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Clin Transl Med 12.6 (2022): e901.PMID:35696531

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实验参考方法

Cell experiment [1]:
Cell lines	Human OS cell lines HOS and 143B
Preparation Method	Cells were cultured in high glucose Dulbecco’s modified Eagle’s medium supplemented with 10% fetal bovine serum and 1% penicillin streptomycin at 37℃.
Reaction Conditions	Different concentrations (0, 2.5, 5, 10, 20, and 40 μg/ml) of atezolizumab were applied to human OS cell lines HOS and 143B for 24 h.
Applications	Atezolizumab inhibits proliferation and induces immune independent apoptosis of osteosarcoma cells. The proliferation of HOS and 143B both were inhibited by atezolizumab in a dose-dependent manner. The IC₅₀ values of HOS and 143B were between 10-20 μg/ml.
Animal experiment [2]:
Animal models	male C57BL/6 mice (age, 8‑10 weeks old; weight, 20‑25 g)
Preparation Method	The sepsis model was generated using the cecal ligation and puncture (CLP) procedure. Mice were anesthetized by intraperiton- eal injection of 40 mg/kg pentobarbital sodium. an incision was made in the lower abdomen. The cecum was ligated in the middle, and the distal cecum was punctured right through using a 21‑gauge needle. Squeezed a small amount of stool into the abdominal cavity, and closed the abdominal incision layer by layer.
Dosage form	100 μg on days 1 and 4
Applications	Atezolizumab treatment reduces endotoxin levels and intestinal mucosal permeability as well as decreases ileum histological scores in septic mice. However, atezolizumab treatment increases the expression of tight junction proteins in the ileum during sepsis.
References: [1]. Liu Z, et al. Targeting autophagy enhances atezolizumab-induced mitochondria-related apoptosis in osteosarcoma. Cell Death Dis. 2021 Feb 8;12(2):164. [2]. Chen J, et al. Atezolizumab alleviates the immunosuppression induced by PD‑L1‑positive neutrophils and improves the survival of mice during sepsis. Mol Med Rep. 2021 Feb;23(2):144.

产品描述

Atezolizumab, a specific monoclonal antibody against PD-L1, can inhibit the combination between PD-L1 and PD-1. Therefore, it showed various promising effects, such as inhibiting the proliferation and induce immune-independent apoptosis of osteosarcoma cells and reducing immunosuppression caused by T lymphocyte apoptosis in various cancer types.^[1][2]

In vitro study indicated that atezolizumab could cause mitochondrial damage to induce the imbalance between oxidants and antioxidants and induce mitochondria-related apoptosis in OS cells by activating JNK pathway. Furthermore, atezolizumab induced autophagy, however, inhibition of autophagy enhances atezolizumab-induced apoptosis in osteosarcoma cells.^[2]

Study demonstrated that atezolizumab could suppress the proliferation of OS cells in vivo, and the suppression was further enhanced by the combination of CQ. Besides, atezolizumab promoted apoptosis of OS cells in vivo, and this phenomenon was exacerbated by the addition of CQ. Moreover, atezolizumab could increase the content of MDA while increasing the positive rate of ROS in OS.^[2]

References:
[1]. Chen J, et al. Atezolizumab alleviates the immunosuppression induced by PD?L1?positive neutrophils and improves the survival of mice during sepsis. Mol Med Rep. 2021 Feb;23(2):144.
[2]. Liu Z, et al. Targeting autophagy enhances atezolizumab-induced mitochondria- related apoptosis in osteosarcoma. Cell Death Dis. 2021 Feb 8;12(2):164.

Atezolizumab 是一种针对 PD-L1 的特异性单克隆抗体，可以抑制 PD-L1 和 PD-1 之间的结合。因此，它显示出多种有前途的作用，例如抑制骨肉瘤细胞的增殖和诱导免疫非依赖性细胞凋亡，以及减轻各种癌症类型中 T 淋巴细胞凋亡引起的免疫抑制。^[1][2]\n

体外研究表明，atezolizumab 可引起线粒体损伤，从而导致氧化剂和抗氧化剂之间的失衡，并通过激活 JNK 通路诱导 OS 细胞中线粒体相关的细胞凋亡。此外，atezolizumab 诱导自噬，然而，抑制自噬会增强 atezolizumab 诱导的骨肉瘤细胞凋亡。^[2]

研究表明，atezolizumab 可以抑制体内 OS 细胞的增殖，并且通过与 CQ 的组合进一步增强抑制作用。此外，atezolizumab 在体内促进 OS 细胞凋亡，而 CQ 的加入加剧了这种现象。此外，atezolizumab可增加MDA含量，同时提高OS中ROS的阳性率。^[2]

Chemical Properties

Cas No.	1380723-44-3	SDF
别名	阿特珠单抗; MPDL3280A
Canonical SMILES	[Atezolizumab]
分子式		分子量	144590.5
溶解度		储存条件	Store at -80°C
General tips	请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。
Shipping Condition	评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。

溶解性数据

制备储备液
		1 mg	5 mg	10 mg
	1 mM	0.0069 mL	0.0346 mL	0.0692 mL
	5 mM	0.0014 mL	0.0069 mL	0.0138 mL
	10 mM	0.0007 mL	0.0035 mL	0.0069 mL

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Research Update

Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma

N Engl J Med 2020 May 14;382(20):1894-1905.PMID:32402160DOI:10.1056/NEJMoa1915745.

Background: The combination of Atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma. Methods: In a global, open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either Atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The coprimary end points were overall survival and progression-free survival in the intention-to-treat population, as assessed at an independent review facility according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Results: The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent. Conclusions: In patients with unresectable hepatocellular carcinoma, Atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT03434379.).

Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma

J Hepatol 2022 Apr;76(4):862-873.PMID:34902530DOI:10.1016/j.jhep.2021.11.030.

Background & aims: IMbrave150 demonstrated that Atezolizumab plus bevacizumab led to significantly improved overall survival (OS) and progression-free survival (PFS) compared with sorafenib in patients with unresectable hepatocellular carcinoma at the primary analysis (after a median 8.6 months of follow-up). We present updated data after 12 months of additional follow-up. Methods: Patients with systemic treatment-naive, unresectable hepatocellular carcinoma were randomized 2:1 to receive 1,200 mg Atezolizumab plus 15 mg/kg bevacizumab intravenously every 3 weeks or 400 mg sorafenib orally twice daily in this open-label, phase III study. Co-primary endpoints were OS and PFS by independently assessed RECIST 1.1 in the intention-to-treat population. Secondary efficacy endpoints included objective response rates and exploratory subgroup efficacy analyses. This is a post hoc updated analysis of efficacy and safety. Results: From March 15, 2018, to January 30, 2019, 501 patients (intention-to-treat population) were randomly allocated to receive Atezolizumab plus bevacizumab (n = 336) or sorafenib (n = 165). On August 31, 2020, after a median 15.6 (range, 0-28.6) months of follow-up, the median OS was 19.2 months (95% CI 17.0-23.7) with Atezolizumab plus bevacizumab and 13.4 months (95% CI 11.4-16.9) with sorafenib (hazard ratio [HR] 0.66; 95% CI 0.52-0.85; descriptive p <0.001). The median PFS was 6.9 (95% CI 5.7-8.6) and 4.3 (95% CI 4.0-5.6) months in the respective treatment groups (HR 0.65; 95% CI 0.53-0.81; descriptive p < 0.001). Treatment-related grade 3/4 adverse events occurred in 143 (43%) of 329 and 72 (46%) of 156 safety-evaluable patients in the respective groups, and treatment-related grade 5 events occurred in 6 (2%) and 1 (<1%) patients. Conclusion: After longer follow-up, Atezolizumab plus bevacizumab maintained clinically meaningful survival benefits over sorafenib and had a safety profile consistent with the primary analysis. Gov identifier: NCT03434379. Lay summary: The primary analysis of IMbrave150 showed that Atezolizumab plus bevacizumab had significantly greater benefits than sorafenib in patients with advanced hepatocellular carcinoma, but survival data were not yet mature. At this updated analysis done 12 months later, median overall survival was 5.8 months longer with Atezolizumab plus bevacizumab than sorafenib, and the severity profile of treatment-related side effects remained similar. These updated results confirm Atezolizumab plus bevacizumab as the first-line standard of care for advanced hepatocellular carcinoma.

Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer

N Engl J Med 2018 Nov 29;379(22):2108-2121.PMID:30345906DOI:10.1056/NEJMoa1809615.

Background: Unresectable locally advanced or metastatic triple-negative (hormone-receptor-negative and human epidermal growth factor receptor 2 [HER2]-negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)-paclitaxel may enhance the anticancer activity of Atezolizumab. Methods: In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive Atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD-L1) expression at baseline (positive vs. negative). The two primary end points were progression-free survival (in the intention-to-treat population and PD-L1-positive subgroup) and overall survival (tested in the intention-to-treat population; if the finding was significant, then it would be tested in the PD-L1-positive subgroup). Results: Each group included 451 patients (median follow-up, 12.9 months). In the intention-to-treat analysis, the median progression-free survival was 7.2 months with Atezolizumab plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); among patients with PD-L1-positive tumors, the median progression-free survival was 7.5 months and 5.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention-to-treat analysis, the median overall survival was 21.3 months with Atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08); among patients with PD-L1-positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86). No new adverse effects were identified. Adverse events that led to the discontinuation of any agent occurred in 15.9% of the patients who received Atezolizumab plus nab-paclitaxel and in 8.2% of those who received placebo plus nab-paclitaxel. Conclusions: Atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in both the intention-to-treat population and the PD-L1-positive subgroup. Adverse events were consistent with the known safety profiles of each agent. (Funded by F. Hoffmann-La Roche/Genentech; IMpassion130 ClinicalTrials.gov number, NCT02425891 .).

Adjuvant Atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial

Lancet 2021 Oct 9;398(10308):1344-1357.PMID:34555333DOI:10.1016/S0140-6736(21)02098-5.

Background: Novel adjuvant strategies are needed to optimise outcomes after complete surgical resection in patients with early-stage non-small-cell lung cancer (NSCLC). We aimed to evaluate adjuvant Atezolizumab versus best supportive care after adjuvant platinum-based chemotherapy in these patients. Methods: IMpower010 was a randomised, multicentre, open-label, phase 3 study done at 227 sites in 22 countries and regions. Eligible patients were 18 years or older with completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system (7th edition). Patients were randomly assigned (1:1) by a permuted-block method (block size of four) to receive adjuvant Atezolizumab (1200 mg every 21 days; for 16 cycles or 1 year) or best supportive care (observation and regular scans for disease recurrence) after adjuvant platinum-based chemotherapy (one to four cycles). The primary endpoint, investigator-assessed disease-free survival, was tested hierarchically first in the stage II-IIIA population subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells (SP263), then all patients in the stage II-IIIA population, and finally the intention-to-treat (ITT) population (stage IB-IIIA). Safety was evaluated in all patients who were randomly assigned and received Atezolizumab or best supportive care. IMpower010 is registered with ClinicalTrials.gov, NCT02486718 (active, not recruiting). Findings: Between Oct 7, 2015, and Sept 19, 2018, 1280 patients were enrolled after complete resection. 1269 received adjuvant chemotherapy, of whom 1005 patients were eligible for randomisation to Atezolizumab (n=507) or best supportive care (n=498); 495 in each group received treatment. After a median follow-up of 32·2 months (IQR 27·4-38·3) in the stage II-IIIA population, Atezolizumab treatment improved disease-free survival compared with best supportive care in patients in the stage II-IIIA population whose tumours expressed PD-L1 on 1% or more of tumour cells (HR 0·66; 95% CI 0·50-0·88; p=0·0039) and in all patients in the stage II-IIIA population (0·79; 0·64-0·96; p=0·020). In the ITT population, HR for disease-free survival was 0·81 (0·67-0·99; p=0·040). Atezolizumab-related grade 3 and 4 adverse events occurred in 53 (11%) of 495 patients and grade 5 events in four patients (1%). Interpretation: IMpower010 showed a disease-free survival benefit with Atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II-IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC. Funding: F Hoffmann-La Roche and Genentech.

Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC

N Engl J Med 2020 Oct 1;383(14):1328-1339.PMID:32997907DOI:10.1056/NEJMoa1917346.

Background: The efficacy and safety of the anti-programmed death ligand 1 (PD-L1) monoclonal antibody Atezolizumab, as compared with those of platinum-based chemotherapy, as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression are not known. Methods: We conducted a randomized, open-label, phase 3 trial involving patients with metastatic nonsquamous or squamous NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells as assessed by the SP142 immunohistochemical assay. Patients were assigned in a 1:1 ratio to receive Atezolizumab or chemotherapy. Overall survival (primary end point) was tested hierarchically according to PD-L1 expression status among patients in the intention-to-treat population whose tumors were wild-type with respect to EGFR mutations or ALK translocations. Within the population with EGFR and ALK wild-type tumors, overall survival and progression-free survival were also prospectively assessed in subgroups defined according to findings on two PD-L1 assays as well as by blood-based tumor mutational burden. Results: Overall, 572 patients were enrolled. In the subgroup of patients with EGFR and ALK wild-type tumors who had the highest expression of PD-L1 (205 patients), the median overall survival was longer by 7.1 months in the Atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; hazard ratio for death, 0.59; P = 0.01). Among all the patients who could be evaluated for safety, adverse events occurred in 90.2% of the patients in the Atezolizumab group and in 94.7% of those in the chemotherapy group; grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the respective groups. Overall and progression-free survival favored Atezolizumab in the subgroups with a high blood-based tumor mutational burden. Conclusions: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. (Funded by F. Hoffmann-La Roche/Genentech; IMpower110 ClinicalTrials.gov number, NCT02409342.).

Atezolizumab (MPDL3280A)

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