July 19 , 2006

Immunotherapy for Alzheimer’s, sometimes referred to as a “vaccine,” has shown great promise, though the first major clinical trial using an active vaccination method was marked by side effects of brain inflammation in about six percent of participants. An active vaccination strategy is treatment or prevention by marshalling the body’s own disease fighting mechanism to attack the disease. This is usually done by giving the person a low level of the disease against which the body produces substances called antibodies (proteins made by the immune system) that fight the disease. A passive immunization strategy is based on treating patients with antibodies that are manufactured.

In Alzheimer’s, immunotherapy has been directed at abnormal beta amyloid protein and amyloid plaques – one of the hallmark lesions found in Alzheimer’s brains. Many researchers are working on improving Alzheimer’s immunotherapy, either by developing active vaccination methods that eliminate the previously seen side effects or by developing passive immunization methods using laboratory created antibodies.

At ICAD, Eric R. Siemers, M.D., of Eli Lilly and Company, Indianapolis, IN, and colleagues reported on investigations of safety and biomarker changes for a passive immunization strategy using a humanized monoclonal antibody directed at the central domain of beta amyloid.

Nineteen people with Alzheimer’s were given a single intravenous infusion over approximately 30 minutes. Four groups of people each were given doses of 0.5 mg/kg, 1.5 mg/kg, 4.0 mg/kg and 10 mg/kg respectively; three controls of similar age and level of dementia received placebo. Magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) samples were obtained at baseline and 21 days after treatment. The Alzheimer’s Disease Assessment Scale - cognition (ADAS-cog) was administered at baseline and at three and 21 days after dosing. Multiple plasma samples were taken for pharmacokinetic and beta amyloid analyses.

The researchers found that reports of side effects were similar among the four groups except that two of the participants receiving 10 mg/kg reported mild shaking and dizziness lasting less than two hours after the infusions. The ADAS-cog scores showed no consistent changes. Plasma levels of a type of beta amyloid called Aß1-40 at baseline were 226 +/- 40 pg/mL, 249 +/- 85 pg/mL, 135 +/- 31 pg/mL, and 163 +/- 83 pg/mL for subjects receiving antibody treatment at doses of 0.5, 1.5, 4.0 and 10.0 mg/kg respectively. These values increased to maximum values of 32,900 +/- 9,150 pg/mL, 52,675 +/- 8,882 pg/mL, 85,600 +/- 26,533 pg/mL, and 81,700 +/- 5,370 pg/mL respectively. The effect of the antibody on beta amyloid in blood was present for more than two months after the infusion.

“While we did not see a change in cognitive function from this single dose of the antibody, there was a very substantial increase in the amount of beta amyloid that we saw in plasma, which we believe was bound to the antibody,” Siemers said. “These single treatments were well tolerated up to a dose of four milligrams of drug per kilogram of body weight. This gives us confidence to study this drug in larger populations of people with Alzheimer’s.”