OX40 is one of the therapeutic targets for its important role as a costimulatory molecule on T cells. The combination of multiple antibodies that target different immune regulatory molecules has become the mainstream in cancer treatment, such as combining the anti-PD-1 antibody, anti-PD-L1 antibody, and anti-OX40 agonist antibody. Creative Biolabs has successfully established an optimized Magic™ “humanized” animal platform to offer specialty manipulated hPD-1/hPD-L1/hOX40 triple humanized mice for our clients all over the world.
Human programmed cell death protein-1 (hPD-1) is only expressed in activated T cells, so PD-1 mediated inhibitory signals only act on T cells that have produced a tumor-specific response, namely PD-1+CD8+ T cells. Human programmed cell death-ligand 1 (hPD-L1) is expressed on many different cell types (including hematopoietic cells and epithelial cells). The hPD-L1 expression could be up-regulated in tumor cells.
Human OX40 (hOX40, also called CD134, TNFRSF4) was originally defined as a T cell activation marker and was later found to belong to the NGFR/TNFR superfamily with co-activation function. The hOX40 gene encodes 277 amino acids and is located on chromosome 1 lp36. The expression of hOX40 is induced 1-2 days after cell activation. It was found to be located in many immune cells including in CD4+ T cells, CD8+ T cells, dendritic cells (DCs), and neutrophils. hOX40 ligand (hOX40L) expressed on antigen-presenting cells (APCs) and activated T cells can activate hOX40.
Tumor cells and the tumor microenvironment limit the host's immune response by up-regulating the hPD-L1 expression on tumor cells and binding to hPD-1 on the surface of tumor-specific CD8+ T cells to achieve "immune escape". Clinically, in patients with a variety of tumors, after applying hPD-1 or hPD-L1 immune checkpoint inhibitors, this block was lifted. And tumor-infiltrating CD8+ T cells expanded, restoring tumor identification and killing effect to achieve anti-tumor effect. As the first line of T cell costimulatory factors, hOX40 together with other immune costimulatory factors promotes the proliferation and expansion of CD8+ T cells and CD4+ T cells. The hOX40/hOX40L signal pathway participates in the immune response through three stages: 1. In lymph nodes, CD4+ T cells activated by the interaction of hOX40/hOX40L signaling migrate to the B follicular area, promoting the germinal center formation and antibody secretion; 2. hOX40/hOX40L signaling promotes CD4+ T cells and other inflammatory cells enter the bloodstream and then migrate to the site of inflammatory response; 3. tissue-derived hOX40L+ APCs lead to CD4+ T cell inflammatory response in local tissues.
Fig.1 The OX40/OX40L signal pathway in T cell priming. (Lane, 2000)
If you compare the effect of the anti-hPD-1 antibody to "release the brake" to the immune system, then the anti-hOX40 agonistic antibody is "step on the throttle" to the immune system. To increase the response rate in more types of cancer patients, the combinational usage of anti-hPD-1 antibody, anti-hPD-L1, and anti-hOX40 agonistic antibody is a useful method without a doubt. Creative Biolabs can provide stable and verified Magic™ “humanized” animal models, including the hPD-1/hPD-L1/hOX40 triple humanized mice. We have provided professional CRO services for our global clients and advanced their preclinical drug development using our humanized mice. If you are interested in these models, 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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