Besponsa
inotuzumab ozogamicin · CD22Rat and cynomolgus monkey (neither cross-reactive; target-independent toxicity only)
Adcetris: which tox species, and why?
brentuximab vedotin · CD30
Species
Rat and cynomolgus monkey (monkey the antigen-binding species)
“Single- and repeat-dose toxicology studies were conducted in rats and monkeys. The pivotal repeat-dose toxicity studies were GLP compliant.”
Why that species
Binds human and cynomolgus CD30 with equal affinity (Kd 0.2 nM), not rat or mouse; rat used for target-independent payload toxicity
“Both brentuximab vedotin and unconjugated brentuximab bound with a Kd of 0.2 nM to human and cynomolgus CD30-positive primary lymphocytes, but not to rat or mouse CD30-positive cells or cells not expressing CD30.”
Surrogate molecule
No surrogate; clinical ADC tested in rat and monkey, with free MMAE and unconjugated cAC10 comparator arms
“The administration of unconjugated brentuximab at all doses was well tolerated, with no apparent target organ toxicity or clinically significant adverse effects.”
Species: general tox
Rat and cynomolgus monkey
“Single- and repeat-dose toxicology studies were conducted in rats and monkeys.”
Species: DART
Rat (embryo-fetal development, IV, organogenesis)
“In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13).”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies with brentuximab vedotin or the small molecule (MMAE) have not been conducted.”
Surrogate used in
No surrogate used; clinical ADC binds human and cynomolgus CD30 equally
“Both brentuximab vedotin and unconjugated brentuximab bound with a Kd of 0.2 nM to human and cynomolgus CD30-positive primary lymphocytes, but not to rat or mouse CD30-positive cells or cells not expressing CD30.”
Same question, other ADCs
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
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