1355. The SARS-CoV-2 Monoclonal Antibody AZD3152 Potently Neutralizes Historical and Emerging Variants and is Being Developed for the Prevention and Treatment of COVID-19 in High-risk Individuals
Joseph R. Francica, Cai Yingyun, Seme Diallo, Kim Rosenthal, Kuishu Ren, Daniel J. Flores, Andrew Dippel, Yuling Wu, Xiaoru Chen, Erin Cantu, Rakesh Choudhary, Michal Sulikowski, Hibret A. Adissu, Bhavna Chawla, Swagata Kar, Nydia van Dyk, Vaheh Oganesyan, Saravanan Rajan, Patricia C. Ryan, Yueh–Ming Loo, Taylor S. Cohen, Mark T. Esser, Wade Blair
Abstract
Abstract Background EVUSHELD was developed for the prevention and treatment of mild-to-moderate COVID-19 for high-risk individuals. However, the SARS-CoV-2 virus continues to evolve in the presence of natural- and vaccine-acquired immunity, escaping previously authorized antibody therapies such as bebtelovimab and EVUSHELD. AZD3152 was selected to neutralize all known SARS-CoV-2 variants of concern and is being developed to provide immunocompromised individuals with continued protection against SARS-CoV-2. Methods Structural analyses were performed to map the AZD3152 binding site. Neutralization assays were employed to determine the potency of AZD3152 across a panel of historical and emerging SARS-CoV-2 variants. Hamsters were prophylactically administered 6.7-60 mg/kg AZD3152 or a control antibody, then challenged intranasally with 6x103 PFU WA-1 SARS-CoV-2, then monitored for weight loss; lung viral load and pathology were evaluated at days 3 and 7. A 3 week GLP repeat IM and IV dose toxicity study in nonhuman primates (NHP) was performed. Results AZD3152 binds to a conserved epitope on the spike receptor binding domain and blocks ACE2 binding. AZD3152 potently neutralizes authentic viral variants (EC50 range, 8.3 to 110.9 ng/mL) and SARS-CoV-2 pseudoviruses (EC50 range of 3.2 to 25.0 ng/mL), including XBB.1.5. Prophylactic administration of AZD3152 conferred dose-dependent protection to hamsters following challenge. Even at a suboptimal dose of 6.7 mg/kg, < 5% weight loss and 2 logs reduction in lung viral subgenomic RNA were observed. AZD3152 was not associated with any adverse findings in NHP and the no observed-adverse-effect-level was the highest dose tested (150 mg/kg). Toxicokinetics demonstrated similar systemic exposure following IM and IV dosing with bioavailability of 94.9% and half-life range of 15.2-26.5 days by IM. Conclusion These results demonstrate that AZD3152 binds a conserved epitope resulting in broad neutralization of SARS-CoV-2 variants, protects hamsters from disease, and has a favorable safety profile in NHP. Thus, AZD3152 may serve as a next-generation antibody for the prevention and treatment of COVID-19. Disclosures Joseph R Francica, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Yingyun Cai, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Seme Diallo, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Kim Rosenthal, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Kuishu Ren, BS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Daniel J. Flores, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Andrew Dippel, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Yuling Wu, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Xiaoru Chen, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Erin Cantu, BS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Rakesh Choudhary, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Michal Sulikowski, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Hibret Adissu, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Nydia van Dyk, MSc, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Vaheh Oganesyan, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Saravanan Rajan, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Patricia C. Ryan, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Yueh-Ming Loo, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Taylor Cohen, PhD, AstraZeneca: Employement|AstraZeneca: Stocks/Bonds Mark T. Esser, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Wade Blair, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds