115025 Pathobody: A proteogenomic pipeline for capture and sequencing and production of pathogen-specific antibodies

Som et ledd i monitorering av kommersielle terapeutiske antistoffer for Covid 19, har vi brukt programvaren og databasen utviklet i dette prosjektet til å se på unikhet og overlapp med CDRH3-domenet fra våre antistoffer med Cov-AbDab-databasen. Vi fant 56 overlappende tilfeller mellom Pathobody-data og data i CoV-AbDab databasen. Av disse fant vi 8 unike sekvenser fra vårt Pathobaody datasett. Disse 8 unike sekvensene binder til 17 forskjellige varianter av SARS-CoV2. Dette antyder på at vi kan identifisere nye antistoffer med terapeutiske effekter som sannsynligvis ikke er dekket av eksisterende kommersielle COVID-antistoffer. Videre har vi i løpet av prosjekt perioden ferdigstilt den første versjonen av databasen og analyse pipeline. Løsningen inkluderer rutiner for import av ønskede sekvensbiblioteker, importering og analyse av Pathobody CDR3-IMGT-sekvenser, importering av sekvensdatabase (i dette prosjektet CoV-AbDab CDRH3-sekvenser), inkludert algoritmer for sammenligning og analyse av Pathobody sekvensdataen opp mot CoV-AbDab sekvensdata. Vi har utviklet algoritmer og rutiner for å beregne sannsynligheten for hvilke SARS-CoV2-varianter våre sekvenser kan binde seg til, ikke binde seg til, nøytralisere eller ikke nøytralisere. Videre har vi inkludert rutiner for parvis sammenligning av Pathobody-sekvenser som ikke samsvarer med den valgte sekvensdatabasen for sammenligning. Til slutt har vi inkludert rutiner og verktøy for å matche Pathobody CDR3-IMGT-sekvenser til PDB 3D-strukture

Through this project we have confirmed that we are able to identify new antibodies with potential therapeutic effects that would not infringe on already existing commercial COVID antibodies. Further more we have together with our partners developed a pipeline with necessary protocols and software that could be used in response to future emerging threats. Regarding the commercialisation and out licensing of the pipeline, this is expected to take a bit more time than originally anticipated. The reason for this is that the envisioned/primary commercialisation partner in the project, AbSano had to withdraw from the project due to a very unfortunate event within the corporate management. We, the remaining partners are currently discussing how to proceed with the commercialisation of the project results.

The development of active vaccines is time-consuming and normally takes 5-10 years. If a rapid response to a pathogen is required, recombinant mAbs provide a faster path towards the protection of sensitive groups. Moreover, mAbs may be important in post-exposure therapies, where active immunization can no longer raise a protective response in time to limit an infectious process. This project aims to develop a fast platform for the recovery of pathogen-specific antibody molecules from exposed patients. High-value monoclonal antibody leads derived from Covid-19 patients will be the first output. The novel combination of NGS, phage display, and proteomics pioneered in our project will be the basis of an offer to industrial parties that wish to develop antibodies against other pathogens and to have a response capability in future pandemics. The PathoBody technology, integrating LC-MS/MS, NGS, phage display and bioinformatics tools, is a breakthrough development that represents a significant improvement over current state-of-the-art methods. Our new approach combines protein and RNA sequence analysis. The protein sequences provided by LC-MS/MS combined NGS of the whole complete immunoglobulin repertoire creates a reference cDNA database, which can be used to make a phage display library. This approach allows us to generate the full relevant Ab sequence to be used for cloning and production. This approach allows fast selection of target-specific mAbs, rather than laborious cell isolation, expansion and clone detection methods. Marketable outputs of this project are 1) safe, efficient patient-derived therapeutic Covid-19 monoclonals 2) an efficiency-demonstrated, novel platform-technology to produce such antibodies and 3) IP covering the different steps of the process. Potential customers of these products are large- and medium-sized pharma companies able to carry drugs through all steps of approval.