Glembatumumab
(Synonyms: 格巴妥木单抗) 目录号 : GC68340Glembatumumab 是一种完全人类 IgG2 单克隆抗体，针对在人类乳腺癌和黑色素瘤中表达的 GPNMB 细胞外结构域。Glembatumumab 可以与微管抑制剂单甲基 auristatin E 偶联，形成 Glembatumumab vedotin。Glembatumumab vedotin 是一种抗体-药物偶联物 (ADC)，具有抗肿瘤活性。
Cas No.:1020264-78-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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Glembatumumab is a fully human IgG2 monoclonal antibody directed against the extracellular structural domain of GPNMB expressed in human breast cancer and melanoma. Glembatumumab can be coupled to the microtubule inhibitor monomethyl auristatin E to form glembatumumab vedotin. Glembatumumab vedotin is an antibody-drug coupling (ADC) with antitumor activity[1].
Glembatumumab vedotin (CR011-vcMMAE) (0-2.5 μg/mL, 72 h) shows little growth inhibition in UACC62 melanoma cells without MEK inhibitor pretreatment at a concentration of 0.16 μg/mL, while the same dose of CR011-vcMMAE shows stronger growth inhibition in UACC62 cells pretreated with MEK inhibitor[3].
Glembatumumab vedotin (i.v., 2.5 mg/kg, 3 times in 7 days) can inhibit tumor growth and is well tolerated in CB17SC scid-/- female mice with sarcomas[2].
[1]. Naumovski L, et al. Glembatumumab vedotin, a conjugate of an anti-glycoprotein non-metastatic melanoma protein B mAb and monomethyl auristatin E for the treatment of melanoma and breast cancer. Curr Opin Mol Ther. 2010 Apr;12(2):248-57.
[2]. E Anders Kolb, et al. Initial testing (stage 1) of glembatumumab vedotin (CDX-011) by the pediatric preclinical testing program. Pediatr Blood Cancer. 2014 Oct;61(10):1816-21.
[3]. Xiaozhong Qian, et al. Pharmacologically enhanced expression of GPNMB increases the sensitivity of melanoma cells to the CR011-vcMMAE antibody-drug conjugate. Mol Oncol. 2008 Jun;2(1):81-93.
| Cas No. | 1020264-78-1 | SDF | Download SDF |
| 别名 | 格巴妥木单抗 | ||
| 分子式 | 分子量 | ||
| 溶解度 | 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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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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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，
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2.
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HSP90 inhibitors induce GPNMB cell-surface expression by modulating lysosomal positioning and sensitize breast cancer cells to Glembatumumab vedotin
Oncogene 2022 Mar;41(12):1701-1717.PMID:35110681DOI:10.1038/s41388-022-02206-z.
Transmembrane glycoprotein NMB (GPNMB) is a prognostic marker of poor outcome in patients with triple-negative breast cancer (TNBC). Glembatumumab Vedotin, an antibody drug conjugate targeting GPNMB, exhibits variable efficacy against GPNMB-positive metastatic TNBC as a single agent. We show that GPNMB levels increase in response to standard-of-care and experimental therapies for multiple breast cancer subtypes. While these therapeutic stressors induce GPNMB expression through differential engagement of the MiTF family of transcription factors, not all are capable of increasing GPNMB cell-surface localization required for Glembatumumab Vedotin inhibition. Using a FACS-based genetic screen, we discovered that suppression of heat shock protein 90 (HSP90) concomitantly increases GPNMB expression and cell-surface localization. Mechanistically, HSP90 inhibition resulted in lysosomal dispersion towards the cell periphery and fusion with the plasma membrane, which delivers GPNMB to the cell surface. Finally, treatment with HSP90 inhibitors sensitizes breast cancers to Glembatumumab Vedotin in vivo, suggesting that combination of HSP90 inhibitors and Glembatumumab Vedotin may be a viable treatment strategy for patients with metastatic TNBC.
Targeting GPNMB with Glembatumumab vedotin: Current developments and future opportunities for the treatment of cancer
Pharmacol Ther 2017 Nov;179:127-141.PMID:28546082DOI:10.1016/j.pharmthera.2017.05.010.
GPNMB has emerged as an immunomodulator and an important positive mediator of tumor progression and metastasis in numerous solid cancers. Tumor intrinsic GPNMB-mediated effects on cellular signaling, coupled with the ability of GPNMB to influence the primary tumor and metastatic microenvironments in a non-cell autonomous fashion, combine to augment malignant cancer phenotypes. In addition, GPNMB is often overexpressed in a variety of cancers, making it an attractive therapeutic target. In this regard, Glembatumumab vedotin, an antibody-drug conjugate (ADC) that targets GPNMB, is currently in clinical trials as a single agent in multiple cancers. In this review, we will describe the physiological functions of GPNMB in normal tissues and summarize the processes through which GPNMB augments tumor growth and metastasis. We will review the pre-clinical and clinical development of Glembatumumab vedotin, evaluate on-going clinical trials, explore emerging opportunities for this agent in new disease indications and discuss exciting possibilities for this ADC in the context of combination therapies.
Glembatumumab vedotin for patients with metastatic, gpNMB overexpressing, triple-negative breast cancer ("METRIC"): a randomized multicenter study
NPJ Breast Cancer 2021 May 20;7(1):57.PMID:34016993DOI:10.1038/s41523-021-00244-6.
The METRIC study (NCT#0199733) explored a novel antibody-drug conjugate, Glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.88 mg/kg IV q21 days) or capecitabine (2500 mg/m2 PO daily d1-14 q21 days). The primary endpoint was RECIST 1.1 PFS per independent, blinded central review. In all, 327 patients were randomized to GV (213 treated) or capecitabine (92 treated). Median PFS was 2.9 months for GV vs. 2.8 months for capecitabine. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine.
The use of an antibody drug conjugate, Glembatumumab vedotin (CDX-011), for the treatment of breast cancer
Expert Opin Biol Ther 2012 Feb;12(2):259-63.PMID:22229970DOI:10.1517/14712598.2012.642357.
Introduction: Breast cancer (BC) is the most common malignancy in women in the USA. Despite the multi-modality treatments that are currently available, advanced BC has a persistent and unacceptable mortality rate. The need for new therapeutic strategies is extremely high. Experimental approaches with targeted therapies such as antibody drug conjugates provide hope for future treatment possibilities. Areas covered: The development status and the possible role of antibody-mediated cytotoxic therapy are discussed in the setting of advanced BC. An overview of, mechanism of action, preclinical and Phase I/II results of Glembatumumab vedotin (CDX-011) are discussed. Expert opinion: The evidence that the glycoprotein NBM (GPNMB) target is a relevant target in BC, along with data showing that CDX-011 is safe and active in patients with advanced BC, provide a strong rationale to continue to explore this drug in patients with GPNMB-expressing breast tumors.
Glembatumumab vedotin, a conjugate of an anti-glycoprotein non-metastatic melanoma protein B mAb and monomethyl auristatin E for the treatment of melanoma and breast cancer
Curr Opin Mol Ther 2010 Apr;12(2):248-57.PMID:20373269doi
Glembatumumab vedotin (CR-011-vc-MMAE) is a mAb-drug conjugate being developed by Celldex Therapeutics Inc for the treatment of glycoprotein non-metastatic melanoma protein B (GPNMB)-expressing cancers. Glembatumumab is a fully human mAb directed against an extracellular domain of GPNMB expressed in human breast cancers and melanomas. Glembatumumab is conjugated to the potent microtubule inhibitor monomethyl auristatin E using a cathepsin cleavable valine-citrulline (vc) dipeptide linker. Glembatumumab vedotin has demonstrated potent antitumor activity in preclinical studies, including in GPNMB-expressing cell lines. In human melanoma xenograft mice, intravenous Glembatumumab vedotin was associated with complete tumor regression without significant toxicity. In two phase I/II clinical trials, intravenous Glembatumumab vedotin demonstrated antitumor activity in patients with breast cancer or melanoma. Skin rash was the most common toxicity reported, which may have been caused by the expression of GPNMB in healthy skin. Glembatumumab vedotin had a relatively short t(1/2) , prompting the evaluation of more frequent dosing schedules. Prospective, randomized clinical trials will likely be required to determine the therapeutic potential of Glembatumumab vedotin in the treatment of breast cancer and melanoma.