Adcetris
brentuximab vedotin · CD30Rat and cynomolgus monkey (monkey the antigen-binding species)
Mylotarg: which tox species, and why?
gemtuzumab ozogamicin · CD33
Species
Rat and cynomolgus monkey (neither pharmacologically relevant; no CD33 cross-reactivity)
“In view of the absence of cross-reactivity of gemtuzumab ozogamicin with CD33 from laboratory species, studies of kinetics in animals can only be of limited value, as there will be no binding, specific intracellular uptake, and metabolism of the conjugate that underlies its therapeutic action in humans.”
Why that species
No relevant species: antibody does not bind monkey CD33 or stain rat/monkey tissues; species used for off-target payload toxicity
“hP67.6 bound strongly to human CD33-transfected CHO cells but did not bind to the monkey CD33-transfected CHO cells (study 084032).”
Surrogate molecule
No surrogate; clinical ADC tested in non-binding rat and monkey (plus old vs new cell line bridging)
“Repeat-dose studies included six cycle intravenous toxicity studies in rats and monkeys and a six cycle comparative study in monkeys for the old and new antibody cell lines.”
Species: general tox
Rat and monkey (six-cycle weekly IV studies, plus monkey cell-line comparability study)
“Repeat-dose studies included six cycle intravenous toxicity studies in rats and monkeys and a six cycle comparative study in monkeys for the old and new antibody cell lines.”
Species: DART
Rat only (fertility and EFD); FDA agreed one species sufficient after positive pilot study
“Based on the unequivocally positive results obtained from a pilot study, the Agency previously agreed with the Applicant that one species would be sufficient to support an NDA application for CMA-676 in a leukemia indication.”
Species: carcinogenicity
Not conducted
“Formal carcinogenicity studies have not been conducted with gemtuzumab ozogamicin.”
Surrogate used in
No surrogate used; antibody shows no specific binding in rat or monkey tissues
“A tissue cross-reactivity study using rat or cynomolgus monkey cryosections determined that specific staining by hP67.6 was absent in all tissues of both animal species.”
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)
Padcev
enfortumab vedotin · Nectin-4Rat and cynomolgus monkey
Polivy
polatuzumab vedotin · CD79bRat and cynomolgus monkey (monkey with clinical ADC plus monkey-CD79b surrogate ADC)
Tivdak
tisotumab vedotin · Tissue factorCynomolgus monkey only for ADC; rat and monkey for MMAE payload
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