Mechanism of Action of Atezolizumab
Atezolizumab is a humanized IgG1 monoclonal antibody that binds to programmed death-ligand 1 (PD-L1) and blocks its interactions with both PD-1 and B7.1 receptors, thereby releasing PD-L1/PD-1 mediated inhibition of the immune response and activating anti-tumor immunity without inducing antibody-dependent cellular cytotoxicity. 1
Core Mechanism
Atezolizumab is an Fc-engineered, humanized, non-glycosylated IgG1 kappa immunoglobulin with a molecular mass of 145 kDa that specifically targets PD-L1. 1
The drug blocks PD-L1 binding to both PD-1 receptors (found on T cells) and B7.1 receptors (found on T cells and antigen presenting cells), which normally suppress cytotoxic T-cell activity, T-cell proliferation, and cytokine production. 1
By inhibiting these interactions, atezolizumab releases the immunosuppressive signals within the tumor microenvironment and increases T-cell-mediated immunity against tumor cells. 1, 2
Distinguishing Features from Other Checkpoint Inhibitors
Atezolizumab is engineered with Fc modifications that eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), unlike avelumab which retains intact ADCC. 3
This Fc engineering distinguishes atezolizumab from anti-PD-1 agents (pembrolizumab and nivolumab), which target the PD-1 receptor directly rather than the PD-L1 ligand. 3
Atezolizumab's dual blockade of both PD-1 and B7.1 pathways provides broader immune checkpoint inhibition compared to anti-PD-1 antibodies that only block the PD-1 pathway. 1
Preclinical Evidence
In syngeneic mouse tumor models, blocking PD-L1 activity with atezolizumab resulted in decreased tumor growth through enhanced anti-tumor immune responses. 1
In mouse models of cancer, dual inhibition of the PD-1/PD-L1 and MAPK pathways suppresses tumor growth and improves tumor immunogenicity through increased antigen presentation and T cell infiltration and activation compared to targeted therapy alone. 1
Clinical Implications of Mechanism
PD-L1 expression on tumor cells and/or tumor-infiltrating immune cells contributes to inhibition of anti-tumor immune response, making atezolizumab's mechanism particularly relevant in tumors with high PD-L1 expression. 1
The mechanism does not induce antibody-dependent cellular cytotoxicity, which could be detrimental to T effector cell activation, making atezolizumab's approach more selective for immune restoration. 3, 1
Atezolizumab's binding to PD-L1 can be detected using radiolabeled [(64)Cu]atezolizumab with PET imaging, demonstrating specific accumulation in tumors with high PD-L1 expression. 4