Pragmatic mAb lead molecule engineering from a developability perspective.

Autor: Chi B; Kymab Ltd., Cambridge, UK., De Oliveira G; Kymab Ltd., Cambridge, UK., Gallagher T; Kymab Ltd., Cambridge, UK.; F-star Therapeutics Ltd., Cambridge, UK., Mitchell L; Kymab Ltd., Cambridge, UK., Knightley L; Kymab Ltd., Cambridge, UK., Gonzalez CC; Kymab Ltd., Cambridge, UK., Russell S; Kymab Ltd., Cambridge, UK., Germaschewski V; Kymab Ltd., Cambridge, UK., Pearce C; Kymab Ltd., Cambridge, UK., Sellick CA; Kymab Ltd., Cambridge, UK.
Jazyk: angličtina
Zdroj: Biotechnology and bioengineering [Biotechnol Bioeng] 2021 Oct; Vol. 118 (10), pp. 3733-3743. Date of Electronic Publication: 2021 Jun 24.
DOI: 10.1002/bit.27802
Abstrakt: As the number of antibody drugs being approved and marketed increases, our knowledge of what makes potential drug candidates a successful product has increased tremendously. One of the critical parameters that have become clear in the field is the importance of mAb "developability." Efforts are being increasingly focused on simultaneously selecting molecules that exhibit both desirable biological potencies and manufacturability attributes. In the current study mutations to improve the developability profile of a problematic antibody that inconsistently precipitates in a batch scale-dependent fashion using a standard platform purification process are described. Initial bioinformatic analysis showed the molecule has no obvious sequence or structural liabilities that might lead it to precipitate. Subsequent analysis of the molecule revealed the presence of two unusual positively charged mutations on the light chain at the interface of VH and VL domains, which were hypothesized to be the primary contributor to molecule precipitation during process development. To investigate this hypothesis, straightforward reversion to the germline of these residues was carried out. The resulting mutants have improved expression titers and recovered stability within a forced precipitation assay, without any change to biological activity. Given the time pressures of drug development in industry, process optimization of the lead molecule was carried out in parallel to the "retrospective" mutagenesis approach. Bespoke process optimization for large-scale manufacturing was successful. However, we propose that such context-dependent sequence liabilities should be included in the arsenal of in silico developability screening early in development; particularly since this specific issue can be efficiently mitigated without the requirement for extensive screening of lead molecule variants.
(© 2021 Wiley Periodicals LLC.)
Databáze: MEDLINE
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