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Apoptosis PD-1/PD-L1 Nivolumab (anti-PD-1)

Nivolumab (anti-PD-1)

Catalog No. T9907   CAS 946414-94-4
Synonyms: Nivolumab, anti-PD-1, BMS-936558, ONO-4538, MDX-1106
Purity 99.9% Datasheet

Nivolumab (anti-PD-1) is a genetically engineered, fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1(PD-1,PCD-1) with immune checkpoint inhibitory and antineoplastic activities.

Nivolumab (anti-PD-1), CAS 946414-94-4
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Purity 99.9%
Biological Description
Chemical Properties
Storage & Solubility Information
Description Nivolumab (anti-PD-1) is a genetically engineered, fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1(PD-1,PCD-1) with immune checkpoint inhibitory and antineoplastic activities.
Targets&IC50 PD-1/PD-L1 interaction,  
In vivo Nivolumab (anti-human PD-1) is well tolerated, dose-limiting toxicities (DLTs) were not reached and the maximum tolerable dose (MTD) was not defined in patients with advanced stage solid tumors. The measured half-life of nivolumab was 12-20 days, the pharmacodynamic effects of PD-1 receptor occupancy was even more prolonged at 85 days, indicating the biological durability of this high-affinity mAb[1]. In monkeys, serum nivolumab has a relatively slow clearance with limited extra vascular distribution, as demonstrated by a Vss value consistent with plasma volume. Mean apparent terminal elimination half-life estimates for males and females at 1 mg/kg were similar (124 and 139 hours, respectively), and the mean half-life estimate for males at 10 mg/kg was 261 hours. Although nivolumab seems to lack toxicity in monkeys, toxicities have been observed in human clinical trials. In a phase I trial, nivolumab had a favorable safety profile. Adverse events were generally similar to those observed with ipilimumab, although with lower incidence and of less severity, and comprised gastrointestinal, endocrine, and skin toxicities, and pulmonary inflammation. Interestingly, pneumonitis has been observed in PD-1-deficient mice bred onto the MRL genetic background, but not in PD-1-deficient mice with other genetic backgrounds[2].
Cell Research
Mixed lymphocyte response assays were performed by co-culturing 1×105 cells CD4+ T cells with allogeneic monocyte-derived dendritic cells (DC) at a ratio of 10:1 (T:DC) in flat-bottom 96-well microtiter plates. CD4+ T cells and DC were incubated for 6 days in the presence or absence of nivolumab titrated 1:10 from 50 mg/mL to 5 ng/mL along with ipilimumab at 0, 5, or 50 μg/mL. Culture supernatants were harvested on day 5 for ELISA analysis of IFN-γ secretion.
Cell lines: Monocyte-derived DC and CD4+ T cells
Animal Research
Rag2-/-IL2Rgnull mice (humanized mice) were injected with 1×107 human PBMCs intraperitoneally (i.p.) and a total of 3.5×106 HT29 human colon carcinoma cells subcutaneously Dosages: 200 μg per injection
Animal Model: Rag2-/-IL2Rgnull mice

Description

Nivolumab (anti-PD-1) is a genetically engineered, fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed death-1(PD-1,PCD-1) with immune checkpoint inhibitory and antineoplastic activities.

Targets&IC50

PD-1/PD-L1 interaction

In Vitro

Nivolumab (anti-human PD-1) binds PD-1 with high affinity (KD 2.6 nmol/l by Scatchard analysis to polyclonally activated human T cells) and blocks its interactions with both B7-H1 and B7-DC[1]. It effectively inhibits the interaction between PD-1 and its ligands. In vitro assays demonstrated the ability of nivolumab to potently enhance T-cell responses and cytokine production in the mixed lymphocyte reaction and superantigen or cytomegalovirus stimulation assays. Nivolumab inhibits 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, as shown by surface plasmon resonance. In a study using FACS to evaluate ligand binding to PD-1 expressed on CHO cells, the IC50 values for nivolumab-mediated inhibition of PD-1 binding to PD-L1 or PD-L2 were similar (1.04 and 0.97 nmol/L, respectively). Nivolumab binds specifically to PD-1 and not to other immunoglobulin superfamily proteins, such as CD28, CTLA-4, ICOS, and BTLA. Nivolumab can, at very low concentrations (~1.5 ng/mL), enhance T-cell reactivity in the presence of a T-cell receptor stimulus. However, nivolumab had no stimulatory effect in the absence of antigen or T-cell receptor stimulus. Specifically, there was no significant release of inflammatory cytokines, including IFNγ, TNFα, IL-2, IL-4, IL-6, or IL-10, from unstimulated whole blood after coincubation with nivolumab. Nivolumab does not cause nonspecific lymphocyte activation[2].

In Vivo

Nivolumab (anti-human PD-1) is well tolerated, dose-limiting toxicities (DLTs) were not reached and the maximum tolerable dose (MTD) was not defined in patients with advanced stage solid tumors. The measured half-life of nivolumab was 12-20 days, the pharmacodynamic effects of PD-1 receptor occupancy was even more prolonged at 85 days, indicating the biological durability of this high-affinity mAb[1]. In monkeys, serum nivolumab has a relatively slow clearance with limited extra vascular distribution, as demonstrated by a Vss value consistent with plasma volume. Mean apparent terminal elimination half-life estimates for males and females at 1 mg/kg were similar (124 and 139 hours, respectively), and the mean half-life estimate for males at 10 mg/kg was 261 hours. Although nivolumab seems to lack toxicity in monkeys, toxicities have been observed in human clinical trials. In a phase I trial, nivolumab had a favorable safety profile. Adverse events were generally similar to those observed with ipilimumab, although with lower incidence and of less severity, and comprised gastrointestinal, endocrine, and skin toxicities, and pulmonary inflammation. Interestingly, pneumonitis has been observed in PD-1-deficient mice bred onto the MRL genetic background, but not in PD-1-deficient mice with other genetic backgrounds[2].

Cell Research

Mixed lymphocyte response assays were performed by co-culturing 1×105 cells CD4+ T cells with allogeneic monocyte-derived dendritic cells (DC) at a ratio of 10:1 (T:DC) in flat-bottom 96-well microtiter plates. CD4+ T cells and DC were incubated for 6 days in the presence or absence of nivolumab titrated 1:10 from 50 mg/mL to 5 ng/mL along with ipilimumab at 0, 5, or 50 μg/mL. Culture supernatants were harvested on day 5 for ELISA analysis of IFN-γ secretion.

Cell lines: Monocyte-derived DC and CD4+ T cells

Animal Research

Rag2-/-IL2Rgnull mice (humanized mice) were injected with 1×107 human PBMCs intraperitoneally (i.p.) and a total of 3.5×106 HT29 human colon carcinoma cells subcutaneously Dosages: 200 μg per injection

Animal Model: Rag2-/-IL2Rgnull mice

Synonyms Nivolumab, anti-PD-1, BMS-936558, ONO-4538, MDX-1106
Purity 99.9%
Appearance solid
Molecular Weight 146000.00
Formula
CAS No. 946414-94-4

Storage

-20℃ 3 years powder

-80℃ 2 years in solvent

Solubility Information

( < 1 mg/ml refers to the product slightly soluble or insoluble )

Citations

References and Literature
1. Sundar R, et al. Nivolumab in NSCLC: latest evidence and clinical potential. Ther Adv Med Oncol. 2015 Mar;7(2):85-96. 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 Immunology Research. 2014 Sep;2(9):846-56.

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