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

Adriana-Michelle Wolf Pérez; Pietro Sormanni; Jonathan Sonne Andersen; Laila Ismail Sakhnini; Ileana Rodriguez-Leon; Jais Rose Bjelke; Annette Juhl Gajhede; Leonardo De Maria; Daniel E Otzen; Michele Vendruscolo; Nikolai Lorenzen

doi:10.1080/19420862.2018.1556082

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

Adriana-Michelle Wolf Pérez, Pietro Sormanni, Jonathan Sonne Andersen, Laila Ismail Sakhnini, Ileana Rodriguez-Leon, Jais Rose Bjelke, Annette Juhl Gajhede, Leonardo De Maria, Daniel E Otzen, Michele Vendruscolo, Nikolai Lorenzen

Interdisciplinary Nanoscience Center - INANO-MBG, iNANO-huset

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

69 Citations (Scopus)

Abstract

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.

Original language	English
Journal	mAbs
Volume	11
Issue	2
Pages (from-to)	388-400
Number of pages	13
ISSN	1942-0862
DOIs	https://doi.org/10.1080/19420862.2018.1556082
Publication status	Published - 2019

Keywords

DISCOVERY
PREDICTION
PROTEIN AGGREGATION
RATIONAL DESIGN
SELF-ASSOCIATION
SEQUENCE
SOLUBILITY
STABILITY
THERAPEUTIC ANTIBODIES
VISCOSITY
biophysical properties
computational predictions
developability assessment
monoclonal antibodies

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10.1080/19420862.2018.1556082

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380425/pdf/kmab-11-02-1556082.pdf

Cite this

@article{fe71ed66c0b7475cb38572fd3e270830,

title = "In vitro and in silico assessment of the developability of a designed monoclonal antibody library",

abstract = "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.",

keywords = "DISCOVERY, PREDICTION, PROTEIN AGGREGATION, RATIONAL DESIGN, SELF-ASSOCIATION, SEQUENCE, SOLUBILITY, STABILITY, THERAPEUTIC ANTIBODIES, VISCOSITY, biophysical properties, computational predictions, developability assessment, monoclonal antibodies",

author = "{Wolf P{\'e}rez}, Adriana-Michelle and Pietro Sormanni and Andersen, {Jonathan Sonne} and Sakhnini, {Laila Ismail} and Ileana Rodriguez-Leon and Bjelke, {Jais Rose} and Gajhede, {Annette Juhl} and {De Maria}, Leonardo and Otzen, {Daniel E} and Michele Vendruscolo and Nikolai Lorenzen",

year = "2019",

doi = "10.1080/19420862.2018.1556082",

language = "English",

volume = "11",

pages = "388--400",

journal = "mAbs",

issn = "1942-0862",

publisher = "Landes Bioscience",

number = "2",

}

In vitro and in silico assessment of the developability of a designed monoclonal antibody library. / Wolf Pérez, Adriana-Michelle; Sormanni, Pietro; Andersen, Jonathan Sonne et al.
In: mAbs, Vol. 11, No. 2, 2019, p. 388-400.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - In vitro and in silico assessment of the developability of a designed monoclonal antibody library

AU - Wolf Pérez, Adriana-Michelle

AU - Sormanni, Pietro

AU - Andersen, Jonathan Sonne

AU - Sakhnini, Laila Ismail

AU - Rodriguez-Leon, Ileana

AU - Bjelke, Jais Rose

AU - Gajhede, Annette Juhl

AU - De Maria, Leonardo

AU - Otzen, Daniel E

AU - Vendruscolo, Michele

AU - Lorenzen, Nikolai

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - DISCOVERY

KW - PREDICTION

KW - PROTEIN AGGREGATION

KW - RATIONAL DESIGN

KW - SELF-ASSOCIATION

KW - SEQUENCE

KW - SOLUBILITY

KW - STABILITY

KW - THERAPEUTIC ANTIBODIES

KW - VISCOSITY

KW - biophysical properties

KW - computational predictions

KW - developability assessment

KW - monoclonal antibodies

UR - http://www.scopus.com/inward/record.url?scp=85060257724&partnerID=8YFLogxK

U2 - 10.1080/19420862.2018.1556082

DO - 10.1080/19420862.2018.1556082

M3 - Journal article

C2 - 30523762

SN - 1942-0862

VL - 11

SP - 388

EP - 400

JO - mAbs

JF - mAbs

IS - 2

ER -

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

Abstract

Keywords

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