{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:39:44Z","timestamp":1787240384000,"version":"build-2736575974"},"reference-count":30,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Generate Biomedicines"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Antibodies against the SARS-CoV-2 spike receptor-binding domain provided effective COVID-19 treatment until resistant variants emerged. GB-0669 is a half-life\u2013extended monoclonal antibody optimized using artificial intelligence. It targets the conserved spike S2 stem helix, a region subject to limited selective pressure from antibody responses induced by natural infection or vaccination.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Preclinical safety studies were conducted in cynomolgus monkeys. In the first-in-human trial, healthy adults aged 18\u201355 received single intravenous doses of GB-0669 or placebo in 5 ascending cohorts (100, 300, 600, 1200, and 2400\u2005mg). Participants were monitored for 43 weeks to evaluate safety, pharmacokinetics (PK), and pharmacodynamics (PD; serum live virus neutralization). In vitro studies assessed neutralization of GB-0669 combined with antiviral drugs (remdesivir, nirmatrelvir, and molnupiravir).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Preclinical studies revealed no safety concerns. In the clinical trial (n = 51; 36 GB-0669, 15 placebo), GB-0669 was well-tolerated without dose-limiting toxicities; all adverse reactions were mild (Grade 1 or 2). Pharmacokinetics showed dose proportionality up to 2400\u2005mg, with a half-life of 54 days. Dose-dependent increases in serum live virus neutralization occurred at 600 and 1200\u2005mg, with separation from placebo. The estimated neutralizing index that adjusts GB-0669 serum concentrations for its in vitro neutralizing potency supported therapeutic efficacy for 2 weeks post-administration. Finally, in vitro experiments showed improved neutralization profiles of GB-0669 in combination with antivirals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The data support exploring GB-0669 at 1200\u2005mg in a Phase 2 trial for treating COVID-19 in immunocompromised individuals. The combination of GB-0669 with antiviral drugs may offer additional therapeutic benefits.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trials Registration<\/jats:title>\n                    <jats:p>ClinicalTrials.gov Identifier. NCT07050511.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/infdis\/jiag349","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T14:01:33Z","timestamp":1784037693000},"source":"Crossref","is-referenced-by-count":0,"title":["Randomized, Double-Blind, Placebo-Controlled First-in-Human Trial of a First-in-Class AI-Designed Monoclonal Antibody (GB-0669) Against the Conserved SARS-CoV-2 Spike S2 Stem Helix"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9074-4828","authenticated-orcid":false,"given":"Francesco","family":"Borriello","sequence":"first","affiliation":[{"name":"Generate:Biomedicines , Somerville, Massachusetts ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin C K W","family":"Koh","sequence":"additional","affiliation":[{"name":"Generate:Biomedicines , Somerville, Massachusetts 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