Delving into the Latest Updates on APO-010 with Synapse

Overview

Basic Info

Drug Type

Fusion protein

Synonyms-

Target

FasR

Mechanism

FasR stimulants(Apoptosis-mediating surface antigen FAS stimulants), Apoptosis stimulants

Therapeutic Areas

NeoplasmsImmune System DiseasesCardiovascular Diseases+ [2]

Active Indication-

Inactive Indication

Hematologic NeoplasmsMultiple MyelomaPlasma cell myeloma refractory+ [2]

Originator Organization

Valerio Therapeutics SA

Active Organization-

Inactive Organization

Allarity Therapeutics, Inc.

Valerio Therapeutics SA

Allarity Therapeutics Europe ApS

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Gene Sequence

Sequence Code 555997694

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.

Start Date13 Jun 2017

Sponsor / Collaborator

Allarity Therapeutics, Inc.

[+2]

NCT00437736 / CompletedPhase 1

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.

Start Date01 Feb 2007

Sponsor / Collaborator

Valerio Therapeutics SA

100 Clinical Results associated with APO-010

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100 Translational Medicine associated with APO-010

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100 Patents (Medical) associated with APO-010

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6

Literatures (Medical) associated with APO-010

01 Jul 2020·Experimental hematologyQ4 · MEDICINE

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

Q4 · MEDICINE

Article

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

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.

01 Sep 2013·Anticancer researchQ4 · MEDICINE

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

Q4 · MEDICINE

Article

Author: Guillaume Decrey ; Günter Eisele ; Fabian Wolpert ; 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.

16 Jun 2011·OncogeneQ1 · MEDICINE

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

Q1 · MEDICINE

Article

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

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 Deals associated with APO-010

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Myeloma	Phase 2	DK	Allarity Therapeutics Europe ApS	13 Jun 2017
Plasma cell myeloma refractory	Phase 2	DK	Allarity Therapeutics, Inc.	13 Jun 2017
Relapse multiple myeloma	Phase 2	DK	Allarity Therapeutics, Inc.	13 Jun 2017
Solid tumor	Phase 1	CH	Valerio Therapeutics SA	01 Feb 2007
Hematologic Neoplasms	Preclinical	CH	Valerio Therapeutics SA	-