Adcetris
brentuximab vedotin · CD30Rat and cynomolgus monkey (monkey the antigen-binding species)
Enhertu: which tox species, and why?
fam-trastuzumab deruxtecan · HER2
Species
Cynomolgus monkey (relevant) plus rat (non-binding species)
“DS-8201a and MAAL-9001 bound to cynomolgus monkey HER2 protein but not to mouse or rat HER2 proteins, showing that the cynomolgus monkey is an appropriate species in which to conduct toxicity evaluation with DS-8201a, based on its binding to HER2.”
Why that species
ADC and naked antibody bind cyno HER2 with affinity similar to human; no binding to mouse or rat HER2
“In the same assay, DS-8201a and MAAL-9001 bound to cynomolgus monkey HER2-His protein (Kd [ED50] = 7.46 ng/mL and 6.77 ng/mL, respectively) but not to mouse or rat HER2-His proteins.”
Surrogate molecule
No surrogate; clinical ADC (process 1 and process 2 material) tested; DXd payload and naked antibody tested separately
“In the studies with trastuzumab deruxtecan, the rodent study and one monkey study were performed with process 1 material, whereas the 2 additional cynomolgus monkey studies were performed with process 2 material.”
Species: general tox
Rat and cynomolgus monkey
“The Applicant conducted GLP-compliant, repeat-dose general toxicology studies to evaluate the toxicity of DS-8201a, MAAA-1181a, or MAAL-9001 in rats and/or monkeys.”
Species: DART
Not conducted (ICH S9: genotoxic payload targeting dividing cells; HER2 antibody oligohydramnios)
“As recommended by ICH S9 guidance, embryo-fetal toxicity studies were not conducted based on the justification that these studies are not warranted to support the proposed indication because MAAA-1181a is genotoxic and targets rapidly dividing cells”
Species: carcinogenicity
Not conducted (ICH S9)
“No carcinogenicity studies have been conducted in accordance with ICH S9.”
Surrogate used in
No surrogate used; clinical ADC tested in cynomolgus monkey, which binds HER2
“DS-8201a and MAAL-9001 bound to cynomolgus monkey HER2 protein but not to mouse or rat HER2 proteins, showing that the cynomolgus monkey is an appropriate species in which to conduct toxicity evaluation with DS-8201a, based on its binding to HER2.”
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)
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
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