A recent sponsored DDW Sitting Down With podcast covered the bamlanivimab story and how this therapeutic went from lab to clinic in eight months during the pandemic. It is available to listen to here. Lu Rahman selects some of the highlights of this chat with Bryan Jones, Senior Research Fellow, BioTechnology Discovery Research, Eli Lilly and Company and Dan Bedinger, Application Science Team Lead, Carterra.
Bamlanivimab was the first neutralising monoclonal antibody to receive Emergency Use Authorisation from the FDA as a treatment for mild to moderate Covid-19 on November 9, 2020, just 94 days after the monoclonal antibody discovery workflow began for the molecule. This achievement, says Lilly, represents the shortest timeline from discovery to public usage for a monoclonal antibody to date. In February 2021, bamlanivimab administered with etesevimab received Emergency Use Authorisation for treatment of recently diagnosed, mild to moderate Covid-19 in patients who are high risk for progression to severe Covid-19.
In the beginning
Jones and Bedinger take us back to 2020 when the pandemic was unfolding. Eli Lilly was strategising and developing collaborations to enable this Covid-19 therapeutic, bamlanivimab to find its way to patients in just over eight months. Part of this process was working with AbCellera – Lilly had had previous interactions with them – and this led to a partnership on this development.
The first scientific meeting with AbCellera took place while they were in the process of screening the first patient sample in early March. This was something of a special collaboration – Lilly hadn’t carried out antiviral research in decades, so knew it would need to find collaborators with appropriate facilities and capabilities – both academic and research organisations.
Within Lilly itself a development team formed to map out what was needed and what could be sped up to get any discovered antibodies into manufacturing and clinical testing. Some creative solutions, frequent dialogue with the FDA enabled speed to both the clinic and ultimately Emergency Use Authorisation.
Getting to market faster
The speed of this project is impressive. Bedinger revealed how epitope binning analysis sped up the drug discovery process. He outlined the Carterra technology that enabled scientists to set up a pair wise competition assay for up to hundreds of clones using just a couple of microplates and small amounts, less than 15ug, of each mAb and modest amounts of antigen, and automate the testing of many thousands of pairwise competition interactions. This allowed for high-resolution competition-based epitope binning profiles to be established on whole panels of antibodies. Up to 384 clones could be run in a single analysis, generating a matrix of up to 147,000 interactions.
Conquering potential escape mutants
The Coronavirus Immunotherapy Consortium (COVIC) which sought and compiled a set of over 300 anti-SARS-COV-2 antibodies from many collaborators had the goal of ascertaining which ones would be the best, what made them the best, which ones could be combined and how they would perform in response to viral mutation.
Carterra performed epitope binning on the panel of antibodies, and found it demonstrated a very impressive amount of epitope diversity. “This was excellent news and impressive given that the vast majority of the clones were receptor binding domain binders which blocked the ACE-2 binding,” revealed Bedinger.
In a more traditional receptor competition assay or low throughput binning assay this level of diversity would not have been apparent given the high level of cross-competition among the clones and broad receptor competition. Therefore, the inclusion of low throughput epitope characterisation would not have been a suitable technique to assess the diversity of the panel or be useful in the funnel to bring a representative panel forward for other types of characterisation. “The COVIC process is a bit unique in that all of the clones were evaluated in many of the assays, which has created a very rich data set, but most drug discovery screening processes apply much more of a narrowing funnel approach,” he added.
Eli Lilly and Covid-19 variants
Having progressed both bamlanivimab and etesevimab into the clinic, Lilly knew variants would be a concern so continued to work with AbCellera on antibody discovery efforts – in particular screening of new/different patient samples, modified screening paradigms, and exploring non-receptor binding domain based monoclonal antibodies.
This led to the selection of a new antibody ‘LY-CoV1404’ or Bebtelovimab, early this year following the surge in variant lineages worldwide. Based on preclinical data, to date, Bebtelovimab is unaffected by known circulating variants and prominent mutations that occur in multiple strains. Bebtelovimab is currently being evaluated in clinical trials.
Volume 22, Issue 4 – Fall 2021