Oral Presentation The 47th Lorne Conference on Protein Structure and Function 2022

Development of Antibody-Based Therapeutics for COVID-19 (#44)

Phillip Pymm 1 , Adam Wheatley 2 , Amy Adair 1 , Damien Drew 1 , Melanie Dietrich 1 , Lynn Tan 1 , Li Jin Chan 1 , Matthew O'Neill 1 , Katrina Black 1 , Miles Davenport 3 , Amy Chung 2 , Alisa Glukhova 1 , Marc Pellegrini 1 , Kanta Subbarao 2 , Stephen Kent 2 , Wai-Hong Tham 1 , MRFF Biologics COVID-19 Consortium 1 2 3 4 5 6 7
  1. Infectious Diseases and Immune Defences, WEHI, Parkville, Vic, Australia
  2. Peter Docherty Institute, University of Melbourne, Parkville, Victoria, Australia
  3. Kirby Institute, University of New South Wales, Kensington, NSW, Australia
  4. Burnet Institute, Melbourne, Victoria, Australia
  5. CSL, Melbourne, Victoria, Australia
  6. Australian Centre for Disease Preparedness, CSIRO, Geelong, Victoria, Australia
  7. Affinity Bio, Scoresby, Victoria, Australia

The ongoing COVID-19 pandemic has challenged health systems around the world and highlighted an urgent need for therapeutics that ameliorate disease. While approval and distribution of vaccines is ongoing, there remains a need for therapies to protect and treat vulnerable populations, to prevent infection in outbreak settings, to protect immunocompromised populations and to treat breakthrough infections caused by circulating variants of concern (VOC’s). As such, these therapeutics must be able to combat current variants and be resistant in the face of emerging and future COVID-19 variants.

Antibody-based therapeutics, collectively termed biologics, are an attractive treatment option for COVID-19 as neutralising antibodies are produced in the majority of patients, and animal models show antibody-mediated protection from re-infection. Human monoclonal antibodies are well established as leading treatments for number of human diseases, comprising 7 of the top 10 selling drugs in 2019. Another biologic, nanobodies, consist of a single heavy chain antibody variable region and have additional advantages in production cost and flexible treatment modalities. Here, we identified high-affinity human antibodies and nanobodies that disrupted RBD engagement with the human receptor angiotensin-converting enzyme 2 (ACE2) and potently neutralized SARS-CoV-2.

We used structural characterisation through both X-ray crystallography, and cryo-electron microscopy in combination with epitope mapping to reveal an antigenic landscape of the SARS-CoV-2 RBD. 16 biologics from multiple epitope classes were identified as lead candidates. Rationally designed cocktails of these biologics were able to bind simultaneously to the RBD and inhibit ACE2 engagement. A subset of these was also able to neutralize infection at low to sub-nanomolar concentrations with SARS-CoV-2 VOC in vitro. Prophylactic administration of either single biologics or cocktail combinations reduced viral loads below the assay limit of detection in mice infected with the N501Y D614G SARS-CoV-2 virus, demonstrating their potential for use in prevention of COVID-19.

  1. Landscape of human antibody recognition of the SARS-CoV-2 receptor binding domain. Wheatley AK, Pymm P, Esterbauer R, Dietrich MH, Lee WS, Drew D, Kelly HG, Chan LJ, Mordant FL, Black KA, Adair A, Tan HX, Juno JA, Wragg KM, Amarasena T, Lopez E, Selva KJ, Haycroft ER, Cooney JP, Venugopal H, Tan LL, O Neill MT, Allison CC, Cromer D, Davenport MP, Bowen RA, Chung AW, Pellegrini M, Liddament MT, Glukhova A, Subbarao K, Kent SJ, Tham WH. Cell Rep. 2021 Oct 12;37(2):109822. doi: 10.1016/j.celrep.2021.109822. Epub 2021 Sep 25.
  2. Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice. Pymm P, Adair A, Chan LJ, Cooney JP, Mordant FL, Allison CC, Lopez E, Haycroft ER, O'Neill MT, Tan LL, Dietrich MH, Drew D, Doerflinger M, Dengler MA, Scott NE, Wheatley AK, Gherardin NA, Venugopal H, Cromer D, Davenport MP, Pickering R, Godfrey DI, Purcell DFJ, Kent SJ, Chung AW, Subbarao K, Pellegrini M, Glukhova A, Tham WH. Proc Natl Acad Sci U S A. 2021 May 11;118(19):e2101918118. doi: 10.1073/pnas.2101918118.