Adcetris
brentuximab vedotin · CD30Rat and cynomolgus monkey (monkey the antigen-binding species)
Tivdak: which tox species, and why?
tisotumab vedotin · Tissue factor
Species
Cynomolgus monkey only for ADC; rat and monkey for MMAE payload
“The data suggests that the cynomolgus monkey was the only relevant toxicological species.”
Why that species
Tisotumab binds human and cynomolgus TF similarly; no binding to mouse, rat, rabbit, pig or dog TF
“Tisotumab did not bind to mouse, rat, rabbit, pig, or dog TF.”
Surrogate molecule
No surrogate; clinical ADC tested in monkey, payload (MMAE) separately in rat and monkey
“A GLP compliant repeat-dose toxicology study with tisotumab vedotin was conducted in monkeys (13-week), and the payload was assessed in rats (4-week) and monkeys (11-week) using the clinical intravenous route of administration.”
Species: general tox
Cynomolgus monkey (ADC, 13-week); rat (4-week) and monkey (11-week) for MMAE payload
“A GLP compliant repeat-dose toxicology study with tisotumab vedotin was conducted in monkeys (13-week), and the payload was assessed in rats (4-week) and monkeys (11-week) using the clinical intravenous route of administration.”
Species: DART
Rat (MMAE embryo-fetal development only); ADC reproductive organ effects assessed in monkey repeat-dose study
“The Applicant assessed the effects tisotumab vedotin on reproductive organs as part of the repeat-dose toxicology study in monkeys and provided results from an EFD study in rats evaluating the MMAE payload.”
Species: carcinogenicity
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted with tisotumab vedotin in accordance with ICH S9 guidance.”
Surrogate used in
Unconjugated tisotumab used as surrogate for tisotumab vedotin in many pharmacology studies
“Many of the studies were conducted with tisotumab as surrogate for tisotumab vedotin.”
Same question, other ADCs
Besponsa
inotuzumab ozogamicin · CD22Rat and cynomolgus monkey (neither cross-reactive; target-independent toxicity only)
Datroway
datopotamab deruxtecan · Trop-2Rat (non-binding) and cynomolgus monkey (relevant); DXd payload in rat and monkey
Decnupaz
pivekimab sunirine · CD123Cynomolgus monkey (no CD123 cross-reactivity; off-target/payload toxicity) plus rat for FGN849 payload
Elahere
mirvetuximab soravtansine · FRαCynomolgus monkey (general tox); rabbit for ocular tox; DM4 payload in monkey and mouse
Emrelis
telisotuzumab vedotin · c-MetCynomolgus monkey (relevant); rat non-binding (exploratory, MMAE-related effects)
Enhertu
fam-trastuzumab deruxtecan · HER2Cynomolgus monkey (relevant) plus rat (non-binding species)
Kadcyla
ado-trastuzumab emtansine · HER2Rat and cynomolgus monkey (monkey pharmacologically relevant; long-term studies in monkey)
Mylotarg
gemtuzumab ozogamicin · CD33Rat and cynomolgus monkey (neither pharmacologically relevant; no CD33 cross-reactivity)
Padcev
enfortumab vedotin · Nectin-4Rat and cynomolgus monkey
Polivy
polatuzumab vedotin · CD79bRat and cynomolgus monkey (monkey with clinical ADC plus monkey-CD79b surrogate ADC)
Trodelvy
sacituzumab govitecan · Trop-2Cynomolgus monkey only (mouse for target-independent toxicity only)
Zynlonta
loncastuximab tesirine · CD19No pharmacologically relevant species; cynomolgus monkey (non-binding) for ADC; rat and dog for payload SG3199