Targeting checkpoint inhibitors using monoclonal antibodies results in significantly successful outcome of cancer patients compared to conventional chemotherapy. Recently, indoleamine (2,3)-dioxygenase (IDO) was identified as a novel checkpoint protein involved in generating the immunosuppressive tumor microenvironment that supports tumor growth. IDO inhibitors have been well-developed and have shown promising antitumor activity in early clinical trials, and seem to be synergistic in combination with chemotherapy and other forms of immunotherapy. Creative Biolabs has successfully established an optimized Magic™ “humanized” animal platform to offer specialty manipulated IDO immune checkpoint knock-in mice for our clients all over the world.
IDO Molecule
Human body utilizes the immune checkpoint to balance the pro- and anti-immune reactions to avoid autoimmune reaction to normal tissues. It has long been understood that the immune system has inherent anti-tumor activity in humans, and that a key mechanism of tumor progression is the ability of a tumor to escape this immune surveillance. Several attempts have been made to regulate and control this anti-tumor immunity in both solid tumor oncology and haematological malignancies with variable success.
IDO, also known as indoleamine (2,3)-dioxygenase, is an enzyme with two isoforms (IDO1 and IDO2) that acts as the first step in the metabolic pathway that breaks down the essential amino acid tryptophan, which is encoded by the IDO1 gene. IDO has been involved in immune modulation due to its ability to limit T cell function and engage mechanisms of immune tolerance. Numerous evidence has demonstrated that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system.
IDO Immune Checkpoint Pathway
IDO exerts its immunomodulatory effects through shutting down the effector T cells of the immune system. Increased IDO protein levels then induce growth arrest and apoptosis of the effector T cells, a group of immune cells such as cytotoxic T cells, helper T cells, and natural killer cells that mediate the ability of immune system to destroy pathogens. IDO overexpression avoids the immune system from effectively destroying tumor cells by reducing the number of effector T cells. Thus, multiple opportunities are allowed for targeting the tumorigenic activities of aberrant IDO signaling.
Fig. 1. Crystal structure of 4-phenylimidazole bound form of human indoleamine 2,3-dioxygenase
Fig. 2. IDO signaling effector pathways. IDO affects differentiation and proliferation of T cells, triggering downstream signaling through GCN2, mTOR and AhR. (Qian, S., et al., 2016)
Development of Humanized SIRPα Immune Checkpoint Knock-In Mice
Immune checkpoint blockade has been investigated in clinical trials and showed great potential in various human cancer. Recently, targeting the IDO pathway via inhibition of the IDO enzyme or blocking its downstream signaling effects has become a prime target for small-molecule immunomodulatory drugs in cancer. With advanced technology, Creative Biolabs has successfully established an array of well-established Magic™ “humanized” animal models, especially for IDO immune checkpoint knock-in mice. Our scientists focused on humanized mouse models are pleased to assist you in your studies of anti-tumor immunotherapies. What's more, we also established comprehensive in vitro immunomodulation assessment service using various approaches. Please feel free to contact us for more details.
Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:
Reference
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