Poster Presentation 50th Lorne Proteins Conference 2025

Nanobody therapeutics against human coronaviruses (#401)

Jackson Feng 1 , Jason Girkin 2 , Matthew Gartner 3 , Amy Adair 1 , Lynn Tan 1 , Francesca Mordant 3 , Nathan Bryant 2 , Mingyang Wang 3 , Li Jin Chan 1 4 , Melanie Dietrich 1 4 , Nathan Bartlett 2 , Kanta Subbarao 3 5 , Wai-Hong Tham 1 4 6 , Phillip Pymm 1 4
  1. Infectious Diseases and Immune Defences, WEHI, Parkville, Vic, Australia
  2. School of Biomedical Sciences and Pharmacy, University of Newcastle and Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
  3. Peter Docherty Institute, University of Melbourne, Parkville, Victoria, Australia
  4. Department of Medical Biology, University of Melbourne, Parkville, Vic, Australia
  5. Département de biologie moléculaire, de biochimie médicale et de pathologie, Université Laval, Quebec, Canada
  6. Research School of Biology, Australian National University, Canberra, ACT, Australia

Coronaviruses are a family of enveloped positive strand RNA viruses that infect many mammalian and avian species. Over the past 20 years, three highly pathogenic coronaviruses, SARS-CoV-1, MERS-CoV and SARS-CoV-2 have emerged. The rapid emergence of the COVID-19 pandemic, and the SARS and MERS epidemics highlight zoonotic coronaviruses as critically important human pathogenic viruses with pandemic potential. In addition, there are four endemic circulating human coronaviruses (HCoV) HCoV-OC43, HCoV-HKU1, HCoV-NL63 and HCoV-229E. There remains no effective vaccine or treatment for coronaviruses other than for SARS-CoV-2.

 

We propose that existing human coronaviruses can be used as templates for developing therapies against future coronavirus outbreaks. Our lab utilises nanobodies to develop targeted therapeutics against infectious diseases. Nanobodies are single domain antibodies and are well-suited for therapeutic development due to their small size, stability across temperature and pH ranges, high yield expression in microbial systems and ease of adaptation into modular designs.

 

Nanobody phage display libraries were screened to identify nanobodies that recognize recombinant MERS-CoV, HCoV-OC43, HCoV-HKU1, and HCoV-229E S1B domains. We have developed a pipeline for functional and structural characterisation of nanobodies to identify lead candidates with therapeutic potential.

 

To date we have identified high affinity nanobodies against MERS-CoV, HCoV-HKU1 and HCoV-229E that block receptor binding and potently neutralize virus in vitro for MERS-CoV and HCoV-OC43. For HCoV OC43 we have demonstrated reductions in viral load in an in vivo mouse model of disease. Structural characterisation of these nanobodies identified both neutralising and non-neutralising epitopes on the HCoV-OC43 S1B, providing insight into its antigenic landscape. This nanobody development pipeline establishes a large collection of nanobodies against human coronaviruses for therapeutic development for preparedness for future coronavirus outbreaks.

 

  1. Human coronavirus OC43 nanobody neutralizes virus and protects mice from infection. Journal of Virology, 2024, Jun 13 Vol. 98, No. 6 Amy Adair, Li Lynn Tan, Jackson Feng, Jason Girkin, Nathan Bryant, Mingyang Wang, Francesca Mordant, Li-Jin Chan, Nathan W. Bartlett, Kanta Subbarao, Phillip Pymm, Wai-Hong Tham https://doi.org/10.1128/jvi.00531-24