title: Development of a human IgG4 bispecific antibody for dual targeting of interleukin-4 (IL-4) and interleukin-13 (IL-13) cytokines.
abstract: Human bispecific antibodies have great potential for the treatment of human diseases. Although human IgG1 bispecific antibodies have been generated, few attempts have been reported in the scientific literature that extend bispecific antibodies to other human antibody isotypes. In this paper, we report our work expanding the knobs-into-holes bispecific antibody technology to the human IgG4 isotype. We apply this approach to generate a bispecific antibody that targets IL-4 and IL-13, two cytokines that play roles in type 2 inflammation. We show that IgG4 bispecific antibodies can be generated in large quantities with equivalent efficiency and quality and have comparable pharmacokinetic properties and lung partitioning, compared with the IgG1 isotype. This work broadens the range of published therapeutic bispecific antibodies with natural surface architecture and provides additional options for the generation of bispecific antibodies with differing effector functions through the use of different antibody isotypes.
authors.affiliation: From the Departments of Antibody Engineering.
authors.forename: Christoph
authors.initials: C
authors.lastname: Spiess
authors.forename: Jack
authors.initials: J
authors.lastname: Bevers
authors.forename: Janet
authors.initials: J
authors.lastname: Jackman
authors.forename: Nancy
authors.initials: N
authors.lastname: Chiang
authors.forename: Gerald
authors.initials: G
authors.lastname: Nakamura
authors.forename: Michael
authors.initials: M
authors.lastname: Dillon
authors.forename: Hongbin
authors.initials: H
authors.lastname: Liu
authors.forename: Patricia
authors.initials: P
authors.lastname: Molina
authors.forename: J Michael
authors.initials: JM
authors.lastname: Elliott
authors.forename: Whitney
authors.initials: W
authors.lastname: Shatz
authors.forename: Justin M
authors.initials: JM
authors.lastname: Scheer
authors.forename: Glen
authors.initials: G
authors.lastname: Giese
authors.forename: Josefine
authors.initials: J
authors.lastname: Persson
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dennis
authors.forename: James
authors.initials: J
authors.lastname: Giulianotti
authors.forename: Prateek
authors.initials: P
authors.lastname: Gupta
authors.forename: Dorothea
authors.initials: D
authors.lastname: Reilly
authors.forename: Enzo
authors.initials: E
authors.lastname: Palma
authors.forename: Jianyong
authors.initials: J
authors.lastname: Wang
authors.forename: Eric
authors.initials: E
authors.lastname: Stefanich
authors.forename: Heleen
authors.initials: H
authors.lastname: Scheerens
authors.forename: Germaine
authors.initials: G
authors.lastname: Fuh
authors.forename: Lawren C
authors.initials: LC
authors.lastname: Wu
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000096:biosynthesis / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology*; D018793:Interleukin-13 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000378:metabolism; D015202:Protein Engineering / Q000379:methods; D020349:Surface Plasmon Resonance
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D018793:Interleukin-13; D015847:Interleukin-4; C561806:lebrikizumab
keywords: Antibody Engineering; Asthma; Cytokine; Immunoglobulin; Knobs-into-holes; Lebrikizumab; Lung; Protein Assembly