Jemperli
dostarlimab
Species
Monkey
Longest study
13 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
Cynomolgus monkey only
“dostarlimab (TSR‐042) bound to human and cynomolgus monkey PD‐1 with similar affinity (KD = 1.8 and 1.5 nM, respectively) but did not bind to mouse PD‐1, supporting the use of cynomolgus monkey as the single pharmacologically relevant species for toxicity assessment.”
Why that species
Similar PD-1 affinity in human and monkey (KD 1.8 vs 1.5 nM); no binding to mouse PD-1
“dostarlimab (TSR‐042) bound to human and cynomolgus monkey PD‐1 with similar affinity (KD = 1.8 and 1.5 nM, respectively) but did not bind to mouse PD‐1”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkey
“The Applicant evaluated the safety of dostarlimab in cynomolgus monkeys in GLP‐compliant repeat‐dose toxicity studies of up to 13 weeks duration.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“The Applicant evaluated the safety of dostarlimab in cynomolgus monkeys in GLP‐compliant repeat‐dose toxicity studies of up to 13 weeks duration.”
Pivotal GLP studies
Cynomolgus monkey 4-week and 13-week once-weekly IV studies at 10, 30 and 100 mg/kg
“The single dose and repeat dose studies of 4- and 13-week duration were all performed with similar dose levels of dostarlimab (10, 30 and 100 mg/kg).”
Route in tox
IV infusion
“Route of administration: Intravenous (IV) infusion”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; not warranted for a biotechnology-derived product
“No genetic toxicology or carcinogenicity studies were conducted or warranted to support this BLA submission, as dostarlimab‐gxly is a biotechnology‐derived pharmaceutical and the proposed indication is for advanced cancer.”
Carcinogenicity
Not conducted (biotechnology product for advanced cancer)
“No genetic toxicology or carcinogenicity studies were conducted or warranted to support this BLA submission, as dostarlimab‐gxly is a biotechnology‐derived pharmaceutical and the proposed indication is for advanced cancer.”
Reproductive & developmental
No dedicated studies; literature: PD-L1 blockade in murine pregnancy models disrupts fetal tolerance and increases fetal loss
“Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in foetal loss.”
Safety pharmacology
Incorporated into 4-week monkey study; no effects on CV, respiratory or CNS function up to 100 mg/kg
“The administration of dostarlimab by a weekly IV dose for 4 weeks (5 total doses) to cynomolgus monkeys at dose levels of 0, 10, 30, or 100 mg/kg did not result in any dostarlimab‐related effects on function of the CV system, respiratory system, or CNS”
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 Jemperli 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
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: NOAEL not established in 13-week monkey study due to an immune-type skin finding in one low-dose (10 mg/kg) animal (EMA assessment report, p. 43)
NOAEL / key findings
NOAEL not established in 13-week monkey study due to an immune-type skin finding in one low-dose (10 mg/kg) animal
“However, in the 13-week repeat dose study, the NOAEL could not be established, due to the finding described above occurring in one animal in the low dose group (10 mg/kg).”
Risksopen answer page →
Immune & cytokine safety
No in vitro cytokine release from human PBMCs at up to 400 µg/well
“Furthermore, in an in vitro cytokine release assay, dostarlimab did not induce cytokine release at concentrations up to 400 µg/well.”
Biodistribution & persistence
TCR: specific membrane binding to lymphocytes in many tissues and to peripheral blood monocytes
“Specific binding of dostarlimab was observed on plasma membrane elements of lymphocytes (including intravascular, perivascular, interstitial, and migrating lymphocytes) in a large number of tissues and to monocytes in peripheral blood.”
Modality-specific risk
Immune-mediated adverse reactions from PD-1 checkpoint blockade
“In clinical trials, toxicities associated with dostarlimab were primarily immune‐mediated adverse reactions that are predicted by its mechanism of action.”