A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug Conjugates
Despite tremendous efforts in the field of targeted cancer therapy with antibody–drug conjugates (ADCs), attrition rates have been high. Historically, the priority in ADC development has been the selection of target, antibody, and toxin, with little focus on the nature of the linker. We show here th...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-02-01
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| Series: | Antibodies |
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| Online Access: | http://www.mdpi.com/2073-4468/7/1/12 |
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| author | Jorge M. M. Verkade Marloes A. Wijdeven Remon van Geel Brian M. G. Janssen Sander S. van Berkel Floris L. van Delft |
| author_facet | Jorge M. M. Verkade Marloes A. Wijdeven Remon van Geel Brian M. G. Janssen Sander S. van Berkel Floris L. van Delft |
| author_sort | Jorge M. M. Verkade |
| collection | DOAJ |
| description | Despite tremendous efforts in the field of targeted cancer therapy with antibody–drug conjugates (ADCs), attrition rates have been high. Historically, the priority in ADC development has been the selection of target, antibody, and toxin, with little focus on the nature of the linker. We show here that a short and polar sulfamide spacer (HydraSpace™, AE Oss, The Netherland) positively impacts ADC properties in various ways: (a) efficiency of conjugation; (b) stability; and (c) therapeutic index. Different ADC formats are explored in terms of drug-to-antibody ratios (DAR2, DAR4) and we describe the generation of a DAR4 ADC by site-specific attachment of a bivalent linker–payload construct to a single conjugation site in the antibody. A head-to-head comparison of HydraSpace™-containing DAR4 ADCs to marketed drugs, derived from the same antibody and toxic payload components, indicated a significant improvement in both the efficacy and safety of several vivo models, corroborated by in-depth pharmacokinetic analysis. Taken together, HydraSpace™ technology based on a polar sulfamide spacer provides significant improvement in manufacturability, stability, and ADC design, and is a powerful platform to enable next-generation ADCs with enhanced therapeutic index. |
| first_indexed | 2024-12-14T18:23:02Z |
| format | Article |
| id | doaj.art-3467b0204f6846e79773a9ba2403fa4a |
| institution | Directory Open Access Journal |
| issn | 2073-4468 |
| language | English |
| last_indexed | 2024-12-14T18:23:02Z |
| publishDate | 2018-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibodies |
| spelling | doaj.art-3467b0204f6846e79773a9ba2403fa4a2022-12-21T22:52:00ZengMDPI AGAntibodies2073-44682018-02-01711210.3390/antib7010012antib7010012A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug ConjugatesJorge M. M. Verkade0Marloes A. Wijdeven1Remon van Geel2Brian M. G. Janssen3Sander S. van Berkel4Floris L. van Delft5Synaffix BV, Industrielaan 63, 5349 AE Oss, The NetherlandsSynaffix BV, Industrielaan 63, 5349 AE Oss, The NetherlandsSynaffix BV, Industrielaan 63, 5349 AE Oss, The NetherlandsSynaffix BV, Industrielaan 63, 5349 AE Oss, The NetherlandsSynaffix BV, Industrielaan 63, 5349 AE Oss, The NetherlandsSynaffix BV, Industrielaan 63, 5349 AE Oss, The NetherlandsDespite tremendous efforts in the field of targeted cancer therapy with antibody–drug conjugates (ADCs), attrition rates have been high. Historically, the priority in ADC development has been the selection of target, antibody, and toxin, with little focus on the nature of the linker. We show here that a short and polar sulfamide spacer (HydraSpace™, AE Oss, The Netherland) positively impacts ADC properties in various ways: (a) efficiency of conjugation; (b) stability; and (c) therapeutic index. Different ADC formats are explored in terms of drug-to-antibody ratios (DAR2, DAR4) and we describe the generation of a DAR4 ADC by site-specific attachment of a bivalent linker–payload construct to a single conjugation site in the antibody. A head-to-head comparison of HydraSpace™-containing DAR4 ADCs to marketed drugs, derived from the same antibody and toxic payload components, indicated a significant improvement in both the efficacy and safety of several vivo models, corroborated by in-depth pharmacokinetic analysis. Taken together, HydraSpace™ technology based on a polar sulfamide spacer provides significant improvement in manufacturability, stability, and ADC design, and is a powerful platform to enable next-generation ADCs with enhanced therapeutic index.http://www.mdpi.com/2073-4468/7/1/12antibody–drug conjugates (ADCs)therapeutic indexspacer technologycarbamoyl sulfamidechemoenzymaticglycan-remodelingcopper-free click chemistry |
| spellingShingle | Jorge M. M. Verkade Marloes A. Wijdeven Remon van Geel Brian M. G. Janssen Sander S. van Berkel Floris L. van Delft A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug Conjugates Antibodies antibody–drug conjugates (ADCs) therapeutic index spacer technology carbamoyl sulfamide chemoenzymatic glycan-remodeling copper-free click chemistry |
| title | A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug Conjugates |
| title_full | A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug Conjugates |
| title_fullStr | A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug Conjugates |
| title_full_unstemmed | A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug Conjugates |
| title_short | A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug Conjugates |
| title_sort | polar sulfamide spacer significantly enhances the manufacturability stability and therapeutic index of antibody drug conjugates |
| topic | antibody–drug conjugates (ADCs) therapeutic index spacer technology carbamoyl sulfamide chemoenzymatic glycan-remodeling copper-free click chemistry |
| url | http://www.mdpi.com/2073-4468/7/1/12 |
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