Adcetris
brentuximab vedotin · CD30Rat and cynomolgus monkey (monkey the antigen-binding species)
Trodelvy: which tox species, and why?
sacituzumab govitecan · Trop-2
Species
Cynomolgus monkey only (mouse for target-independent toxicity only)
“Cynomolgus monkeys were identified as the only relevant toxicity species due to cross-reactivity of the target, Trop-2 with the hRS7antibody, the binding moiety of sacituzumab govitecan.”
Why that species
hRS7 binds human and monkey Trop-2 comparably; no binding to mouse or rat Trop-2 despite ~80% homology
“Despite approx. 80% sequence homology at the protein level between human and rodent Trop-2, hRS7 did not bind to mouse and rat Trop-2.”
Surrogate molecule
No surrogate; clinical ADC tested in monkey; no separate SN-38 general tox (irinotecan literature)
“General toxicity studies with the toxin moiety SN-38 were not conducted. This is acceptable, in line with ICH S9 and taking into account published literature on the toxicity of irinotecan and its active metabolite SN-38.”
Species: general tox
Cynomolgus monkey (repeat-dose); mouse (acute, target-independent)
“The toxicity of sacituzumab govitecan was assessed in mice (acute toxicity) and in cynomolgus monkeys (long-term toxicity).”
Species: DART
Not conducted (not warranted per ICH S9)
“No embryo-fetal developmental toxicology studies were conducted or warranted to support this BLA submission, based on ICH S9.”
Species: carcinogenicity
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or warranted to support this NDA, as the proposed indication was for advanced cancer.”
Surrogate used in
No surrogate used; clinical ADC in monkey (target-dependent) and mouse (target-independent)
“In mice, sacituzumab govitecan does not recognise the target antigen Trop-2, thus these studies provide information on target-independent toxicity. Target-dependent toxicity was assessed in cynomolgus monkeys.”
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)
Tivdak
tisotumab vedotin · Tissue factorCynomolgus monkey only for ADC; rat and monkey for MMAE payload
Zynlonta
loncastuximab tesirine · CD19No pharmacologically relevant species; cynomolgus monkey (non-binding) for ADC; rat and dog for payload SG3199