In vitro: A key feature of atezolizumab is that it is FcγR-binding deficient, so it cannot bind to Fc receptors on phagocytes and therefore does not cause antibody-dependent cell-mediated cytotoxicity (ADCC). atezolizumab treatment could bring cytokine changes include transient increases in IL-18, IFNγ, and CXCL11, and a transient decrease in IL-6; cellular changes include increases in proliferating CD8+ T cells.
In vivo: By blocking the PD-L1/PD-1 immune checkpoint, atezolizumab reduces immunosuppressive signals found within the tumor microenvironement and consequently increases T cell mediated immunity against the tumor. The pharmacokinetics of atezolizumab were initially studied in cynomolgus monkeys and mice where its volume of distribution was calculated to be approximately that of the plasma volume. The in vivo biodistribution of atezolizumab 24 hours after infusion is, in order of magnitude, the spleen, lungs, kidneys, liver, heart, and muscle. In tumor bearing animals, the drug also accumulates intratumorally, initially at the pushing border of the tumor and progressing later to the tumor core, particularly if the tumor is necrotic. The pharmacokinetic curve of atezolizumab is dose-dependent (non-linear) because of target mediated drug disposition (binding of drug to the PD-L1 ligand in the body). Saturation of PD-L1 receptors by atezolizumab on circulating CD4 and CD8 T cells occurs between 24 and 48 hours after dosing with serum concentrations > 0.5 μg/mL. MPDL3280A binds to PD-L1 in monkey and human with comparable affinity between species.
|Cell lines||DCCIKs lymphocytes|
|Preparation method||The in vitro cytotoxicity of the DCCIKs used as effector cells in the absence or presence of 5 μg/mL MPDL3280A against CaSki cells employed as target cells at a ratio of 10:1, 30:1 and 90:1 was determined using a CCK8 kit. The effector and target cells were added to 96-well plates and incubated for 24 h. The groups comprising a mixture of cell types were the experimental groups, whereas the control groups contained only one cell type of the CaSki cells, DCCIKs or 1640 RPMI cultivating solution. The CCK8 assay was performed in triplicate and optical density (OD) was read at 570 nm.|
|Incubation time||24 h|
|Animal models||Cynomolgus monkeys|
|Formulation||20 mM his-acetate, 0.02% polysorbate 20, 240 mM sucrose, pH 5.5|
|Dosages||0.5, 5 and 20 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
PD-L1 Detection in Tumors Using [(64)Cu]Atezolizumab with PET.
Lesniak WG, et al. Bioconjug Chem. 2016 Sep 21;27(9):2103-10. PMID: 27458027.
Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.
Fehrenbacher L, et al. Lancet. 2016 Apr 30;387(10030):1837-46. PMID: 26970723.
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