Engineered Albumin-Fused Truncated ACE2 Dimer: Revolutionizing Prophylactic and Therapeutic Strategies for SARS-CoV-2 Variants

A tailored angiotensin-converting enzyme 2 (ACE2) fusion design provides extended plasma half-life and allows for efficient delivery across mucosal barriers upon nasal administration to arrest SARS-CoV-2 virus variants, according to a study published in PNAS Nexus.

“While monoclonal antibodies have been approved for therapy and prophylaxis, they have shown to lose efficacy against the Omicron lineages of SARS-CoV-2,” wrote Sopisa Benjakul, Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Department of Immunology, Oslo University Hospital Rikshospitalet, Precision Immunotherapy Alliance (PRIMA), University of Oslo, Norway, and coauthors. “As the virus requires binding to its host receptor, angiotensin-converting enzyme 2 (ACE2), the prophylactic and therapeutic use of recombinant truncated human ACE2 is an attractive strategy. However, such soluble ACE2 has a plasma half-life of only few hours, which severely hampers its utility,” they added.

A new protein fusion was developed using albumin and truncated dimeric ACE2. This fusion was engineered to enhance the engagement of neonatal fragment crystallizable receptors (FcRn), which are expressed on mucosal epithelial cell barriers and on the endothelial cells lining blood vessels. The protein has an extended plasma half-life and can be efficiently delivered through mucosal barriers upon nasal administration. When the fusions were injected intravenously into human FcRn Tg32 mice, the plasma half-life was 2.6 days compared to 1.1 days for the wild-type version of the protein, resulting in a 2.4-fold longer half-life. The fusion also includes an ACE2 engineered for higher affinity to SARS-CoV-2, which can block infection of Omicron subvariants. Results from the study show that the dimeric ACE-2-albumin fusion design effectively blocks SARS-CoV-2 cellular infection.

“Taken together, our study shows that soluble truncated dimeric human ACE2 can be tailored for favorable pharmacokinetic properties and efficient needle-free delivery across mucosal barriers by fusion to engineered human albumin with improved pH-dependent engagement to human FcRn,” concluded the study authors.

Reference

Benjakul S, Anthi AK, Kolderup A, et al. A pan-SARS-CoV-2-specific soluble angiotensin-converting enzyme 2-albumin fusion engineered for enhanced plasma half-life and needle-free mucosal delivery. PNAS Nexus. 2023:2(12);pgad403. doi:10.1093/pnasnexus/pgad403