DNA-delivered antibody cocktail exhibits improved pharmacokinetics and confers prophylactic protection against SARS-CoV-2

Abstract

Monoclonal antibody therapy has played an important role against SARS-CoV-2. Strategies to deliver functional, antibody-based therapeutics with improved in vivo durability are needed to supplement current efforts and reach underserved populations. Here, we compare recombinant mAbs COV2-2196 and COV2-2130, which compromise clinical cocktail Tixagevimab/Cilgavimab, with optimized nucleic acid-launched forms. Functional profiling of in vivo-expressed, DNA-encoded monoclonal antibodies (DMAbs) demonstrated similar specificity, broad antiviral potency and equivalent protective efficacy in multiple animal challenge models of SARS-CoV-2 prophylaxis compared to protein delivery. In PK studies, DNA-delivery drove significant serum antibody titers that were better maintained compared to protein administration. Furthermore, cryo-EM studies performed on serum-derived DMAbs provide the first high-resolution visualization of in vivo-launched antibodies, revealing new interactions that may promote cooperative binding to trimeric antigen and broad activity against VoC including Omicron lineages. These data support the further study of DMAb technology in the development and delivery of valuable biologics.

A deep generative model of the SARS-CoV-2 spike protein predicts future variants

“…To assess the binding between SARS-CoV-2 spike and the ACE2 receptor, a cryo-EM solved protein structure of the S-ACE2 complex available on the RCSB Protein Data Bank at accession 7DF4 was used [35]. To assess the potential for mutations in SARS-CoV-2 spike protein to escape from existing therapies, a cryo-EM solved protein structure of SARS-CoV-2 Spike RBD in complex with tixagevimab/cilgavimab at accession 8D8Q was used [36]. Point substitutions that caused both a predicted increase in binding affinity between S and ACE2 as well as a predicted decrease in binding affinity between S and tixagevimab/cilgavimab were highlighted as potentially high-risk variants.…”

Targeting SARS-CoV-2 and host cell receptor interactions

“…To overcome developability issues encountered with conventional Abs, DNA plasmids encoding antibody cocktails have been employed as delivery vehicles and are undergoing phase I trials ( Table 2 ; Parzych et al, 2022 ). Similarly, bovine-derived antibodies and camelid-derived nanobodies against S protein have been proposed for use in countering SARS-CoV-2 and its emerging variants and mutants ( Saied et al, 2022 ).…”

SARS-CoV-2 antibodies recognize 23 distinct epitopic sites on the receptor binding domain

“…One example, Evushield™, which consists of two Abs, tixagevimab (AZD 8895) and cligavimab (AZD 1061) illustrates this point. These Ab have been studied by X-ray crystallography (tixagevimab, PDB 7L7D, and cligavimab 7L7E 52 ) and by cryo-EM 53 . By our analysis, tixagevimab interacts with ES13, 16, 18, 19, and 20 and cligavimab with ES2, 10, 11, and 12.…”