Elsevier

Drug Discovery Today

Volume 26, Issue 8, August 2021, Pages 1857-1874
Drug Discovery Today

Keynote (green)
Duocarmycin-based antibody–drug conjugates as an emerging biotherapeutic entity for targeted cancer therapy: Pharmaceutical strategy and clinical progress

https://doi.org/10.1016/j.drudis.2021.06.012Get rights and content
Under a Creative Commons license
open access

Highlights

  • Duocarmycins and analogues are DNA-alkylators highly cytotoxic to cancer cells.

  • Up to now, none of duocarmycins have not been approved for oncological practice.

  • Novel features make duocarmycins an ideal payload for targeted drug delivery.

  • Various duocarmycin-based antibody-drug conjugates are in clinical development.

  • An emerging era of duocarmycin-based anticancer biotherapeutics is in the horizon.

Abstract

Duocarmycins are a class of DNA minor-groove-binding alkylating molecules. For the past decade, various duocarmycin analogues have been used as payloads in the development of antibody–drug conjugates (ADCs). Currently, more than 15 duocarmycin-based ADCs have been studied preclinically, and some of them such as SYD985 have been granted Fast-Track Designation status. Nevertheless, progress in duocarmycin-based ADCs also faces challenges, with setbacks including the termination of BMS-936561/MDX-1203. In this review, we discuss issues associated with the efficacy, pharmacokinetic profile, and toxicological activity of these biotherapeutics. Furthermore, we summarize the latest advances in duocarmycin-based ADCs that have different target specificities and linker chemistries. Evidence from preclinical and clinical studies has indicated that duocarmycin-based ADCs are promising biotherapeutics for oncological application in the future.

Keywords

Antibody–drug conjugate
Clinical trials
Cytotoxic payload
Drug targets
Duocarmycins
Linker chemistry
Monoclonal antibody
Pharmacokinetics
Preclinical development
Therapeutic efficacy
Toxicological activity

Abbreviations

ADC
antibody–drug conjugate
CAR
chimeric antigen receptor
CBI
cyclopropabenzindole
cBu
cyclobutene-1,1-dicarboxamide
CPI
cyclopropapyrroloindole
CTN
cotinine
DAR
drug to antibody ratio
DCM
duocarmycin
DM1
maytansinoid derivative 1
DMEA
dimethylethanolamine
DUBA
duocarmycin-hydroxybenzamide-azaindole
EGFR
epidermal growth factor receptor
ESLR
endosialin receptor
FDA
US Food and Drug Administration
GPC3
glypican-3
HCC
hepatocellular carcinoma
HER-2
human epidermal growth factor receptor-2
IGN
indolinobenzodiazepine
mAb
monoclonal antibody
Mb
maleimide-based
MMAE
monomethyl auristatin E
NCI
National Cancer Institute
NHL
non-Hodgkin lymphoma
NHS
N-hydroxysuccinimide
ORR
overall response rate
PAB
p-aminobenzyl
PABC
p-aminobenzyloxycarbonyl
PBD
pyrrolobenzodiazepine
PD
pharmacodynamic
PDD
pyridinobenzodiazepines
PDGFR-β
platelet-derived growth factor receptor-β
PDX
patient-derived xenografts
PEG
polyethylene glycol
PK
pharmacokinetic(s)
PSI
plexin-semaphorin-integrin
PSMA
prostate-specific membrane antigen
RCC
renal cell carcinoma
RTK
receptor tyrosine kinase
SCLC
small cell lung cancer
SMCC
N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate
SMKI
small molecule kinase inhibitor
SPP
N-succinimidyl-4-(2-pyridyldithio)pentanoate
Val-Cit
valine-citrulline

Cited by (0)

Ming-Hai Wang MD, PhD holds an Amarillo Community Endowed Chair for Cancer Biology Research and is the Director of the Cancer Biology Research Center at the Jerry H. Hodge School of Pharmacy at Texas Tech University Health Sciences Center. Dr Wang also is a tenured Professor in the Department of Pharmaceutical Sciences at Texas Tech University. For the past 30 years, Dr Wang has focused his research on the pathogenesis of receptor tyrosine kinases such as RON and MET in colon, breast, and pancreatic cancers, with emphasis on the clinical development of targeted biotherapeutics such as antibody–drug conjugates. Dr Wang has published extensively on these topics and has presented his research findings at various conferences across the world.

1

Author contributions: HPY and HZ contributed equally to this work.