Case study: Neutralisation screening to resistance characterisation
Scientific challenge
Supporting SARS-CoV-2 antibody development
A biopharmaceutical company developing therapeutic antibodies against SARS-CoV-2 required comprehensive in vitro characterisation of multiple antibody candidates throughout an extended development programme.
The initial objective was to identify antibodies capable of potently neutralising circulating SARS-CoV-2 variants. As the pandemic evolved and new variants emerged, the programme expanded to evaluate activity against successive variants of concern, including multiple Omicron lineages.
Following identification of a broadly neutralising lead candidate, the project progressed to evaluating the potential for viral resistance. This required the selection of resistant virus populations, identification of resistance-associated mutations and detailed assessment of their impact on antibody susceptibility and viral fitness.
Virus |
SARS-CoV-2 (multiple variants including early pandemic isolates and Omicron variants) |
Project |
Functional characterisation and resistance assessment of therapeutic antibodies |
Assay |
Neutralisation assay, resistance selection, virus sequencing, multistep growth curves |
Client |
Biopharmaceutical company |
Stage |
Antibody discovery and preclinical development |
Services |
Neutralisation assays, bespoke assay development, resistance studies, virus sequencing coordination, virus fitness characterisation |
Related expertise |
SARS-CoV-2, antibody therapeutics, viral evolution, antiviral resistance, variant characterisation |
Key considerations
Rapidly changing epidemiology
The project evolved alongside the rapidly changing epidemiology of SARS-CoV-2 and required continual adaptation of experimental workflows.
Key considerations included:
- rapidly acquiring newly emerging SARS-CoV-2 variants, and developing and qualifying neutralisation assays for each,
- generating reproducible quantitative neutralisation data across multiple antibody candidates,
- selecting resistant virus populations through serial passaging under antibody pressure,
- coordinating sequencing to identify resistance-associated mutations,
- determining whether resistance mutations affected susceptibility to additional therapeutic antibodies,
- evaluating the impact of resistance mutations on viral replication and fitness.
Maintaining assay consistency throughout the programme was essential to allow meaningful comparison of antibody potency across variants and over time.
Our Approach
A structured workflow
VRS established a structured workflow supporting every stage of antibody characterisation. The programme began with neutralisation testing of a panel of candidate antibodies against early SARS-CoV-2 isolates. As new variants emerged, VRS rapidly acquired clinically relevant isolates, established the corresponding neutralisation assays and incorporated them into the ongoing testing programme without disrupting project timelines.
Following selection of the lead broadly neutralising antibody, VRS performed tighly controlled serial resistance passaging experiments under increasing antibody pressure to promote the emergence of resistant virus populations.
Virus samples were subsequently analysed through sequencing performed in collaboration with specialist partners to identify resistance-associated mutations.
To understand the biological significance of these mutations, VRS further characterised resistant viruses using multistep growth curve experiments to evaluate viral replication kinetics and overall fitness. Neutralisation assays were repeated to confirm shifts in IC₅₀ values associated with resistance and to determine whether individual mutations conferred cross-resistance to additional antibody candidates.
Throughout the programme, close collaboration with the client enabled experimental priorities to evolve alongside emerging scientific findings and the rapidly changing landscape of SARS-CoV-2 variants.
Outcome
Informed progression of candidates
Over the course of the programme, VRS generated a comprehensive functional characterisation of therapeutic antibody candidates across multiple SARS-CoV-2 variants, facilitating the transition from screening to full characterisation of escape mutants.
The integrated dataset provided the client with a detailed understanding of antibody performance, resistance potential and viral adaptation, supporting informed progression of therapeutic candidates, and proof-of-concept confirmation of their novel antibody design strategy, currently applied to multiple therapeutics in their pipeline.
VRS INSIGHT
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As new variants emerge and selective pressure drives viral evolution, experimental systems must evolve alongside.
This programme demonstrated the value of integrating neutralisation assays, resistance selection, sequencing and viral fitness studies within a single coordinated workflow. By combining assay development with detailed virological characterisation, VRS generated a comprehensive understanding of both antibody efficacy and viral adaptation, enabling robust evaluation of therapeutic candidates throughout development.
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