Bürdek Maja, Prinz Petra U, Mutze Kathrin, Tippmer Stefanie, Geiger Christiane, Longinotti Giulia, Schendel Dolores J
Medigene Immunotherapies GmbH, 82152 Planegg-Martinsried, Germany.
Medigene AG, 82152 Planegg-Martinsried, Germany.
Cancers (Basel). 2025 Jan 13;17(2):242. doi: 10.3390/cancers17020242.
BACKGROUND/OBJECTIVES: MDG1011 is an autologous TCR-T therapy developed as a treatment option for patients with myeloid malignancies, including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM). It is specific for the target antigen PReferentially expressed Antigen in MElanoma (PRAME). The recombinant TCR used in MDG1011 recognizes PRAME VLD-peptide presented by HLA-A*02:01-encoded surface molecules.
Two preclinical batches of MDG1011, produced from enriched CD8+ T cells of healthy donors, underwent rigorous evaluation of on-target and off-target recognition of tumor cells and test cells representing healthy tissues. MDG1011 investigational medicinal products (IMPs) were produced for 13 patients. VLD-TCR surface expression was assessed using dual-marker flow cytometry using TCR V-beta-specific antibody and VLD/HLA-A2-specific multimer. Functionality was assessed by interferon-gamma (IFN-γ) secretion and cell-mediated cytotoxicity of target cells.
Preclinical MDG1011 batches displayed strong VLD-TCR expression, cytokine secretion, and cytotoxicity after antigen-specific activation, while showing no signals of on-target/off-tumor or off-target recognition. All IMPs had good VLD-TCR expression as well as functionality after activation by multiple target cells.
Preclinical studies demonstrated that MDG1011 displayed key 3S attributes of high specificity, sensitivity, and safety required for regulatory approval of a first-in-human (FIH) clinical study of patients with myeloid malignancies (CD-TCR-001: ClinicalTrials.gov Identifier: NCT03503968). MDG1011 IMP manufacturing was successful at 92%, even including heavily pretreated elderly patients with very advanced disease. The IMPs applied in nine patients all displayed antigen-specific functionality. Elsewhere, clinical study results for MDG1011 showed no dose-limiting toxicity and signs of biological and/or clinical activity in several patients.
背景/目的：MDG1011是一种自体TCR-T疗法，开发用于治疗髓系恶性肿瘤患者，包括急性髓系白血病（AML）、骨髓增生异常综合征（MDS）和多发性骨髓瘤（MM）。它对黑色素瘤中优先表达的抗原（PRAME）具有特异性。MDG1011中使用的重组TCR识别由HLA-A*02:01编码的表面分子呈递的PRAME VLD肽。
从健康供体的富集CD8+ T细胞中制备了两批临床前MDG1011，对代表健康组织的肿瘤细胞和测试细胞进行了严格的靶向和脱靶识别评估。为13名患者生产了MDG1011研究用药品（IMPs）。使用TCR V-β特异性抗体和VLD/HLA-A2特异性多聚体，通过双标记流式细胞术评估VLD-TCR表面表达。通过干扰素-γ（IFN-γ）分泌和靶细胞的细胞介导细胞毒性评估功能。
临床前MDG1011批次在抗原特异性激活后表现出强烈的VLD-TCR表达、细胞因子分泌和细胞毒性，同时未显示靶向/肿瘤外或脱靶识别信号。所有IMPs在被多个靶细胞激活后均具有良好的VLD-TCR表达和功能。
临床前研究表明，MDG1011显示出髓系恶性肿瘤患者首次人体（FIH）临床研究监管批准所需的高特异性、敏感性和安全性这三个关键属性（CD-TCR-001：ClinicalTrials.gov标识符：NCT03503968）。MDG1011 IMP的生产成功率为92%，甚至包括病情非常严重的老年患者，这些患者此前接受过大量治疗。应用于9名患者的IMPs均显示出抗原特异性功能。在其他地方，MDG1011的临床研究结果显示没有剂量限制性毒性，并且在几名患者中出现了生物学和/或临床活性迹象。
