Monoclonal antibodies (mAbs) are a rapidly growing class of human therapeutics representing an increasing number of drugs under development. Monoclonal antibodies have been used for treating cancer, autoimmune diseases, and infectious diseases in clinical practice. Antibody therapy directly targeted several immune checkpoints is demonstrating significant success in the past few years. Particularly, cancer therapy based on monoclonal antibodies against checkpoints of immune reaction is now regarded as a breakthrough method in oncological immunology. Nowadays, it is an urgent need to increase success rates of this immunotherapeutic approach and to extend it to more cancer types. Creative Biolabs, who always focuses on drug discovery and animal model, has successfully launched and established an exclusive Magic™ “humanized” animal model platform, which can provide the humanized PD-L1/CTLA-4 dual immune checkpoint knock-in mice to our clients all over the world.

PD-L1 Pathway

PD-L1 (Programmed death ligand 1), also known as B7-H1, is an immune checkpoint expressed on the tumor cell surface, or on neighboring host immune cells in the tumor microenvironment. It binds to PD-1 on T-cell lymphocytes and negatively regulates the activity of T cells and other immune cells.

Magic™ Humanized PD-L1/CTLA-4 Dual Immune Checkpoint Knock-In MiceFig.1. PD-L1-mediated inhibition of T cells. T cells recognizing tumor antigens can be activated to proliferate, secrete inflammatory cytokines, and resist cell death. Prolonged TCR stimulation during an ongoing immune response can cause upregulated PD-1 expression. Tumor cells can express PD-L1 (and PD-L2, not shown) as a consequence of inflammatory cytokines and/or oncogenic signaling pathways. PD-1: PD-L1 binding inhibits TCR-mediated positive signaling, leading to reduced proliferation, reduced cytokine secretion, and reduced survival. (Buchbinder and Desai, 2016)

CTLA-4 Pathway

CTLA-4 (the cytotoxic T-lymphocyte antigen 4) is an immune checkpoint receptor expressed on the surface of T cells, which is a homolog of the immune co-stimulatory protein CD28. When bound to CD80 (B7-1) and CD86 (B7-2) proteins on antigen presenting cells (APCs), the cell surface molecule CD28 generates positive modulatory signals to the immune response. CTLA-4 competes with CD28 for binding the B7 family proteins with approximately 20 times greater affinity and provides negative modulatory signals in the early stages of an immune response.

Magic™ Humanized PD-L1/CTLA-4 Dual Immune Checkpoint Knock-In MiceFig.2. CTLA-4-mediated inhibition of T cells. T cells are activated when TCRs bind antigen displayed in the MHC on antigen-presenting cells in concert with CD28:B7-mediated costimulation. A, In the case of a weak TCR stimulus, CD28:B7 binding predominates, resulting in a net positive activating signal and IL-2 production, proliferation, and increased survival. B, In the case of a strong TCR stimulus, CTLA-4 expression is upregulated by increased transport to the cell surface from intracellular stores and decreased internalization. CTLA-4 competes with CD28 for binding of B7 molecules. Increased CTLA-4:B7 binding can result in a net negative signal, which limits IL-2 production and proliferation, and limits survival of the T cell. CTLA-4 indicates cytotoxic T-lymphocyte–associated antigen 4; IL-2, interleukin-2; MHC, major histocompatibility complex; TCR, T-cell receptor. (Buchbinder and Desai, 2016)

Combination of Anti-PD-L1 and Anti-CTLA-4 Immunotherapies

The cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) immune checkpoints are negative regulators of T-cell immune function. It has been demonstrated that combinational immunotherapy, by blockade of alternative inhibitory receptor pathways on T cells or accessory regulatory cells may lead to more efficient restoration of T cell function and improved tumor suppression capacity. Anti-CTLA-4 significantly inhibits T-regulatory cells (Treg cells), thus increasing the CD8+ T-cell to Treg (CD8+/Treg) ratio. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8+/Treg ratio and further encourages T-cell expansion. According to a phase Ib data published in The Lancet Oncology, the combination checkpoint blockade with the PD-L1inhibitor and the anti-CTLA-4 agent induced a response rate of 23% in patients with advanced non–small cell lung cancer (NSCLC).

Development of Humanized PD-L1/CTLA-4 Dual Immune Checkpoint Knock-In Mice

With extensive experience and advanced technology in the field of animal model, especially for humanized mouse model, Creative Biolabs has already established a group of well-established Magic™ “humanized” animal models. We take full account of the factors that may have impact on the expression of humanized protein to ensure fully humanization as well as the protein expression and signal transmission. Now we are proud to provide you with the humanized PD-L1/CTLA-4 dual immune checkpoint knock-in mice to make your antibody validation more reliable. Please feel free to contact us for more detailed information.

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

Reference

  1. Buchbinder, E. I.; Desai, A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. American journal of clinical oncology. 2016, 39(1), 98.

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