Enzymatic Glycan Remodeling-metal Free Click (GlycoConnect™) Provides Homogenous Antibody-drug Conjugates with Improved Stability and Therapeutic Index Without Sequence Engineering

Overview

Journal MAbs

Specialty Allergy & Immunology

Date 2022 May 31

PMID 35634725

Authors

Marloes A Wijdeven

Remon van Geel

Jorin H Hoogenboom

Jorge M M Verkade

Brian M G Janssen

Inge Hurkmans

Laureen de Bever

Sander S van Berkel

Floris L van Delft

Affiliations

Soon will be listed here.

Abstract

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 -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.

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