Mahendra P. Deonarain 1,2,* and Quinn Xue3
 
1Antikor Biopharma Ltd, Stevenage Bioscience Catalyst, Gunnels Wood Road, Stevenage, Hertfordshire SG12FX,UK, 2Department of Chemistry, Imperial College London, Exhibition Road, London SW72AZ, UK, and 3Essex Bio-Technology Ltd, Shun Tak Centre, Room 2818, China Merchants Tower, Connaught Road Central, Hong Kong168-200, SAR China
 
Received: August 26, 2020; Revised: November 11, 2020; Accepted: November 13, 2020
 
ABSTRACT
 
The pharmacokinetic–pharmacodynamic relationship is extremely complex and tumour drug penetration is one key parameter influencing therapeutic efficacy. In the context of antibody–drug conjugates (ADCs), which has undergone many innovation cycles and witnessed many failures, this feature is being addressed by a number of alternative technologies. Immunoglobulin-based ADCs continue to dominate the industrial landscape, but smaller formats offer the promise of more-effective cytotoxic payload delivery to solid tumours, with a higher therapeutic window afforded by the more rapid clearance. To make these smaller formats viable as delivery vehicles, a number of strategies are being employed, which will be reviewed here. These include identifying the most-appropriate size to generate the larger therapeutic window, increasing the amount of functional, cytotoxic payload delivered through conjugation or half-life extending technologies or other ways of extending the dosing without inducing toxicity.
 
Statement of Significance: Antibody–drug conjugates are a clinically and commercially established modality of cancer therapy with five new agents approved over the last 2 years. Treating solid tumours remains a major challenge with many failures and small-format drug conjugates offer a solution to the tumour penetration issue.
 
KEYWORDS: antibody–drug conjugate; fragments; scaffolds; solid tumours