SLC3A2 inhibitors(solute carrier family 3 member 2 inhibitors), ADCC(Antibody-dependent cell-mediated cytotoxicity (ADCC) effects), Complement dependent cytotoxicity (CDC) effects

Therapeutic Areas

NeoplasmsHemic and Lymphatic Diseases

Active Indication-

Inactive Indication

Refractory acute myeloid leukemiaRelapsing acute myeloid leukemia

Originator Organization

Igenica Biotherapeutics, Inc.

Active Organization-

Inactive Organization

Igenica Biotherapeutics, Inc.

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

Clinical Trials associated with IGN-523

NCT02040506 / CompletedPhase 1

A Phase 1, Open-Label Study Evaluating the Safety, Pharmacokinetics, and Clinical Activity of IGN523 in Subjects With Relapsed or Refractory Acute Myeloid Leukemia

This study will examine the safety and tolerability of IGN523 administered as an IV infusion. The main purpose of the study is to determine the maximum tolerated dose (MTD), which is the highest dose that does not cause unacceptable side effects of IGN523 in patients with acute myeloid leukemia (AML). The MTD will be determined by observing the dose-limiting toxicities (the side effects that prevent further increases in dose) of IGN523. In addition, the pharmacokinetic profile and anti-leukemia activity of IGN523 will be assessed. A recommended Phase 2 dose (RP2D) of IGN523 will be identified, on the basis of safety, pharmacokinetic (PK), and pharmacodynamic (PD) data.

Start Date01 Feb 2014

Sponsor / Collaborator

Igenica Biotherapeutics, Inc.

100 Clinical Results associated with IGN-523

100 Translational Medicine associated with IGN-523

100 Patents (Medical) associated with IGN-523

Literatures (Medical) associated with IGN-523

01 Aug 2015·International Journal of CancerQ1 · MEDICINE

Antitumor activity of an anti‐CD98 antibody

Q1 · MEDICINE

Article

Author: Levashova, Zoia ; Cantor, Joseph M. ; H. van der Horst, Edward ; Chinn, Lawrence ; Velilla, Timothy ; Hayes, Gregory M. ; Tran, Hoang ; Ginsberg, Mark H. ; Lippincott, John ; Duey, Dana ; Zachwieja, Joseph ; Cairns, Belinda

CD98 is expressed on several tissue types and specifically upregulated on fast-cycling cells undergoing clonal expansion. Various solid (e.g., nonsmall cell lung carcinoma) as well as hematological malignancies (e.g., acute myeloid leukemia) overexpress CD98. We have identified a CD98-specific mouse monoclonal antibody that exhibits potent preclinical antitumor activity against established lymphoma tumor xenografts. Additionally, the humanized antibody designated IGN523 demonstrated robust tumor growth inhibition in leukemic cell-line derived xenograft models and was as efficacious as standard of care carboplatin in patient-derived nonsmall lung cancer xenografts. In vitro studies revealed that IGN523 elicited strong ADCC activity, induced lysosomal membrane permeabilization and inhibited essential amino acid transport function, ultimately resulting in caspase-3 and -7-mediated apoptosis of tumor cells. IGN523 is currently being evaluated in a Phase I clinical trial for acute myeloid leukemia (NCT02040506). Furthermore, preclinical data support the therapeutic potential of IGN523 in solid tumors.

01 Dec 2005·Journal of Biological ChemistryQ2 · BIOLOGY

The Vitamin D Receptor, Runx2, and the Notch Signaling Pathway Cooperate in the Transcriptional Regulation of Osteopontin

Q2 · BIOLOGY

Article

Author: Qi Shen ; Sylvia Christakos

Osteopontin (OPN), a glycosylated phosphoprotein that binds calcium, is present in bone extracellular matrix and has been reported to modulate both mineralization and bone resorption. Targeted disruption in mice of the vitamin D receptor (VDR) or Runx2 results in marked inhibition of OPN expression in osteoblasts. In this study, we addressed possible cross-talk between VDR and Runx2 in regulating OPN transcription. 1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) or Runx2 stimulated OPN transcription (mouse OPN promoter -777/+79) 2-3-fold. However, coexpression of Runx2 and VDR in COS-7 cells and treatment with 1,25(OH)(2)D(3) resulted in an 8-fold induction of OPN transcription, indicating for the first time functional cooperation between Runx2 and VDR in the regulation of OPN transcription. In ROS 17/2.8 and MC3T3-E1 cells that contain endogenous Runx2, AML-1/ETO, which acts as a repressor of Runx2, significantly inhibited 1,25(OH)(2)D(3) induction of OPN transcription, OPN mRNA, and protein expression. Both a Runx2 site (-136/-130) and the vitamin D response element (-757/-743) in the OPN promoter are needed for cooperative activation. Chromatin immunoprecipitation analyses showed that 1,25(OH)(2)D(3) can enhance VDR and Runx2 recruitment on the OPN promoter, further indicating cooperation between these two factors in the regulation of OPN. In osteoblastic cells, Hes-1, a downstream factor of the Notch signaling pathway, was found to enhance basal and 1,25(OH)(2)D(3)-induced OPN transcription. This enhancement was inhibited by AML-1/ETO, an inhibitor of Runx2. Immunoprecipitation assays indicated that Hes-1 and Runx2 interact and that 1,25(OH)(2)D(3) can enhance this interaction. Taken together, these findings define novel mechanisms involving the intersection of three pathways, Runx2, 1,25(OH)(2)D(3), and Notch signaling, that play a major role in the regulation of OPN in osteoblastic cells and therefore in the process of bone remodeling.

01 Nov 2001·Cellular ImmunologyQ3 · MEDICINE

Involvement of ADAM9 in Multinucleated Giant Cell Formation of Blood Monocytes

Q3 · MEDICINE

Article

Author: Masato Tsurudome ; Mitsuo Kawano ; Yasuhiko Ito ; Kazuyoshi Namba ; Atsumasa Uchida ; Kouki Mori ; Machiko Nishio ; Noriki Miyamoto ; Morihiro Ito

Monocytes-macrophages are converted to multinucleated giant cells by stimulation with various cytokines, and osteoclasts are the multinucleated giant cells derived from a monocyte-macrophage lineage. However, at present, the fusion peptides have not been clearly identified in monocytes-macrophages. The ADAM are a family of transmembrane glycoproteins that have a role in various biological functions. Interestingly, fertilin-alpha, ADAM9, and ADAM11 have potential fusion peptides. In this study, which ADAM was specifically expressed in monocytes stimulated with anti-CD98 antibody or RANKL and which factor(s) was functioning in monocytes as a fusion protein were investigated. ADAM1, 8, 10, 12, 15, 17, 20, and 21 mRNAs are expressed in blood monocytes incubated with control antibody, anti-FRP-1/CD98 antibody, or RANKL + M-CSF, while ADAM2, 7, 11, 13, 19, 23, 29, and 30 mRNAs could not be detected in these blood monocytes. Expression of ADAM9 and ADAM10 mRNAs are enhanced by either RANKL + M-CSF or anti-CD98 antibody. The expression of ADAM9 and ADAM10 is also induced in blood monocytes by anti-CD98 mAb. An anti-ADAM9 antibody enhances CD98-mediated cell aggregation, while it blocks CD98-mediated and RANKL-mediated multinucleated giant cell formation. A hydroxamate-based metalloprotease inhibitor, SI-27, which is found to suppress ADAM9 activity, suppresses multinucleated giant cell formation. New protein synthesis is necessary for the expression of ADAM9 mRNA and genistein suppresses induction of ADAM9 mRNA. This is the first report that ADAM9 is involved in monocyte fusion, such as CD98-mediated and RANKL-mediated cell fusion of blood monocytes. Furthermore, AMAM9 is one candidate for a fusion peptide in blood monocytes.

100 Deals associated with IGN-523

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Refractory acute myeloid leukemia	Phase 1	US	Igenica Biotherapeutics, Inc.	01 Feb 2014
Relapsing acute myeloid leukemia	Phase 1	US	Igenica Biotherapeutics, Inc.	01 Feb 2014

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