Adcetris
brentuximab vedotin · CD30Rat and cynomolgus monkey (monkey the antigen-binding species)
Emrelis: which tox species, and why?
telisotuzumab vedotin · c-Met
Species
Cynomolgus monkey (relevant); rat non-binding (exploratory, MMAE-related effects)
“In addition, these studies support the use of cynomolgus monkey as the pharmacologically relevant species for toxicity assessments of telisotuzumab vedotin.”
Why that species
Binds human and monkey c-Met with similar EC50 (1.3 vs 1.5 nM); no binding to mouse, rat, rabbit c-Met
“In vitro, telisotuzumab bound to cells overexpressing human or monkey c-Met with EC50 values of 1.3 and 1.5 nM, respectively, but did not bind to cells expressing mouse, rat, or rabbit c-Met.”
Surrogate molecule
No surrogate; clinical ADC in monkey; MMAE payload data via Seagen right of reference
“The Applicant used information on the pharmacology, pharmacokinetics (PK), and toxicology profile of MMAE provided via right of reference from Seagen.”
Species: general tox
Cynomolgus monkey (GLP 4- and 13-week IV studies)
“The Applicant evaluated the safety of telisotuzumab vedotin in GLP-compliant 4- and 13-week studies in cynomolgus monkeys with the intended IV route of administration.”
Species: DART
Not conducted with the ADC (MMAE genotoxic, advanced cancer; ICH S9)
“The Applicant did not conduct reproductive or embryofetal development (EFD) toxicology studies with telisotuzumab vedotin as MMAE is genotoxic and affects rapidly dividing cells and the intended indication is for the treatment of patients with advanced cancer, in accordance with the ICH S9 guidance.”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies in animals have not been performed with telisotuzumab vedotin-tllv or the small molecule MMAE.”
Surrogate used in
No surrogate used; cynomolgus monkey is the pharmacologically relevant species
“In addition, these studies support the use of cynomolgus monkey as the pharmacologically relevant species for toxicity assessments of telisotuzumab vedotin.”
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
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