Adcetris
brentuximab vedotin · CD30Rat and cynomolgus monkey (monkey the antigen-binding species)
Polivy: which tox species, and why?
polatuzumab vedotin · CD79b
Species
Rat and cynomolgus monkey (monkey with clinical ADC plus monkey-CD79b surrogate ADC)
“Polatuzumab does not bind to its target epitope on species typically used in toxicology studies. Both polatuzumab vedotin and a surrogate ADC that binds monkey CD79b were used in the toxicology studies.”
Why that species
Polatuzumab does not bind non-human primate or rodent CD79b (3 amino-acid epitope difference); surrogate binds cyno CD79b
“Peptide sequence alignment of CD79b between humans and cynomolgus monkeys showed a variation in three amino acids in the N-terminal epitope region.”
Surrogate molecule
Yes: surrogate ADC DCDS5017A (chimeric anti-cyno CD79b IgG1-vcMMAE, DAR 3.5) for target-mediated effects
“Therefore, a surrogate ADC (DCDS5017A) that binds specifically to cynomolgus monkey CD79b was generated for testing target-mediated effects.”
Species: general tox
Rat and cynomolgus monkey (polatuzumab vedotin, surrogate ADC and MMAE)
“The toxicological profile of polatuzumab vedotin has been evaluated during single and repeat-dose toxicity studies in rats and Cynomolgus monkeys using polatuzumab vedotin, surrogate ADC or unconjugated MMAE, genotoxicity studies, reproductive and developmental toxicity studies in rats and phototoxicity.”
Species: DART
Rat (MMAE embryo-fetal development only); no fertility study
“In an embryo-fetal developmental study, pregnant rats were given 2 intravenous doses of 0.2 mg/kg MMAE during the period of organogenesis on gestation Days 6 and 13.”
Species: carcinogenicity
Not conducted (not warranted for the indication)
“Carcinogenicity studies in animals have not been performed with polatuzumab vedotin or MMAE and are not warranted for the proposed indication.”
Surrogate used in
Yes: surrogate ADC binding monkey CD79b used in monkey repeat-dose toxicity
“Both polatuzumab vedotin and a surrogate ADC that binds monkey CD79b were used in the 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)
Padcev
enfortumab vedotin · Nectin-4Rat and cynomolgus monkey
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