title: Improving the serum stability of site-specific antibody conjugates with sulfone linkers.
abstract: Current routes for synthesizing antibody-drug conjugates commonly rely on maleimide linkers to react with cysteine thiols. However, thioether exchange with metabolites and serum proteins can compromise conjugate stability and diminish in vivo efficacy. We report the application of a phenyloxadiazole sulfone linker for the preparation of trastuzumab conjugates. This sulfone linker site-specifically labeled engineered cysteine residues in THIOMABs and improved antibody conjugate stability in human plasma at sites previously shown to be labile for maleimide conjugates. Similarly, sulfone conjugation with selenocysteine in an anti-ROR1 scFv-Fc improved human plasma stability relative to maleimide conjugation. Kinetically controlled labeling of a THIOMAB containing two cysteine substitutions was also achieved, offering a strategy for producing antibody conjugates with expanded valency.
authors.affiliation: The Skaggs Institute for Chemical Biology, Department of Chemistry, and Department of Cell and Molecular Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: James T
authors.initials: JT
authors.lastname: Patterson
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Asano
authors.forename: Xiuling
authors.initials: X
authors.lastname: Li
authors.forename: Christoph
authors.initials: C
authors.lastname: Rader
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Barbas
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D018796:Immunoconjugates / Q000097:blood / Q000737:chemistry*; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry; D008958:Models, Molecular; D010069:Oxadiazoles / Q000737:chemistry; D011487:Protein Conformation; D055550:Protein Stability; D057127:Single-Chain Antibodies / Q000737:chemistry; D013379:Substrate Specificity; D013450:Sulfones / Q000737:chemistry*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D007141:Immunoglobulin Fc Fragments; D010069:Oxadiazoles; D057127:Single-Chain Antibodies; D013450:Sulfones; D000068878:Trastuzumab
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