APO-010(APO-010) - 药物靶点：FasL_在研适应症：肿瘤_专利_临床

Phase I, Open Label, Dose Escalation Study to Investigate the Tolerability and Efficacy of APO010 in Patients With Relapsed/Refractory Multiple Myeloma Selected by Drug Response Predictor (DRP)

Multicentre, open label, uncontrolled, phase I pharmacokinetic study, to determine the Maximum Tolerated Dose (MTD) of APO010 administered intravenously on D1, D8 and D15 followed by a one-week drug rest, in patients with multiple myeloma for who have relapsed or are refractory to 2 (in high-risk patients 1) or more different prior therapies and who have Drug Response Predictor (DRP) for APO010 indicating a higher likelihood for response to APO010. The study will contain an extension phase where the recommended Dose will be tested on additional patients.

开始日期2017-06-13

申办/合作机构

Allarity Therapeutics, Inc.

[+2]

NCT00437736 / Completed临床1期

Phase I Dose Finding and Pharmacokinetic Study of Intravenous APO010, a Recombinant Form of Human Fas Ligand, in Patients With Solid Tumors

Two-centre, open label, uncontrolled, dose-finding phase I study, to determine the safety and tolerability of APO010 administered by intravenous bolus injection once per week. It will be the first time this agent will be administered to humans. At lower dose levels, the first cycle duration is 7 weeks. In subsequent cycles, APO010 is administered as 4 weekly doses followed by a two-week drug rest, cycle duration is 6 weeks. Based on preclinical studies of APO010 may cause liver toxicity and a drop in platelets, that recover within 5 days. The main aim of the study is to identify the recommended dose of APO010 for future clinical studies of APO010.

开始日期2007-02-01

申办/合作机构

Valerio Therapeutics SA

100 项与 APO-010 相关的临床结果

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100 项与 APO-010 相关的转化医学

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100 项与 APO-010 相关的专利（医药）

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6

项与 APO-010 相关的文献（医药）

2020-07-01·Experimental Hematology4区 · 医学

Characterization of resistance to a recombinant hexameric Fas-ligand (APO010) in human cancer cell lines

4区 · 医学

Article

作者: Brunner, Nils ; Stenvang, Jan ; Jensen, Peter B ; Jandu, Haatisha ; Nielsen, Annette ; Hansen, Anker ; Knudsen, Steen

Multiple myeloma remains a hard-to-treat cancer as all patients eventually progress because of drug resistance. Thus, there is a need for novel and non-cross-resistant treatment options, and we aimed to address this issue by introducing a new immuno-oncology drug (APO010) in multiple myeloma treatment. APO010 is a hexameric Fas-ligand that mimics cytotoxic T-lymphocyte signaling through the Fas-receptor to induce apoptosis. APO010 is currently in clinical trials with multiple myeloma patients. Thus, an understanding of the mechanisms contributing to resistance to APO010 will be essential for future clinical studies with APO010, and it might be possible to develop strategies to circumvent this resistance. We developed APO010-resistant variants of human multiple myeloma cell lines (LP1, MOLP-8, and KMS-12-BM) and a human Burkitt's lymphoma cell line (Raji) by exposing the cells to gradually increasing concentrations of APO010 over a period of 6-12 months. The resistant cell lines were characterized on the basis of immunocytochemistry, Fas-receptor protein expression, mRNA expression analysis, and pathway analysis. APO010-resistant cell lines exhibited a 4- to 520-fold increase in resistance to APO010 and still remained sensitive to other chemotherapeutics. Downregulation of the Fas-receptor protein expression was observed in all resistant cell lines. mRNA expression analysis of the resistant versus parental cell lines confirmed a significant alteration in FAS expression between sensitive and resistant cell lines (p = 0.03), while pathway analysis revealed alterations in mRNA signaling pathways of Fas. On the basis of the pre-clinical data obtained, it can be concluded that downregulation of Fas-receptor can mediate resistance to APO010.

2013-09-01·Anticancer research4区 · 医学

APO010, a synthetic hexameric CD95 ligand, induces death of human glioblastoma stem-like cells.

4区 · 医学

Article

作者: Fabian Wolpert ; Günter Eisele ; Guillaume Decrey ; Michael Weller

The treatment of glioblastoma remains a major challenge in the field of neuro-oncology. There is emerging evidence that glioblastomas consist of heterogeneous cell populations with a small subset of cells with stem cell-like properties which might be resistant to conventional therapy and are thus crucial for tumor recurrence. These glioma-initiating cells (GICs) are therefore an attractive therapeutic target. Death receptor activation is one promising approach of cancer therapy. The synthetic hexameric cluster of differentiation 95 (CD95) agonist APO010 exhibits strong antiglioma activity towards human glioma cell lines, as well as in cell cultures of primary glioblastoma. Here, we investigated the ability of APO010 to induce cell death in a panel of previously well-defined GIC lines. The GIC lines and their derived differentiated cultures expressed CD95 on the cell surface and were sensitive towards APO010-mediated cell death to a variable extent. Temozolomide enhanced sensitivity of GICs to APO010. APO010 warrants being further evaluated as a tool to target GICs.

2011-06-16·Oncogene1区 · 医学

NF-κB-dependent cytokine secretion controls Fas expression on chemotherapy-induced premature senescent tumor cells

1区 · 医学

Article

作者: E D'Aiuto ; A Leonardi ; R De Palma ; G Palumbo ; A Lavorgna ; F Pacifico ; E Crescenzi ; S Formisano

Induction of a senescent phenotype in tumor cells has been linked to anticancer immune response, however, the molecular mechanisms mediating these phenomenon have not yet been determined. In this study, we present evidence that induction of premature senescence in human cancer cell lines induces Fas expression, and loss of resistance to Fas-induced apoptosis. Triggering of Fas by using the agonistic antibody CH11 or the recombinant ligand APO010, activates an apoptotic pathway responsible for cell death. Secretion of pro-inflammatory cytokines by the senescent cells, particularly TNF-α and IFN-γ, mediates Fas upregulation. Indeed, treatment of proliferating cancer cell lines with TNF-α and IFN-γ, upregulates Fas expression, while blocking TNF-α and IFN-γ by using neutralizing antibodies, decreases Fas expression in senescent cells. We also demonstrate that NF-κB has a central role in controlling the senescence-associated secretory phenotype (SASP) by the premature senescent cells, and that TNF-α and IFN-γ, transcriptionally controlled by NF-κB, are the main mediators of Fas upregulation. Our data suggest the existence of an NF-κB-dependent autocrine loop, mediated by TNF-α and IFN-γ, responsible for expression of Fas on the surface of senescent cells, and for their killing.

100 项与 APO-010 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
肿瘤	临床前	瑞士	University of Lausanne	2023-03-27
肿瘤	临床前	瑞士	Apotech SA	2023-03-27
多发性骨髓瘤	药物发现	丹麦	Allarity Therapeutics Europe ApS	2017-06-13
浆细胞骨髓瘤难治	药物发现	丹麦	Allarity Therapeutics, Inc.	2017-06-13
复发性多发性骨髓瘤	药物发现	丹麦	Allarity Therapeutics, Inc.	2017-06-13
实体瘤	药物发现	瑞士	Valerio Therapeutics SA	2007-02-01
血液肿瘤	药物发现	瑞士	Valerio Therapeutics SA	-