Balixafortide (POL6326)
目录号 : GC25120Balixafortide (POL6326) is an orally bioavailable peptidic CXC chemokine receptor 4 (CXCR4) antagonist
Cas No.:1051366-32-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
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Balixafortide (POL6326) is an orally bioavailable peptidic CXC chemokine receptor 4 (CXCR4) antagonist.
POL6326 enhances systolic function in a porcine closed-chest model of reperfused acute MI. POL6326 mobilizes Treg cells, enhances Treg cell recruitment to the infarct, attenuates tumor necrosis factor expression in monocytes and macrophages in the infarcted region, enhances infarct border-zone capillarization, reduces infarct scar size, and attenuates LV remodeling and systolic dysfunction in mice.[2]
[1] Darja Karpova, et al. J Transl Med. 2017 Jan 3;15(1):2. [2] Yong Wang, et al. Circulation. 2019 Apr 9;139(15):1798-1812.
| Cas No. | 1051366-32-5 | SDF | Download SDF |
| 分子式 | C84H118N24O21S2 | 分子量 | 1864.11 |
| 溶解度 | Water: 100 mg/mL (53.64 mM); | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 0.5364 mL | 2.6822 mL | 5.3645 mL |
| 5 mM | 0.1073 mL | 0.5364 mL | 1.0729 mL |
| 10 mM | 0.0536 mL | 0.2682 mL | 0.5364 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Clinical significance of chemokine receptor antagonists
Expert Opin Drug Metab Toxicol 2020 Jan;16(1):11-30.PMID:31903790DOI:10.1080/17425255.2020.1711884.
Introduction: Chemokine receptors are important therapeutic targets for the treatment of many human diseases. This study will provide an overview of approved chemokine receptor antagonists and promising candidates in advanced clinical trials.Areas covered: We will describe clinical aspects of chemokine receptor antagonists regarding their clinical efficacy, mechanisms of action, and re-purposed applications.Expert opinion: Three chemokine antagonists have been approved: (i) plerixafor is a small-molecule CXCR4 antagonist that mobilizes hematopoietic stem cells; (ii) maraviroc is a small-molecule CCR5 antagonist for anti-HIV treatment; and (iii) mogamulizumab is a monoclonal-antibody CCR4 antagonist for the treatment of mycosis fungoides or Sézary syndrome. Moreover, phase 3 trials are ongoing to evaluate many potent candidates, including CCR5 antagonists (e.g. leronlimab), dual CCR2/CCR5 antagonists (e.g. cenicriviroc), and CXCR4 antagonists (e.g. Balixafortide, mavorixafor, motixafortide). The success of chemokine receptor antagonists depends on the selective blockage of disease-relevant chemokine receptors which are indispensable for disease progression. Although clinical translation has been slow, antagonists targeting chemokine receptors with multifaced functions offer the potential to treat a broad spectrum of human diseases.
At the Bedside: Profiling and treating patients with CXCR4-expressing cancers
J Leukoc Biol 2021 May;109(5):953-967.PMID:33089889DOI:10.1002/JLB.5BT1219-714R.
The chemokine receptor, C-X-C chemokine receptor type 4 (CXCR4) and its ligand, C-X-C motif chemokine 12, are key mediators of hematopoietic cell trafficking. Their roles in the proliferation and metastasis of tumor cells, induction of angiogenesis, and invasive tumor growth have been recognized for over 2 decades. CXCR4 is a promising target for imaging and therapy of both hematologic and solid tumors. To date, Sanofi Genzyme's plerixafor is the only marketed CXCR4 inhibitor (i.e., Food and Drug Administration-approved in 2008 for stem cell mobilization). However, several new CXCR4 inhibitors are now being investigated as potential therapies for a variety of fluid and solid tumors. These small molecules, peptides, and Abs include Balixafortide (POL6326, Polyphor), mavorixafor (X4P-001, X4 Pharmaceuticals), motixafortide (BL-8040, BioLineRx), LY2510924 (Eli Lilly), and ulocuplumab (Bristol-Myers Squibb). Early clinical evidence has been encouraging, for example, with motixafortide and Balixafortide, and the CXCR4 inhibitors appear to be generally safe and well tolerated. Molecular imaging is increasingly being used for effective patient selection before, or early during CXCR4 inhibitor treatment. The use of radiolabeled theranostics that combine diagnostics and therapeutics is an additional intriguing approach. The current status and future directions for radioimaging and treating patients with CXCR4-expressing hematologic and solid malignancies are reviewed. See related review - At the Bench: Pre-Clinical Evidence for Multiple Functions of CXCR4 in Cancer. J. Leukoc. Biol. xx: xx-xx; 2020.
Mobilization of hematopoietic stem cells with the novel CXCR4 antagonist POL6326 (Balixafortide) in healthy volunteers-results of a dose escalation trial
J Transl Med 2017 Jan 3;15(1):2.PMID:28049490DOI:10.1186/s12967-016-1107-2.
Background: Certain disadvantages of the standard hematopoietic stem and progenitor cell (HSPC) mobilizing agent G-CSF fuel the quest for alternatives. We herein report results of a Phase I dose escalation trial comparing mobilization with a peptidic CXCR4 antagonist POL6326 (Balixafortide) vs. G-CSF. Methods: Healthy male volunteer donors with a documented average mobilization response to G-CSF received, following ≥6 weeks wash-out, a 1-2 h infusion of 500-2500 µg/kg of Balixafortide. Safety, tolerability, pharmacokinetics and pharmacodynamics were assessed. Results: Balixafortide was well tolerated and rated favorably over G-CSF by subjects. At all doses tested Balixafortide mobilized HSPC. In the dose range between 1500 and 2500 µg/kg mobilization was similar, reaching 38.2 ± 2.8 CD34 + cells/µL (mean ± SEM). Balixafortide caused mixed leukocytosis in the mid-20 K/µL range. B-lymphocytosis was more pronounced, whereas neutrophilia and monocytosis were markedly less accentuated with Balixafortide compared to G-CSF. At the 24 h time point, leukocytes had largely normalized. Conclusions: Balixafortide is safe, well tolerated, and induces efficient mobilization of HSPCs in healthy male volunteers. Based on experience with current apheresis technology, the observed mobilization at doses ≥1500 µg/kg of Balixafortide is predicted to yield in a single apheresis a standard dose of 4× 10E6 CD34+ cells/kg from most individuals donating for an approximately weight-matched recipient. Exploration of alternative dosing regimens may provide even higher mobilization responses. Trial Registration European Medicines Agency (EudraCT-Nr. 2011-003316-23) and clinicaltrials.gov (NCT01841476).
Macrocycle Therapeutics to Treat Life-threatening Diseases
Chimia (Aarau) 2021 Jun 30;75(6):508-513.PMID:34233814DOI:10.2533/chimia.2021.508.
Polyphor's macrocycle platform led to the discovery of novel antibiotics addressing specifically Gramnegative bacteria by targeting outer membrane proteins. Furthermore, POL6014, an inhibitor of neutrophile elastase and Balixafortide, a CXCR4 inhibitor have been discovered and developed from the platform. Currently a combination of Balixafortide and eribulin is in Phase III clinical trial for the treatment of patients with advanced metastatic HER2-negative breast cancer.
Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial
Lancet Oncol 2018 Jun;19(6):812-824.PMID:29706375DOI:10.1016/S1470-2045(18)30147-5.
Background: The C-X-C chemokine receptor type 4 (CXCR4)-stromal cell-derived factor-1α (SDF-1α) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, Balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer. Methods: This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and Balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus Balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1·4 mg/m2 on days 2 and 9 of a 21-day cycle and Balixafortide from a starting dose of 2 mg/kg with dose increments of 0·5 or 1 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Both drugs were administered as intravenous infusions. All patients were to receive treatment until disease progression or unacceptable toxicity. The primary endpoints were dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters. Safety analysis was done in all patients who received at least one dose of study treatment. Analysis of antitumour activity was done in all patients who received at least one full cycle of study treatment. The trial is registered at ClinicalTrials.gov, number NCT01837095, and is closed to accrual. Findings: Between Jan 28, 2014, and Oct 4, 2016, 56 patients were enrolled into the trial. No dose-limiting toxicities were confirmed and the maximum tolerated dose was not reached. The highest dose was established as eribulin 1·4 mg/m2 on days 2 and 9, and Balixafortide 5·5 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Objective responses (all partial responses) were observed in 16 (30%; 95% CI 18-44) of 54 patients who were evaluable for antitumour activity. The most common treatment-emergent adverse events of any grade were fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]). Serious adverse events occurred in 21 (38%) of 56 patients, including febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients. Two (4%) of 56 patients died while receiving study treatment; one from septic shock and one from pneumonia. Interpretation: The safety and tolerability of Balixafortide plus eribulin seems to be similar to that of eribulin or Balixafortide monotherapy, and the preliminary activity of the combination seems promising in patients with HER-negative metastatic breast cancer. The results suggest that Balixafortide plus eribulin has potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer and warrants further investigation in randomised trials. Funding: Polyphor.