Targeted immune checkpoint blockade augments anti-tumor immunity and induces durable responses in patients with melanoma and other solid tumors. Tumor necrosis factor (TNF or TNF-α) is a major pro-inflammatory cytokine involved in early inflammatory events and has proved to be highly effective in clinical trials. Creative Biolabs, who is focused on the discovery and development of antibody-based drugs, has successfully launched a well-established Magic™ “humanized” animal platform to offer humanized TNF-α immune checkpoint knock-in mice for our clients all over the world.

TNF-α Immune Checkpoint Pathway

The primary concept of cancer immunotherapy is to enable the immune system to detect neoplastic growth and to either prevent carcinogenesis and/or reject transformed cells with a potential for malignant tumor growth. Tumor necrosis factor, also known as TNF, tumor necrosis factor alpha, TNFα, cachexin, or cachectin, is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. The TNF gene is localized in the highly polymorphic region of human chromosome 6p21. It is expressed as a 26 kDa membrane-bound protein and is then cleaved by TNF-α converting enzyme (TACE) to release the soluble 17 kDa monomer that forms homotrimers in circulation. TNF-α is produced predominantly by activated macrophages in response to immunological challenges such as bacteria (lipopolysaccharides), viruses, parasites, mitogens and other cytokines, while it can also be produced by many other cell types such as CD4+ lymphocytes, NK cells, neutrophils, mast cells, eosinophils, and neurons.

Magic™ Humanized TNF-α Immune Checkpoint Knock-In MiceFig.1. Potential targets for the inhibition of TNF-α signaling pathways or protein expression. (Theodorakis, 2003)

The Significance of TNF-α Signaling

TNF-α plays a vital role in anti-tumor activity, immune modulation, inflammation, anorexia, cachexia, septic shock, viral replication, and hematopoiesis etc. TNF-α is cytotoxic for many transformed cells (its namesake activity) but in normal diploid cells, it can stimulate proliferation (fibroblasts), differentiation (myeloid cells) or activation (neutrophils). TNF-α also shows antiviral effects against both DNA and RNA viruses and it induces production of several other cytokines. Through binding to and activation of two receptors, TNF-R1 and TNF-R2, Tumor Necrosis Factor α (TNF) modulate various biological processes in the immune system.

Development of Humanized TNF-α Immune Checkpoint Knock-In Mice

The function of the immune system is finely balanced by the activities of pro-inflammatory and anti-inflammatory mediators or cytokines. Unregulated activities of these mediators can result in the development of serious inflammatory diseases. Particularly, enhanced tumor-necrosis factor-α (TNF-α) synthesis is associated with the development of rheumatoid arthritis, psoriatic arthritis, and inflammatory bowel disease. Inhibiting TNF-α activities in these diseases has been proved a great success. As a world leader in the industry of drug discovery, Creative Biolabs has successfully launched an array of well-characterized Magic™ “humanized” animal models, which can provide you with humanized immune checkpoint knock-in mouse models including humanized TNF-α knock-in mouse. Please feel free to contact us for more detailed information.

Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:

Reference

  1. Theodorakis, E.A. Anti-TNF-alpha therapies: the next generation. Nature Reviews Drug Discovery. 2003, 2(9):736.

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