U.S. announces results of synthesis of bispecific antibodies that cross the blood-brain barrier

Researchers from GENNTECH INC. Bypassed the general rules of antibody synthesis in the new research and synthesized a new type of genetically engineered antibody that can pass the blood-brain barrier and has bispecificity. This new technology may drive scientists to develop new methods of antibody-based encephalopathy treatment in the future. The researchers published two articles in Science Translational Medicine on May 25, describing the design process of this antibody in detail.

Antibodies are a specific protein used by the immune system in the body to neutralize harmful foreign substances. The capture of natural antibodies or the preparation of highly specific antibodies has been a hot field in proteomics research. In recent years, researchers from various research institutions and companies are also working on constructing antibodies with multiple targets.

"A new wave of synthetic bispecific antibodies is coming," said Ryan Watts, a neurobiologist at Genentech. "They will become a research hotspot in this field."

The blood-brain barrier is an important internal barrier for the body to participate in innate immunity. It can block pathogens and other large molecules from entering the brain tissue and ventricles from the blood circulation. Thereby protecting the brain tissue from the damage of toxic substances in the circulating blood. Because antibodies usually cannot pass the blood-brain barrier, the concentration of antibodies in the brain is about a thousand times lower than in the blood.

In the new study, Watts et al. Synthesized an antibody that can cross the blood-brain barrier and has dual protein targeting. Its targeted β-secretase (β-secretase) is an important drug development target for the current treatment of Alzheimer's disease. Past studies have confirmed that β-secretase plays an important role in the production of amyloid peptides in the brain.

The second protein targeted by this antibody is the transferrin receptor. Normally, transferrin receptors can mediate iron uptake in the brain through interaction with transferrin. The researchers used transferrin to deliver the antibody to the brain to ensure that it could act on β-secretase in the brain.

The researchers confirmed that this bispecific antibody can function well in Alzheimer's disease model mice. After receiving the antibody injection once a day, the concentration of amyloid β in the brain of the mouse dropped by 47%.

"Our design and synthesis of this new antibody is based on a unique concept that challenges an important rule in antibody engineering," Watts said.

The interaction force between an antibody and an antigen is often called the affinity of the antibody. The higher the affinity, the stronger the interaction between antibody and antigen. For a long time, most antibody engineering technicians have been devoted to synthesizing antibodies with high affinity, so as to ensure that the antibodies can tightly bind to the antigen.

Watts and another antibody engineer Mark Dennis originally hoped to be able to synthesize antibodies with high affinity for transferrin. However, they found that these high-affinity antibodies were prevented from passing through brain tissue in blood vessels. Dennis speculated that the antibody might be trapped in the blood vessel by the transferrin receptor, so he began to design and synthesize low-affinity antibodies. As Dennis expected, synthetic low-affinity antibodies can be more widely distributed in the brain.

"This is an excellent example, which shows that when considering multispecific protein therapy, we must put aside some rules and patterns we have learned from monoclonal antibodies," said David Hilbert, the head of the study.

Hilbert is currently working on the development of multispecific antibodies that can simultaneously recognize five different target proteins. Hilbert believes that the design concept of multispecific antibodies can also be applied to other fields, such as cancer stem cells. Scientists usually identify cancer stem cells based on the cell surface marker proteins they express. However, these surface markers sometimes exist in other healthy cells. Conventional high-affinity monoclonal antibodies can target cancer cells while killing healthy cells, while low-affinity multi-targeting antibodies can more selectively target cancer stem cells.

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