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Ontuxizumab Overview

Introduction of Ontuxizumab

Ontuxizumab (as known as MORAB-004) is a recombinant chimeric/humanized hybrid (mouse/human) monoclonal antibody expressed in Chinese hamster ovary (CHO) cells binding to human designed for the treatment of cancer. This drug, with a structure comprising two heavy chains and two light chains with disulfide bonds, was developed by Morphotek and Ludwig Institute for Cancer Research and binds to endosialin (tumor endothelial marker-1, TEM1 or CD248). The first-in-human study of ontuxizumab was conducted in the US, and was an open-label, phase I trial in patients with solid tumors (without intracranial involvement or metastases) who had failed standard chemotherapy. This study evaluated the safety and pharmacokinetics (PK) of ontuxizumab in patients with solid tumors at doses ranging. Phase I trials of ontuxizumab are complete and the drug was granted orphan drug status by the FDA for sarcoma. It is currently in phase II trials for melanoma, colorectal cancer, sarcoma, and lymphoma.

Mechanism of Action of Ontuxizumab

Angiogenesis is a critical step in the growth, progression, and metastatic spread of cancer cells. Tumor endothelial markers are a group of proteins that have been associated with tumor-specific angiogenesis. Endosialin is expressed in the stromal compartment, including pericytes and fibroblasts, of most human tumors and also expressed in the tumor cells in certain cancers. In preclinical studies, endosialin has been shown to play a key role in tumor growth and neovascular formation in numerous cancer types. The overexpression of endosialin in colorectal cancer tissue compared with healthy tissue suggests its role in colorectal cancer blood vessel formation. When endosialin expression in normal human pericytes was downregulated, pericyte proliferation was disrupted, suggesting that the endosialin-dependent signaling pathway may be a target for modulating tumor angiogenesis and stromal development. Immunohistochemistry studies of human tumor biopsy samples have shown endosialin expression in tumor stromal cells, especially in the mural cell compartment of new vessels and cancer-associated fibroblasts. Ontuxizumab is a humanized immunoglobulin G (IgG)1/κ monoclonal antibody directed against human endosialin. Ontuxizumab binds to human endosialin on the surface of cells expressing the antigen. In preclinical studies, immunofluorescent staining of ontuxizumab-treated human pericytes showed cellular internalization of the antibody, with a corresponding reduction of surface endosialin. Using a human endosialin knock-in mouse tumor model, treatment with ontuxizumab resulted in reduced tumor growth, inhibited metastases, and reduced new vessel formation. In vivo, ontuxizumab significantly affected syngeneic tumor growth and tumor metastasis in human CD248 knock-in mice. Compared with untreated tumors, the blood vessels of ontuxizumab-treated tumors were shortened and distorted. Additionally, CD248 levels on the cell surfaces of neovascular pericytes were significantly reduced due to CD248 internalization. This was accompanied by reduced smooth muscle α-actin expression, depolarization of pericytes and endothelium, and ultimately, dysfunctional microvessels.

Mechanism of Action of Ontuxizumab Fig 1. Mechanism of Action of Ontuxizumab

What We Provide

Therapeutic Antibody

We provide high-quality Ontuxizumab (IgG1 - kappa type) for use in Neut, ELISA, IF, IP, FuncS, FC, ICC and most other immunological methods. For lab research use only, not for diagnostic, therapeutic or any in vivo human use.

For research use only. Not intended for any clinical use.

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