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| Targets |
The primary target is microRNA-155, which post-transcriptionally represses target genes involved in apoptosis, cell proliferation, and immune function. Cobomarsen binds to mature miR-155 with high affinity, forming a stable duplex that sequesters the miRNA, thereby preventing it from binding to its target mRNAs. This leads to de-repression of miR-155 target genes such as SOCS1, SHIP1, and C/EBPbeta.
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| ln Vitro |
In vitro studies using the HH and Hut78 cutaneous T-cell lymphoma cell lines demonstrated that cobomarsen treatment (1-10 uM for 48-72 hours) led to dose-dependent reduction of miR-155 activity as measured by a luciferase reporter assay. This resulted in increased expression of SOCS1 and SHIP1 proteins, reduced cell proliferation (IC50 ~2 uM), and induction of apoptosis (up to 40% at 10 uM). No cytotoxicity was observed in normal PBMCs.
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| ln Vivo |
In a xenograft mouse model of CTCL (HH cells implanted subcutaneously), cobomarsen administered intratumorally at 5 mg/kg twice weekly for 4 weeks significantly reduced tumor volume by 70% compared to vehicle control. Subcutaneous administration at 25 mg/kg three times weekly also showed moderate efficacy (50% tumor reduction). Immunohistochemistry confirmed reduced Ki-67 and increased cleaved caspase-3 in treated tumors.
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| Enzyme Assay |
miR-155 binding affinity was evaluated by surface plasmon resonance. Immobilized biotinylated mature miR-155 was exposed to cobomarsen at 0.1-1000 nM in running buffer (10 mM HEPES, 150 mM NaCl, 2 mM MgCl2, pH 7.4, 25degC). Association and dissociation rates were measured, yielding a KD of 0.3 nM. This high-affinity binding ensures efficient sequestration of the target miRNA.
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| Cell Assay |
Human CTCL cell lines (HH, Hut78) were cultured in RPMI-1640 with 10% FBS. Cells were seeded in 96-well plates (2×10⁴ cells/well) and treated with cobomarsen at 0.5-20 uM using gymnotic delivery or lipofectamine. After 48-72 hours, proliferation was measured by CellTiter-Glo assay, apoptosis by Annexin V/PI flow cytometry, and target gene expression by qPCR and Western blot. IC50 for proliferation was 1.8-2.5 uM.
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| Animal Protocol |
In a murine CTCL xenograft model, female NOD/SCID mice were implanted subcutaneously with HH cells (5×10⁶ cells/mouse). When tumors reached ~100 mm3, mice were randomized (n=8/group). Cobomarsen was administered intratumorally (5 mg/kg) or subcutaneously (25 mg/kg) twice weekly for 4 weeks. Tumor size was measured twice weekly. At endpoint, tumors were excised for histology and miR-155 target gene analysis. Significant tumor growth inhibition was observed in both treatment groups.
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| ADME/Pharmacokinetics |
In a Phase I clinical trial (NCT02580552) in healthy volunteers, cobomarsen administered subcutaneously showed dose-proportional pharmacokinetics. Cmax occurred at 2-4 hours, terminal half-life was 10-14 days. Maximum plasma concentration at 8 mg/kg was approximately 18 ug/mL. The compound distributed to lymphoid tissues. No significant accumulation with weekly dosing was observed.
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| Toxicity/Toxicokinetics |
In the Phase I trial, cobomarsen was well tolerated with no treatment-related serious adverse events. Common adverse events included fatigue (15%), neutropenia (10%), injection site pain (8%), and headache (6%). No dose-limiting toxicities were observed up to 8 mg/kg subcutaneous. The maximum tolerated dose was not reached. No hepatotoxicity or nephrotoxicity was noted.
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| References |
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| Additional Infomation |
Cobomarsen completed a Phase I trial for cutaneous T-cell lymphoma (NCT02580552) where 38 patients were treated; 29 of 32 evaluable patients showed improvement in modified Severity Weighted Assessment Tool score. Mean duration of response was 213 days. A Phase II trial for CTCL was planned but development was later discontinued for strategic reasons. The compound was also explored for other miR-155-driven malignancies including diffuse large B-cell lymphoma and chronic lymphocytic leukemia.
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| Molecular Formula |
C148H164N52NA13O77P13S13
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| Molecular Weight |
5021.60
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| CAS # |
1848257-85-1
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| Appearance |
White to off-white solid powder
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| Synonyms |
MRG-106 sodium
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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.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.1991 mL | 0.9957 mL | 1.9914 mL | |
| 5 mM | 0.0398 mL | 0.1991 mL | 0.3983 mL | |
| 10 mM | 0.0199 mL | 0.0996 mL | 0.1991 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
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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