Tzield
teplizumab
Species
MonkeyMouse
Longest study
1 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse (surrogate antibody) for repeat-dose and DART; single-dose chimpanzee study with teplizumab
“As teplizumab was shown to only cross-react with CD3+ T cells from humans, gorillas, chimpanzees, and gibbons, minimal nonclinical investigations were conducted with teplizumab itself.”
Why that species
Teplizumab binds CD3+ T cells only from humans, gorillas, chimpanzees and gibbons; no rodent activity, so a mouse surrogate was used
“As teplizumab was shown to only cross-react with CD3+ T cells from humans, gorillas, chimpanzees, and gibbons, minimal nonclinical investigations were conducted with teplizumab itself.”
Surrogate molecule
Yes: anti-mouse CD3 epsilon surrogate mAb with same Fc modifications, used for mouse repeat-dose, fertility, EFD and PPND studies
“evaluation continued in mice with a surrogate antibody in a GLP 6 days repeat dose toxicology (RDT) study, male/female fertility and early embryonic (FEED) studies, embryonic development (EFD) and a pre-postnatal development (PPND) study.”
Study lengthopen answer page →
Longest pivotal study
1 weeks
“One GLP repeated dose toxicology study of 6 days duration with 6 weeks of recovery have been performed in CD-1 mice (study 7608-797).”
Pivotal GLP studies
GLP 6-day CD-1 mouse study with surrogate antibody (SC and IV) plus recovery; no chronic studies
“One GLP repeated dose toxicology study of 6 days duration with 6 weeks of recovery have been performed in CD-1 mice (study 7608-797).”
Route in tox
Subcutaneous and intravenous
“This study utilized the surrogate antibody which was administrated both subcutaneously and intravenously to assess toxicity and toxicokinetic.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“No genetic toxicology studies have been conducted with teplizumab or the surrogate.”
Carcinogenicity
Not conducted (short treatment, no rodent activity, anaphylaxis with surrogate); weight-of-evidence assessment
“The short duration of treatment, the absence of pharmacologic activity in the rodent (for teplizumab itself), and the observations of anaphylaxis and hypersensitivity following various dosing regimens in the rodent limit the utility of carcinogenic assessments”
Reproductive & developmental
Mouse surrogate: no fertility effects; EFD post-implantation loss at 20 mg/kg (NOAEL 0.3); PPND: impaired offspring immune response and F1 fertility
“In an embryofetal development study there was an increased incidence of post-implantation loss at the HD of 20 mg/kg that included the loss of the entire litter for multiple females leading to identifications of the MD (0.3 mg/kg) as the NOAEL.”
Safety pharmacology
Incorporated into single-dose chimpanzee study; no effects on temperature, ECG, heart rate, blood pressure or respiration
“No treatment-related effects on safety pharmacology endpoints, including body temperature, ECGs, heart rate, blood pressure, or respiratory rate were seen.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Tzield don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for monoclonal antibodies outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: NOAEL <0.3 mg/kg in intermittent-dose mouse surrogate study due to severe hypersensitivity; T-cell depletion and thymic medulla hypocellularity (FDA pharmacology/toxicology review, p. 8)
NOAEL / key findings
NOAEL <0.3 mg/kg in intermittent-dose mouse surrogate study due to severe hypersensitivity; T-cell depletion and thymic medulla hypocellularity
“The NOAEL was <0.3 mg/kg based on severe hypersensitivity reactions.”
Risksopen answer page →
Immune & cytokine safety
Transient cytokine increases (TNF, IL-6, IL-10, IFN-gamma) in chimpanzees; slight IL-6/IL-12 rise with surrogate in mice; anaphylaxis on intermittent surrogate dosing
“At both doses evaluated, slight increases (<3.5-fold) in IL-6 and IL-12 levels were evident, consistent with the release of cytokines seen following treatment of chimps with teplizumab.”
Biodistribution & persistence
Human TCR: staining restricted to T-cell regions of spleen, lymph nodes, MALT and thymus; no B-region staining
“Staining of lymphoid cells in B regions or non-T regions of lymphoid tissues was not observed.”
Modality-specific risk
T-cell depletion/immunosuppression (infection, EBV-like lymphoproliferation), cytokine release syndrome, hypersensitivity/anaphylaxis
“Increases in cytokines were also noted, indicating that cytokine release syndrome (CRS) may occur.”
Similar precedents
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