Therapeutic antibodies designed to block immune checkpoint receptors or activate immune-stimulatory receptors are a potent strategy to treat cancer and function by modulating a patient's own immune system. The combination immunotherapies that associate multiple immune inhibitory receptors, has shown potentially better therapeutic outcomes compared with treatment of a single blockade. Given this, Creative Biolabs has developed a series of Magic™ dual immune checkpoint “humanized” mouse models for in vivo assay of novel combination immunotherapies, including the humanized PD-L1/OX40 dual immune checkpoint knock-in mice.

PD-L1 and OX40 Immune Checkpoint Pathway

PD-L1 (Programmed death-ligand 1), alternatively named CD274 (cluster of differentiation 274) or B7-H1 (B7 homolog 1), is a ligand of PD-1 and act as a coinhibitory receptor. PD-L1 is expressed on resting T cells, B cells, dendritic cells, macrophage, vascular endothelial cells and pancreatic islet cells; and it has also been found on the tumor cell surface, or on neighboring host immune cells in the tumor microenvironment. PD-L1 inhibits the activation of T-cells and thus suppressing T-cell attack and inducing tumor immune escape, through binding with PD-1 receptor on T cells. Blockading the PD-1/PD-L1 pathway could reverse the tumor microenvironment and enhance the endogenous antitumor immune responses.

OX40, alternatively called CD134 (cluster of differentiation 274) or TNFRSF4 (Tumor necrosis factor receptor superfamily member 4), is a member of the TNFR-superfamily of receptors and functions as a secondary co-stimulatory molecule. OX40 is expressed on the surface of activated cytotoxic T cells and regulatory T cells (Tregs) and is not constitutively expressed on resting naïve T cells. The interaction of OX40 and OX40L could recruit TNFR-associated (TRAFs) molecules to the intracellular domain of OX40. TRAF2 and 3 play a crucial role in cell survival by activating either the canonical NF-κB1 pathway or the noncanonical NF-κB2 pathway.

Combination of Anti-PD-L1 and Anti-OX40 Immunotherapies

According to an outcome of a phase Ib study, a combination therapy regimen of a PD-L1 inhibitor and the investigational OX40 agonist shows good tolerance and early signs of antitumor activity in solid tumors. Preclinical models have shown that anti-OX40 antibodies have a dual mechanism of action. When binding to OX40, the antibodies can attack the tumor through both reduction of regulatory T cells and co-stimulation of effector T cells. Some researchers hypothesized that this dual mechanism of action would synergistically improve the anti-tumor performance with PD-L1 blockade since OX40 promotes T-cell priming and generation of T-cell memory which results in PD-L1 induction via IFN-γ-upregulation.

Development of Humanized PD-L1/OX40 Dual Immune Checkpoint Knock-In Mice

Numerous clinical trials demonstrate that combination therapies depend on checkpoint inhibitor antibodies (Abs) such as for PD-1 or its ligand (PD-L1) together with other immune checkpoint receptors are showing improved antitumor effects. Consequently, combination of novel mAbs that targeted various immune checkpoint receptors is now widely been evaluated. Our experienced scientists in Creative Biolabs has generated dual “humanized” immune checkpoint knock-in mouse models with comprehensive validation and immune-profiling data for your drug discovery, including the PD-L1/OX40. We guarantee both the humanized transgene to be effective and fully-functional. We also provide the most professional technical support to assist you in your drug discovery studies. Please feel free to contact us for more information.

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

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