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Synthetic Antibodies Shown to Control Blood Glucose

DNAmolcule model

(Skeeze, Pixabay)

22 Mar. 2021. A company creating biologics derived from synthetic DNA and genes discovered antibodies that control blood glucose levels in lab animals. Researchers from Twist Biosciences Corp. in South San Francisco, California describe their findings in the 12 Mar. issue of the peer-reviewed journal mAbs.

People with diabetes need to constantly monitor and control their blood glucose, usually by injections of insulin or insulin pumps. Since insulin injections are difficult for many people, researchers are looking for other ways to control glucose levels in blood. One strategy is to activate a type peptide that acts like glucagon, a hormone produced in the pancreas that works with insulin to keep blood glucose levels in a safe range. Proteins known as glucagon-like peptide 1, or GLP-1 receptor agonists are known to activate GLP-1 peptides to promote production of insulin in the pancreas.

The paper’s authors, led by Twist Biosciences’ chief scientist Aaron Sato, note that antibodies are one technique for activating receptor proteins, and often have superior active lifetimes, better targeting, and fewer side effects than peptides or small molecule drugs. But to date only two antibodies targeting receptor proteins are approved by the Food and Drug Administration.

Twist Biosciences develops synthetic genetic materials on a silicon platform, patterned after semiconductors, instead of traditional plastic plates and receptacles. This process, says the company, overcomes conventional limitations and inefficiencies to design and construct genes, and from these synthetic genes, produce libraries of genetic variations. To find antibodies that target GLP-1 receptors, the Twist Bio team used its technology to generate a library of protein interactions called a phage display, derived from viruses that infect bacteria called bacteriophages, and a tool used increasingly to discover immunotherapies.

Created and tested synthetic antibody drugs

In this case, the phage display represents some 10 billion receptor proteins, with the researchers focusing on GLP-1 receptors. This screening tool made it possible to find 13 antibody candidates meeting desirable binding properties and peptide chemistry. Also among the candidates are antibodies that depress GLP-1 receptors, which can help reduce hypoglycemia incidents. Tests in lab cultures verified that these antibodies acted against GLP-1 receptors as designed, either to produce or reduce insulin concentrations.

In addition, the Twist Bio team created synthetic antibody drugs addressing GLP-1 receptors. One synthetic formulation combined a GLP-1 peptide to a lightweight antibody that by itself did not interact with GLP-1 receptors. The result, which the company code-names TB59-2, in lab cultures binds like the larger GLP-1 receptor antibodies and has a longer active lifetime. In tests with lab mice, say the researchers, TB59-2 is able to control blood glucose with a single weekly dose.

The team designed another synthetic antibody, this one acting as an antagonist or reducer of GLP-1 receptors, code-named TB01-3. The researchers gave TB01-3 antibodies to lab mice six hours before giving the same mice an extra dose of insulin. The results show mice receiving TB01-3 are able to raise their glucose levels, even more than a current GLP-1 receptor antagonist. And like the GLP-1 receptor or GLP-1R agonist antibody, TB01-3 remains active in the mice for at least a week.

“GLP-1R agonists and antagonists are widely used to control blood glucose levels to treat multiple diseases,” says Twist Bio CEO and co-founder Emily Leproust in a company statement, “which suggests our potent antibodies could have multiple clinical indications. We continue to advance these antibody leads and in parallel, work with a wide variety of partners to discover and optimize their antibodies across modalities and disease areas.”

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