In early March of 2020, when COVID-19 was officially designated a pandemic by the World Health Organization, many were quick to realize that, barring an effective containment strategy, a vaccine was the best hope for returning to global safety and normalcy. Despite the success of recent vaccination efforts, , there are minimal antiviral therapeutic interventions currently available to treat COVID-19. While several neutralizing antibodies have been identified for SARS-CoV, they have been ineffective against SARS-CoV-2; reported nanobodies (Nbs) that bind it have mediocre affinities and low neutralization potencies.
Description
Researchers have recently identified thousands of potent SARS-CoV-2 neutralizing nanobodies by in vivo (camelid) antibody affinity maturation followed by advanced proteomic identification. Multiple elite Nbs with up to femtomolar affinities—the highest known in nature—inhibit viral infection at sub-ng/ml concentration, more potent than some of the best human neutralizing antibodies and hundreds to tens of thousands of times more potent than other available neutralizing Nbs. A crystal structure of such an elite neutralizing Nb in complex with RBD has been determined, and structural proteomics and integrative modeling reveal multiple distinct and non-overlapping epitopes and indicate an array of potential neutralization mechanisms. Structural characterization facilitated the bioengineering of novel multivalent Nb constructs into multi-epitope cocktails that achieved ultrahigh neutralization potency, with IC50s as low as 0.058 ng/ml—the most potent biotherapeutics to date—and may prevent mutational escape. Our thermostable Nb cocktails can be rapidly produced in bulk from microbes and resist lyophilization and aerosolization. These promising agents are now being translated into efficient, cost-effective, and convenient therapeutics to help end this health crisis.
Applications
· COVID-19 early-stage treatment, prevention and disease diagnosis
Advantages
· Development of a large repertoire of neutralizing Nbs
· The majority of high-affinity Nbs neutralize SARS-CoV-2
· Elite Nbs have pico- to femtomolar affinity and sub-ng/ml SARS-CoV-2 neutralization potency
· Crystal structure determination of an elite neutralizing Nb
· Mapping multiple neutralizing epitopes on RBD by integrative structure determination with various possible neutralization mechanisms
· Outstanding stability and antiviral activity of elite Nbs enables aerosolization for efficient and flexible delivery
· Novel multivalent constructs for improved neutralization potency at double-digit pg/ml—the most potent biotherapeutics available to date—and the suppression of SARS-CoV-2 mutations
Invention Readiness
Finished preclinical studies with hamster model
IP Status
https://patents.google.com/patent/US20240043505A1
