Cusatuzumab
目录号 : GC66356
Cusatuzumab 是一种人 αCD70 单克隆抗体。 Cusatuzumab 显示出增强抗体依赖性的细胞毒性。 Cusatuzumab 可减少白血病干细胞 (LSC) 并触发与骨髓分化和凋亡 apoptosis 相关的基因特征。Cusatuzumab 具有研究急性白血病 (AML) 的潜力。
Cas No.:1864871-20-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Datasheet
Cusatuzumab is a human αCD70 monoclonal antibody. Cusatuzumab shows cytotoxicity activity with enhanced antibody-dependent cellular. Cusatuzumab reduces leukemia stem cells (LSCs) and triggers gene signatures related to myeloid differentiation and apoptosis. Cusatuzumab has the potential for the research of Acute myeloid leukemia (AML)[1].
| Cas No. | 1864871-20-4 | SDF | Download SDF |
| 分子式 | 分子量 | ||
| 溶解度 | 储存条件 | Store at -20°C | |
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Targeting CD70 with Cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents
Nat Med 2020 Sep;26(9):1459-1467.PMID:32601337DOI:10.1038/s41591-020-0910-8.
Acute myeloid leukemia (AML) is driven by leukemia stem cells (LSCs) that resist conventional chemotherapy and are the major cause of relapse1,2. Hypomethylating agents (HMAs) are the standard of care in the treatment of older or unfit patients with AML, but responses are modest and not durable3-5. Here we demonstrate that LSCs upregulate the tumor necrosis factor family ligand CD70 in response to HMA treatment resulting in increased CD70/CD27 signaling. Blocking CD70/CD27 signaling and targeting CD70-expressing LSCs with Cusatuzumab, a human αCD70 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity activity, eliminated LSCs in vitro and in xenotransplantation experiments. Based on these preclinical results, we performed a phase 1/2 trial in previously untreated older patients with AML with a single dose of Cusatuzumab monotherapy followed by a combination therapy with the HMA azacitidine ( NCT03030612 ). We report results from the phase 1 dose escalation part of the clinical trial. Hematological responses in the 12 patients enrolled included 8 complete remission, 2 complete remission with incomplete blood count recovery and 2 partial remission with 4 patients achieving minimal residual disease negativity by flow cytometry at <10-3. Median time to response was 3.3 months. Median progression-free survival was not reached yet at the time of the data cutoff. No dose-limiting toxicities were reported and the maximum tolerated dose of Cusatuzumab was not reached. Importantly, Cusatuzumab treatment substantially reduced LSCs and triggered gene signatures related to myeloid differentiation and apoptosis.
Cusatuzumab for treatment of CD70-positive relapsed or refractory cutaneous T-cell lymphoma
Cancer 2022 Mar 1;128(5):1004-1014.PMID:34726773DOI:10.1002/cncr.34005.
Background: The clinical benefit of Cusatuzumab, a CD70-directed monoclonal antibody with enhanced effector functions, was investigated in patients with relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL). Methods: In this cohort expansion of the ARGX-110-1201 study, 27 patients with R/R CTCL received Cusatuzumab at 1 (n = 11) or 5 mg/kg (n = 16) once every 3 weeks to investigate its safety, dose, and exploratory efficacy. The pharmacokinetics, immunogenicity, CD70 expression, and CD70/CD27 biology were also assessed. Results: The most common adverse events included infusion-related reactions, pyrexia, and asthenia. Eighteen serious adverse events (grade 1-3) were reported in 11 patients; 1 of these (vasculitis) was considered drug-related. For 8 of the 11 patients receiving 1 mg/kg, anti-drug antibodies (ADAs) affected the minimal concentration, and this resulted in undetectable Cusatuzumab concentrations at the end of treatment and, in some cases, a loss of response. This effect was greatly reduced in the patients receiving 5 mg/kg. The overall response rate was 23%; this included 1 complete response and 5 partial responses (PRs) in 26 of the 27 evaluable patients. In addition, 9 patients achieved stable disease. The mean duration on Cusatuzumab was 5.2 months, and the median duration was 2.5 months. Patients with Sézary syndrome (SS) achieved a 60% PR rate with a dosage of 5 mg/kg and a 33% PR rate with a dosage of 1 mg/kg; this resulted in an overall response rate of 50% for patients with SS at both doses. Conclusions: Cusatuzumab was well tolerated, and antitumor activity was observed at both 1 and 5 mg/kg in highly pretreated patients with R/R CTCL. The observed dose-dependent effect on exposure supports the use of 5 mg/kg for future development.
Cusatuzumab plus azacitidine in Japanese patients with newly diagnosed acute myeloid leukemia ineligible for intensive treatment
Cancer Sci 2023 Mar;114(3):1037-1044.PMID:36394119DOI:10.1111/cas.15663.
We present the results of a phase 1 study that evaluated the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary disease response to Cusatuzumab, a novel anti-CD70 monoclonal antibody, in combination with azacitidine, in newly diagnosed acute myeloid leukemia Japanese participants who were not candidates for intensive treatment. In this multicenter, single-arm study, six participants were enrolled and treated. Only in cycle 1, participants received Cusatuzumab monotherapy on day 14. Subsequently, Cusatuzumab was administered intravenously on days 3 and 17 at 20 mg/kg in combination with azacitidine (75 mg/m2 ) on days 1-7 of each 28-day cycle. All six participants had at least one treatment-emergent adverse event, and the most common treatment-emergent adverse events (all grades) were leukopenia (four participants [66.7%]) and constipation (three participants [50.0%]). No dose-limiting toxicity was observed during the study period. The combination of Cusatuzumab and azacitidine is generally well tolerated in Japanese participants, and further exploration of this combination is warranted.
An open-label, nonrandomized, phase Ib feasibility study of Cusatuzumab in patients with nasopharyngeal carcinoma
Clin Transl Sci 2021 Nov;14(6):2300-2313.PMID:34405542DOI:10.1111/cts.13089.
CD70 is expressed in up to 80% of nasopharyngeal carcinoma (NPC) cases. Cusatuzumab is a humanized anti-CD70 monoclonal antibody, with dual action mechanisms: induction of cytotoxicity against CD70+ tumor cells and reduction in CD70-CD27 signaling mediated immune evasion. The aim of this study was to assess the safety, pharmacokinetic profile, immunogenicity, pharmacodynamic profile, and preliminary activity of Cusatuzumab in advanced NPC. Eleven patients were enrolled: one patient was assigned to arm A (adjuvant Cusatuzumab monotherapy after curative chemoradiation), nine patients to arm B (Cusatuzumab monotherapy; noncurative setting), and one patient to arm C (Cusatuzumab + chemotherapy; noncurative setting); irrespective of tumoral CD70 expression. Both patients in arms A and C completed the study. All patients in arm B discontinued at an early stage. Five patients experienced grade greater than or equal to 3 nondrug related treatment-emergent adverse events, most commonly fatigue and pneumonia (18%). An infusion-related reaction was observed in two of 11 patients. Laboratory results showed no trend over time. Seven patients were eligible for response evaluation. No objective response to Cusatuzumab was observed with stable disease being the best response. The current study indicates that the safety profile of Cusatuzumab (with or without concurrent chemotherapy) is manageable in patients with advanced NPC, which is consistent with known safety profile. Limited activity of Cusatuzumab in advanced NPC was observed. Combination therapies of Cusatuzumab and other types of therapy should be explored for the improvement of activity in NPC and other CD70-expressing malignancies.
[Management of AML in the elderly]
Bull Cancer 2023 Apr;110(4):424-432.PMID:36870810DOI:10.1016/j.bulcan.2023.02.005.
Elderly patients with acute myeloid leukemia, ineligible for intensive chemotherapy, have long had a very poor prognosis and have always represented one of the main patient populations included in early phase clinical research trials. In recent years, many molecules have shown very interesting efficacy, often targeted therapies whose indication is based on a specific mutation profile (gilteritinib, ivosidenib), or mutation-independent (venetoclax), but also drugs whose indication is based on a specific biomarker (tamibarotene) or on new generation immunotherapies targeting macrophages (magrolimab) or other immune effectors while targeting leukemic cells resulting in forced immunological synapse (flotetuzumab) or activation of lymphocyte effectors associated with inhibition of the AML cells' stem signature in their microenvironment (Cusatuzumab sabatolimab). All of these new strategies are discussed in this review, as well as the challenges of this frail population, which has benefited in recent months from all the major advances in the field, questioning in a second phase the modification of practices in younger patients.