Readily Accessible Bicyclononynes for Bioorthogonal Labeling and Three‐Dimensional Imaging of Living Cells

Dommerholt, Jan; Schmidt, Samuel; Temming, Rinske P.; Hendriks, Linda; Rutjes, Floris P. J. T.; Hest, Jan C. M. van; Lefeber, Dirk; Friedl, Peter; Delft, Floris L. van

doi:10.1002/ange.201003761

Cited by 159 publications

(99 citation statements)

References 37 publications

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“…35 Some of us (S.V.B., F.V.D.) contributed to the field (2010) bicyclo[6.1.0]nonyne (BCN) 36 and dibenzoazacyclooctyne (DBCO, originally named DiBAC), 37 two cyclooctynes with a significantly improved reactivity profile, which have nowadays firmly established themselves in the field of strain-promoted azide−alkyne cycloaddition.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Chemoenzymatic Conjugation of Toxic Payloads to the Globally Conserved N-Glycan of Native mAbs Provides Homogeneous and Highly Efficacious Antibody–Drug Conjugates

Geel¹,

Wijdeven²,

Heesbeen³

et al. 2015

Bioconjugate Chem.

226

190

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A robust, generally applicable, nongenetic technology is presented to convert monoclonal antibodies into stable and homogeneous ADCs. Starting from a native (nonengineered) mAb, a chemoenzymatic protocol allows for the highly controlled attachment of any given payload to the N-glycan residing at asparagine-297, based on a two-stage process: first, enzymatic remodeling (trimming and tagging with azide), followed by ligation of the payload based on copper-free click chemistry. The technology, termed GlycoConnect, is applicable to any IgG isotype irrespective of glycosylation profile. Application to trastuzumab and maytansine, both components of the marketed ADC Kadcyla, demonstrate a favorable in vitro and in vivo efficacy for GlycoConnect ADC. Moreover, the superiority of the native glycan as attachment site was demonstrated by in vivo comparison to a range of trastuzumab-based glycosylation mutants. A side-by-side comparison of the copper-free click probes bicyclononyne (BCN) and a dibenzoannulated cyclooctyne (DBCO) showed a surprising difference in conjugation efficiency in favor of BCN, which could be even further enhanced by introduction of electron-withdrawing fluoride substitutions onto the azide. The resulting mAb-conjugates were in all cases found to be highly stable, which in combination with the demonstrated efficacy warrants ADCs with a superior therapeutic index.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Chemoenzymatic Conjugation of Toxic Payloads to the Globally Conserved N-Glycan of Native mAbs Provides Homogeneous and Highly Efficacious Antibody–Drug Conjugates

Geel¹,

Wijdeven²,

Heesbeen³

et al. 2015

Bioconjugate Chem.

226

190

View full text Add to dashboard Cite

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“…Triplikate der Messungen (Abbildung 2 c) ergaben im Mittel eine 4-bis 5-fach erhçhte Fluoreszenz für die Zielzellen. Die beobachtete Einfärbung der Plasmamembranen (Fluoreszenzmikroskopie, weißer Pfeil in Abbildung 3 j) ist konsistent mit anderen Untersuchungen hydrophiler BCN-Derivate [25,26] und ist im Unterschied zu der insgesamt schwächeren Färbung der Kontrollzellen (Abbildung 3 b,e) auch weniger punktiert (was darüber hinaus auch für eine unspezifische Aufnahme in die Kontrollzellen spricht). Weiterhin untersuchten wir den Einfluss von CrA und BCN auf die Spezifität des Biosensors, da beide Einheiten als Ursache unspezifischer Bindung bekannt sind.…”

Section: Angewandte Zuschriftenunclassified

Xenon‐MRT an lebenden Zellen mit Hyper‐CEST‐Biosensoren für metabolisch markierte Glykane an der Zelloberfläche

et al. 2015

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Das Targeting von metabolisch markierten Glykanen mit herkçmmlichen MRT-Kontrastmitteln erschien bislang als nicht realisierbar. Hier erweitern wir die Anwendungen von Xenon-Hyper-CEST-Biosensoren in Zellen und präsentieren damit die erste erfolgreiche molekulare Bildgebung dieser Glykane mittels MRT. Hyper-CEST-Biosensoren sind eine neue Klasse von MRT-Kontrastmitteln mit sehr hoher Empfindlichkeit. Darauf basierend wurde ein multimodaler Biosensor für sowohl Fluoreszenz-als auch Xenon-MRT-Detektion entwickelt, der selektiv mit metabolisch markierten Sialinsäuren durch bioorthogonale Chemie verknüpft wurde. Die Verwendung eines kürzlich entwickelten Bioreaktors zur Untersuchung lebender Zellen ermçglicht somit den Nachweis von Zelloberflächenglykanen mittels Xenon-MRT bei nanomolaren Konzentrationen.

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“…[105] Figure 10: Strained alkyne substrates for SPAAC reactions and use of cyclonorbornadiene as a "masked" alkyne . [100][101][102][103][104][105] An impressive application of SPAAC is the non-invasive in vivo imaging of membrane-associated glycans in living zebrafish embryos reported by the group of Bertozzi. [106] In this study, peracetylated N-azidoacetylgalactosamine was introduced in zebrafish glycoproteins.…”

Section: Ruaac Reactionsmentioning

confidence: 99%

Highly Active Dinuclear Copper Catalysts for Homogeneous Azide–Alkyne Cycloadditions

et al. 2012

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It is better to light a candle than to curse the dark. AbstractThe copper-catalyzed azide-alkyne cycloaddition for the synthesis of 1,4-disubstituted 1,2,3-triazoles (CuAAC) is a variant of Huisgen's 1,3-dipolar cycloaddition which disburdens the thermal reaction from its major drawbacks such as poor regioselectivity, long reaction times and harsh conditions. In contrast to the widely used "black box" reagent mixtures, a molecularly defined, highly active catalyst system for homogeneous CuAAC reactions has been developed in this PhD project. In dependence on the postulated stepwise mechanism, its most important structural feature is the presence of two copper(I) ions irreversibly bound in the same catalyst molecule.A highly modular and profitable synthesis for bistriazolium hexafluorophosphate salts as precursors for the ancillary ligand system was devised. In analogy to the CuAAC catalyst systems of general formula [(NHC) 2 Cu]PF 6 described in literature, novel dinuclear copper(I) complexes with a bistriazolylidene ligand backbone and 1,3-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene (IPr) as sacrificial ligand were prepared.However, these complexes did not show the expected high catalytic activity, most probably due to the strong coordination of the IPr ligands. In consequence, another family of dinuclear copper(I) complexes with m-coordinated acetate as labile ligand was synthesized by reaction of the bistriazolium hexafluorophosphate ligand precursors with copper(I) acetate in the presence of a base.The broad applicability and high catalytic activity of one of these bistriazolylidene dicopper acetate complexes was confirmed by a series of gaschromatographically mo-

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Readily Accessible Bicyclononynes for Bioorthogonal Labeling and Three‐Dimensional Imaging of Living Cells

Cited by 159 publications

References 37 publications

Chemoenzymatic Conjugation of Toxic Payloads to the Globally Conserved N-Glycan of Native mAbs Provides Homogeneous and Highly Efficacious Antibody–Drug Conjugates

Chemoenzymatic Conjugation of Toxic Payloads to the Globally Conserved N-Glycan of Native mAbs Provides Homogeneous and Highly Efficacious Antibody–Drug Conjugates

Xenon‐MRT an lebenden Zellen mit Hyper‐CEST‐Biosensoren für metabolisch markierte Glykane an der Zelloberfläche

Highly Active Dinuclear Copper Catalysts for Homogeneous Azide–Alkyne Cycloadditions

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