsid protein will be established in in vitro [and in vivo models and] the ability of the vector to retain PA expression will be established in vitro. We envision the creation of our shielded Ad vectors as a major progress in the development of clinically and commercially feasible [Ad drug candidates] that can be dosed multiple times for maximum effectiveness to prevent bio-terrorism provoked illness in humans. There are currently no prophylactic vaccines, which act rapidly to protect the population against the emerging threat of bio-terrorism, and this was highlighted by recent anthrax attacks. It is clear that new options are needed. The development of the proposed shielded Ad vector technology can provide an efficient, cost-effective and creative approach to combat anthrax attacks. In addition, the development of the immunologically shielded vector system approach would have further application for many biological threats such as plague and botulism.

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