title: Structure reveals function of the dual variable domain immunoglobulin (DVD-Ig™) molecule.
abstract: Several bispecific antibody-based formats have been developed over the past 25 years in an effort to produce a new generation of immunotherapeutics that target two or more disease mechanisms simultaneously. One such format, the dual-variable domain immunoglobulin (DVD-Ig™), combines the target binding domains of two monoclonal antibodies via flexible naturally occurring linkers, which yields a tetravalent IgG - like molecule. We report the structure of an interleukin (IL)12-IL18 DVD-Ig™ Fab (DFab) fragment with IL18 bound to the inner variable domain (VD) that reveals the remarkable flexibility of the DVD-Ig™ molecule and how the DVD-Ig™ format can function to bind four antigens simultaneously. An understanding of how the inner variable domain retains function is of critical importance for designing DVD-Ig™ molecules, and for better understanding of the flexibility of immunoglobulin variable domains and linkers, which may aid in the design of improved bi- and multi-specific biologics in general.
authors.affiliation: Department of Structural Biology; AbbVie Inc.; North Chicago, IL USA.
authors.forename: Clarissa G
authors.initials: CG
authors.lastname: Jakob
authors.affiliation: Global Protein Sciences; AbbVie Inc.; North Chicago, IL USA.
authors.forename: Rohinton
authors.initials: R
authors.lastname: Edalji
authors.affiliation: Department of Structural Biology; AbbVie Inc.; North Chicago, IL USA.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Judge
authors.affiliation: Global Protein Sciences; AbbVie Inc.; North Chicago, IL USA.
authors.forename: Enrico
authors.initials: E
authors.lastname: DiGiammarino
authors.affiliation: Cancer Research; AbbVie Inc.; North Chicago, IL USA.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Global Biologics; AbbVie BioResearch Center; Worcester, MA USA.
authors.forename: Jijie
authors.initials: J
authors.lastname: Gu
authors.affiliation: Global Biologics; AbbVie BioResearch Center; Worcester, MA USA.
authors.forename: Tariq
authors.initials: T
authors.lastname: Ghayur
mesh_terms: D018033:Antibodies, Bispecific / Q000737:chemistry* / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use; D000918:Antibody Specificity; D000941:Antigens / Q000276:immunology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000737:chemistry*; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000276:immunology; D020382:Interleukin-18 / Q000737:chemistry* / Q000276:immunology; D011485:Protein Binding; D015202:Protein Engineering; D017434:Protein Structure, Tertiary
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000941:Antigens; D007135:Immunoglobulin Variable Region; D020382:Interleukin-18; D018664:Interleukin-12
keywords: DFab; DVD-Ig™; Dual Specific Antibody; IL12; IL18
references.citation: Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
references.pmid: 15299374
references.citation: Acta Crystallogr D Biol Crystallogr. 2000 Dec;56(Pt 12):1622-4
references.pmid: 11092928
references.citation: Nat Biotechnol. 2007 Nov;25(11):1290-7
references.pmid: 17934452
references.citation: Sci Transl Med. 2011 May 25;3(84):84ra44
references.pmid: 21613623
references.citation: Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
references.pmid: 15299926
references.citation: MAbs. 2011 Sep-Oct;3(5):487-94
references.pmid: 21814039
references.citation: Proc Natl Acad Sci U S A. 2011 May 17;108(20):8194-9
references.pmid: 21536919
references.citation: Acta Crystallogr D Biol Crystallogr. 2010 Apr;66(Pt 4):486-501
references.pmid: 20383002
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2126-32
references.pmid: 15572765
references.citation: Cancer Lett. 2010 Dec 28;299(2):130-6
references.pmid: 20826049
references.citation: Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):293-302
references.pmid: 21460447
references.citation: J Synchrotron Radiat. 2003 Jan 1;10(Pt 1):23-5
references.pmid: 12511787
references.citation: J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674
references.pmid: 19461840
references.citation: Methods Enzymol. 1997;276:307-26
references.pmid: 27754618
references.citation: J Appl Physiol (1985). 2008 Jun;104(6):1793-800
references.pmid: 18292296
references.citation: J Mol Biol. 1993 Dec 20;234(4):946-50
references.pmid: 8263940
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2210-21
references.pmid: 15572774
references.citation: J Biol Chem. 2009 Sep 4;284(36):24478-89
references.pmid: 19553661
references.citation: J Clin Oncol. 2011 Jun 20;29(18):2493-8
references.pmid: 21576633
references.citation: MAbs. 2009 Jul-Aug;1(4):339-47
references.pmid: 20068402
references.citation: Int J Cancer. 2010 Nov 1;127(9):2209-21
references.pmid: 20473913