Antigen Express advances immunotherapy

October 17, 2014 ctheodoropulos

Antigen Express is developing a novel way to boost the immune system, developing a therapeutic platform that can produce off-the-shelf, synthetic peptide vaccines for major diseases, including cancer, HIV, influenza, diabetes and, potentially, Ebola.

“Our focus is on modulating the activity of the CD4+ T cells, which are critical mediators of the immune response,” Eric von Hofe, President, said. To do this, Antigen Express uses peptides modified by its proprietary technology. Peptides, he explained, are protein fragments that are the minimal unit capable of generating an immune response. By eliminating the other, unrelated components of a protein, the use of peptides can minimize toxicity and many potential side effects.

Eric von Hofe, Antigen Express

Eric von Hofe, Antigen Express

The approach Antigen Express uses is based upon Ii-Key hybrid technology, which modifies antigen fragments to increase their ability to stimulate CD4+ T cells in a specific manner. This generates a more robust immune response to specific antigens and confers a more long-term immunological memory.

More specifically, the Ii-Key modification helps antigenic epitopes to bind more effectively to the molecules required to generate an immune response. As Antigen Express explained, the Ii-Key interacts with an allosteric site on MHC class II molecules, causing them to discharge any resident epitope peptides. That, in turn, allows the therapeutic peptide’s epitope linked to the Ii-Key to fill the empty MHC class II molecule.

Historically, von Hofe said, CD4+ T cells have been an afterthought. When researchers began trying to stimulate an active immune response to cancer they looked at CD8+ T cells. These cells were known to kill cancer cells and, therefore, were logical targets for active immunotherapy. While those cells did boost the immune system, the improvement was less robust than scientists hoped. “Activity didn’t translate into efficacy,” he said.

The specific activation of CD4+ T cells changes that. “When CD8+ T cells are stimulated in the presence of CD4+ T cells, they expand when they encounter tumor cells and develop into memory cells,” von Hofe explained. Therefore, they remain in the immune system as active cancer-fighting agents for a long time, recognizing tumor cells when they are encountered later and re-initiating a robust anti-cancer response.

This same platform also has the potential to down-regulate the immune system to prevent disease progression in cases of autoimmunity. For example, early research indicates that suppression of CD4+ T cells also may be used to inhibit aberrant autoimmune responses that contribute to diabetes and multiple sclerosis. This tolerizing strategy can be accomplished by repeated administration of low doses of Ii-Key hybrids.

Understanding the immune system

A large part of the work to develop active immunotherapies involves understanding the immune system and how to harness it. For example, “it’s asking a lot of the immune system to target established tumors. Once established, they learn to evade the immune system,” von Hofe said. Therapeutic vaccines, therefore, can be expected to be more effective during the early stages of diseases as adjuvants to other therapies to minimize disease recurrence.

The notion of immunotherapy has been considered since the beginning of the 20th century, when researchers suggested that the immune system may play a role in killing cancer cells. “Until 2010, however, the outlook for active immunotherapy was pretty bleak,” von Hofe recalled. The turning point came with the approval of Provenge® for prostate cancer.

With its approval came a better understanding of cancer immunotherapy and what could be possible. One important milestone is that “people have realized that it takes time to generate an effective immune response. Immunotherapy isn’t like cytotoxic drug therapies, where you can expect to see some results within a couple weeks. Instead, it make take an immunotherapy 8–12 months to produce the desired effect.”

Von Hofe sees Antigen Express developing its active immunotherapy ultimately as something that will be combined with other methods of immune system modulation. Patient therapy, for example, may combine checkpoint inhibitors to reverse tumors’ immune system suppression and an active immunotherapeutic vaccine such as Antigen Express is developing.

To use an analogy, “checkpoint inhibitors take the brakes off the immune system. Then, by activating the T cells, we’re stepping on the gas.”

Phase II trials near completion

The most advanced compound at Antigen Express is AE37, which is completing a controlled and randomized Phase II trial in patients who have had breast cancer. “We have enrolled more than 300 women with early stage breast cancer, administering standard of care therapy plus AE37 or placebo to see if can prevent relapse,” von Hofe said.

“We’re seeing good effects in reducing relapse,” he added. When compared to placebo (GM-CSF), AE37 reduced the risk of relapse by 40 percent in patients with low HER2 expression. The relapse risk declined by 60 percent in patients with triple negative breast cancer. “Managing patients with triple negative breast cancer is one of the greatest areas of unmet need,” von Hofe said.

Particularly in the triple negative patients AE37 helps bridge a therapeutic gap for patients for whom neither trastuzumab (Herceptin®) nor hormone therapy (e.g., tamoxifen) is effective.

As von Hofe said, “The initial studies of AE37 in patients indicated that it was capable of generating specific immunogenicity without the GM-CSF adjuvant, which speaks to the added potency imparted by their Ii-Key technology. Those studies also reported that a more robust immune response was elicited by AE37 than for similar HER2-targeted peptide vaccines that did not contain the Ii-Key modification.”

A Phase I study involving late stage prostate cancer patients also appears promising. “While this was not a controlled, randomized trial like our Phase II breast cancer study,” von Hofe cautioned, “patients did better than anticipated. We expected about 40 percent of the patients to develop metastases by the five year follow-up based on their stage of disease, but none did. That was an encouraging surprise for us.”

This platform has the potential of stimulating an effective immune response against Ebola, also. According to the FDA, the current therapeutic vaccines are experimental and are just beginning human trials. At this point in their development, von Hofe said, some of those vaccines require repeated administration to generate six-month protection in animal models. Such limits show the need for better CD4+ T cell activation to elicit a more robust early response and more durable immunologic memory. Therefore, he concluded, “It is reasonable to assume that our technology could benefit in the development of an Ebola vaccine.”

Partnering opportunities

The goal of Antigen Express is to develop active immunotherapy so patients’ own immune system can combat specific diseases more effectively. “This creates unparalleled specificity with minimal side effects,” von Hofe said.

“We’re looking for partners willing to collaborate in clinical trials for AE37.” The most advanced therapeutic areas are breast and prostate cancer, and the company is particularly interested in partnering to advance this platform as a therapy for triple-negative breast cancer and/or in participating in a combination study involving checkpoint inhibitors or other immunomodulators.

The business model for Antigen Express positions it firmly as a developer of early-stage platform technology and product development. Using its active immunotherapy platform, the company plans to develop a deep pipeline that targets major diseases. It holds 33 patents throughout the world, with 29 pending.

In terms of development, “we will take an idea from discovery through proof of concept in the clinic, and then partner for Phase III, licensing and distribution. Our platform can modify virtually any peptide out there,” von Hofe said. The company is interested both in developing its platform technology and in collaborating to develop specific products.

Antigen Express was founded in 1995, and in 2003 became a wholly-owned subsidiary of Generex, which specializes in drug delivery platforms. Now, its goals include spinning out from Generex into a separate, publicly-traded company listed on national stock exchanges. “This is an exciting time for us,” von Hofe said.



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