Antibody fragments help with Alzheimer's disease

Researchers at the Autonomous University of Barcelona, working under the guidance of Dr. Sandra Villegas, managed to achieve a significant improvement in the condition of the mouse model of Alzheimer's disease. Five days after a single intraperitoneal injection of antibody fragments, the animals showed an improvement in memory and learning ability, which, apparently, was due to a decrease in the number of toxic aggregates in brain tissue and an increase in the number of neurons.

Traditionally, it was believed that Alzheimer's disease is associated with the accumulation of insoluble aggregates in the brain tissue, called amyloid plaques. However, over the past decade, researchers have concluded that the death of neurons in this disease is due not to the presence of insoluble amyloid plaques, but to the toxicity of the soluble aggregates preceding them, formed by beta-amyloid oligomers.

Experimental immunotherapy of Alzheimer's disease with the help of passive vaccination with an antibody drug against beta-amyloid, known as bapineuzumab, aroused great enthusiasm among specialists. However, a clinical study of the effectiveness of this therapeutic approach was discontinued in 2012 due to serious side effects. Many experts are inclined to believe that the adverse reactions observed in patients were due to the introduction of complete antibodies that cause an inflammatory reaction in brain tissue.

The authors suggested that it would be safer to use antibody fragments as a therapeutic vaccine. They developed the active ingredient of such a drug, which is a fragment of a recombinant antibody, called scFv-h3D6 (from the English "single-chain variable Fragment" – a single-chain variable fragment). This fragment is a derivative of an antibody that is part of bapineuzumab, consisting only of its active part responsible for interaction with the etiological agent of the disease. In earlier experiments on human cell cultures, researchers demonstrated that this antibody fragment protects cells from death and described a molecular mechanism that ensures the removal of beta-amyloid oligomers.

In their latest work, the authors studied the effectiveness of a new experimental drug on a mouse model of Alzheimer's disease. Just five days after intraperitoneal administration of scFv-h3D6, they observed an improvement in the animals' memory and memory ability, as well as a decrease in their anxiety levels.

At the molecular level, two important changes were revealed. Firstly, the new therapeutic approach ensured the removal of beta-amyloid oligomers from the cerebral cortex. Secondly, it was associated with the restoration of the concentration of certain apolipoproteins, which were considered responsible for the natural removal of beta-amyloid aggregates.

In order to improve the properties of the therapeutic molecule, in particular, to increase the period of its circulation in the bloodstream, the researchers made adjustments to the molecular structure. This significantly increased the thermodynamic stability of the molecule and reduced its tendency to form aggregates. The authors believe that the modifications described by them can significantly increase the therapeutic power of scFv-h3D6 against Alzheimer's disease. Moreover, the approach used to make modifications can be used to improve antibody fragments developed by other laboratories as agents for the treatment of various diseases.

Articles by Lydia Gimenez-Llort et al. Early intervention in the 3xTg-AD mice with an amyloid b-antibody fragment ameliorates first hallmarks of Alzheimer disease, Gisela Esquerda-Canals et al. Loss of deep cerebellar nuclei neurons in the 3xTg-AD mice and protection by an anti-amyloid beta antibody fragment and Geovanny Rivera-Hernandez et al. The extension of the C-terminal domain of an anti-amyloid beta single-chain variable fragment increases its thermodynamic stability and decreases its aggregation tendency are published in the journal mAbs.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the Universitat Autonoma de Barcelona:
Antibody fragment designed by the UAB effectively fights Alzheimer's in mice. 

30.10.2013