Adcetris
brentuximab vedotin · CD30Conducted on MMAE: Ames and mouse lymphoma negative; rat micronucleus positive (aneugenic)
Zynlonta: genotox, carcinogenicity and repro: done or skipped?
loncastuximab tesirine · CD19
Genotoxicity
Not conducted with ADC; SG3199 clastogenic in vitro (micronucleus, chromosome aberration); Ames not assessable (cytotoxicity)
“No genotoxicity studies were conducted with ADCT-402. SG3199 was genotoxic in GLP in vitro studies (in vitro micronucleus assay and the chromosome aberration assay in human lymphocytes from whole blood).”
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”
Instead of carcinogenicity
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Instead of genotoxicity
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
DRG histopathology
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reproductive & developmental
Not conducted (ICH S9); irreversible testicular toxicity in monkey; fertility assessed in repeat-dose study
“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.”
Safety pharmacology
Incorporated into 4- and 13-week monkey studies (ECG, BP, respiration, neurobehavior); no hERG
“Consistent with International Council for Harmonization (ICH) S6(R1), no stand‐alone safety pharmacology studies were conducted with loncastuximab tesirine, and safety pharmacology endpoints were evaluated as part of the GLP‐compliant 4‐ and/or 13‐week repeat‐dose toxicity studies in cynomolgus monkeys.”
Genotox: Ames
SG3199: Ames not assessable (cytotoxic at all concentrations)
“A GLP bacterial reverse mutation assay (Ames test) was also conducted; however, mutagenicity could not be assessed due to cytotoxicity at all concentrations tested.”
Genotox: in vitro mammalian
SG3199: positive (clastogenic) in in vitro micronucleus and chromosome aberration assays in human lymphocytes
“The payload, SG3199, was genotoxic in GLP in vitro studies (in vitro micronucleus assay and the chromosome aberration assay in human lymphocytes from whole blood).”
Genotox: in vivo
Not conducted (SG3199 evaluated in in vitro assays only)
“Genotoxicity of SG3199 was evaluated in two in vitro assays in human lymphocytes, a micronucleus assay, and a chromosome aberration assay.”
Carcinogenicity model
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.”
Carcinogenicity timing
Not required: genotoxic payload, advanced cancer (ICH S9, S6(R1), S1A)
“In accordance with ICH S9, ICH S6(R1) and ICH S1A, no carcinogenicity studies were conducted with loncastuximab tesirine or SG3199 given the genotoxic mode of action of SG3199 (see Section 5.5.2) and the intended clinical use in patients with advanced cancer.”
hERG / QT
No hERG assay; monkey ECG/cardiovascular changes not adverse or ADC-related
“No evaluation for hERG inhibition was submitted for the ADC or SG3199. There was large variability in the individual ECG data in monkeys, but overall any observed changes in cardiovascular parameters assessed as part of the GLP toxicology studies in monkeys were not considered adverse or ADC‐related.”
Same question, other ADCs
Besponsa
inotuzumab ozogamicin · CD22Conducted: calicheamicin positive in Ames and in vitro micronucleus; ADC clastogenic in mouse micronucleus
Datroway
datopotamab deruxtecan · Trop-2Not conducted with ADC; DXd Ames negative, clastogenic in vitro chromosome aberration and in vivo rat micronucleus
Decnupaz
pivekimab sunirine · CD123Not conducted with ADC (ICH S9); FGN849 positive in Ames TA102, in vitro and in vivo micronucleus
Elahere
mirvetuximab soravtansine · FRαNot conducted with ADC; DM4 and S-methyl-DM4 Ames negative, rat bone marrow micronucleus positive
Emrelis
telisotuzumab vedotin · c-MetNot conducted with ADC; MMAE aneugenic (positive rat micronucleus), Ames and mouse lymphoma negative
Enhertu
fam-trastuzumab deruxtecan · HER2Not conducted with ADC; DXd clastogenic (rat micronucleus, CHL chromosome aberration), Ames negative
Kadcyla
ado-trastuzumab emtansine · HER2Conducted on DM1: Ames negative; rat micronucleus positive (aneugenic/clastogenic); monkey micronucleus inconclusive
Mylotarg
gemtuzumab ozogamicin · CD33Conducted: ADC clastogenic in mouse micronucleus; free calicheamicin DMH mutagenic and clastogenic in vitro
Padcev
enfortumab vedotin · Nectin-4Not conducted with ADC; MMAE Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
Polivy
polatuzumab vedotin · CD79bNot conducted with ADC; MMAE Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
Tivdak
tisotumab vedotin · Tissue factorNot conducted with ADC; MMAE: Ames and mouse lymphoma negative, rat micronucleus positive (aneugenic)
Trodelvy
sacituzumab govitecan · Trop-2Not conducted with ADC; SN-38 Ames negative, in vitro micronucleus positive (clastogenic)