Immunotherapy with single immune checkpoint blockade has shown remarkable rapid and durable clinical benefit for various cancer patients, providing a new method of immuno-oncology for cancer treatment. Nowadays, combining immunotherapeutic antibodies in cancer treatment has shown benefits over single agents. The prospect of combining agonistic with antagonistic agents is of great potential since this combination therapy represents a real immunologic opportunity to ‘step on the gas' while ‘cutting the brakes'. As always being a leading company providing genetically customized mouse models, Creative Biolabs develops the Magic™ dual immune checkpoint “humanized” mouse models for your study of novel antibody drug discovery, including the humanized CTLA-4/OX40 dual immune checkpoint knock-in mice with the best guarantee in the industry.
CTLA-4 and OX40 Immune Checkpoint Pathway
CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), which is also known as CD152 (cluster of differentiation 152), is a transmembrane glycoprotein that functions as an immune checkpoint. CTLA-4 is a homolog of the immune co-stimulatory protein CD28 and downregulates immune responses. It is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation. When binding to CD80 (B7-1) and CD86 (B7-2) on the surface of antigen-presenting cells (APCs), CTLA-4 transmits an inhibitory signal to T cells by recruiting a phosphatase to the T cell receptor (TCR), thus attenuating the signal.
OX40 is a co-stimulatory transmembrane glycoprotein receptor, which is expressed on activated cytotoxic T cells and regulatory T cells (Tregs). When binding to its ligand, OX40L expressed on APCs, the interaction of OX40 and OX40L would recruit TNFR-associated (TRAFs) molecules to the intracellular domain of OX40 and then induce nuclear factor kappa enhancer of activated B cells, which results in increased T-cell proliferation, cytotoxic activity (e.g. IL-2, IL-4, IL-5, IFN-γ), and survival.
Fig.1. Activating and suppressive interactions between T-lymphocytes, tissue macrophages and dendritic cells in tumour microenvironment at molecular level. (Paglialunga, et al., 2016)
Combination of Anti-CTLA-4 and Anti-OX40 Immunotherapies
Ligation of OX40 with an agonist anti-OX40 mAb could enhance anti-tumor immunity by amplifying CD4+ and CD8+ T cell clonal expansion, effector differentiation, as well as turning off the suppressive activity of FoxP3+CD4+ regulatory T cells (Treg). What's more, blockade of CTLA-4 also enhances anti-tumor immunity by promoting effector T cell responses and alleviating the suppressive capacity of Treg. Nevertheless, monotherapies with anti-OX40 or anti-CTLA-4 mAbs may have limited efficacy, particularly for the poorly immunogenic tumors. Preclinical studies have shown that combination of anti-OX40/anti-CTLA-4 therapy induces CD8+ T cell proliferation and differentiation as well as the expansion of effector CD4+ T cells, which are responsible for producing Th1 and Th2 cytokines. But the combination therapy doesn't inhibit the expansion or suppressive function of regulatory T cells (Treg). Moreover, combined anti-OX40/anti-CTLA-4 therapy has been proved to significantly enhance tumor regression and survival of prostate or sarcoma tumor-bearing hosts relative to therapy with either agent alone.
Development of Humanized CTLA-4/OX40 Dual Immune Checkpoint Knock-In Mice
Preclinical research data demonstrates that combined anti-CTLA-4 /anti-OX40 immunotherapy contributes to potent anti-tumor immunity, and thus indicate that more research and evaluations of this combination regimen to boost tumor immunotherapy is warranted. To meet this end, Creative Biolabs has already established a series of validated dual “humanized” immune checkpoint knock-in mouse models using our exclusive homologous recombination technology, which ensures fully humanization as well as the precise protein secretion. Currently, we are ready to provide the customized CTLA-4/OX40 dual immune checkpoint knock-in mouse for researchers around the world, with assurance of functional humanized gene for both targets. And our experienced scientists also provide various laboratory evaluation of assays as well as professional technical support. 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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