Adcetris
brentuximab vedotin · CD30Rat and cynomolgus monkey (monkey the antigen-binding species)
Zynlonta: which tox species, and why?
loncastuximab tesirine · CD19
Species
No pharmacologically relevant species; cynomolgus monkey (non-binding) for ADC; rat and dog for payload SG3199
“No pharmacologically relevant nonclinical species for safety evaluation—as defined in ICH S6(R1)—exists for loncastuximab tesirine, due its antibody component being selective for human CD19.”
Why that species
Antibody not cross-reactive with any nonclinical CD19; monkey chosen for PK predictivity, lower ADA impact, and PBD class-toxicity translation
“The monoclonal antibody (mAb) component of loncastuximab tesirine, RB4v1.2, is selective for human CD19 and not cross‐reactive with CD19 from any nonclinical species.”
Surrogate molecule
No surrogate; clinical ADC in non-binding monkey (off-target only), free payload SG3199 in rat and dog
“Importantly, on‐target (ie, CD19‐mediated) toxicity cannot be evaluated in this or any other nonclinical species; however, a considerable body of data on the nonclinical and clinical safety of CD19‐ and CD20‐specific B‐cell‐depleting agents exists.”
Species: general tox
Cynomolgus monkey (ADC, 4- and 13-week, 12-week recovery)
“The Applicant conducted GLP 4‐week and 13‐week repeat‐dose general toxicology studies in which cynomolgus monkeys were dosed with the ADC, followed by a 12‐week recovery period.”
Species: DART
Not conducted (genotoxic cytotoxic ADC expected to be embryo-fetal toxic and teratogenic)
“Reproductive and developmental toxicology studies were not conducted since cytotoxic (i.e. genotoxic) drugs that affect actively dividing cells, such as loncastuximab tesirine, are expected to be embryo/feto toxic and teratogenic.”
Species: carcinogenicity
Not conducted (ICH S9; genotoxic payload, advanced cancer)
“In accordance with ICH S9, ICH S6(R1) and ICH S1A (Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals) no carcinogenicity studies were conducted or are planned with ADCT-402 or SG3199 given the genotoxic mode of action of SG3199 (covalent DNA crosslinking/ alkylating agent) and the intended clinical use in patients with advanced cancer.”
Surrogate used in
No surrogate used; CD19-mediated toxicity could not be evaluated in any nonclinical species
“Importantly, on‐target (ie, CD19‐mediated) toxicity cannot be evaluated in this or any other nonclinical species; however, a considerable body of data on the nonclinical and clinical safety of CD19‐ and CD20‐specific B‐cell‐depleting agents exists.”
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
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)