Varlilumab
(Synonyms: 伐立鲁单抗,CDX-1127) 目录号 : GC64839
Varlilumab (CDX-1127) 是一种首创的人 IgG1 抗 CD27 单克隆抗体。Varlilumab 具有抗肿瘤活性。
Cas No.:1393344-72-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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Purity: >96.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Varlilumab (CDX-1127) is a first-in-class human IgG1 anti-CD27 monoclonal antibody. Varlilumab has an anti-tumor activity[1].
[1]. Stephen M Ansell, et al. Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, for hematologic malignancies. Blood Adv. 2020 May 12;4(9):1917-1926.
| Cas No. | 1393344-72-3 | SDF | Download SDF |
| 别名 | 伐立鲁单抗,CDX-1127 | ||
| 分子式 | 分子量 | ||
| 溶解度 | 储存条件 | Store at -80°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。 | ||
| 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 | ||||||||||
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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。
New emerging targets in cancer immunotherapy: CD27 (TNFRSF7)
ESMO Open 2020 Mar;4(Suppl 3):e000629.PMID:32152062DOI:10.1136/esmoopen-2019-000629.
Cluster of differentiation 27 (CD27) is a member of the tumour necrosis factor receptor superfamily and plays a key role in T-cell activation by providing a costimulatory signal. Bound to its natural ligand CD70, CD27 signalling enhances T-cell proliferation and differentiation to effector and memory T cells and therefore has potential as an immune modulatory target in cancer treatment. The CD27 agonistic antibody Varlilumab showed promising efficacy in haematological as well as solid cancers. Current studies investigate the combination of the CD27 agonistic antibody Varlilumab in combination with the PD1 axis targeting immune checkpoint inhibitors like nivolumab or atezolizumab. Further, CD70 expression is used as a therapeutic target for ADCs, antibodies inducing ADCC, as well as the immunological target for chimeric antigen receptor gene-modified T cells and specific dendritic cell vaccination. In line with this, targeting the CD27 axis was shown to be feasible and safe in early clinical trials with the most commonly occurring side effects being thrombocytopenia, fatigue and nausea. In this mini review, we aimed to elucidate the immunobiology of CD27 and its potential as a target in cancer immunotherapy.
Safety, tolerability and efficacy of agonist anti-CD27 antibody (Varlilumab) administered in combination with anti-PD-1 (nivolumab) in advanced solid tumors
J Immunother Cancer 2022 Aug;10(8):e005147.PMID:35940825DOI:10.1136/jitc-2022-005147.
Background: Phase 1/2 dose-escalation and expansion study evaluating Varlilumab, a fully human agonist anti-CD27 mAb, with nivolumab in anti-PD-1/L1 naïve, refractory solid tumors. Methods: Phase 1 evaluated the safety of Varlilumab (0.1-10 mg/kg) with nivolumab (3 mg/kg) administered once every 2 weeks. Phase 2 evaluated Varlilumab regimens (3 mg/kg once every 2 weeks, 3 mg/kg once every 12 weeks, and 0.3 mg/kg once every 4 weeks) with nivolumab 240 mg once every 2 weeks in tumor-specific cohorts. Primary objective was safety; key clinical endpoints included objective response rate (ORR) and overall survival rate at 12 months (OS12) (glioblastoma (GBM) only). Exploratory objectives included determination of effects on peripheral blood and intratumoral immune signatures. Results: 175 patients were enrolled (36 in phase 1 and 139 in phase 2). Phase 1 dose-escalation proceeded to the highest Varlilumab dose level without determining a maximum tolerated dose. In phase 2, ORR were ovarian 12.5%, squamous cell carcinoma of the head and neck 12.5%, colorectal cancer 5%, and renal cell carcinoma 0%; GBM OS12 was 40.9%. Increased tumor PD-L1 and intratumoral T cell infiltration were observed in ovarian cancer patients, with increases of ≥5% associated with better progression-free survival. The most common treatment related adverse events were fatigue (18%), pruritus (16%), and rash (15%). Conclusion: Varlilumab and nivolumab were well tolerated, without significant toxicity beyond that expected for each agent alone. Clinical activity was observed in patients that are typically refractory to anti-PD-1 therapy, however, overall was not greater than expected for nivolumab monotherapy. Treatment was associated with proinflammatory changes in the tumor microenvironment, particularly in ovarian cancer where the changes were associated with better clinical outcomes. Trial registration number: NCT02335918.
Safety and activity of Varlilumab, a novel and first-in-class agonist anti-CD27 antibody, for hematologic malignancies
Blood Adv 2020 May 12;4(9):1917-1926.PMID:32380537DOI:10.1182/bloodadvances.2019001079.
CD27, a costimulatory molecule on T cells, induces intracellular signals mediating cellular activation, proliferation, effector function, and cell survival on binding to its ligand, CD70. Varlilumab, a novel, first-in-class, agonist immunoglobulin G1 anti-CD27 antibody, mediates antitumor immunity and direct killing of CD27+ tumor cells in animal models. This first-in-human, dose-escalation, and expansion study evaluated Varlilumab in patients with hematologic malignancies. Primary objectives were to assess safety and the maximum tolerated and optimal biologic doses of Varlilumab. Secondary objectives were to evaluate pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity. In a 3 + 3 dose-escalation design, 30 patients with B-cell (n = 25) or T-cell (n = 5) malignancies received Varlilumab (0.1, 0.3, 1, 3, or 10 mg/kg IV) as a single dose with a 28-day observation period, followed by weekly dosing (4 doses per cycle, up to 5 cycles, depending on tumor response). In an expansion cohort, 4 additional patients with Hodgkin lymphoma received Varlilumab at 0.3 mg/kg every 3 weeks (4 doses per cycle, up to 5 cycles). No dose-limiting toxicities were observed. Treatment-related adverse events, generally grade 1 to 2, included fatigue, decreased appetite, anemia, diarrhea, and headache. Exposure was linear and dose-proportional across dose groups and resulted in increases in proinflammatory cytokines and soluble CD27. One patient with stage IV Hodgkin lymphoma experienced a complete response and remained in remission at >33 months with no further anticancer therapy. These data support further investigation of Varlilumab for hematologic malignancies, particularly in combination approaches targeting nonredundant immune regulating pathways. This trial was registered at www.clinicaltrials.gov as #NCT01460134.
Safety and Activity of Varlilumab, a Novel and First-in-Class Agonist Anti-CD27 Antibody, in Patients With Advanced Solid Tumors
J Clin Oncol 2017 Jun 20;35(18):2028-2036.PMID:28463630DOI:10.1200/JCO.2016.70.1508.
Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of Varlilumab in patients with advanced solid tumors. Methods In a 3 + 3 dose-escalation design (n = 25), patients received a single dose of Varlilumab (0.1, 0.3, 1.0, 3.0, or 10 mg/kg intravenously) with a 28-day observation, followed by up to five multidose cycles (one dose per week for 4 weeks), depending on tumor response. Expansion cohorts were initiated at 3.0 mg/kg in patients with melanoma (n = 16) and renal cell carcinoma (RCC; n = 15). Primary objectives were to assess the safety and the maximum tolerated and optimal biologic doses of Varlilumab. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics, and clinical antitumor activity of Varlilumab. Results Exposure to Varlilumab was linear and dose proportional across dose groups. Only one patient experienced a dose-limiting toxicity-grade 3 transient asymptomatic hyponatremia at the 1.0-mg/kg dose level. Treatment-related adverse events were generally grade 1 or 2 in severity. Evidence of biologic activity consistent with CD27 stimulation-chemokine induction, T-cell stimulation, regulatory T cell depletion-was observed at all dose levels. A patient with metastatic RCC experienced a partial response (78% shrinkage, progression-free survival > 2.3 years). Eight patients experienced stable disease > 3 months, including a patient with metastatic RCC with progression-free survival of > 3.9 years. Conclusion Dose escalation of Varlilumab to 10 mg/kg was well tolerated without identification of a maximum tolerated dose. Varlilumab was biologically and clinically active.
Characterization of the human T cell response to in vitro CD27 costimulation with Varlilumab
J Immunother Cancer 2015 Aug 18;3:37.PMID:26500773DOI:10.1186/s40425-015-0080-2.
Background: Clinical targeting of TNFR family of receptors (CD40, CD134 and CD137) with immunostimulatory monoclonal antibodies has been successful in cancer immunotherapy. However, targeting of CD27 with a mAb is a relatively new approach to provide costimulation of immune cells undergoing activation. Thus, activation of human CD27 (TNFRSF7) with a monoclonal antibody (Varlilumab) has previously been demonstrated to result in T cell activation and anti-tumor activity in preclinical models, and is currently in early phase clinical trials in patients with advanced malignancies. In this study we used an in vitro system using human peripheral blood T cells to characterize the varlilumab-mediated costimulatory effects in combination with TCR stimulation in terms of phenotypic, transcriptional and functionality changes. Methods: T cells were isolated from normal volunteer PBMCs using magnetic bead isolation kits and stimulated in vitro with plate bound anti-CD3 Ab (OKT3) and Varlilumab or control Ab for 72 h. Activation profiles were monitored by ELISA or Luminex-based testing cytokine/chemokine releases, cell surface phenotyping for costimulatory and coinhibitory markers and CFSE dye dilution by proliferating T cells and Tregs. Changes in gene expression and transcriptome analysis of varlilumab-stimulated T cells was carried on Agilent Human whole genome microarray datasets using a suite of statistical and bioinformatic software tools. Results: Costimulation of T cells with Varlilumab required continuous TCR signaling as pre-activated T cells were unable to produce cytokines with CD27 signaling alone. Analysis of T cell subsets further revealed that memory CD4+ and CD8+ T cells were specifically activated with a bias toward CD8+ T lymphocyte proliferation. Activation was accompanied by upregulated cell surface expression of costimulatory [4-1BB, OX40, GITR and ICOS] and coinhibitory [PD-1] molecules. Importantly, Varlilumab costimulation did not activate purified Tregs as measured by cytokine production, proliferation and suppression of dividing non-Treg T cells. Analysis of changes in gene expression during Varlilumab stimulation of T cells revealed modulation of pro-inflammatory signatures consistent with cellular activation and proliferation, with the IL-2 pathway showing the highest frequency of gene modulation. Conclusions: Altogether, the data reveal the requirements and T cell subtype-specific effects of CD27 costimulation, and helps select relevant biomarkers for studying the effects of Varlilumab in patients.