Unsatisfactory efficacy of existing therapies against cancer mainly results from immune evasion of tumor. The immunosuppressive environment generated by tumor cells and stromal through multiple mechanisms including insufficient expression of immune co-stimulatory molecules. OX40 and 4-1BB, as their significant roles in co-stimulation involving the activation of T cells, have become alluring dual-targets in cancer treatment. Creative Biolabs has successfully established an optimized Magic™ “humanized” animal platform to offer specialty manipulated hOX40/h4-1BB dual humanized mice for our clients all over the world.
Human OX40 (hOX40, also known as TNFRSF4 or CD134) and human 4-1BB (h4-1BB, also known as TNFRSF9 or CD137) belong to the tumor necrosis factor receptor superfamily (TNFRSF). They both serve as immune co-stimulatory receptors. In humans, their dominant expressions have been reported on the activated CD4+ and CD8+ T cells. hOX40 is a 50 kDa protein, composing of an extracellular region (86 amino acid (AA)) and a cytoplasmic tail (49 AA). hOX40 is one of the adhesion molecules, prolonging the time frame during which the T cells stick to antigen-presenting cells (APCs) closely. h4-1BB is a 27 kDa protein, consisting of an intracellular domain (42 AA), an extracellular domain (169 AA), a transmembrane region (27 AA), and a putative signal peptide (17 AA).
In tumor immunotherapy, long-lasting functionally active T cells are thought to be requisites. Multiple molecules and cells participate in the activation of naïve T cells and this complicated mechanism could be summarized into two signal pathways. The primary pathway depends on the T-cell receptor (TCR): MHC: antigen complex. The second pathway relies on the co-stimulation process with many co-stimulatory receptors participating, such as h4-1BB, hOX40, etc. Studies demonstrated that h4-1BB and hOX40 signals could promote proliferation, enhance expansion, prolong the survival of T cells activated by the primary pathway, and also increase the production of cytokines.
Fig.1 Diagrammatic presentation of the T-cell activation process. (Cheuk, 2004)
Using anti-h4-1BB or anti-hOX40 agonist antibodies could potentiate anti-tumor immunity. However, clinically targeting either h4-1BB or hOX40 as a monotherapy reveals limited capacity to treat advanced cancer. Besides, anti-h4-1BB agonist antibodies result in systematic adverse effects (AEs) due to h4-1BB’s widespread expression over the whole body. Therefore, to enhance efficacy against tumor and minimize the AEs, combinational use of anti-h4-1BB and anti-hOX40 agonist antibodies is considered as a promising approach in cancer treatment and synergistic effects have been confirmed. Studies suggest that the effect in enhancing the immune function of CD8+ T cells by activating both h4-1BB and hOX40 receptors exceeded either monotherapy. Co-stimulating hOX40 and h4-1BB receptors could expand not only CD8+ T cells, but CD4+ T cells as well. Moreover, the expansion of T regulatory cells (Tregs) was limited by dual co-stimulation.
Fig.2 Targeting 4-1BB mediates immune response. (Chester, 2018)
The co-stimulatory receptors expressed on the tumor-infiltrating T cells could serve as targets just like the co-inhibitory receptors (CTLA-4 and PD-1). hOX40- and h4-1BB-targeted therapies have been evidenced with the capability of augmenting the anti-tumor immunity in multiple types of cancers. Synergistically combinational utilization of anti-hOX40 and anti-h4-1BB agonist antibodies seems to be a promising tumor therapy. With advanced technology, Creative Biolabs has years of experience in providing CRO services for our global clients. We can not only provide the well-established hOX40/4-1BB dual humanized mice, but also the related analysis services. Our scientists will work closely with you to advance your drug development. Please feel free to contact us for further discussions.
Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:
References
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