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Correction published on 30 August 2018, see Antibodies 2018, 7(3), 34.

Open AccessArticle
Antibodies 2018, 7(1), 12; https://doi.org/10.3390/antib7010012

A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug Conjugates

Synaffix BV, Industrielaan 63, 5349 AE Oss, The Netherlands
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Author to whom correspondence should be addressed.
Received: 11 January 2018 / Revised: 8 February 2018 / Accepted: 17 February 2018 / Published: 20 February 2018
(This article belongs to the Special Issue Antibody Drug Conjugates)
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Abstract

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™, Oss, The Netherlands) 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. View Full-Text
Keywords: antibody–drug conjugates (ADCs); therapeutic index; spacer technology; carbamoyl sulfamide; chemoenzymatic; glycan-remodeling; copper-free click chemistry antibody–drug conjugates (ADCs); therapeutic index; spacer technology; carbamoyl sulfamide; chemoenzymatic; glycan-remodeling; copper-free click chemistry
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Verkade, J.M.M.; Wijdeven, M.A.; van Geel, R.; Janssen, B.M.G.; van Berkel, S.S.; van Delft, F.L. A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug Conjugates. Antibodies 2018, 7, 12.

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