Tecentriq
atezolizumab
Species
MonkeyMouse
Longest study
26 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 (pivotal); mouse pilot study
“The Applicant conducted repeat-dose toxicology studies in mice and Cynomolgus monkeys.”
Why that species
Binds human, murine and cynomolgus monkey PD-L1
“In vitro pharmacology studies demonstrated that atezolizumab binds to human, murine, and Cynomolgus monkey PD-L1”
Surrogate molecule
Yes: mouse IgG2a chimeric antibodies with atezolizumab binding region, used to minimize immunogenicity in mouse studies
“To minimize immunogenicity in mice, the Applicant generated two mouse IgG2a chimeric antibodies (PRO304397 and PRO314483), containing the binding region of atezolizumab.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“In GLP-compliant toxicology studies, Cynomolgus monkeys received atezolizumab at doses up to 50 mg/kg/week given SC for 8 weeks or administered IV for up to 26 weeks.”
Pivotal GLP studies
GLP cynomolgus monkey studies: 8-week SC and IV, and 26-week IV, weekly up to 50 mg/kg
“In GLP-compliant toxicology studies, Cynomolgus monkeys received atezolizumab at doses up to 50 mg/kg/week given SC for 8 weeks or administered IV for up to 26 weeks.”
Route in tox
IV and SC
“In GLP-compliant toxicology studies, Cynomolgus monkeys received atezolizumab at doses up to 50 mg/kg/week given SC for 8 weeks or administered IV for up to 26 weeks.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted, which is in accordance with ICH S6(R1).”
Carcinogenicity
Not conducted (ICH S6(R1), ICH S9); no increased carcinogenic risk expected from mechanism
“Carcinogenicity studies have not been conducted in accordance with ICH S6(R1) and ICH S9. Furthermore, due to its mechanism of action, atezolizumab is not expected to be associated with an increased carcinogenic risk.”
Reproductive & developmental
No dedicated studies; chronic monkey study: irregular menstrual cycles and no new corpora lutea at high dose
“Reproductive and developmental toxicity studies have not been conducted with atezolizumab. However, in the chronic toxicity study in sexually mature monkeys, atezolizumab treatment at the high-dose resulted in irregular menstrual cycles and a lack of newly formed corpora lutea in the ovaries.”
Safety pharmacology
Incorporated into 8- and 26-week monkey studies (CNS, cardiovascular telemetry, respiratory)
“Central nervous system, cardiovascular (telemetry and/or surface leads), and respiratory safety pharmacology parameters were evaluated as part of the 8- and 26-week GLP Cynomolgus monkey toxicology studies (Studies 08-1148 and 13-3278).”
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 Tecentriq 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: Arteritis/periarteritis in monkeys and sciatic neuropathy in mice, possibly enhanced autoreactive immune response (EMA assessment report, p. 36)
NOAEL / key findings
Arteritis/periarteritis in monkeys and sciatic neuropathy in mice, possibly enhanced autoreactive immune response
“Atezolizumab-related findings in the repeated dose toxicity studies were sciatic neuropathy in C57BL/6 mice and arteritis/periarteritis in Cynomolgus monkeys. Both findings may be due to enhancement of an autoreactive immune-response in pre-disposed animals.”
Risksopen answer page →
Immune & cytokine safety
No cytokine release from human PBMCs up to 250 µg/mL; minimal Fcγ receptor binding, no ADCC up to 10 µg/mL
“Atezolizumab showed minimal binding to human Fcγ receptors and did not stimulate cytokine release from human PBMCs at concentrations up to 250 µg/mL or ADCC activity at concentrations up to 10 µg/mL.”
Biodistribution & persistence
Human TCR staining in placenta (syncytiotrophoblasts), lymph node, tonsil and thymus
“staining was detected in the placenta, lymph node, tonsil, and thymus. Frequent, moderate, apical cytoplasmic and membranous staining was observed in syncytiotrophoblasts of the placenta.”
Modality-specific risk
Immune-mediated tissue damage and multi-organ inflammation from PD-L1 blockade; irregular menstruation
“Toxicological effects of atezolizumab administration in animals were limited to irregular menstruation in female monkeys and immune-mediated effects, including tissue damage and multi-organ inflammation.”