Adcetris
brentuximab vedotin · CD30Rat and cynomolgus monkey (monkey the antigen-binding species)
Kadcyla: which tox species, and why?
ado-trastuzumab emtansine · HER2
Species
Rat and cynomolgus monkey (monkey pharmacologically relevant; long-term studies in monkey)
“Nonclinical single- and repeat-dose toxicology studies submitted to this BLA were conducted in rats and Cynomolgus monkeys.”
Why that species
Trastuzumab binds cynomolgus HER2 with similar affinity to human; does not bind rat HER2 (rat for off-target payload toxicity)
“it was previously demonstrated that trastuzumab binds to the Cynomolgus monkey receptor with similar affinity as to human HER2, but does not bind with high avidity to the rat receptor indicating Cynomolgus monkey is the more relevant pharmacologic species.”
Surrogate molecule
No surrogate; clinical ADC tested, plus free DM1 and MCC-DM1 studies in rat
“Likewise, studies in rats with ado-trastuzumab emtansine or DM1 alone resulted in similar toxicities, suggesting toxicities were mediated primarily by DM1.”
Species: general tox
Rat and cynomolgus monkey
“Nonclinical single- and repeat-dose toxicology studies submitted to this BLA were conducted in rats and Cynomolgus monkeys.”
Species: DART
Not conducted (embryo-fetal studies not required under ICH S9)
“Based on these findings and consistent with ICH S9, embryo-fetal developmental toxicity studies were not required for the indicated patient population.”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies have not been conducted with ado-trastuzumab emtansine.”
Surrogate used in
No surrogate used; clinical ADC tested, plus DM1 alone in rats
“Likewise, studies in rats with ado-trastuzumab emtansine or DM1 alone resulted in similar toxicities, suggesting toxicities were mediated primarily by DM1.”
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)
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)
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