4-1BB is known as a costimulatory molecule, while programmed cell death-ligand 1 (PD-L1) is taken as an inhibitory molecule present on T cells. The combinational usage of anti-PD-L1 and anti-4-1BB agonistic antibodies could enhance anti-tumor immunity, thus attracting increasing interest as a clinical therapy for cancer patients. Creative Biolabs has successfully established an optimized Magic™ “humanized” animal platform to offer specialty manipulated hPD-L1/h4-1BB dual humanized mice for our clients all over the world.

hPD-L1/h4-1BB Molecule

Human programmed cell death-ligand 1 (hPD-L1) is a 40kD transmembrane protein and encoded by the CD274 gene. It is found on the surface of various cells, including T cells, B cells, dendritic cells (DCs), macrophages, etc. The hPD-L1 also presents on tumor cells and its expression level would be rapidly up-regulated in the tumor microenvironment.

Human 4-1BB (h4-1BB), also called CD137, is a member of the tumor necrosis factor receptor family (TNFRSF). h4-1BB molecule is composed of 255 amino acids and has four parts, including a signal peptide, an extracellular region, a transmembrane region, and an intracellular region. h4-1BB is an inducible costimulatory receptor expressed on activated CD4+ and CD8+ T cells, natural killer T cells (NKT), natural killer cells (NKs), DCs, macrophages, eosinophils, neutrophils, mast cells, and regulatory T cells (Tregs).

hPD-L1/h4-1BB Signal Pathway

hPD-L1 binding to its receptor hPD-1 is related to the suppression of the immune system. Once hPD-1 and hPD-L1 combine, they will transmit a negative regulatory signal to T cells, inducing T cells to enter a resting state. Specifically, the hPD-1/hPD-L1 signaling pathway reduces the proliferation or induce apoptosis of CD8+ T cells, resulting in that the host immune system unable to recognize cancer cells. Thus, cancer cells escape the attack from immune cells.

As a powerful T cell-specific costimulatory molecule, h4-1BB can stimulate T cell activation and maintain B-7: CD28-mediated cell activation and further enhance CD8+ T cell proliferation and survival. h4-1BB signaling in DCs upregulates B7-1 and B7-2, and increases the secretion of IL-6 and IL-12 from DCs. The agonistic anti-h4-1BB monoclonal antibody enhances DCs’ ability to stimulate T cell proliferation and increases STAT3 phosphorylation, thereby enhancing the CD8+ T cell response. The activation of primary monocytes by immobilized anti-h4-1BB agonist antibody in monocytes can induce the production of IL-8 and TNF-α. After h4-1BB is triggered, NKs up-regulate h4-1BB and increase cytotoxicity in response to h4-1BB activation.

4-1BB pathway in non-T cells. Fig.1 4-1BB pathway in non-T cells. (Vinay, 2011)

Development of hPD-L1/h4-1BB Dual Humanized Mice

Blocking hPD-1/hPD-L1 axis using the anti-hPD-L1 antibody could promote the activation of the T cells. Activating h4-1BB costimulatory signal by anti-h4-1BB agonist antibody can induce cell proliferation, cytokine expression, and support T cell effector function. Thus, combining the anti-hPD-L1 antibody and anti-h4-1BB agonist antibody would increase the activity of cytotoxic T cells against tumor cells, which is a new strategy for cancer treatment. With advanced technology, Creative Biolabs provides stable and verified hPD-L1/h4-1BB dual humanized mice for our global clients. Also, our professional R&D team is willing to work with you to assist you in our study projects. We have provided preclinical CRO services for many years and accumulated much experience. If you have any questions about your study, please let us know and our scientists will provide you with scientific solutions.

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

Reference

  1. Vinay, D. S.; et al. 4-1BB signaling beyond T cells. Cell Mol Immunol. 2011, 8(4): 281-284.

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