Immune checkpoint inhibitors have appeared to be an effective novel class of anti-cancer therapy. They have changed the treatment perspective for a series of tumors, including melanoma, non-small cell lung cancer, and breast cancer, particularly those with a high mutational load. Several studies demonstrate that dual checkpoint blockade with specific monoclonal antibodies could profoundly attenuate the growth of tumors in vivo and improve survival in a wide range of tumors. Creative Biolabs currently provides you with unique transgenic mouse models based on our Magic™ “humanized” animal model platform, including the humanized PD-1/CTLA-4 dual immune checkpoint knock-in mice.
PD-1 and CTLA-4 Immune Checkpoint Pathway
Programmed death-1 (PD-1) is a costimulatory receptor that belongs to the B7/CD28 family. PD-1 is expressed on numerous immune cells such as activated T cells, natural killer (NK) cells, B cells and some myeloid cells. PD-1 regulates T-cell activation by delivering a negative signal to T cells to suppress the immune response when binding to its ligands PD-L1 or PD-L2. This kind of PD-1 binding inhibits T-cell proliferation, and interferon-g (IFN-g), tumor necrosis factor-a, and IL-2 production, and decreases T-cell survival. PD-1 expression is a hallmark of “exhausted” T cells which have experienced high levels of stimulation or reduced CD4+ T-cell help.
T-cell activation is a complex process that requires more than 1 stimulatory signal. CTLA-4 (the cytotoxic T-lymphocyte antigen 4), which is also known as CD152 (cluster of differentiation 152), is a CD28 homolog functioning as a costimulatory immune checkpoint. CTLA-4 is constitutively expressed on regulatory T cells but only upregulated on conventional T cells after activation, a phenomenon that is particularly notable in tumors. CTLA-4 acts as an "off" switch when binding to CD80 or CD86 on the surface of antigen-presenting cells (APCs).
Combination of Anti-PD-1 and Anti-CTLA Immunotherapies
The use of PD-1 monoclonal antibodies significantly enhances antitumor immunity by inhibiting the exhaustion of cytotoxic T cells. On the other hand, the CTLA-4/B7-1 or CTLA-4/B7-2 pathway also plays a vital role in the function of regulatory T cells (Treg), which are crucial for maintaining homeostasis and could negatively regulate antitumor immunity. CTLA-4 pathway blockade allows for activation and proliferation of more T-cell clones and reduces Treg-mediated immunosuppression. PD-1 pathway blockade restores the activity of antitumor T cells that have become quiescent. The differences in location, timing, and nonredundant effects of their actions indicate that anti-PD-1 therapies and anti-CTLA-4 therapies have the potential for additive or possibly synergistic effects in the treatment of advanced malignancy.
Fig.1. CTLA-4 and PD-1 pathway blockade. CTLA-4 indicates cytotoxic T-lymphocyte–associated antigen 4; MHC, major histocompatibility complex; PD-1, programmed death 1; PD-L1, programmed death ligand 1; TCR, T-cell receptor; Treg, regulatory T cell. (Buchbinder and Desai, 2016)
Development of Humanized PD-L1/CTLA-4 Dual Immune Checkpoint Knock-In Mice
Plenty of preclinical studies have shown decreased tumor growth and improved survival with CTLA-4 or PD-1 pathway blockade. Monoclonal antibodies (mAbs) that block CTLA-4 or PD-1 are now approved for treating melanoma and lung cancer and are in development for other tumor types, such as kidney cancer, prostate cancer, head and neck cancer. A dual pathway blockade of PD-1 and CTLA-4 could have a synergistic effect, resulting in a larger and longer lasting antitumor immune response. With extensive experience and advanced technology, Creative Biolabs has launched an array of well-established Magic™ “humanized” animal models. Our humanized PD-1/CTLA-4 dual immune checkpoint knock-in mice are generated via homologous recombination, which can express human PD-1 and CTLA-4 in the uncompromised immune system. 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
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