In vitro and in silico assessment of the developability of a designed monoclonal antibody library.


Despite major advances in antibody discovery technologies, the successful development of monoclonal antibodies (mAbs) into effective therapeutic and diagnostic agents can often be impeded by developability liabilities, such as poor expression, low solubility, high viscosity and aggregation. Therefore, strategies to predict at the early phases of antibody development the risk of late-stage failure of antibody candidates are highly valuable. In this work, we employ the in silico solubility predictor CamSol to design a library of 17 variants of a humanized mAb predicted to span a broad range of solubility values, and we examine their developability potential with a battery of commonly used in vitro and in silico assays. Our results demonstrate the ability of CamSol to rationally enhance mAb developability, and provide a quantitative comparison of in vitro developability measurements with each other and with more resource-intensive solubility measurements, as well as with in silico predictors that offer a potentially faster and cheaper alternative. We observed a strong correlation between predicted and experimentally determined solubility values, as well as with measurements obtained using a panel of in vitro developability assays that probe non-specific interactions. These results indicate that computational methods have the potential to reduce or eliminate the need of carrying out laborious in vitro quality controls for large numbers of lead candidates. Overall, our study provides support to the emerging view that the implementation of in silico tools in antibody discovery campaigns can ensure rapid and early selection of antibodies with optimal developability potential.

Submission Details

ID: LkrLYH38

Submitter: Paul Chang

Submission Date: Jan. 16, 2019, 1:41 p.m.

Version: 1

Publication Details
Wolf PĂ©rez AM;Sormanni P;Andersen JS;Sakhnini LI;Rodriguez-Leon I;Bjelke JR;Gajhede AJ;De Maria L;Otzen DE;Vendruscolo M;Lorenzen N,MAbs (2018) In vitro and in silico assessment of the developability of a designed monoclonal antibody library. PMID:30523762
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 H Unliganded mAb7 P01857 IGHG1_HUMAN
96.0 H Unliganded mAb7 P01860 IGHG3_HUMAN
91.9 H Unliganded mAb7 P01861 IGHG4_HUMAN
90.9 H Unliganded mAb7 P01859 IGHG2_HUMAN
100.0 L Unliganded mAb7 P01834 IGKC_HUMAN