Mylotarg
gemtuzumab ozogamicin
Species
MonkeyRat
Longest study
12 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (neither pharmacologically relevant; no CD33 cross-reactivity)
“In view of the absence of cross-reactivity of gemtuzumab ozogamicin with CD33 from laboratory species, studies of kinetics in animals can only be of limited value, as there will be no binding, specific intracellular uptake, and metabolism of the conjugate that underlies its therapeutic action in humans.”
Why that species
No relevant species: antibody does not bind monkey CD33 or stain rat/monkey tissues; species used for off-target payload toxicity
“hP67.6 bound strongly to human CD33-transfected CHO cells but did not bind to the monkey CD33-transfected CHO cells (study 084032).”
Surrogate molecule
No surrogate; clinical ADC tested in non-binding rat and monkey (plus old vs new cell line bridging)
“Repeat-dose studies included six cycle intravenous toxicity studies in rats and monkeys and a six cycle comparative study in monkeys for the old and new antibody cell lines.”
Study lengthopen answer page →
Longest pivotal study
12 weeks
“A GLP-compliant general toxicity study in monkeys was also completed in which 12 doses of gemtuzumab ozogamicin were given once weekly by intravenous bolus injection to groups of 3 male and 3 female cynomolgus monkeys at doses of 0 (sterile water), 2.2, 6.6, or 11 mg/m2 /week.”
Pivotal GLP studies
6-week (weekly IV) rat and monkey with 4-week recovery; 6-cycle monkey cell-line bridging study; 12-week weekly IV monkey
“Rats were administered 6 weekly doses at 0 (PBS control), 7.2 (hP67.6 antibody control), or CL 555,201 (GO) at doses of 0.6, 2.4, or 7.2 mg/m2 /week and observed for an additional 4 weeks.”
Route in tox
IV (weekly bolus/infusion)
“Monkeys were administered 6 weekly IV doses at 0 (PBS control), 22 (hP67.6 antibody control), or CL 555,201 at doses of 2.4, 7.2, or 22 mg/m2 /week (5, 15 or 45 mcg/kg/week calicheamicin equivalents) and observed for an additional 4 weeks.”
Skipped studiesopen answer page →
Genotoxicity
Conducted: ADC clastogenic in mouse micronucleus; free calicheamicin DMH mutagenic and clastogenic in vitro
“Gemtuzumab ozogamicin was found to be clastogenic. This is consistent with the known induction of DNA breaks by calicheamicin and other enediyne antitumour antibiotics.”
Carcinogenicity
Not conducted; rat liver preneoplastic oval cell hyperplasia noted in tox studies
“No carcinogenicity studies have been conducted with gemtuzumab ozogamicin (see discussion on non-clinical aspects).”
Reproductive & developmental
Rat male/female fertility and rat EFD (one species agreed); embryolethal, teratogenic, male fertility impaired; no PPND
“Based on the unequivocally positive results obtained from a pilot study, the Agency previously agreed with the Applicant that one species would be sufficient to support an NDA application for CMA-676 in a leukemia indication.”
Safety pharmacology
Standalone non-GLP studies (mouse, rat, dog CV) plus payload hERG; dog BP decrease and HR increase at >=13 mg/m2
“Gemtuzumab ozogamicin was evaluated for potential effects on nervous, cardiovascular, gastrointestinal, hepatic, and renal systems in vivo and/or in vitro.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
6-week NOAEL 2.4 mg/m2/wk monkey, 0.6 rat; 12-week monkey no NOAEL; liver, kidney, marrow, lymphoid, reproductive organs
“The NOAEL was defined at 2.4 mg/m2 /week based on target organ toxicity in the kidney, liver, and lympho-hematopoietic organs at ≥7.2 mg/m2 /week.”
Risksopen answer page →
Immune & cytokine safety
ADA in rats (reduced exposure) and some monkeys; marked eosinophilia and hypersensitivity reactions in monkeys
“Marked eosinophilia occurred at all dose levels and was associated with hypersensitivity reactions in few monkeys dosed with the old cell line.”
Biodistribution & persistence
Rat [3H]-ADC tissue distribution limited (tissue/plasma <=0.54; liver, kidney, spleen highest); little in vivo payload release
“In rats, distribution of [3H]gemtuzumab ozogamicin radioequivalents into red blood cells and tissues was limited, with tissue-to-plasma AUC ratios ≤ 0.54 for all tissues evaluated.”
Modality-specific risk
Target-independent calicheamicin toxicity: hepatotoxicity/VOD via sinusoidal endothelium, myelosuppression, nephrotoxicity, genotoxicity
“Toxicity is suspected to arise from uptake by liver sinusoidal cells and breakdown of gemtuzumab ozogamicin leading to local cellular toxicity where this occurs.”