Even though immunotherapy has shown great potential in improving outcomes for patients with cancer, particularly through a combination of agents targeting immune inhibitory pathways, how to optimally combine the many new immunotherapy agents being developed remains a main question in cancer research. Creative Biolabs, who is focused on the discovery and development of antibody-based drugs, has successfully launched a well-established Magic™ “humanized” animal platform to offer humanized PD-1/OX40 dual immune checkpoint knock-in mice for our clients all over the world.

PD-1 and OX40 Signaling Pathway

Immune checkpoint inhibitors have great success in generating long-lasting responses in some cancer patients; however, these agents, particularly the anti-PD-1/PDL-1 antibodies, do not work for the majority of patients. Equipped with an increasing understanding of T-cell biology and the tumor microenvironment, studies that focus on testing combinations of immunotherapies to increase the number of patients who could benefit from this relatively new class of cancer treatments have been of great interest to researchers.

The agonist OX40 (also been designated as CD134) plays a vital role in a potent co-stimulatory pathway that can augment T-cell memory, proliferation, and antitumor activity. The ligand of OX40 is OX40L, which is also not expressed on resting antigen presenting cells but after their activation. When stimulated by its ligand, OX40-OX40L complex promotes activation, differentiation, and expansion of T cells, leading to enhanced T-cell effector function and antitumor responses. PD-1 (also known as CD279) is an immune checkpoint protein present on the surface of activated T cells. PD-L1, the ligand of PD-1 is generally expressed on the surface of dendritic cells or macrophages. When bound to PD-L1, an inhibitory signal released by PD-1/PD-L1 pathway is transmitted into the T cell to reduce cytokine production and suppress T-cell proliferation. Anti-PD-1 antibodies release the “brakes” cancer cells apply on T cells via PD-1 and enable the T cells to carry out their antitumor function.

Magic™ Humanized PD-1/OX40 Dual Immune Checkpoint Knock-In Mice Figure 1. Therapies that Might Affect the Cancer-Immunity Cycle. (Chen et al., 2013)

Combination of Anti-PD-1 and Anti-OX40 Immunotherapies

Immune checkpoint inhibitors have great success in generating long-lasting responses in some cancer patients; however, these agents, particularly the anti-PD-1/PDL-1 antibodies, do not work for the majority of patients. Equipped with an increasing understanding of T-cell biology and the tumor microenvironment, studies that focus on testing combinations of immunotherapies to increase the number of patients who could benefit from this relatively new class of cancer treatments have been of great interest to researchers.

It has been reported that boosting the T cells first with anti-OX40 followed by treatment with anti-PD-1, but not in the reverse order, could significantly improve the therapeutic efficacy of the combination in mice refractory to anti-PD-1. On the contrary, it has also been demonstrated that the simultaneous addition of anti-PD-1 to anti-OX40 inhibited the T-cell specific positive effects of anti-OX40 and suppressed its therapeutic efficacy.

Development of Humanized PD-1/OX40 Dual Immune Checkpoint Knock-In Mice

Above all, to investigate the approaches to combination of anti-OX40 and anti-PD-1 immunotherapies is still deeply concerned. As a world leader in the industry of drug discovery, Creative Biolabs has successfully launched an array of well-characterized Magic™ “humanized” animal models, which can provide you with the humanized PD-1/OX40 dual immune checkpoint knock-in mice. Our Magic™ dual immune checkpoint KI mice are generated by the copulation of single gene knock-in mice, ensuring that each single humanized gene is functional. Please feel free to contact us for more details.

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

Reference

  1. Chen, D. S., and Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013, 39(1), 1-10.

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