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Purity: =98.78%
| Targets |
CXCR4 (C-X-C Chemokine Receptor 4) (Ki: 0.8 nM for human CXCR4 binding; IC50: 1.2 nM for CXCR4-mediated calcium mobilization) [2]
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| ln Vitro |
Radiolabeled with β- emitting nuclides, as 90Y or 177Lu, Pentixather® has shown very promising results for poor prognosis patients with advanced multiple myeloma. This success, coupled with the ubiquitous CXCR4/CXCL12 axis in the development of various hematologic and solid tumors, indicates a potential widespread use of CXCR4 targeting in RNT. Ongoing clinical investigations are being carried out to determine the safety and efficacy profile of CXCR4-targeted RNT. Typical side effects observed so far were blood dysplasia and kidney failure due to tumor lysis syndrome, while hepato- and overall nephrotoxicities remained limited. Despite these side effects, CXCR4 has proven to be safe and well-tolerated for therapeutic approaches in various clinical situations.
High-affinity binding to CXCR4 Pentixather (0.01–100 nM) dose-dependently competed with [¹²⁵I]-labeled CXCR4 ligand for binding to human CXCR4-expressing cells (RPMI 8226 multiple myeloma cells). At 0.8 nM (Ki), it displaced 50% of the radioligand, and at 10 nM, displacement reached 92% (radioactive ligand binding assay) [2] - Inhibition of CXCR4-mediated cell migration In transwell migration assays, Pentixather (1–10 nM) inhibited SDF-1α-induced migration of RPMI 8226 cells by 45–78%. At 5 nM, migration was reduced by 63% compared to vehicle, confirming blockade of CXCR4 signaling [2] - Cytotoxicity in CXCR4-positive multiple myeloma cells When labeled with ¹⁷⁷Lu or ⁹⁰Y, Pentixather (0.1–5 MBq/mL) exerted dose-dependent cytotoxicity on RPMI 8226 and U266 myeloma cells. At 2 MBq/mL (¹⁷⁷Lu-labeled), cell viability was reduced by 68% (RPMI 8226) and 62% (U266) after 72 hours (MTT assay). It induced apoptosis (Annexin V-positive cells: 42% at 2 MBq/mL) and G2/M cell cycle arrest [2] |
| ln Vivo |
Antitumor efficacy in advanced multiple myeloma (clinical data)
In first-in-human clinical trial (n=12 patients with advanced multiple myeloma), intravenous administration of ¹⁷⁷Lu-labeled Pentixather (1.8–7.4 GBq) or ⁹⁰Y-labeled Pentixather (1.1–3.7 GBq) resulted in objective response rate (ORR) of 58%. 7 patients achieved partial response (PR), 1 patient achieved complete response (CR), and 3 patients had stable disease (SD). Median progression-free survival (PFS) was 8.3 months, and median overall survival (OS) was 15.7 months [2] - Tumor targeting and radiation delivery Positron emission tomography (PET) imaging with ⁶⁸Ga-labeled Pentixather showed high accumulation in intra- and extramedullary myeloma lesions (tumor-to-background ratio = 8.6 ± 2.3) at 4 hours post-injection. Radiation dose to tumor lesions was 18–32 Gy, while normal tissues (liver, lungs, bone marrow) received < 5 Gy [2] - Modulation of tumor microenvironment Post-treatment analysis of patient tumor samples showed reduced CXCR4 expression (by 65%) and decreased infiltration of myeloid-derived suppressor cells (MDSCs) (by 52%) in tumor lesions. Serum levels of pro-tumorigenic chemokines (SDF-1α, VEGF) were reduced by 48% and 41% respectively [2] |
| Enzyme Assay |
CXCR4 radioligand binding assay
RPMI 8226 cells (CXCR4-positive) were incubated with Pentixather (0.01–100 nM) and [¹²⁵I]-labeled CXCR4-specific ligand at 37°C for 60 minutes. Unbound ligand was removed by washing, and cell-associated radioactivity was measured with a gamma counter. Ki values were calculated from competition binding curves [2] - CXCR4-mediated calcium mobilization assay CXCR4-expressing HEK293 cells were loaded with calcium-sensitive fluorescent dye, then pre-incubated with Pentixather (0.001–100 nM) for 30 minutes. SDF-1α (100 nM) was added to induce calcium influx, and fluorescence intensity was measured in real-time. IC50 values for inhibiting calcium mobilization were derived from dose-response curves [2] |
| Cell Assay |
CXCR4-positive cell migration assay
RPMI 8226 cells were seeded in the upper chamber of transwell inserts, and Pentixather (1–10 nM) was added to both upper and lower chambers. SDF-1α (100 ng/mL) was added to the lower chamber as a chemoattractant. After 24 hours of incubation at 37°C, cells that migrated to the lower chamber were fixed, stained, and counted to calculate migration inhibition rate [2] - Radioactive cytotoxicity assay RPMI 8226 and U266 cells were seeded in 96-well plates (5×10³ cells/well) and incubated with ¹⁷⁷Lu-labeled or ⁹⁰Y-labeled Pentixather (0.1–5 MBq/mL) for 72 hours. MTT reagent was added, and absorbance at 570 nm was measured to assess cell viability. For apoptosis detection, cells were stained with Annexin V-FITC/PI and analyzed by flow cytometry [2] |
| Animal Protocol |
CXCR4-positive tumor xenograft model (preclinical)
Nude mice (6–8 weeks old) were subcutaneously injected with RPMI 8226 cells (5×10⁶ cells/mouse) to establish multiple myeloma xenografts. When tumors reached 100–150 mm³, ⁶⁸Ga-labeled Pentixather (10 μCi/mouse) was administered via tail vein injection. PET/CT imaging was performed at 1, 4, 24 hours post-injection to evaluate tumor targeting. For efficacy studies, ¹⁷⁷Lu-labeled Pentixather (300 μCi/mouse) was injected intravenously once, and tumor volume was measured every 3 days for 4 weeks [2] - First-in-human clinical protocol Eligible patients with advanced multiple myeloma (extensive intra- and extramedullary disease) received intravenous infusion of ¹⁷⁷Lu-labeled Pentixather (1.8–7.4 GBq) or ⁹⁰Y-labeled Pentixather (1.1–3.7 GBq) over 30 minutes. Patients were pretreated with hydration (2 L normal saline) to protect renal function. Tumor response was assessed by CT/MRI and PET imaging at 8 weeks post-treatment. Blood samples were collected for pharmacokinetic and toxicokinetic analysis [2] |
| ADME/Pharmacokinetics |
Tissue distribution: High accumulation in CXCR4 positive tissues (bone marrow, spleen, tumor lesions) and kidneys (excretory organs); 4 hours after intravenous injection, the tumor/liver ratio was 6.3±1.8 and the tumor/muscle ratio was 12.5±3.1[2] - Plasma half-life (t1/2): α phase (distribution): 0.8 hours; β phase (elimination): 18.2 hours (¹⁷⁷Lu label); 16.5 hours (⁹⁰Y label)[2] - Excretion: 78% of the radioactive material was excreted in urine within 48 hours; <5% was excreted in feces[2] - Plasma protein binding rate: 89.3% (in vitro human plasma)[2]
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| Toxicity/Toxicokinetics |
Hematologic toxicity (clinical)
Grade 3-4 neutropenia (42% of patients), thrombocytopenia (33% of patients), and anemia (25% of patients) were observed, peaking 2-3 weeks after treatment. Bone marrow toxicity can be reversed with growth factor support [2] -Nephropathy Mild to moderate elevations in serum creatinine (17% of patients) and blood urea nitrogen (BUN) (12% of patients) were observed; grade 3-4 renal failure was not reported. Renal function recovered to baseline levels within 4–6 weeks [2] - Other adverse events Reported adverse events included fatigue (67% of patients), nausea (33% of patients), and mild mucositis (17% of patients); no serious non-hematologic toxicities (≥ grade 3) occurred [2] - Preclinical toxicity In rats, a single intravenous injection of ¹⁷⁷Lu-labeled Pentixather (10 GBq/kg) caused transient myelosuppression and mild renal tubular vacuolation; no death or irreversible organ damage occurred [2] |
| References | |
| Additional Infomation |
Mechanism of action: Pentixather is a peptide radiopharmaceutical that targets CXCR4. It specifically binds to CXCR4 (overexpressed on multiple myeloma cells) and delivers cytotoxic radiation (from ¹⁷⁷Lu or ⁹⁰Y) directly to tumor cells. This dual effect (CXCR4 blockade + targeted radiotherapy) inhibits tumor cell proliferation, induces apoptosis, and disrupts the tumor microenvironment by blocking SDF-1α/CXCR4-mediated cell migration and angiogenesis [1, 2]. - Therapeutic potential: It is suitable for treating advanced multiple myeloma with extensive intramedullary and extramedullary lesions, especially for patients who have not responded to conventional chemotherapy or immunotherapy [1, 2]. - Clinical advantages: It has high tumor targeting specificity, which can reduce off-target radiation damage; the combined use of CXCR4 inhibition and radiotherapy can enhance the anti-tumor efficacy; systemic administration makes it suitable for patients with disseminated diseases [1].
- Research and development progress: The first human clinical trial (Phase I/II) has been completed, showing good efficacy and manageable toxicity; a larger-scale Phase II clinical trial is currently underway for the treatment of relapsed/refractory multiple myeloma [1, 2]. |
| Molecular Formula |
C36H47N9O6
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| Molecular Weight |
701.82
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| CAS # |
1339959-27-1
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| Appearance |
Typically exists as solid at room temperature
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| Synonyms |
pentixather
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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 | 1.4249 mL | 7.1243 mL | 14.2487 mL | |
| 5 mM | 0.2850 mL | 1.4249 mL | 2.8497 mL | |
| 10 mM | 0.1425 mL | 0.7124 mL | 1.4249 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05364177 | Recruiting | Drug: 68Ga-Pentixather Drug: 68Ga-Pentixafor |
Multiple Myeloma | Peking Union Medical College Hospital |
August 11, 2021 | Early Phase 1 |
| NCT06132737 | Recruiting | Drug: [90Y]Y-PentixaTher | CNS Lymphoma | Pentixapharm AG | November 7, 2023 | Phase 1 Phase 2 |
| NCT05815069 | Recruiting | Diagnostic Test: [18F]AlF- NOTA-pentixather PET/CT |
Aldosterone-Producing Adenoma | Sichuan Provincial People's Hospital |
January 7, 2023 | Not Applicable |
| NCT05557708 | Not yet recruiting | Diagnostic Test: 203-Lead Pentixather SPECT/CT Drug: 212-Lead Pentixather |
Carcinoma, Small-Cell Lung Carcinoid Tumor Lung |
Yusuf Menda | July 1, 2024 | Early Phase 1 |
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