Magic™ Humanized PD-1/4-1BB Dual Immune Checkpoint Knock-In Mice

Immunotherapy is a speedily expanding field of oncology aimed at targeting, not the tumor itself, but the immune system combating the cancerous lesion. And immune checkpoint inhibitors are now widely accepted as a key component of the therapeutic strategies in cancer. Several recent clinical studies show that the various immune checkpoint pathways play a critical role in the maintenance of tumor tolerance in humans since checkpoint blockade is associated with objective tumor responses and improved overall survival. With extensive experience in antibody-based drug discovery, Creative Biolabs has successfully established an efficient Magic™ “humanized” animal platform and can provide humanized PD-1/4-1BB dual immune checkpoint knock-in mice for our clients all over the world.

PD-1 and 4-1BB Signaling Pathway

Programmed death-1 (PD-1) is an inhibitory receptor expressed on activated T cells as well as other immune cells, and its expression can be relevant with T-cell exhaustion. PD-1 binds to two ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC) that are often overexpressed on tumor cells. The interactions of PD-1 and its ligands deliver a negative signal to T cells to dampen the immune response. Anti-PD1 therapies show a significant improvement in response to many standards of care regimens, but there is a significant need to further increase cancer patient responses.

4-1BB (also known as TNFRSF9 and CD137) belongs to the TNF receptor family, which includes multiple T cell co-stimulatory receptors that have been targeted with agonist antibodies including GITR, CD40, CD27, HVEM, LIGHT, APRIL, and TWEAK. 4-1BB plays a crucial role in sustaining effective T cell immune responses and in generating immunological memory. The expression profile of 4-1BB, as well as its unique ability to enhance robust effector responses in multiple subsets of lymphocytes relevant for tumor immunity, makes 4-1BB a uniquely appealing target for immunotherapy. Anti-4-1BB agonist has been investigated extensively in preclinical studies to treat cancer when combined with other immunomodulatory antibodies.

Combination of Anti-PD-1 and Anti-4-1BB Immunotherapies

It has been reported that 4-1BB activation and PD-1 blockade resulted in synergistic antitumor effects in murine B16F10 melanoma. The efficacy of anti-4-1BB/anti-PD-1 combination was dependent on IFNγ and CD8⁺ T cells. Anti-4-1BB/anti-PD-1 combination allows increasing availability of target molecules for therapeutic antibodies on CD8⁺ T cells and could promote antitumor immune response in the tumor microenvironment.

Magic™ Humanized PD-1/4-1BB Dual Immune Checkpoint Knock-In Mice Fig.1. Overview of the immune inhibitory molecules that compromise endogenous T-cell antitumour activity. (Khalil et al. 2016)

Development of Humanized PD-1/4-1BB Dual Immune Checkpoint Knock-In Mice

Immune checkpoint inhibitors, like anti-PD-1/PD-L1 antibodies, are regarded as revolutionizing therapeutic concepts in the treatment of cancer. Moreover, the latest clinical data combining different blockade in cancer patients showed an increased rate of objective tumor responses as compared with blocking one checkpoint alone, supporting the notion that combinatorial checkpoint blockade may result in increased clinical benefit. Cotreatment of anti-4-1BB with anti-PD-1 was supposed to represent a mechanistically rational combination to maximize the antitumor potential. As a world leader in this field, Creative Biolabs has already launched an array of well-established Magic™ “humanized” animal models, including the humanized PD-1/4-1BB dual immune checkpoint knock-in mice. Please feel free to contact us for more detailed information.