{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T03:51:27Z","timestamp":1787025087453,"version":"build-2736575974"},"reference-count":44,"publisher":"American Diabetes Association","issue":"9","license":[{"start":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T00:00:00Z","timestamp":1687737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,9,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic \u03b2-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the \u03b2-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration\u2013approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein\u2013coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1\u2212\/\u2212 mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1\u2212\/\u2212 mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db22-1039","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T08:05:18Z","timestamp":1687766718000},"page":"1320-1329","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":7,"title":["Optimization of a Glucagon-Like Peptide 1 Receptor Antagonist Antibody for Treatment of Hyperinsulinism"],"prefix":"10.2337","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4873-0283","authenticated-orcid":false,"given":"Sean M.","family":"Peterson","sequence":"first","affiliation":[{"name":"1Twist Bioscience, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A.","family":"Juliana","sequence":"additional","affiliation":[{"name":"2Division of Endocrinology and Diabetes, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron F.","family":"Hu","sequence":"additional","affiliation":[{"name":"1Twist Bioscience, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghua","family":"Chai","sequence":"additional","affiliation":[{"name":"2Division of Endocrinology and Diabetes, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carson","family":"Holliday","sequence":"additional","affiliation":[{"name":"1Twist Bioscience, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara Y.","family":"Chan","sequence":"additional","affiliation":[{"name":"1Twist Bioscience, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana G.","family":"Lujan Hernandez","sequence":"additional","affiliation":[{"name":"1Twist Bioscience, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe","family":"Challocombe","sequence":"additional","affiliation":[{"name":"1Twist Bioscience, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linya","family":"Wang","sequence":"additional","affiliation":[{"name":"1Twist Bioscience, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Han","sequence":"additional","affiliation":[{"name":"1Twist Bioscience, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikhil","family":"Haas","sequence":"additional","affiliation":[{"name":"1Twist Bioscience, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Stafford","sequence":"additional","affiliation":[{"name":"1Twist Bioscience, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiko","family":"Axelrod","sequence":"additional","affiliation":[{"name":"1Twist Bioscience, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom Z.","family":"Yuan","sequence":"additional","affiliation":[{"name":"1Twist Bioscience, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1225-8087","authenticated-orcid":false,"given":"Diva D.","family":"De Le\u00f3n","sequence":"additional","affiliation":[{"name":"2Division of Endocrinology and Diabetes, The Children\u2019s Hospital of Philadelphia, Philadelphia, PA"},{"name":"3Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron K.","family":"Sato","sequence":"additional","affiliation":[{"name":"1Twist Bioscience, South San Francisco, 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