atezolizumab

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Ligands
atezolizumab

GtoPdb Ligand ID: 7990

Synonyms: MPDL3280A | Tecentriq®

atezolizumab is an approved drug (FDA (2016), EMA (2017))

Comment: Atezolizumab (MPDL3280A) is a monoclonal antibody directed against programmed death-1 ligand-1 (PD-L1, aka CD274), an important immunopharmacological drug discovery target in immuno-oncology.
Peptide sequence and structural information for this antibody are available from its IMGT/mAb-db record. Peptide sequence analysis using the light chain variable region of atezolizumab provides a 100% match to sequence 21 from patent US8217149. An X-ray crystal structure of the PD-L1/atezolizumab complex has been submitted to the RCSB PDB (accession 5X8L) [3].

No information available.

No information available.

Summary of Clinical Use
In May 2016, the US FDA granted accelerated approval for atezolizumab as a therapy for locally advanced or metastatic urothelial carcinoma (UC), in patients whose disease has progressed during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum (Pt)-containing chemotherapy. As a result of the Phase 3 clinical trial NCT02008227 (which assessed MPDL3280A vs. docetaxel as a treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) unresponsive to Pt therapy) [5], FDA approval was granted in October 2016 for NSCLC that has progressed during or following Pt-containing chemotherapy, for tumours with EGFR or ALK gene abnormalities. Patients in NCT02008227 receiving atezolizumab lived 4.2 months longer than those treated with docetaxel chemotherapy. Across the EU, EMA marketing authorisation is in place for atezolizumab's use as a monotherapy in the same patient groups as indicated in the FDA approvals. In December 2018 the FDA approved a combination therapy that combines atezolizumab, bevacizumab, paclitaxel, and carboplatin as a first-line treatment for metastatic non-squamous NSCLC tumours that harbour no EGFR or ALK genomic abnormalities. This was based on results from NCT02366143 [6]. FDA approval was further expanded in March 2019 to include a combination of atezolizumab plus carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage SCLC, based on results from the IMpower133 trial (NCT02763579) [1]. FDA approval for BRAF^V600 unresectable or metastatic melanoma was granted in July 2020.

Summary of Clinical Use

In May 2016, the US FDA granted accelerated approval for atezolizumab as a therapy for locally advanced or metastatic urothelial carcinoma (UC), in patients whose disease has progressed during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum (Pt)-containing chemotherapy.
As a result of the Phase 3 clinical trial NCT02008227 (which assessed MPDL3280A vs. docetaxel as a treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) unresponsive to Pt therapy) [5], FDA approval was granted in October 2016 for NSCLC that has progressed during or following Pt-containing chemotherapy, for tumours with EGFR or ALK gene abnormalities. Patients in NCT02008227 receiving atezolizumab lived 4.2 months longer than those treated with docetaxel chemotherapy. Across the EU, EMA marketing authorisation is in place for atezolizumab's use as a monotherapy in the same patient groups as indicated in the FDA approvals.
In December 2018 the FDA approved a combination therapy that combines atezolizumab, bevacizumab, paclitaxel, and carboplatin as a first-line treatment for metastatic non-squamous NSCLC tumours that harbour no EGFR or ALK genomic abnormalities. This was based on results from NCT02366143 [6].
FDA approval was further expanded in March 2019 to include a combination of atezolizumab plus carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage SCLC, based on results from the IMpower133 trial (NCT02763579) [1].
FDA approval for BRAF^V600 unresectable or metastatic melanoma was granted in July 2020.

Mechanism Of Action and Pharmacodynamic Effects
MPDL3280A binds to PD-L1 and inhibits its binding to its receptor, PD-1 (programmed death 1) which acts as a negative regulator of the immune system, limiting the expansion and survival of CD8+ T cells. As PD-L1 is overexpressed on many human cancer cell types the PD-L1/PD-1 mechanism effects immune evasion by tumour cells. MPDL3280A inhibits activation of PD-1, thereby reversing the PD-1 effect on T-cell inactivation and enhances the T-cell-mediated immune response to neoplasms. The Fc region of MPDL3280A is modified so that it does not induce either antibody-dependent cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).

Mechanism Of Action and Pharmacodynamic Effects

MPDL3280A binds to PD-L1 and inhibits its binding to its receptor, PD-1 (programmed death 1) which acts as a negative regulator of the immune system, limiting the expansion and survival of CD8+ T cells. As PD-L1 is overexpressed on many human cancer cell types the PD-L1/PD-1 mechanism effects immune evasion by tumour cells. MPDL3280A inhibits activation of PD-1, thereby reversing the PD-1 effect on T-cell inactivation and enhances the T-cell-mediated immune response to neoplasms. The Fc region of MPDL3280A is modified so that it does not induce either antibody-dependent cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).

Clinical Trials
Clinical Trial ID	Title	Type	Source	Comment	References
NCT02008227	A Study of Atezolizumab Compared With Docetaxel in Participants With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Who Have Failed Platinum-Containing Therapy	Phase 3 Interventional	Hoffmann-La Roche
NCT02366143	A Study of Atezolizumab in Combination With Carboplatin Plus (+) Paclitaxel With or Without Bevacizumab Compared With Carboplatin+Paclitaxel+Bevacizumab in Participants With Stage IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC)	Phase 3 Interventional	Hoffmann-La Roche
NCT02763579	A Study of Carboplatin Plus Etoposide With or Without Atezolizumab in Participants With Untreated Extensive-Stage (ES) Small Cell Lung Cancer (SCLC)	Phase 3 Interventional	Hoffmann-La Roche