Adcetris
brentuximab vedotin · CD30Conducted on MMAE: Ames and mouse lymphoma negative; rat micronucleus positive (aneugenic)
Besponsa: genotox, carcinogenicity and repro: done or skipped?
inotuzumab ozogamicin · CD22
Genotoxicity
Conducted: calicheamicin positive in Ames and in vitro micronucleus; ADC clastogenic in mouse micronucleus
“Inotuzumab ozogamicin was clastogenic in mice at doses ≥28 µg/kg (approximately 1.1 mg/m2 of the ADC), consistent with the known DNA-reactive activity of the calicheamicin payload.”
Carcinogenicity
Not conducted (ICH S9); liver adenomas and preneoplastic changes in 6-month rat study
“No carcinogenicity studies were conducted or required to support a marketing application for the current indication.”
Reproductive & developmental
Rat fertility and rat/rabbit EFD conducted: rat embryo-fetal toxicity (resorptions, low fetal weight); no PPND (ICH S9)
“Embryo-fetal development studies were conducted in rabbits and rats.”
Safety pharmacology
Dedicated studies: CV in cynomolgus (transient BP effect), CNS and respiratory in rats
“A cardiovascular (CV) safety pharmacology study with inotuzumab ozogamicin in cynomolgus monkeys identified a small and transient effect on arterial blood pressure; the toxicological significance of this finding is unclear.”
Genotox: Ames
Calicheamicin payload: positive in bacterial reverse mutation test
“The calicheamicin payload was positive in both the bacterial reverse mutation test and the in vitro micronucleus assay.”
Genotox: in vitro mammalian
Calicheamicin payload: positive in in vitro micronucleus assay
“The calicheamicin payload was positive in both the bacterial reverse mutation test and the in vitro micronucleus assay.”
Genotox: in vivo
ADC clastogenic in mouse micronucleus assay at doses ≥28 µg/kg (~1.1 mg/m2)
“Inotuzumab ozogamicin was clastogenic in mice at doses ≥28 µg/kg (approximately 1.1 mg/m2 of the ADC), consistent with the known DNA-reactive activity of the calicheamicin payload.”
Carcinogenicity model
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or required to support a marketing application for the current indication.”
Carcinogenicity timing
Not required for the current indication; none conducted
“No carcinogenicity studies were conducted or required to support a marketing application for the current indication.”
hERG / QT
Calicheamicin payload hERG IC50 >6.77 µM (10,000 ng/mL)
“The IC50 for the inhibitory effect of N-Ac-γ-calicheamicin DMH on hERG potassium channels was >6.77 μM (10,000 ng/mL)”
Same question, other ADCs
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)
Zynlonta
loncastuximab tesirine · CD19Not conducted with ADC; SG3199 clastogenic in vitro (micronucleus, chromosome aberration); Ames not assessable (cytotoxicity)