A full manuscript detailing this work is now available on bioRxiv, and this blog serves as a brief introduction to that research.
Sarbecoviruses—a group of coronaviruses including SARS-CoV‑1 and SARS-CoV‑2—pose ongoing risks due to their circulation in the human population (SARS-CoV‑2) and their potential to jump from animals to humans, leading to outbreaks or even pandemics. Despite global vaccination efforts, SARS-CoV‑2 continues to evolve and produce immune evasive variants. This highlights the pressing need for durable antibody therapies that can stand up to viral mutation.
Using our generative optimization approach—iterative, ML-driven protein generation with in-the-loop experiments—we identified two monoclonal antibodies targeting the SARS-CoV‑2 spike protein: PRO-37587 and GB-0669.
We hypothesized that by explicitly optimizing for neutralization across multiple SARS-CoV‑2 strains, we would identify molecules resilient to viral evolution. Excitingly, this has proven true: both antibodies remain exceptionally durable against mutations in SARS-CoV‑2, including the challenging Omicron variants that previously evaded monoclonal antibody therapies. Furthermore, they have shown promising potential for broader neutralization across members of the sarbecovirus family.
The two antibodies utilize different neuralization mechanisms. PRO-37587 targets the spike protein’s receptor-binding domain. Other antibodies acting in this way have generally quickly lost activity as the virus evolved, so explicit optimization for neutralization breadth was key here. On the other hand, GB-0669 binds to the spike’s S2 stem helix. While this region exhibits minimal mutation across sarbecoviruses, antibodies targeting this region have generally been poor neutralizers. Thus, optimization for neutalization potency was key in this case. This illustrates the power of generative optimization, where the same general-purpose methodology can be used with arbitrary and diverse objectives, as appropriate for the specific therapeutic hypothesis and mechanism of action.
The Power of Combination Therapy
Excitingly, when PRO-37587 and GB-0669 were combined, their antiviral effectiveness increased beyond what either antibody could achieve alone. Preclinical studies demonstrated that this combination more potently neutralized SARS-CoV‑2 variants, substantially reducing the likelihood of viral escape. This effect may be explained by simultaneous blockade of two distinct and critical mechanisms of infection: PRO-37587 inhibits the interaction of SARS-CoV‑2 with its cellular receptor, whereas GB-0669 prevents SARS-CoV‑2 fusion with host cells. Animal models confirmed the protective efficacy of this approach.
Further Reading & Resources
While these programs have been deprioritized for internal development, opportunities for further evaluation and advancement in partnership with external collaborators are under active consideration.
- GB-0669, PRO-37587
- GB-0669