Adcetris
brentuximab vedotin · CD30Rat and cynomolgus monkey (monkey the antigen-binding species)
Padcev: which tox species, and why?
enfortumab vedotin · Nectin-4
Species
Rat and cynomolgus monkey
“Binding affinity of enfortumab vedotin to Nectin-4 was similar between humans, cynomolgus monkeys, and rats, but enfortumab vedotin bound to murine Nectin-4 at 10-fold lower affinity, thus supporting the use of the rat and monkey in the nonclinical toxicology studies.”
Why that species
Nectin-4 homology >99% monkey, ~94% rat; similar binding affinity in human, monkey and rat (mouse 10-fold lower)
“Orthologs of Nectin-4 share >99%, ~94%, and ~92% homology to the human protein in cynomolgus monkeys, rats, and mice, respectively.”
Surrogate molecule
No surrogate; early hybridoma-derived ADC (AGS-22M6E) bridged to clinical material in monkey
“Enfortumab vedotin and AGS-22M6E comparability was confirmed in a subsequent bridging toxicology study in monkeys (20021751), and comparable PK, immunogenicity, and toxicity profiles were observed.”
Species: general tox
Rat (4- and 13-week) and cynomolgus monkey (4-week), weekly IV
“The Applicant conducted GLP intravenous repeat-dose (weekly) general toxicology studies in rats (4 and 13-week) with enfortumab vedotin, and the unconjugated antibody (AGS-22M6); and in monkeys (4-week) with enfortumab vedotin”
Species: DART
Rat only (pilot embryo-fetal study with the ADC; complete litter loss at 5 mg/kg)
“In a rat pilot embryo-fetal development study, administration of enfortumab vedotin-ejfv on gestation day 6 and 13 during the period of organogenesis resulted in a complete litter loss in all pregnant rats at the maternally toxic dose of 5 mg/kg”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies with enfortumab vedotin-ejfv or the small molecule cytotoxic agent (MMAE) have not been conducted.”
Surrogate used in
No surrogate used; rat and monkey Nectin-4 bind the clinical ADC with similar affinity
“Binding affinity of enfortumab vedotin to Nectin-4 was similar between humans, cynomolgus monkeys, and rats, but enfortumab vedotin bound to murine Nectin-4 at 10-fold lower affinity, thus supporting the use of the rat and monkey in the nonclinical toxicology studies.”
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)
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