Development of antibody-drug conjugates in cancer: Overview and prospects

Abstract

In recent years, remarkable breakthroughs have been reported on antibody-drug conjugates (ADCs), with 15 ADCs successfully entering the market over the past decade. This substantial development has positioned ADCs as one of the fastest-growing domains in the realm of anticancer drugs, demonstrating their efficacy in treating a wide array of malignancies. Nonetheless, there is still an unmet clinical need for wider application, better efficacy, and fewer side effects of ADCs. An ADC generally comprises an antibody, a linker and a payload, and the combination has profound effects on drug structure, pharmacokinetic profile and efficacy. Hence, optimization of the key components provides an opportunity to develop ADCs with higher potency and fewer side effects. In this review, we comprehensively reviewed the current development and the prospects of ADC, provided an analysis of marketed ADCs and the ongoing pipelines globally as well as in China, highlighted several ADC platforms and technologies specific to different pharmaceutical enterprises and biotech companies, and also discussed the new related technologies, possibility of next-generation ADCs and the directions of clinical research.

FIGURE 1

The developing landscape of ADCs. (A) Number of new ADCs entering clinical trials from 2011 to 2022 worldwide and in China, respectively. (B) Number of ADCs under clinical evaluation in different stages worldwide (left panel) and in China (right panel). Abbreviations: ADCs, antibody‐drug conjugates; IND, investigational new drug; NDA, new drug application.

FIGURE 2

The diversity in target and mechanism of action of ADCs pipeline currently under clinical evaluation. (A) The top 10 targets of ADCs pipeline currently under clinical evaluation. (B) Comparison of target diversity of ADCs worldwide and in China. (C) Payload diversity in ADC pipeline of both worldwide and in China. Abbreviations: ADCs, antibody‐drug conjugates; CLDN 18.2, claudin 18 isoform 2; c‐Met, hepatocyte growth factor receptor; EGFR, epidermal growth factor receptor; FRα, folate receptor alpha; HER2, human epidermal growth factor receptor‐2; IND, investigational new drug; NDA, new drug application; TROP2, trophoblast cell surface antigen 2.

FIGURE 3

Strategies for ADC structural innovation and treatment optimization. (A) Novel antibody‐designation strategies such as a conditional antibody (top left), bispecific antibody (top right; the left represented dual epitope ADC, and the right represented dual target ADC), non‐internalizing antibody (bottom left) and novel drug carriers such as peptides, aptamer, virus‐like, small molecules (bottom right). (B) Innovations of ADC linkers such as UV (ultraviolet) or NIR (near infrared) controlled linkers (top) and “click release” linker (bottom). (C) ADC payload‐engineering approaches, including but not limited to dual‐payload ADCs (top left), prodrug‐ADC (top right; PBD) and ADCs carried novel payloads such as antibody‐NK cell conjugate drugs, radionuclide‐drug conjugates and antibody‐siRNA conjugates (bottom). (D) Using methods such as pharmacogenomic profiling and organoids/PDX model‐based drug screening to realize individualized treatment and tailor ADC administration accordingly. (E) Paradigms of ADC combination treatment include combination with chemotherapy (top left), targeted therapy (top right), immunotherapy (bottom left) and novel combination strategies such as combination with radiotherapy or other ADCs (bottom right). Abbreviations: ADC, antibody‐drug conjugate; UV, ultraviolet; NIR, near‐infrared; NK cell, natural killer cell; PBD, pyrrolobenzodiazepine; PDX, patient‐derived xenograft; PD‐1, programmed death‐1; PD‐L1, programmed death‐1 ligand.