Investigational Antibody IgG1-iS18 Reduces Amyloid Load, Improves Memory in Mice

An investigational antibody effectively targeted toxic protein aggregation in the brain of a mouse model of Alzheimer’s disease, improving memory and cognitive functions in the animals.

University of the Witwatersrand researchers are now planning Phase 1 of human clinical trials with 30 to 50 volunteers who have Alzheimer’s. If the results are positive, the team hopes to get regulatory approval on a nasal spray containing the specific antibody.

The study, “LRP/LR specific antibody IgG1-iS18 impedes neurodegeneration in Alzheimer’s disease mice” was published at Oncotarget.

“If we can slow down the progression of the disease, we can dramatically improve the quality of life for patients, as well as extend their lifespan,” Stefan Weiss, lead researcher and professor at the Faculty of Science at Wits University, said in a news release.

Laminin receptor, also known as LRP/LR, is an important protein that establishes the contact between cells and their exterior environment. It can transport several components into cells, including viruses, proteins, and beta-amyloid molecules  — a hallmark biomarker of Alzheimer’s disease. Studies have shown that LRP/LR can also interact with important proteins implicated in the underlying mechanisms of Alzheimer’s disease.

“With the anti-LRP/LR specific antibody, there is the potential to actually target the protein clumping and stop the formation of amyloid plaque,” Weiss said.

Given the important role of LRP/LR, researchers developed IgG1-iS18, an engineered antibody that can effectively bind and block this receptor’s activity.

To test IgG1-iS18’s therapeutic potential, researchers administered the antibody nasally, twice a week for eight weeks, in a mouse model of Alzheimer’s disease. After completion of the treatment, researchers evaluated animals’ capacity to identify objects.

Mice treated with a placebo did not show significant differences in the time spent exploring familiar or new objects. Animals treated with the antibody spent 16.18% more time exploring new objects, suggesting that these animals had better memory skills.

Additional experiments revealed that IgG1-iS18-treated animals had better short-term and long-term memory, as well as enhanced learning capacity, compared to placebo-treated mice.

When analyzing the brains of treated mice, the team found that the amyloid load in the hippocampus  — the brain area most affected in Alzheimer’s disease  — was almost 2.4 times reduced in IgG1-iS18-treated mice compared to the placebo group. This represented a reduction of 24.72% and 38.49% in the amount of insoluble and soluble beta-amyloid in the brain after IgG1-iS18 intranasal treatment, respectively.

Also, by inhibiting LRP/LR activity, the treatment enhanced the levels of some enzymes known to contribute to the DNA damage repair process and protect against neurodegeneration.

“This is the first report proposing that intranasal administration of the anti-LRP/LR antibody, IgG1-iS18, is able to reduce levels of [beta-amyloid molecules] in the whole brain and diminish accumulation of amyloid plaques in the hippocampus,” the authors wrote.

Weiss said that the team’s focus  is to further explore the potential of the IgG1-iS18 as a therapeutic agent for people with Alzheimer’s disease.

“Although we have not conducted any study into the potential of the antibody as a prophylactic drug for preventing Alzheimer’s, it is certainly a possibility,” he said.

“This discovery is indeed a giant leap forward in the treatment of Alzheimer’s disease and we are very excited about the recent results obtained from the mouse studies. We are looking forward to the next stage of the project, which is to investigate whether the compound will be as effective in humans as it has been in the mice,” said Anne Gabathuse, innovation support manager at Wits Commercial Enterprise, which is assisting Weiss in further development and commercial negotiations.