LAMP-Vax VACCINES ACHIEVE AN ENHANCED IMMUNE RESPONSE
The degradative and secretory functions of lysosomes play important regulatory roles in the immune system. In Antigen Presenting Cells (APCs), the lysosome spatially connects foreign-derived antigens with MHC class II antigen processing necessary for coordination of an appropriate immune response.
Lysosomal Associated Membrane Protein (LAMP) is a glycoprotein found on 80% of the surface area of the lysosomal membrane. LAMP localizes to the lysosomal MHC-II compartment in APCs. LAMP-vax™ DNA vaccines utilize the natural biochemistry of LAMP to intersect with the process that APCs use to internalize, digest, and present exogenously derived antigens to the immune system as part of the lysosomal/MHC-II complex. The result is enhanced antigen presentation and a greatly enhanced immune system response to a vaccine.
Upon immunization with a LAMP-vax™ DNA vaccine, APCs take up the DNA and produce the encoded protein sequence inside the cell as part of a fusion protein with LAMP.
In this way, LAMP-DNA vaccines activate APCs to the immunized antigen(s) through the CD4+ helper T-cell pathway. This initiates a more complete immune response including antibody production, cytokine release and critical immunological memory. LAMP-DNA immunization also contrasts with the immune response to conventional DNA vaccines, which are processed and primarily presented through MHC-I and elicit a cytotoxic T response. LAMP-vax™ DNA plasmids show no decrease in CD8+ cytotoxic T-cell response.
Conclusion: LAMP-Vax vaccines active the entire immune system.
COMPETITIVE ADVANTAGES OF LAMP TECHNOLOGY
MHC-II Targeting Strategy Necessary for Clinical Relevancy
MHC-II antigen presentation is key to improving DNA vaccines and increasing the likelihood of clinical success. The addition of LAMP Technology to DNA vaccine design is necessary to avoid the limited immune response that occurs when antigen is processed in somatic cells and presented through the generic MHC-I pathway. By accessing the MHC-II antigen presentation pathway, ITIís LAMP-vax vaccine formulations induce high titers of protective or therapeutic antibodies and cell-mediated immunity.
For Lysosomal Targeting, a Stablization Domain is Required
The luminal domain of LAMP stabilizes the antigenic-fusion protein and the glycosylated domain protects the antigenic sequence from pre-mature proteolysis, while permitting proteolysis in mature lysosomes. Including the LAMP luminal domain in a LAMP-antigen vaccine enhances protein expression, antigen accumulation in MHC-II containing lysosomes, and the breadth and scope of immune response.
Proven Safety in the Clinic
The LAMP-vax platform has been incorporated into clinical studies: high risk AML patients were given the cancer immunotherapy vaccine, GRNVAC1, in a Phase II study sponsored by the Geron Corporation. The clinical experience of these patients demonstrates that the LAMP formulation is safe and well tolerated, with some patients receiving up to 30 injections of therapy. An earlier Phase I study of GRNVAC1 in prostate cancer patients also revealed a strong interferon-gamma response and a boostable memory capability.
LAMP-vax antigen vaccines can be designed against multiple cancer antigens.. For the cancer market, this has strong advantages over other approach that only deliver one antigen or antigenic epitope at a time. Further, although the current proposed study will initially use an intramuscular injection for our safety studies, we believe the vaccine is well suited for a variety of different delivery protocols including subcutaneous, intranasal, or electroporation depending on the target population and market dynamics.
Plug & Play Vaccine Design for Rapid Product Line Development
LAMP-vax vaccines utilize a standardardized plasmid backbone that includes the appropriate LAMP elements. The target antigen is inserted into this plasmid easily at a multi-cloning site and then validated for proper expression characteristics. This process takes only 30 days in design and development and 30 days for validation of the construct. Thus, any given target can be developed into a working vaccine candidate (or component of a multi-vector formulation) within a business quarter and with limited expense. This versatility enables ITI to quickly expand both its product line and that of its partner companies.
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