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 PDB Entries

Structure ID Release Date Resolution Structure Title
4HAG 2012-09-26T00:00:00+0000 3.4 Crystal structure of fc-fragment of human IgG2 antibody (centered crystal form)
4HAF 2012-09-26T00:00:00+0000 2.04 Crystal structure of fc-fragment of human IgG2 antibody (primitive crystal form)
4L4J 2013-06-07T00:00:00+0000 1.92 Crystal structure of fc-fragment of human IgG2-Sigma antibody
5W38 2017-06-07T00:00:00+0000 1.8 1.80A resolution structure of human IgG3 Fc (N392K)
6D58 2018-04-19T00:00:00+0000 2.39 Crystal structure of a Fc fragment of Human IgG3
4ZNC 2015-05-04T00:00:00+0000 2.28 Fc fragment of human IgG in complex with the C domain of staphylococcal protein A mutant - Q9W
4WWI 2014-11-11T00:00:00+0000 2.31 Crystal structure of the C domain of staphylococcal protein A in complex with the Fc fragment of human IgG at 2.3 Angstrom resolution
3EO1 2008-09-26T00:00:00+0000 3.1 Structure of the Fab Fragment of GC-1008 in Complex with Transforming Growth Factor-Beta 3
5LG1 2016-07-05T00:00:00+0000 2.7 Room temperature structure of human IgG4-Fc from crystals analysed in situ
4D2N 2014-05-12T00:00:00+0000 2.7 Crystal structure of deglycosylated serum-derived human IgG4 Fc

Relevant UniProtKB Entries

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