Enzymatic glycan remodeling-metal free click (GlycoConnect™) provides homogenous antibody-drug conjugates with improved stability and therapeutic index without sequence engineering
Antibody-drug conjugates (ADCs) are increasingly powerful medicines for targeted cancer therapy. Inspired by the trend to further improve their therapeutic index by generation of homogenous ADCs, we report here how the clinical-stage GlycoConnect™ technology uses the globally conserved N-glycosylati...
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| Veröffentlicht in: | mAbs 2022-12, Vol.14 (1), p.2078466 |
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| creator | Wijdeven, Marloes A. van Geel, Remon Hoogenboom, Jorin H. Verkade, Jorge M. M. Janssen, Brian M. G. Hurkmans, Inge de Bever, Laureen van Berkel, Sander S. van Delft, Floris L. |
| description | Antibody-drug conjugates (ADCs) are increasingly powerful medicines for targeted cancer therapy. Inspired by the trend to further improve their therapeutic index by generation of homogenous ADCs, we report here how the clinical-stage GlycoConnect™ technology uses the globally conserved N-glycosylation site to generate stable and site-specific ADCs based on enzymatic remodeling and metal-free click chemistry. We demonstrate how an engineered endoglycosidase and a native glycosyl transferase enable highly efficient, one-pot glycan remodeling, incorporating a novel sugar substrate 6-azidoGalNAc. Metal-free click attachment of an array of cytotoxic payloads was highly optimized, in particular by inclusion of anionic surfactants. The therapeutic potential of GlycoConnect™, in combination with HydraSpace™ polar spacer technology, was compared to that of Kadcyla® (ado-trastuzumab emtansine), showing significantly improved efficacy and tolerability. |
| doi_str_mv | 10.1080/19420862.2022.2078466 |
| format | Article |
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Metal-free click attachment of an array of cytotoxic payloads was highly optimized, in particular by inclusion of anionic surfactants. The therapeutic potential of GlycoConnect™, in combination with HydraSpace™ polar spacer technology, was compared to that of Kadcyla® (ado-trastuzumab emtansine), showing significantly improved efficacy and tolerability.</description><identifier>ISSN: 1942-0862</identifier><identifier>EISSN: 1942-0870</identifier><identifier>DOI: 10.1080/19420862.2022.2078466</identifier><identifier>PMID: 35634725</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>Ado-Trastuzumab Emtansine ; Antibody-drug conjugates (ADCs) ; Antineoplastic Agents ; chemoenzymatic ; glycan remodeling ; Immunoconjugates - therapeutic use ; metal-free click chemistry ; non-genetic ; Polysaccharides ; Rapid Communication ; Short Communications ; Therapeutic Index</subject><ispartof>mAbs, 2022-12, Vol.14 (1), p.2078466</ispartof><rights>2022 The Author(s). Published with license by Taylor & Francis Group, LLC. 2022</rights><rights>2022 The Author(s). 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We demonstrate how an engineered endoglycosidase and a native glycosyl transferase enable highly efficient, one-pot glycan remodeling, incorporating a novel sugar substrate 6-azidoGalNAc. Metal-free click attachment of an array of cytotoxic payloads was highly optimized, in particular by inclusion of anionic surfactants. The therapeutic potential of GlycoConnect™, in combination with HydraSpace™ polar spacer technology, was compared to that of Kadcyla® (ado-trastuzumab emtansine), showing significantly improved efficacy and tolerability.</description><subject>Ado-Trastuzumab Emtansine</subject><subject>Antibody-drug conjugates (ADCs)</subject><subject>Antineoplastic Agents</subject><subject>chemoenzymatic</subject><subject>glycan remodeling</subject><subject>Immunoconjugates - therapeutic use</subject><subject>metal-free click chemistry</subject><subject>non-genetic</subject><subject>Polysaccharides</subject><subject>Rapid Communication</subject><subject>Short Communications</subject><subject>Therapeutic Index</subject><issn>1942-0862</issn><issn>1942-0870</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>0YH</sourceid><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNp9ksFu1DAQhiMEolXpI4B8hEOK7Ti294JAq1IqVeICZ8uxx1kvib04Tttw5kl4CB6IJyHptit6wQd7NP7-f-bwF8VLgs8IlvgtWTGKJadnFNPlEpJx_qQ4XvollgI_PdScHhWnw7DFyxGYCPy8OKpqXjFB6-Pi93n4MfU6e4PabjI6oAR9tND50JY9ZN0hlwCQ6bz5hl5fzExcxxDA5D8_f71BuxSvvYUBbWIfWwhxHJAO2TfRTqVNY4tMDNux1XlmbnzeIN8vGrBoyLrxnc_TLLAobyDpHYzLJj5YuL2j45jRAN9HCAYQhNYHgDSv9qJ45nQ3wOn9e1J8_Xj-Zf2pvPp8cbn-cFWaumK5NLwRNak4k9qAq62rODSSNCAJo4I1gvOVds4JueKMOk2pc5qsZDOTghFdnRSXe18b9Vbtku91mlTUXt01YmqVTvPKHSjJpK3wqqGMa0a10ZiQ2grGOLUNr8js9W7vtRubHqyBkJPuHpk-_gl-o9p4rVakZoLL2aDeG5gUhyGBO2gJVksu1EMu1JILdZ-LWffq38EH1UMKZuD9HvDBxdTrm5g6q7Keuphc0sH4QVX_n_EXZcnPIQ</recordid><startdate>20221231</startdate><enddate>20221231</enddate><creator>Wijdeven, Marloes A.</creator><creator>van Geel, Remon</creator><creator>Hoogenboom, Jorin H.</creator><creator>Verkade, Jorge M. 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Inspired by the trend to further improve their therapeutic index by generation of homogenous ADCs, we report here how the clinical-stage GlycoConnect™ technology uses the globally conserved N-glycosylation site to generate stable and site-specific ADCs based on enzymatic remodeling and metal-free click chemistry. We demonstrate how an engineered endoglycosidase and a native glycosyl transferase enable highly efficient, one-pot glycan remodeling, incorporating a novel sugar substrate 6-azidoGalNAc. Metal-free click attachment of an array of cytotoxic payloads was highly optimized, in particular by inclusion of anionic surfactants. 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| subjects | Ado-Trastuzumab Emtansine Antibody-drug conjugates (ADCs) Antineoplastic Agents chemoenzymatic glycan remodeling Immunoconjugates - therapeutic use metal-free click chemistry non-genetic Polysaccharides Rapid Communication Short Communications Therapeutic Index |
| title | Enzymatic glycan remodeling-metal free click (GlycoConnect™) provides homogenous antibody-drug conjugates with improved stability and therapeutic index without sequence engineering |
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