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| 1mg |
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| Targets |
Medium-affinity IL-2 receptor (IL-2Rβγ) and the IL-2 receptor alpha (IL-2Rα) subunit. Nemvaleukin alfa is a selective agonist of the medium-affinity IL-2 receptor. The fusion protein is composed of a circularly permuted IL-2 linked to the IL-2Rα subunit. This unique design allows Nemvaleukin alfa to preferentially bind to the intermediate-affinity IL-2 receptor (IL-2Rβγ) on NK cells and effector T cells, while avoiding high-affinity binding to the IL-2Rαβγ complex on regulatory T cells. By selectively activating the medium-affinity IL-2 receptor, Nemvaleukin alfa promotes the expansion and activation of cytotoxic lymphocytes without the unwanted expansion of immunosuppressive Tregs, thereby enhancing antitumor immunity.
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| ln Vitro |
In cynomolgus monkey and human samples, nemvaleukin alfa activates lymphocyte subsets with EC50s ranging from 0.45 to 2.2 nM[2]. On human cells (HH cells), nemvaleukin alfa (0-100 nM, 30 minutes) causes the activation of medium-affinity IL-2R [3]. With an EC50 of 0.45 nM, nemvaleukin alfa (0-100 nM, 30 minutes) activates pSTAT5 in NK cells [3]. Effector cells derived from human peripheral blood get activated in response to 0.5 nM nemvaleukin alfa administered over a 5-day period [3].
In vitro, Nemvaleukin alfa activates lymphocyte subsets in cynomolgus monkeys and human samples, with EC50 values ranging from 0.45 to 2.2 nM. At concentrations of 0-100 nM for 30 minutes, Nemvaleukin alfa induces activation of the medium-affinity IL-2 receptor on human cells (HH cells). Under the same conditions, Nemvaleukin alfa induces pSTAT5 expression in NK cells with an EC50 of 0.45 nM. Furthermore, when Nemvaleukin alfa is administered at a concentration of 0.5 nM for 5 days, it induces the activation of effector lymphocytes isolated from human peripheral blood. These results demonstrate the potent and selective activation of immune effector cells by Nemvaleukin alfa. |
| ln Vivo |
Mice's SCLC tumor growth is inhibited by nemvaleukin alfa (6 mg/kg, subcutaneous injection, once every 4 days)[1].
In vivo, Nemvaleukin alfa has been evaluated in mouse models of small cell lung cancer (SCLC). When administered subcutaneously at a dose of 6 mg/kg every 4 days, Nemvaleukin alfa significantly inhibits SCLC tumor growth. The antitumor activity of Nemvaleukin alfa is attributed to its selective activation of NK cells and effector T cells, which mediate tumor cell killing. In preclinical studies, Nemvaleukin alfa has demonstrated superior efficacy and reduced toxicity compared to recombinant IL-2, which is associated with significant systemic toxicity due to its broad activation of immune cells. Nemvaleukin alfa is being investigated in clinical trials for the treatment of various cancers, including melanoma, renal cell carcinoma, and non-small cell lung cancer. |
| Enzyme Assay |
The in vitro receptor binding assay for Nemvaleukin alfa typically involves surface plasmon resonance (SPR) or ELISA-based methods to measure the binding affinity of the fusion protein to the medium-affinity IL-2 receptor (IL-2Rβγ). In the SPR assay, the IL-2Rβγ complex is immobilized on a sensor chip, and varying concentrations of Nemvaleukin alfa are flowed over the surface to determine the equilibrium dissociation constant (Kd). The binding kinetics, including association rate (ka) and dissociation rate (kd), are calculated using appropriate mathematical models. Competition binding assays can be performed to confirm the selectivity of Nemvaleukin alfa for the medium-affinity IL-2 receptor over the high-affinity IL-2 receptor (IL-2Rαβγ).
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| Cell Assay |
In vitro cellular assays for Nemvaleukin alfa are performed using human peripheral blood mononuclear cells (PBMCs), NK cells, or T cells. Cells are treated with varying concentrations of Nemvaleukin alfa for 30 minutes to 5 days. The activation of lymphocytes is assessed by measuring the phosphorylation of STAT5 (pSTAT5) using flow cytometry or Western blotting. The proliferation and expansion of NK cells and effector T cells are measured by CFSE dilution or [³H]-thymidine incorporation. The activation of effector lymphocytes is assessed by measuring the expression of activation markers (CD25, CD69) and the production of cytokines (IFN-γ, perforin, granzyme B) by flow cytometry or ELISA.
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| Animal Protocol |
Animal/Disease Models: SCLC orthotopic model[1]
Doses: 6 mg/kg Route of Administration: sc, every 4 days Experimental Results: Delayed tumor growth and prolonged survival. Animal/Disease Models: Male cynomolgus monkeys (PK Assay)[2] Doses: 0.3 or 1 mg /kg Route of Administration: iv or sc Experimental Results: pharmacokinetic/PK profile of Nemvaleukin alfa. Dose Route dose (mg/kg) Cmax (ng/mL) Tmax (h) T1/2 (h) iv 0.3 6119 0.083 49.5 sc 0.3 549 8 61.9 sc 1 1035 8 37.3 In vivo animal experiments for Nemvaleukin alfa are conducted in mouse tumor models, particularly small cell lung cancer (SCLC) xenografts. Immunocompromised mice bearing SCLC tumors are administered Nemvaleukin alfa subcutaneously at a dose of 6 mg/kg every 4 days. Tumor growth is monitored by measuring tumor volumes with calipers. At the end of the experiment, tumors are excised for histopathological analysis, and immune cell infiltration is assessed by immunohistochemistry for NK cells and CD8+ T cells. The antitumor activity of Nemvaleukin alfa is calculated relative to vehicle-treated controls. |
| ADME/Pharmacokinetics |
Nemvaleukin alfa exhibits pharmacokinetic properties consistent with other IL-2 fusion proteins. Following subcutaneous administration, the fusion protein displays sustained release and a relatively long half-life compared to recombinant IL-2. The volume of distribution is consistent with the extracellular space, and clearance is primarily mediated by receptor-mediated endocytosis and proteolytic degradation. Bioavailability following subcutaneous administration is estimated to be approximately 60-80%. The pharmacokinetic profile of Nemvaleukin alfa supports dosing intervals of every 4-7 days in preclinical studies.
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| Toxicity/Toxicokinetics |
In preclinical toxicology studies, Nemvaleukin alfa has demonstrated an improved safety profile compared to recombinant IL-2. The selective activation of the medium-affinity IL-2 receptor reduces the systemic toxicity associated with high-affinity IL-2 receptor activation, including vascular leak syndrome and cytokine release syndrome. In animal models, Nemvaleukin alfa is well-tolerated at doses that achieve therapeutic efficacy. In clinical trials, Nemvaleukin alfa has been generally well-tolerated, with adverse events being mild to moderate in severity. Common adverse events include fatigue, injection site reactions, and transient cytokine-related symptoms.
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| References |
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| Additional Infomation |
Nemvaleukin alfa (ALKS 4230) is an IL-2 fusion protein that acts as a selective agonist of the medium-affinity IL-2 receptor. It is produced by fusing a circularly permuted IL-2 with the IL-2Rα subunit. Nemvaleukin alfa selectively activates NK cells and effector T cells while minimizing the expansion of regulatory T cells. It drives antitumor immunity and inhibits tumor growth in small cell lung cancer. Nemvaleukin alfa is being investigated in clinical trials for the treatment of various cancers, including melanoma, renal cell carcinoma, and non-small cell lung cancer. Nemvaleukin alfa is not approved by any regulatory authority and is intended for research purposes only.
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| CAS # |
2315268-27-8
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| Appearance |
Colorless to light yellow liquid
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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