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Nivolumab (BMS-936558)

目录号 GC34218

Nivolumab, an anti-cancer monoclonal antibody, is a programmed death receptor-1 blocking human IgG4 antibody to treat advanced (metastatic) non-small cell lung cancer.

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实验参考方法

Cell experiment [1]:

Cell lines

MCF7 human breast cancer cell line

Preparation Method

Various concentrations of nivolumab (0, 2, 4, 8, 16, and 32 nM) and OCT4&SOX2 CTLs with an effector-target ratio of 20:1 were used to treat MCF7 BCSCs for 24 h; cell proliferation was detected busing the CCK-8 assay.

Reaction Conditions

0, 2, 4, 8, 16, and 32 nM; 24 h

Applications

Nivolumab improved the cytotoxic activity of OCT4&SOX2 CTLs against MCF7 BCSCs in a dose-dependent manner by the CCK-8 assay.

Animal experiment [2]:

Animal models

cynomolgus macaques

Preparation Method

In a single-dose pharmacokinetic study, cynomolgus monkeys (Macaca fascicularis) received i.v. nivolumab, 1 mg/kg (3 males and 3 females) or 10 mg/kg (3 males).

Dosage form

1 mg/kg or 10 mg/kg; i.v.

Applications

Single, i.v. administration of nivolumab to cynomolgus monkeys at 1 and 10 mg/kg was well tolerated with no effects on body weight or clinical observations.

References:

[1]. Peng W, et al. OCT4 and SOX2 Specific Cytotoxic T Cells Exhibit Not Only Good Efficiency but Also Synergize PD-1 Inhibitor (Nivolumab) in Treating Breast Cancer Stem-Like Cells and Drug-Resistant Breast Cancer Mice. Front Oncol. 2022 Mar 24;12:781093.

[2]. Wang C, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res. 2014 Sep;2(9):846-56.

产品描述

Nivolumab, an anti-cancer monoclonal antibody, is a programmed death receptor-1 blocking human IgG4 antibody to treat advanced (metastatic) non-small cell lung cancer.[1]

In vitro efficacy test it shown that Nivolumab bound to CHO cells expressing PD-1 with an EC50 of 1.66 nmol/L and bound to PD-1 on activated T cells with an EC50 of 0.64 nmol/L. In the meanwhile, Nivolumab can inhibit the interaction between PD-1 and its ligands, PD-L1 and PD-L2, with IC50 values of 2.52 and 2.59 nmol/L, respectively. In vitro, at 1.5 ng/mL concentrations of nivolumab enhances T-cell reactivity in the presence of a T-cell receptor stimulus.[1]

In vivo study it indicated that mice were treated with 50 mg/kg nivolumab, there were no changes in T3, T4, or TSH levels. After administration of 10 mg/kg and 50 mg/kg nivolumab in cynomolgus monkeys, the results shown that there were dramatically more CD8+ effector memory T cells in the 50 mg/kg group than in the 10 mg/kg and untreated groups and Naïve T-cell populations were decreased in the 50 mg/kg group.[1] In vivo, Nivolumab treatment (30 mg/kg, i.p.) inhibits growth of the TNBC MDA-MB-231 cell line in hu-CB-BRGS mice.[3] BLT-NOG-EXL mice treated with either saline, 2.5, 5, or 10 mg/kg of nivolumab i.p. for 28 days, the results demonstrated a dose-dependent relationship in mortality.[4] In vivo test it suggested that anti-PD-1 treatment with Nivolumab (10 mg/kg, i.v.) diminishes morphine antinociception in wild-type mice.[5]

References:
[1].Wang C, et al. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res. 2014 Sep;2(9):846-56.
[2].Ramos-Levi AM, et al. Nivolumab-induced thyroid dysfunction in patients with lung cancer. Endocrinol Diabetes Nutr (Engl Ed). 2019 Jan;66(1):26-34. English, Spanish.
[3].Capasso A, et al. Characterization of immune responses to anti-PD-1 mono and combination immunotherapy in hematopoietic humanized mice implanted with tumor xenografts. J Immunother Cancer. 2019 Feb 8;7(1):37.
[4].Weaver JL, et al. BLT-Immune Humanized Mice as a Model for Nivolumab-Induced Immune-Mediated Adverse Events: Comparison of the NOG and NOG-EXL Strains. Toxicol Sci. 2019 May 1;169(1):194-208.
[5].Wang Z, et al. Anti-PD-1 treatment impairs opioid antinociception in rodents and nonhuman primates. Sci Transl Med. 2020 Feb 19;12(531):eaaw6471.

Chemical Properties

Cas No. 946414-94-4 SDF
别名 BMS-936558, ONO-4538, MDX-1106
化学名 N/A
Canonical SMILES [Nivolumab]
分子式 N/A 分子量 143599.09
溶解度 N/A 储存条件 Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

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Research Update

Nivolumab for the treatment of colorectal cancer

Expert Rev Anticancer Ther2018 Jul;18(7):611-618.PMID: 29792730DOI: 10.1080/14737140.2018.1480942

Despite a variety of therapies for advanced metastatic colorectal cancer being available, the outcomes in this malignancy remain suboptimal. Immunotherapy has been slow to impact the management of this patient group. Checkpoint inhibitors, such as nivolumab, have had disappointing results when used broadly. However, for the subset of patients with microsatellite unstable colorectal cancer, the use of checkpoint inhibitors such as nivolumab appears to be transformative, and will provide a new therapeutic option for patient with advanced disease. Areas covered: Nivolumab gained regulatory approval for the treatment of dMMR/MSI-H metastatic colorectal cancer in mid 2017. The current review will summarize the clinical evidence of checkpoint inhibitors in metastatic colorectal cancer, with a focus on nivolumab. Expert commentary: For patients with dMMR/MSI-H mCRC, the use of nivolumab has now been shown to have objective and sustained clinical responses in a pivotal phase II trial. While additional data are limited, the therapeutic role for augmenting an immune response in metastatic colorectal cancer is likely to continue to expand. Further combination trials of nivolumab with immunologic and non-immunologic agents are ongoing.

Nivolumab for the treatment of hepatocellular carcinoma

Expert Rev Anticancer Ther2018 Dec;18(12):1169-1175.PMID: 30304963DOI: 10.1080/14737140.2018.1535315

T-cell checkpoint inhibition as a cancer treatment approach has been the main breakthrough in cancer treatment during the last years. Since the approval of the first commercial CTLA-4 antibody ipilimumab in 2011 for the treatment of melanoma, research and drug development in this field has accelerated massively. In 2014, the US Food and Drug Administration (FDA) approved the first PD-1 targeting agent, namely pembrolizumab, shortly followed by nivolumab. Areas covered: Nivolumab is a fully human immunoglobulin G4 anti-PD-1 monoclonal antibody which is approved for multiple advanced malignancies, including melanoma, non-small cell lung cancer, renal cell cancer, Hodgkin's lymphoma, squamous head and neck cancer, and urothelial carcinoma. In September 2017, nivolumab was approved by the FDA for liver cancer as a second line treatment after failure of sorafenib based on the data of the multi-cohort phase 1/2 trial CheckMate-040. This article reviews the concept of immunotherapy in liver cancer with focus on nivolumab. Expert commentary: Immunotherapy in hepatocellular carcinoma is safe and is a new treatment option for patients with advanced stage disease besides sorafenib and regorafenib in the US. Randomized phase III trials of nivolumab, pembrolizumab, atezolizumab, durvalumab and tislelizumab as mono- or combination-therapy are ongoing.

Checkpoint immunotherapy by nivolumab for treatment of metastatic melanoma

J Cancer Res Ther2018 Oct-Dec;14(6):1167-1175.PMID: 30488824DOI: 10.4103/jcrt.JCRT_1290_16

Clinical management of metastatic melanoma suffered historically from a lack of effective targeted and immunotherapies due to short-lived clinical responses. Recent advances in our understanding of tumor-immune signaling pathways, discovery of immunosuppressive checkpoints, and subsequent development of antibodies that target these checkpoints reverses the situation to some extent. Two antibodies ipilimumab and nivolumab gained Food and Drug administration approval for the treatment of metastatic melanoma and target two major immunosuppressive checkpoints cytotoxic T lymphocyte antigen and programmed cell death protein 1 (PD-1), respectively. Nivolumab binds to PD-1, prevents PD-1 interaction with ligand Programmed death ligand 1 (PD-L1), and thus releases the T-cell exhaustion events (such as T cell apoptosis, decrease in T cell proliferation, etc.) leading to buildup of potent tumor-specific immune response. Successful Phase I-III results with remarkable antitumor activity and safety led to approval of nivolumab against ipilimumab refractory metastatic melanoma. Nivolumab therapy is exciting in that it not only provides substantial benefit but also provides durable responses. This review focuses on the evolution of immunotherapy leading to nivolumab approval and its potential in treating melanoma either alone or in combination with other therapies.

Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression

Oral Oncol2018 Jun;81:45-51.PMID: 29884413DOI: 10.1016/j.oraloncology.2018.04.008

Objectives: We report 2-year results from CheckMate 141 to establish the long-term efficacy and safety profile of nivolumab and outcomes by tumor PD-L1 expression in patients with recurrent or metastatic (R/M),platinum-refractory squamous cell carcinoma of the head and neck (SCCHN).
Methods: Patients with R/M SCCHN with tumor progression/recurrence within 6 months of platinum therapy were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks or investigator's choice (IC). Primary endpoint: overall survival (OS). Data cutoff: September 2017.
Results: With 24.2 months' minimum follow-up, nivolumab (n = 240) continued to improve OS vs IC (n = 121), hazard ratio (HR) = 0.68 (95% CI 0.54-0.86). Nivolumab nearly tripled the estimated 24-month OS rate (16.9%) vs IC (6.0%), and demonstrated OS benefit across patients with tumor PD-L1 expression ≥1% (HR [95% CI] = 0.55 [0.39-0.78]) and < 1% (HR [95% CI] = 0.73 [0.49-1.09]), and regardless of tumor HPV status. Estimated OS rates at 18, 24, and 30 months with nivolumab were consistent irrespective of PD-L1 expression (<1%/≥1%). In the nivolumab arm, there were no observed differences in baseline characteristics or safety profile between long-term survivors and the overall population. Grade 3-4 treatment-related adverse event rates were 15.3% and 36.9% for nivolumab and IC, respectively.
Conclusion: Nivolumab significantly improved OS at the primary analysis and demonstrated prolonged OS benefit vs IC and maintenance of a manageable and consistent safety profile with 2-year follow-up. OS benefit was observed with nivolumab irrespective of PD-L1 expression and HPV status. (Clinicaltrials.gov: NCT02105636).

Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer

J Immunother Cancer2020 Sep;8(2):e001282.PMID: 32929052DOI: 10.1136/jitc-2020-001282

Background: We conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab.
Methods: Patients with resectable stage IB (≥4 cm)-IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint.
Results: While the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations.
Conclusions: Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.