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Pandemic Preparedness Capabilities

Rapid discovery of neutralising monoclonal antibodies for first line defense


PI(s)/Head responsible for the resource:

Gunilla Karlsson Hedestam

Host organisation(s):

Karolinska Institutet

Resource description:

With the ongoing SARS-CoV-2 pandemic, there is a need to identify broadly neutralising monoclonal antibodies (mAbs) that can be used as first-line defense against newly emerging variants. Already in the first year of the pandemic, the scientific community showed that highly effective neutralising mAbs can be isolated from convalescent donors, some of which were rapidly approved for clinical use. Because of their exquisite specificities, monoclonal antibodies are generally safe and rarely give side effects. Furthermore, by targeting conserved epitopes on the virus spike, antibodies that resist changes in the virus can be identified. We recently developed a high throughput technique to clone large numbers of human antibody heavy and light chains from single-sorted memory B cells, for subsequent expression in mammalian cells. In collaboration with the Murrell group at KI, we screened the mAbs for their neutralising activities against a panel of SARS-CoV-2 variants. Of several evaluated mAbs, we identified antibodies that cross-neutralise all SARS-CoV-2 variants of concern, including the recent Omicron sub-variants, BA.5 and BA2.75. Furthermore, in collaboration with the Hällberg group at KI, we determined high resolution structures of some of the most interesting mAbs by cryo-EM. These studies reveal the mode of antibody binding to the SARS-CoV-2 spike and demonstrate how B cell affinity maturation increases the potency and breadth of antibody neutralising activity.

Research findings:

Broadly neutralizing monoclonal antibodies (mAbs) have significant value as first-line defense against newly emerging pathogens. Already in the first year of the SARS-CoV-2 pandemic, the scientific community showed that highly effective neutralizing mAbs can be isolated from convalescent donors, some of which were rapidly approved for clinical use. Because of their exquisite specificities, mAbs are generally safe and rarely give side effects. Furthermore, by targeting conserved epitopes on virus spike glycoproteins, antibodies that resist changes in the virus can be identified. We recently developed a high throughput technique to clone large numbers of human antibody heavy and light chains from single-sorted memory B cells, for subsequent expression in mammalian cells and isolation of neutralizing mAbs against the influenza virus.

Impact on prepardness for future pandemics:

In the current project, we developed the ISCAPE technique for rapid isolation of antigen-specific monoclonal antibodies from human donors. The antibodies are full-length IgG and fully human, which means that they can be developed for clinical use without further time-consuming engineering. In this PLP project, we applied ISCAPE and isolated a large set of neutralizing mAbs, several which were directed against the HA stem and neutralized several influenza variants, including H2N2 A/Singapore/1/1957, H5N1 A/Vietnam/1203/2004, H5N1 A/Chile/25945/2023, H5N1 A/Cambodia/NPH2300/2023 and H5N1 A/Texas/37/2024. Critically, the last three strains are human isolates from H5N1 clade 2.3.4.4b, a clade causing mass mortality in birds and some mammalian species. Furthermore, A/Texas/37/2024 is from the H5N1 outbreak ongoing in dairy cattle in the US at present. With both the wet lab and software analysis parts of the ISCAPE technique now fully developed, we can rapidly apply this approach to the isolation of monoclonal antibodies from any emerging pathogen and as such the project has significant societal benefits for pandemic preparedness.

Contact information:

Gunilla Karlsson Hedestam
Professor
Email: gunilla.karlsson.hedestam@ki.se