Twist Bioscience, offering synthetic DNA using its silicon platform, has published preclinical data supporting the potential use of the highly potent and optimized GLP-1R antagonist antibody, TB-222-023, as a treatment for congenital hyperinsulinism (CHI). CHI is a paediatric genetic disorder with an estimated of prevalence ranging from 1 in 25,000 to 1 in 50,000 live births in the US, which could translate into a steady-state treatable population of up to 2,500 cases in the US. It is caused by excessive pancreatic beta cell insulin secretion, resulting in hypoglycemia that can cause brain damage or death without treatment.
The findings were featured in the paper, ‘Optimization of a glucagon-like peptide 1 receptor antagonist antibody for treatment of hyperinsulinism”, published in Diabetes, and were the accumulation from several preclinical experiments using TB-222-023 as part of a research collaboration between Twist and the laboratory of Dr Diva D De León-Crutchlow, Chief of the Division of Endocrinology and Diabetes and Director of the Congenital Hyperinsulinism Center at Children's Hospital of Philadelphia.
“Patients with congenital hyperinsulinism have few treatment options,” said De León-Crutchlow. “The promising results from our studies described in the Diabetes paper demonstrate that targeting GLP-1R with an antibody antagonist, such as TB-222-023, could be an effective strategy for the treatment of this very serious condition.”
Twist researchers had previously identified a highly potent and specific GLP-1R antagonist antibody, TB-001-003, from synthetic antibody libraries designed to target G protein-coupled receptors. Subsequently, this lead was optimized further for greater activity against GLP-1R using the Twist Antibody Optimization (TAO) library platform. One antagonist, TB-222-023, was identified and shown to be more potent than exendin-(9-39), a clinical stage GLP-1R antagonist peptide.
The results of the studies conducted at Children's Hospital of Philadelphia showed that TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with hyperinsulinism. TB-222-023 also increased plasma glucose and decreased the insulin to glucose ratio in Sur1-/- mice.
“GLP-1R is very high profile within the industry and targeting this receptor with potent therapeutic candidates has potential in several medical conditions in addition to CHI, such as post-bariatric hypoglycemia (PBH),” said Dr Emily M Leproust, CEO and co-founder of Twist Bioscience. “This paper describes the power of Twist’s highly specific and potent antibody libraries as well as our ability to then optimize and improve on resulting candidates. The fact that TB-222-023 showed potency higher than a Phase 3 ready clinical candidate peptide is very promising. TB-222-023 has the potential to be a first-in-class antibody, a modality with advantages over peptides. We are now looking for partners to help take TB-222-023 and related antibodies forward in development.”