Intrinsic physicochemical profile of marketed antibody-based biotherapeutics.
antibody
biologics
computation
developability
drug discovery
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
14 09 2021
14 09 2021
Historique:
accepted:
03
08
2021
entrez:
10
9
2021
pubmed:
11
9
2021
medline:
15
12
2021
Statut:
ppublish
Résumé
Feeding biopharma pipelines with biotherapeutic candidates that possess desirable developability profiles can help improve the productivity of biologic drug discovery and development. Here, we have derived an in silico profile by analyzing computed physicochemical descriptors for the variable regions (Fv) found in 77 marketed antibody-based biotherapeutics. Fv regions of these biotherapeutics demonstrate significant diversities in their germlines, complementarity determining region loop lengths, hydrophobicity, and charge distributions. Furthermore, an analysis of 24 physicochemical descriptors, calculated using homology-based molecular models, has yielded five nonredundant descriptors whose distributions represent stability, isoelectric point, and molecular surface characteristics of their Fv regions. Fv regions of candidates from our internal discovery campaigns, human next-generation sequencing repertoires, and those in clinical-stages (CST) were assessed for similarity with the physicochemical profile derived here. The Fv regions in 33% of CST antibodies show physicochemical properties that are dissimilar to currently marketed biotherapeutics. In comparison, physicochemical characteristics of ∼29% of the Fv regions in human antibodies and ∼27% of our internal hits deviated significantly from those of marketed biotherapeutics. The early availability of this information can help guide hit selection, lead identification, and optimization of biotherapeutic candidates. Insights from this work can also help support portfolio risk assessment, in-licensing, and biopharma collaborations.
Identifiants
pubmed: 34504010
pii: 2020577118
doi: 10.1073/pnas.2020577118
pmc: PMC8449350
pii:
doi:
Substances chimiques
Antibodies, Monoclonal
0
Complementarity Determining Regions
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2021 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
Références
MAbs. 2016;8(2):216-28
pubmed: 26736022
J Pharm Sci. 2012 Jan;101(1):102-15
pubmed: 21935950
Pharm Res. 2011 May;28(5):949-61
pubmed: 21437790
J Pharmacokinet Pharmacodyn. 2015 Oct;42(5):553-71
pubmed: 26373957
Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4025-4030
pubmed: 30765520
Protein Eng Des Sel. 2016 Aug;29(8):285-9
pubmed: 27284085
MAbs. 2019 Oct;11(7):1197-1205
pubmed: 31216939
Pharm Res. 2010 Aug;27(8):1512-29
pubmed: 20422267
Protein Eng Des Sel. 2010 Aug;23(8):643-51
pubmed: 20543007
Nat Rev Drug Discov. 2016 Jun;15(6):379-80
pubmed: 27199245
J Pharm Biomed Anal. 2021 Jan 5;192:113650
pubmed: 33065403
Pharm Res. 2014 Nov;31(11):3161-78
pubmed: 24906598
MAbs. 2015;7(1):212-30
pubmed: 25559441
J Pharm Sci. 2012 Aug;101(8):2686-701
pubmed: 22619033
Front Immunol. 2020 Oct 29;11:614856
pubmed: 33193460
Drug Discov Today Technol. 2004 Dec;1(4):337-41
pubmed: 24981612
PLoS Comput Biol. 2019 Aug 23;15(8):e1007207
pubmed: 31442220
J Mol Biol. 2009 May 29;389(1):115-23
pubmed: 19361524
Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):11937-42
pubmed: 19571001
MAbs. 2014;6(5):1255-64
pubmed: 25517310
Pharm Res. 2020 Jan 3;37(2):23
pubmed: 31900680
Pharm Res. 2014 Sep;31(9):2549-58
pubmed: 24639233
J Biol Chem. 2006 Mar 10;281(10):6625-31
pubmed: 16373345
Commun Biol. 2019 Aug 9;2:304
pubmed: 31428692
J Chromatogr A. 2006 Feb 24;1107(1-2):110-9
pubmed: 16384569
MAbs. 2017 Apr;9(3):476-489
pubmed: 28125318
MAbs. 2019 Jan;11(1):26-44
pubmed: 30541416
Immunology. 2018 Jan;153(1):31-41
pubmed: 28898398
Protein Eng Des Sel. 2012 Oct;25(10):531-7
pubmed: 22915597
Nature. 1982 Sep 23;299(5881):371-4
pubmed: 7110359
Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
pubmed: 11259830
Proc Natl Acad Sci U S A. 1984 Jan;81(1):140-4
pubmed: 6582470
Structure. 1993 Oct 15;1(2):83-93
pubmed: 8069628
Pharm Res. 2018 Aug 20;35(10):193
pubmed: 30128780
Exp Ther Med. 2018 Apr;15(4):3161-3168
pubmed: 29556253
PLoS One. 2015 Mar 25;10(3):e0120451
pubmed: 25807114
MAbs. 2019 Feb/Mar;11(2):239-264
pubmed: 30543482
MAbs. 2018 Oct;10(7):1073-1083
pubmed: 30130444
MAbs. 2012 Mar-Apr;4(2):243-55
pubmed: 22453096
Med Sci (Paris). 2019 Dec;35(12):1171-1174
pubmed: 31903933
MAbs. 2015;7(6):1084-93
pubmed: 26337808
Mol Pharm. 2020 Jul 6;17(7):2555-2569
pubmed: 32453957
J Pharmacol Toxicol Methods. 2000 Jul-Aug;44(1):235-49
pubmed: 11274893
MAbs. 2015;7(3):483-93
pubmed: 25695748
J Pharm Pharmacol. 2018 May;70(5):595-608
pubmed: 28155992
Bioconjug Chem. 2010 Dec 15;21(12):2153-63
pubmed: 21053952
Sci Adv. 2020 Aug 05;6(32):eabb0372
pubmed: 32923611
J Pharm Sci. 2015 Jun;104(6):1885-1898
pubmed: 25821140
Curr Opin Biotechnol. 2019 Dec;60:119-127
pubmed: 30822699
J Pharm Sci. 2011 Feb;100(2):354-87
pubmed: 20740683
Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):944-949
pubmed: 28096333
MAbs. 2020 Jan 1;12(1):1770028
pubmed: 32486889
MAbs. 2020 Jan-Dec;12(1):1787121
pubmed: 32658605
Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18601-6
pubmed: 25512516