title: Generating site-specifically modified proteins via a versatile and stable nucleophilic carbon ligation.
abstract: There is a need for facile chemistries that allow for chemo- and regioselectivity in bioconjugation reactions. To address this need, we are pioneering site-specific bioconjugation methods that use formylglycine as a bioorthogonal handle on a protein surface. Here we introduce aldehyde-specific bioconjugation chemistry, the trapped-Knoevenagel ligation. The speed and stability of the trapped-Knoevenagel ligation further advances the repertoire of aldehyde-based bioconjugations and expands the toolbox for site-specific protein modifications. The trapped-Knoevenagel ligation reaction can be run at near neutral pH in the absence of catalysts to produce conjugates that are stable under physiological conditions. Using this new ligation, we generated an antibody-drug conjugate that demonstrates excellent efficacy in vitro and in vivo.
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Romas
authors.initials: R
authors.lastname: Kudirka
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Barfield
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: McFarland
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Albers
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: de Hart
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Penelope M
authors.initials: PM
authors.lastname: Drake
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Holder
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Banas
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Lesley C
authors.initials: LC
authors.lastname: Jones
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA.
authors.forename: Albert W
authors.initials: AW
authors.lastname: Garofalo
authors.affiliation: Redwood Bioscience, 5703 Hollis Street, Emeryville, CA 94608, USA. Electronic address: drabuka@redwoodbioscience.com.
authors.forename: David
authors.initials: D
authors.lastname: Rabuka
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D000079963:Brentuximab Vedotin; D002244:Carbon / Q000737:chemistry*; D002384:Catalysis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018796:Immunoconjugates / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry; D000068878:Trastuzumab / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D018796:Immunoconjugates; D011506:Proteins; D011720:Pyrazoles; D002244:Carbon; D000079963:Brentuximab Vedotin; D000068878:Trastuzumab