The technologies being developed at Antigen Express are applicable for antigen-specific immune stimulation or suppression, depending upon the dosing and formulation of its products. Using active stimulation, we are focusing on major diseases such as breast and prostate cancer, HPV-associated cancers, influenza, HPV and HIV.  In addition, by altering the dosing regimen, pre-clinical investigations are establishing the potential of using our antigen-specific peptide technology to inhibit the aberrant autoimmune response at the root of diseases such as diabetes and multiple sclerosis.

 

Cancer

Stimulating the immune system to recognize cancer cells has clear advantages over classical and even targeted cancer therapies.  One of the most important distinguishing features of this treatment strategy is the lack of toxicity.  Studies of roughly 400 patients and volunteers who have received our Ii-Key hybrid peptide vaccines show that these agents are remarkably safe and well tolerated.  This is very consistent with previous peptide vaccine studies reported by other groups.  A further advantage is that Ii-Key hybrid peptides are synthetic off-the-shelf products that are easy to use.

Antigen Express is currently testing its lead immunotherapeutic in patients with HER-2/neu positive breast cancer in a randomized and controlled Phase II clinical trial. We have also completed a Phase I trial in patients with prostate cancer.  In addition to breast and prostate cancer, a variety of other cancers express HER-2/neu and thus are potential targets for immunotherapy using the same compound. 

Another cancer-associated target being pursued at Antigen Express (gp100) is specifically expressed in melanoma.  Using transgenic animal models (expressing human MHC class II alleles) we have identified an Ii-Key/gp100 peptide hybrid that elicits a robust antigen-specific response.  Late pre-clinical stage studies employing PBMC from patients with melanoma are continuing to establish the feasibility of conducting clinical trials.

 

HPV-related Cancers

Human papillomavirus (HPV) induced cancers are attractive targets for active immunotherapy using Ii-Key hybrid technology. The fact that some HPV proteins are both expressed by the cancer cells and are also causative cancer agents indicates that they are ideal targets for active immunotherapy.  Furthermore, these oncogenic gene products represent proteins naturally foreign to the body, suggesting that we may be able to capitalize on the body’s natural defense mechanisms in generating a specific immune response against them and thereby target the cancer cells.  We have identified several active Ii-Key hybrid peptides using transgenic animal models expressing human MHC class II alleles.  Late pre-clinical stage studies are ongoing.

 

Influenza

Influenza viruses are endemic to the human population and easily mutate, forming the various strains of virus that emerge year to year. Common influenza causes many deaths throughout the world each year but on occasion a more virulent and or more infectious strain emerges that is very different from common influenza and is not recognized by the human immune system. These pandemic strains present a threat to human health that could be catastrophic. As was seen with the H5N1 avian influenza outbreak, traditional vaccine manufacturing may not be able to generate sufficient amounts of vaccine for large populations during the rapid spread of disease in a pandemic situation.  Given that our influenza vaccine is produced by entirely synthetic means, it would be available far quicker and in larger amounts than vaccine manufactured by traditional methods. Our research has also indicated that there is shared homology between different influenza virus strains. We believe that a specific cellular immune response could provide some level of protection against the potentially lethal effects of an emerging pandemic influenza virus and, when combined with a traditional vaccine, provide added protection required for elderly individuals and others with compromised immune systems.

 

HIV

Antigen Express remains interested in development of an HIV vaccine.  Although no HIV vaccines have been efficacious thus far, it is clear from the studies reported by many labs that the CD4 and CD8 T cell response to Gag is critical in the control of HIV replication following primary infection in humans and primates, and that the T cell response to Gag in the population of long term non progressors (LTNPs) is essential for control of HIV.  This suggests that HIV vaccines that elicit a strong T cell response to Gag may be effective in eliciting a controlling immunologic response in people who are infected with HIV.  Through a collaboration with Dr. Bruce Walker (Professor of Medicine at Harvard, MIT and MGH) we have identified Ii-Key/gag peptide hybrids that are recognized by PBMC from HIV patients, suggesting their utility as an HIV vaccine.  Studies using a combination of HIV hybrids and recombinant Gag protein are progressing in an effort to identify an optimal dosing regimen for an HIV vaccine.

 

Diabetes

There is a strong association between specific MHC class II alleles and Type I diabetes, which suggests the direct involvement of CD4+ T helper cells in the etiology of this autoimmune disease.  Further, specific targets of the autoimmune response include both insulin and glutamic acid decarboxylase (GAD).  Ii-Key/insulin or Ii-Key/GAD peptide hybrids have two potential applications in the management of diabetics, the first being diagnostic and the second therapeutic.  Given that Ii-Key peptide hybrids are more potent at stimulating CD4+ T cells, they would be useful in detecting the presence of GAD- or insulin-specific autoimmune T cells in the blood.  Initial studies done with outside collaborators suggest that this is indeed an achievable goal.  The importance of detecting these auto-reactive T cells early is that it would greatly facilitate the management of patients in the early stages of the disease, for instance siblings of previously diagnosed Type I diabetics.  Using specific dosing regimens, Ii-Key/GAD or Ii-Key/insulin peptides could be used to specifically suppress the autoimmune response underlying Type I diabetes. 

 

Intracellular and DNA vaccines

In addition to our Ii-Key hybrid peptide platform, another technology platform being developed at Antigen Express is based on inhibition of the MHC class II-associated invariant chain (or Ii protein).  A number of studies from our group, as well as others, have clearly documented that inhibition of the Ii protein in cancer cells (generating the MHC class II+/Ii- phenotype) turns them into very effective cancer cell vaccines.  We have developed active Ii-specific inhibitory agents (antisense oligonucleotides, reverse gene and Ii-RNAi constructs) to effectively suppress Ii protein expression in murine and human cancer cell lines, as well as in fresh acute myelogenous leukemia (AML) cells from patients.  We are optimizing methodology applicable to clinical trials.  Because the Ii protein prevents MHC class II molecules from presenting antigenic epitopes present in the cytoplasm to CD4+ T helper cells, inhibition of the Ii protein can also amplify the immunogenicity of DNA vaccines.  As DNA vaccines are expressed intracellularly, producing antigens in the cytoplasm, suppression of Ii expression can augment their specific immunogenicity.  We are assessing the potential of this technology as applied to an HIV vaccine.

 

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