Table 3 Landscape of unconventional ADC payloads investigated at the preclinical stage
From: Payload diversification: a key step in the development of antibody–drug conjugates
Payload mechanism | Payload family | Payload name {ADC name} | Target antigen | DAR | First publication date | Reference(s) |
|---|---|---|---|---|---|---|
Topoisomerase II inhibitors | Anthracyclines | Doxorubicin | N/A | N/A | 2010 | 109 |
HER2 | 4 | 2017 | 110 | |||
CD30 | 4 | 2017 | 110 | |||
PNU-159682 | LGR5 | 2 | 2015 | 111 | ||
CD22 | 2 | 2015 | 114 | |||
CD30 | 4 | 2017 | 109 | |||
tenascin-C | 2 | 2017 | 116 | |||
HER2 | 4 | 2019 | 115 | |||
CD46 | 2 | 2020 | 117 | |||
EREG | n.d | 2022 | 118 | |||
PNU-159682 + MMAF | HER2 | 2 + 2 | 2019 | 119 | ||
Daunorubicin | alpha-fetoprotein | 1.2 | 1984 | 120 | ||
ganglioside | 20 | 1991 | 121 | |||
Idarubicin | Ly2.1 | 2 to 4 | 1988 | 122 | ||
CD19 | 3.2 | 1993 | 123 | |||
HER2 | 1 | 2019 | 124 | |||
Transcription inhibitors | RNApolII inhibitors | Beta-amanitin | Albumin | 1.9 | 1973 | 130 |
MUC1 | n. d | 2006 | 131 | |||
PSMA | 2 | 2014 | 132, 133 | |||
Alpha-amanitin and derivatives | Thy 1.2 | 3.6–6.3 | 1981 | 134 | ||
EpCam | 4 to 8 | 2012 | 137 | |||
HER2 | 2 | 2018 | 138 | |||
PSMA | 2 | 2018 | 138 | |||
CD19 | 2 | 2018 | 138 | |||
Amanitin + MMAE | FGFR1 | 1 + 1 | 2018 | 139 | ||
Phalloidin | Albumin | n. d | 1986 | 140 | ||
Trichothecene T-2 | murine EL-4 lymphoma | n.d | 1991 | 141 | ||
Verrucarin A | oncofetal glycoprotein | n.d | 1991 | 141 | ||
Roridin A | oncofetal glycoprotein | n.d | 1991 | 141 | ||
Transcription Factor inhibitors | Triptolide | CD26 | 6.5 | 2019 | 145 | |
EGFR | 5.5 | 2020 | 146 | |||
HER2 | 2 to 3 | 2021 | 147 | |||
HDAC inhibitors | ST7464AA1 | EGFR | 4.5 | 2018 | 150 | |
HER2 | 5 | 2020 | 151 | |||
Vorinostat (SAHA) | EGFR, HER2 | 4 to 6 | 2021 | 152 | ||
Dacinostat (VP-LAQ824) | EGFR, HER2 | 3 | 2021 | 152 | ||
Kinase inhibitors | PTK inhibitors | Genistein | EGFR | n.d | 1998 | 168 |
17.1A mAb | 3 | 2003 | 169 | |||
PIKK inhibitors | Neolymphostin | HER2 | 2 | 2019 | 170 | |
multi-kinase inhibitors | Dasatinib | CXCR4 | 3 | 2015 | 171 | |
Staurosporine | EGFR | n.d | 2018 | 172 | ||
Immune stimulants | TLR7/8 agonists | UC-1V150 | CD20 | 1 to 3 | 2015 | 184 |
CL264 | HER2 | 2 | 2020 | 185 | ||
D18 | PDL1 | 2 | 2021 | 186 | ||
n.d | PDL1 | 2 | 2022 | 181 | ||
n.d {BDC-2034} | CEACAM5 | 2.5 | 2021 | 179, 180 | ||
T785 | HER2 | 2 | 2020 | 185 | ||
TLR7 agonists | AmberX ADC | HER2 | n.d | 2022 | 187 | |
STING agonists | {CRD5500} | HER2 | n.d | 2019 | 189 | |
XMT-1621 | FcyR | 2 | 2022 | 192 | ||
XMT-1621 {XMT-2056} | HER2 | 8 | 2021 | 190, 191 | ||
Protein synthesis inhibitors | HSP90 inhibitors | Geldanamycin | HER2 | n.d | 2000 | 195, 196, 197 |
CD70 | 4 | 2009 | 198 | |||
HER2 | n.d | 2021 | 199 | |||
Splicing inhibitors | Thailanstatin A | HER2 | 2 to 3 | 2016 | 25, 202 | |
Translation inhibitors | Psymberin (irciniastatin A) | CD30, CD70 | 5.4 | 2010 | 204 | |
Proteasome inhibitors | carmaphycin B analogues | HER2 | 1 to 2 | 2019 | 205 | |
PROTACs/glue degraders | BET/BRD4 degraders | GNE-987 | CCL1/HER2 | 6 | 2019 | 209 |
MZ1 analogue | HER2 | 4 | 2020 | 212 | ||
STEAP1 | 2 or 6 | 2021 | 210, 211 | |||
BRD4/VHL | STEAP1/CCL1 | 6 | 2021 | 213 | ||
BRD4/CRBN | HER2 | 2 | 2019 | 213 | ||
ERa degraders | ERa/XIAP | HER2/CD22/B7-H4 | 2 to 6 | 2020 | 214 | |
ERa/VHL | HER2/CD22/B7-H4 | 2 to 6 | 2020 | 214 | ||
TGFbR2 degraders | TGFbR2/VHL | HER2 | 2 to 4 | 2020 | 208 | |
BRM degraders | BRL/VHL | CD22 | 6 | 2020 | 208 | |
GSTP1 degraders | Smol006 {ORM-5029} | HER2 | 4 | 2022 | 215 | |
Others | NAMPT inhibitors | FK-866 analogues | c-kit or HER2 | 2 to 4 | 2018 | 217 |
CD30 | 8 to 10 | 2018 | 216 | |||
KSP inhibitors | Filanesib derivative | HER2, c-kit | 3 to 4.5 | 2019 | 218 | |
HER‐2, TWEAKR/Fn14 | 2 to 4 | 2018 | 219, 202 | |||
carbonic anhydrase inhibitors | CA IX and XII peptides | CA IX and XII | n.d | 2022 | 230 | |
Beyond cytotoxic payloads | lipid homeostasis and inflammation | LXR agonist | CD11a | 2 | 2016 | 235 |
Enzymatic activity inhibition | CGS27023A | MMP9 | 4 to 8 | 2019 | 229 |