89. First-in-human study of a novel half-life extended monoclonal antibody (GB-0669) against SARS-CoV2 and related sarbecoviruses
Authors: De Alwis Dinesh , Borriello Francesco , Carlin Eric , Nassirpour Rounak , Straley Stephanie , Allen Anna , Robertson Andrew W , Troconiz Iñaki F , Safder Akber , Hazuda Daria , Goyal Lovely , CKW Koh Gavin , Robertson Nicholas , Snyder Alexandra 
Published: January 2025

Abstract

Background
GB-0669 is a novel half-life extended monoclonal antibody for the prophylaxis of SARS-CoV2 infection and is one of the first biologics designed using artificial intelligence/machine learning to reach clinical development and the first against SARS-CoV2. GB-0669 targets the previously undruggable S2 domain of the SARS-CoV2 spike protein, which contains the fusion peptide and stem-helix peptides, and was selected because the S2 domain is conserved across all SARS-CoV2 variants to-date. The S2 domain is not immunodominant and is therefore not subject to selective pressure from natural infection or vaccine induced immunity. This suggesting GB-0669 will maintain its activity, unlike monoclonal antibodies directed against the SARS-CoV2 receptor-binding domain. GB-0669 is also able to neutralize other sarbecoviruses, such as SARS-CoV2 and WIV1 (Table).Table:GB-0669 EC50 against SARS-CoV2 variants and other sarbecoviruses in a VSV pseudoneutralisation assay

Methods
In this single-ascending dose study, healthy volunteers aged 18–55 years were administered either GB-0669 or placebo intravenously. There were five sequential dosing cohorts 100 mg, 300 mg, 600 mg, 1200 mg, 2400 mg and each cohort was randomized to receive either GB-0669 or placebo in ratios of 3:3, 3:3, 10:3, 10:3, 10:3 respectively. Total follow-up will be 43 weeks; although dosing is now complete, follow-up is ongoing.Figure:Simulated GB-0669 drug concentrations over 43 weeks (plasma and lung) following a single dose of 1200 mg

Results
No dose-limiting toxicity has been observed to date and all treatment-related adverse reactions observed were mild (grade 1 or 2) at all doses. Preliminary pharmacokinetic data shows dose-proportionality up to 2400 mg the highest dose tested, with a half-life of approximately 70 days. An exploratory analysis of live virus neutralization shows a clear dose response and separation from placebo at 600 and 1200 mg. Limited anti-drug antibodies were observed in a few participants, but had no observable impact on PK or viral neutralization titers. Simulated PK of GB-0669 confirmed with observed data (assuming 10% lung penetration) are at levels anticipated to protect against COVID-19 for at least 150 days (Figure).

Conclusion
The preliminary data support the hypothesis that GB-0669 will be able to provide a six-month duration of prophylactic efficacy against currently circulating viral variants when administered as part of a combination.

Disclosures
Dinesh De Alwis, PhD, Generate Biomedicines: Stocks/Bonds (Private Company) Iñaki F. Troconiz, Pharmacy, Generate Biomedicines: Advisor/Consultant Daria Hazuda, PhD, Generate Biomedicines: Stocks/Bonds (Private Company) Gavin CKW Koh, PhD, AstraZeneca: Stocks/Bonds (Public Company)|Generate:Biomedicines: Stocks/Bonds (Private Company)|GlaxoSmithKline: Stocks/Bonds (Public Company) Alexandra Snyder, MD, Generate Biomedicines: employee