

1 Structures of the clinically-approved ADCs, with linkers in blue and payloads in red. Indeed, the field has enjoyed significant clinical and commercial success in recent years, with nine ADCs receiving approval from the US Food and Drug Administration and >80 others in clinical development ( Fig. 3 This marriage of macromolecular biology and small molecule chemistry is at the heart of the clinical success of ADCs. 1,2 Critical to the success of this strategy is a covalent linker between the two therapeutic components, which facilitates the ADC's mechanism of action.

By harnessing the cell selectivity of monoclonal antibodies (mAbs) and the cytotoxicity of small molecule toxins, malignant cells can be selectively destroyed whilst sparing healthy tissue. Photos are in order of the author list (left to right, top to bottom).ġ Introduction Antibody–drug conjugates (ADCs) are a class of targeted therapeutics, typically developed for the treatment of cancer. Stephen Walsh is also a postdoctoral research associate in the Carroll lab in the Cancer Research UK Cambridge Institute.

Stephen Walsh, Jonathan Bargh, Friederike Dannheim, Abigail Hanby, Hikaru Seki, Andrew Counsell, Xiaoxu Ou, Elaine Fowler, Nicola Ashman and Yuri Takada are members of the Spring lab in the University of Cambridge Department of Chemistry. Albert Isidro-Llobet is an Investigator and Associate Fellow at GSK in Stevenage. Jeremy Parker is Senior Director and Head of Early Chemical Development at AstraZeneca in Macclesfield. Jason Carroll is Professor of Molecular Oncology at the University of Cambridge and a Senior Group Leader at the Cancer Research UK Cambridge Institute. In this review, we discuss advances in chemical and enzymatic methods for site-specific antibody modification that result in the generation of homogeneous ADCs.ĭavid Spring is currently Professor of Chemistry and Chemical Biology at the University of Cambridge within the Chemistry Department. A wide range of methods have been developed in the pursuit of homogeneity, comprising chemical or enzymatic methods or a combination thereof to afford precise modification of specific amino acid or sugar residues. Homogeneous ADCs have repeatedly demonstrated superior overall pharmacological profiles compared to their heterogeneous counterparts. Efforts have now shifted towards generating homogeneous constructs with precise drug loading and predetermined, controlled sites of attachment. Whilst early generation ADCs were primarily synthesised as heterogeneous mixtures, these were found to have sub-optimal pharmacokinetics, stability, tolerability and/or efficacy. Extensive research over the past decade has highlighted the critical nature of the linkage strategy adopted to attach the payload to the antibody. Nine ADCs have received approval from the US Food and Drug Administration and more than 80 others are currently undergoing clinical investigations for a range of solid tumours and haematological malignancies. They have garnered widespread interest in drug discovery, particularly in oncology, as discrimination between healthy and malignant tissues or cells can be achieved. Antibody–drug conjugates (ADCs) harness the highly specific targeting capabilities of an antibody to deliver a cytotoxic payload to specific cell types.
