BioWorld Today Correspondent

ATLANTA - Vaccine therapies against autoimmune diseases, such as multiple sclerosis, Type I diabetes and atherosclerosis, are an enticing prospect, but the issues of how to elicit the highly specific immune tolerance required to target disease while leaving the rest of the immune system untouched, which epitopes to adopt and how to deliver them, remain significant obstacles.

However, early constructs are now entering the clinic that build on increasing knowledge of the immune system, to address the fundamental defect of recognition of self vs. nonself that lies at the heart of autoimmune disease.

According to panelists at a session on "The New Frontier of Vaccines for Auto Immune Disease - Development of Novel Tolerance-Inducing Immunotherapeutics," the field holds the promise of disease-modifying treatments.

That has been a long time coming for Steven Miller, professor at the Interdepartmental Immunobiology Center at Northwestern Medical School, who has been working in the area for 30 years.

Now a vaccine against relapsing/remitting multiple sclerosis based on his research is about to enter a Phase I/II trial at the University of Hamburg, Germany.

Miller's approach involves "gluing" the relevant epitopes onto the surface of antigen-presenting cells extracted from the patient and administering that back to the patient as an injection.

Current understanding of multiple sclerosis is that it is initiated by one epitope, but then the disease is maintained by "spread epitopes," Miller said, "There is a need to pursue the ensuing epitopes, rather than the one that initiated [the disease]."

His preclinical work showed that it is possible to ameliorate progression of multiple sclerosis if spread epitopes are administered during remission. The technique is applicable to other autoimmune diseases also. For example, in Type I diabetes, if mice are tolerized at the early stages of disease, before there are overt symptoms, there is no progression.

"In any autoimmune disease, epitope spreading takes place, and you need to get the epitope appropriate to the phase of the disease," Miller said.

He suggested that a two-pronged strategy would be needed to treat advanced multiple sclerosis in which the underlying autoimmune response is suppressed and then followed by restorative treatment to induce myelin repair.

Bayhill Therapeutics Inc., of Palo Alto, Calif., is building on experience of using DNA vaccines against cancer, to use naked DNA to deliver antigen-specific therapy in multiple sclerosis and cancer. It has two products in Phase II development.

Although no DNA vaccines against cancer have succeeded in the clinic, the 200 trials to date have established a very good safety profile for those constructs, noted Hideki Garren, co-founder and chief scientific officer of the company.

In the Phase I/IIa trial of BHT-3009, which delivers myelin basic protein epitope, the vaccine did not interfere with the rest of the immune response and MRI scans showed a reduction in lesions in the treatment period of six months. In the one year follow-up, the effect on lesions was maintained.

While there was no difference in relapse rate in the active vs. placebo arms in the treatment period, in the follow-up, the relapse rate in treated patients dropped dramatically.

A Phase IIb trial is now in the planning stages.

Meanwhile, Bayhill is still recruiting patients in the Phase I/IIa trial of BHT-3021, which delivers pro-insulin antigen, in treating Type I diabetes.

Early patients have maintained beta cell function, as assessed by C-peptide levels. "In addition, one patient has crossed over from placebo.

There was C-peptide decline for nine months and following crossover, there is now a stabilization of C-peptide," Garren said.

Despite that encouraging progress, as a veteran of the field, Miller said antigen-specific therapy is still in it infancy. "There is a gold-standard of treating autoimmune disease by only targeting cells involved in disease to avoid all problems of immune suppression."

One of many hurdles is the problem in which auto-antigens are involved.

"At the moment we don't have a clue," Garren said. "We think myelin protein [is the relevant epitope] in multiple sclerosis; in diabetes, we know some epitopes, but the list is growing."