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Generex Biotechnology, and their wholly owned subsidiary Antigen Express, are developing promising new drugs to treat diabetes, as well as synthetic peptide vaccines targeting HER2/neu cancer and pandemic flu. The flagship product for Generex is Oral-lyn buccal insulin. Antigen Express' leading vaccine is the AE37 HER2/neu synthetic peptide vaccine to prevent breast cancer recurrence. I am not qualified to offer investment or medical advice, and make no claims that I am an expert in these areas. I am a layman and a shareholder in this company. The left side of Pipeline Review holds blogs regarding Generex and Antigen Express, while the right side offers items of due diligence mixed with my analysis which may be of interest to others seeking to learn about Generex's pipeline. If the left side only shows the latest blog, click on the word home to view them all.

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Thursday, September 8, 2011

AE37: A Novel T-Cell Eliciting Vaccine for HER2/neu Breast Cancer

Antigen Express is a wholly owned subsidiary of Generex Biotechnology. Col George Peoples, and the United States Military Cancer Institute researchers studying Antigen Express' AE37 vaccine, have published a new article that will appear in a future edition of Expert Opinion on Biological Therapy. The title is AE37: a novel T-cell-eliciting vaccine for breast cancer.


Introduction: Immunotherapy, including vaccines targeting the human EGFR2 (HER-2/neu) protein, is an active area of investigation in combating breast cancer. Several vaccines are currently undergoing clinical trials, most of which are CD8+ T-cell-eliciting vaccines. AE37 is a promising primarily CD4+ T-cell-eliciting HER-2/neu breast cancer vaccine currently in clinical trials.

Areas covered: This article reviews preclinical investigations as well as findings from completed and ongoing Phase I and Phase II clinical trials of the AE37 vaccine.

Expert opinion: Clinical trials have shown the AE37 vaccine to be safe and capable of generating peptide-specific, durable immune responses. This has been shown in patients with any level of HER-2/neu expression. Early clinical findings suggest there may be benefit to AE37 vaccination in preventing breast cancer recurrence.

HER-2/neu, Herceptin, and Cancer Vaccines

I purchased the entire article, and will highlight certain findings. A complete re-paste of the article would infringe on certain copyright protections, so I'll do my best to report on the article. The authors begin by noting that in addition to expression in breast cancer, HER-2/neu is over expressed in 11% of ovarian cancers, 39% of prostate cancers, 7 – 34% of gastric cancers, 10 – 82% of pancreatic adenocarcinomas, and is expressed at some level in the majority of epithelial-derived cancers. Immunological agents targeting HER-2/neu include Roche's Herceptin, as well as other monoclonal antibodies that are in development.

In the adjuvant setting, or before metastatic late stage disease, Herceptin has been shown to reduce breast cancer recurrence by 50%. Currently, Herceptin is reserved for breast cancer patients who over express the HER-2/neu protein, or those that are HER2 3+. The authors note that the HER-2/neu protein is an attractive target for immunotherapy, since it is well characterized, contains multiple immunogenic epitopes, and promotes cancer cell growth. This review focuses on AE37, an example of a HER-2/neu-targeted vaccine, with comparison to Herceptin and RXi Pharmaceuticals E75, also known as NeuVax.

The authors state that vaccines targeting HER-2/neu may add additional therapeutic options for breast cancer patients with any level of HER-2/neu expression, which as previously noted is in contrast to Herceptin, and may bring even greater immunological and clinical benefit to those patients with lower levels of HER-2/neu expression. The patients that express HER2 in lower levels, or HER2 1+ and 2+, are not eligible for treatment with Herceptin. Additionally, successfully developed vaccines may allow the generation of long-term immunological protection from cancer, without the need for repeat infusions required with monoclonal antibodies. Several breast cancer vaccines are currently under investigation, though none have yet been approved by the FDA.

E75 and AE37

RXi Pharma's E75, a CD8+ T-cell-eliciting vaccine, is a HLA-A2/A3-restricted MHC class I epitope, which limits the amount of HER2/neu expressing breast cancer patients it may benefit. I'll note that AE37 is a promiscuous peptide vaccine, with no such HLA restrictions. The authors remark that immunity from the E75 vaccine wanes over time, although a booster inoculation series helps sustain an effective peptide-specific immune response. While such a CD8+ T-cell vaccine appears effective at eliciting cytolytic activity against HER2/neu tumors, the authors acknowledge that there is concern that a long memory vaccine specific immune response will require the use of a CD4+ helper T cell epitope, such as AE37.

The report continues to highlight preclinical and Phase I findings for Antigen Express' AE37 vaccine. To give some background, which is difficult to understand, let's look at the natural, or unmodified, peptide called AE36. AE36 is a HER2-derived peptide from the intracellular domain of the HER-2/neu protein, 776-790. AE37 is the Ii-Key hybrid modified peptide of HER2/neu, 776-790 (AE36). AE37 represents the natural AE36 peptide with the addition of the four amino acid Ii-Key peptide moiety from the Ii protein.

Ii-Key Hybrids, the General in this War against Cancer

Ii-Key hybrid technology is patented by Antigen Express. The first four amino acids of the Ii protein, or the Ii-Key peptide, increase the binding potency of MHC class II epitopes up to 250-fold, all while bypassing the usual intracellular antigen processing. There is much more to this, but if we take our time, we can understand some of these basics.

AE37 is thought of primarily as a CD4+ T-cell-eliciting vaccine, but the authors state that preclinical research has shown that while the Ii-Key hybrid AE37 enhanced proliferation of CD4+ T cells, it also significantly enhanced CD8+ T-cells' anti tumor activity. This is important, and groundbreaking. AE37, the Ii-Key hybrid vaccine, acts as the General (CD4+ T cells), and move the troops (CD8+ T cells) into action to kill cancer tumors. The authors didn't word this that way, but this is my silly explanation.

The authors continue to reveal that the Phase I study of AE37 with breast cancer patients yielded important findings. AE37 resulted in peptide-specific immune responses, which were significantly increased from baseline to completion of the vaccination series. Unlike with E75, the responses to AE37 were long lasting. The adjuvant used in all of the peptide vaccines (AE37, E75, and the CD8+ T cell eliciting vaccine named GP2), is GM-CSF. Certain patients were not given the immunoadjuvant GM-CSF. AE37 induced significant increases in both in vivo and in vitro immune responses in those patients who were not given the immunoadjuvant GM-CSF. AE37 is the first peptide vaccine to exhibit such potency in the absence of an adjuvant, as this General fires a strong weapon.

Adjuvants, Toxicity, and Hope

Concern existed that AE37's potent stimulation of CD4+ T cells could also stimulate regulatory T cells, called Tregs. Findings from the Phase I study have shown the opposite, that AE37 vaccination resulted in a decrease in the level of Tregs. Also boding well for AE37, was the findings that DTH reactions were more robust for AE37 as opposed to other peptide vaccines, with mild levels of toxicity to the vaccine amongst patients. Most reactions, although nearly always mild, to peptide based vaccines stem from the adjuvant, and AE37 requires the smaller amounts of adjuvant versus any others.

The HER-2/neu protein is also overexpressed in many prostate cancers, and the authors detailed findings from a Phase I study of AE37 in prostate cancer patients. DTH reactions were similarly positive. Toxicity was again very low, with long term immunity measured. Tregs cells were decreased six months after vaccination from pre-vaccination levels. The prostate cancer study found that found that patients with metastatic disease had smaller in vivo responses as opposed to patients with non-metastatic disease, and patients with low levels of HER-2/neu, 1+ and 2+, had significantly enhanced in vitro immune responses.

The findings from the prostate cancer Phase I study helped the investigators choose this element of the path being taken for the breast cancer Phase III. AE37 is currently being tested in a Phase II study for breast cancer patients with early stage disease, with a Phase III being designed with patients exhibiting lower levels of HER2/neu expression. This group is not eligible for Herceptin, and they have an unmet need with no current targeted options. AE37 may fill that unmet need, offering hope to the hopeless.

AE37's Ongoing Phase II Shows Success

The authors remark upon positive early findings from the ongoing Phase II study with breast cancer patients. As of January 2011, they had enrolled 206 patients, with 330 making the final tally. Toxicity is again very mild. Immunological responses have been significant, as well as in vivo measurements by DTH reactions, to the AE37 vaccine. Once again, there is a noted decrease in the levels of Tregs for the patients receiving AE37, with no changes in the control group. Basically, wow. A quote from the report:

Although preliminary, in the current Phase II trial we have observed an approximately 40% reduction in breast cancer recurrence at 17 months of median follow-up in patients treated with the AE37 peptide vaccine. Per trial design, patients are being followed for clinical recurrences and data regarding the efficacy of the vaccine will be reported after a median follow-up of 24 months.

The authors conclude that these clinical trials of the AE37 vaccine, administered with GM-CSF, have shown it to be safe and well-tolerated. Immune responses have been persistent, measured as long as 12 months after completion of the vaccine series. The authors state that these early findings suggest a clinical benefit of the AE37 vaccine in the prevention of breast cancer recurrence. We all look forward to learning more, as Generex gears up to spin out Antigen Express to a national exchange.

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