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.”
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