The expression of immune checkpoint molecules on T cells represents a significant mechanism that the immune system utilizes to regulate responses to self-proteins. Antibodies that recognize certain immune cell surface molecules can be used to enhance or target immune responses against tumors. Such monoclonal antibodies do not directly eliminate the tumor cells but are directed at membrane receptors or ligands that regulate the T-cell response. Therapies with these monoclonal antibodies aim to generate new tumor-specific CTLs (cytotoxic T-lymphocyte) from naive CD8+ T cells and to reactivate potentially pre-existing tumor-specific CTLs. Nowadays, the key issue is to increase success rates of this immunotherapeutic approach and to extend it to other cancer types. As always being focused on drug discovery and animal model, Creative Biolabs has successfully established an array of Magic™ “humanized” animal models that can be delivered to our clients all over the world, including the humanized PD-1/CD27 dual immune checkpoint knock-in mice.

PD-1 and CD27 Signaling Pathway

Programmed death-1 (PD-1) is an inhibitory receptor that expressed on activated T cells as well as other immune cells including natural killer (NK) cells, B cells, and some myeloid cells. When interacting with its ligands PD-L1 or PD-L2, PD-1 deliver a negative signal to T cells to suppress the immune response. PD-1 plays a vital role in tolerance to self-antigens and in modulating T cell responses. Chronic infection models have shown that blocking PD1 interactions can reverse T cell exhaustion and induce an anti-tumor response.

The costimulatory molecule CD27 is a member of the tumor necrosis factor receptor superfamily (TNFRSF) and is constitutively expressed on most of the mature T cells, memory B cells, and a portion of natural killer (NK) cells. The interaction of CD27 with its ligand CD70 plays key roles in the following processes: 1) costimulation through CD27 on T cells causes activation, proliferation, survival, and maturation of effector capacity and memory; 2) costimulation through CD27 on B cells activates and promotes the generation of plasma cells, proliferation, and the production of immunoglobulin; 3) costimulation through CD27 on NK cells induces cytolytic activity.

Magic™ Humanized PD-1/CD27 Dual Immune Checkpoint Knock-In MiceFig.1. Costimulatory and coinhibitory receptors in the immune synapse. (Coaña, et al. 2015)

Combination of Anti-PD-1 and Anti- CD27 Immunotherapies

Research has shown that anti-CD27-mediated co-stimulation synergized with co-inhibitory checkpoint blockade to restore functions of exhausted, helpless CD8+ T cells. When combined with anti-PD-L1, stimulation of T cells through CD27 primarily acted to block molecular programs for anergy or quiescence, driving CD8+ T cells to undergo rapid proliferation and terminal differentiation. CD27-mediated co-stimulation activates several pathways downstream of the TCR that are inhibited through PD-1 signaling, including PI3K-Akt, NF-κB, and NFAT. Clinical results indicate that the combination of anti-CD27 agonist antibody and anti-PD1 antibody is well tolerated, associated with strong biological signals, and has evidence of clinical activity in subsets of patients with tumor types that are typically resistant to PD-1 inhibitor monotherapy.

Development of Humanized PD-1/CD27 Dual Immune Checkpoint Knock-In Mice

Previous clinical studies have identified individual roles for each of the immune checkpoint molecules, but more recent data indicate that coexpression of these immune checkpoint molecules occurs frequently on cancer-specific T cells as well as on pathogen-specific T cells in chronic infections. It has been demonstrated that blocking multiple checkpoints with specific monoclonal antibodies results in improved outcomes in various chronic viral infections as well as in a wide range of preclinical models of cancer. With extensive experience and advanced technology, Creative Biolabs has already established a group of well-established Magic™ “humanized” animal models, which can provide you with the humanized PD-1/CD27 dual immune checkpoint knock-in mice. Please feel free to contact us for more detailed information.

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

References

  1. Ahrends, T.; et al. CD27 Agonism Plus PD-1 Blockade Recapitulates CD4+ T-cell Help in Therapeutic Anticancer Vaccination. Cancer Research. 2016, 76(10):2921.
  2. Coaña, P. D.; et al. Checkpoint blockade for cancer therapy: Revitalizing a suppressed immune system. Trends in Molecular Medicine. 2015, 21(8):482.

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