Zynlonta
loncastuximab tesirine
Species
no relevantMonkeyRatDog
Longest study
13 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
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.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“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.”
Pivotal GLP studies
GLP monkey 4-week (0.3, 0.6 mg/kg q3w) and 13-week (0.075-0.3 mg/kg q3w) IV, 12-week recovery; SG3199 4-week rat
“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.”
Route in tox
IV (30-minute infusion; clinical route)
“All in vivo studies with ADCT-402 or SG3199 used the IV route of administration, the intended clinical route of administration”
Skipped studiesopen answer page →
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”
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.”
First doseopen answer page →
First-in-human starting dose
1/6 HNSTD in cynomolgus monkey cited as rationale for species choice; actual FIH calculation not detailed
“The cynomolgus monkey was selected as nonclinical species for safety evaluation of loncastuximab tesirine, given the greater predictive value of PK data generated in this species for humans, potential for reduced impact of antidrug antibody (ADA) formation on drug exposure, and the proven utility of 1/6th highest non‐severely toxic dose (HNSTD) for setting clinical starting doses with ADCs.”
NOAEL / key findings
No NOAEL stated; 13-week monkey kidney and testis findings at all doses (≥0.075 mg/kg); skin hyperpigmentation dose-limiting; bone marrow, lung
“Also, adverse findings in male reproductive organs were present at 0.6 mg/kg only in the 4‐week study and at all doses (≥ 0.075 mg/kg) in the 13‐week study.”
Risksopen answer page →
Immune & cytokine safety
Pro-inflammatory responses (WBC, fibrinogen, multi-organ inflammation) typical of PBD ADCs; ADA in few monkeys
“Treatment of monkeys with loncastuximab tesirine resulted in pro‐inflammatory responses as indicated by increases in the white blood cells (WBCs) and/or differentials, increased fibrinogen, and histopathology observations (multi‐organ inflammation, particularly the lung, kidney, or injection site).”
Biodistribution & persistence
ADC confined to plasma volume, t1/2 8-17 days, stable; [3H]-SG3199 rapid wide distribution, no brain/melanin uptake, biliary excretion
“There was no apparent distribution of SG3199 to melanin‐ containing tissues or the brain or spinal cord.”
Modality-specific risk
PBD payload toxicities: skin hyperpigmentation (photoreactive), myelosuppression, nephropathy, testicular atrophy, effusions/edema, inflammation
“In repeat‐dose toxicity studies in cynomolgus monkeys, loncastuximab tesirine exhibited a safety profile consistent with SG3199‐mediated effects on the skin (epidermal hyperpigmentation with hyperplasia/hyperkeratosis), bone marrow (hypocellularity associated with regenerative anemia)”