title: Self-assembled antibody multimers through peptide nucleic acid conjugation.
abstract: With the recent clinical success of bispecific antibodies, a strategy to rapidly synthesize and evaluate bispecific or higher order multispecific molecules could facilitate the discovery of new therapeutic agents. Here, we show that unnatural amino acids (UAAs) with orthogonal chemical reactivity can be used to generate site-specific antibody-oligonucleotide conjugates. These constructs can then be self-assembled into multimeric complexes with defined composition, valency, and geometry. With this approach, we generated potent bispecific antibodies that recruit cytotoxic T lymphocytes to Her2 and CD20 positive cancer cells, as well as multimeric antibody fragments with enhanced activity. This strategy should accelerate the synthesis and in vitro characterization of antibody constructs with unique specificities and molecular architectures.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Kazane
authors.forename: Jun Y
authors.initials: JY
authors.lastname: Axup
authors.forename: Chan Hyuk
authors.initials: CH
authors.lastname: Kim
authors.forename: Mihai
authors.initials: M
authors.lastname: Ciobanu
authors.forename: Erik D
authors.initials: ED
authors.lastname: Wold
authors.forename: Sofia
authors.initials: S
authors.lastname: Barluenga
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Hutchins
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.forename: Nicolas
authors.initials: N
authors.lastname: Winssinger
authors.forename: Vaughn V
authors.initials: VV
authors.lastname: Smider
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D020135:Peptide Nucleic Acids / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D007140:Immunoglobulin Fab Fragments; D020135:Peptide Nucleic Acids