Blocking the PD-1/PD-L1 axis which is the most attractive negative-regulatory signaling pathway has significant efficacy in multiple cancer patients, however, some limitations still exist. To promote the anti-tumor efficacy and expand the number of beneficiaries, simultaneously inhibiting both the PD-1/PD-L1 pathway and the SIRPα/CD47 pathway seems more potential in clinical treatment. Creative Biolabs has successfully established an optimized Magic™ “humanized” animal platform to offer specialty manipulated hPD-1/hPD-L1/hSIRPα/hCD47 quadruple humanized mice for our clients all over the world.
Human programmed cell death protein-1 (hPD-1) is an important immunosuppressive molecule, which belongs to the CD28 superfamily and is a transmembrane protein encoded by the PDCD1 gene. hPD-1 is an induced protein, that is, T cells hardly express hPD-1 when they are not activated. Only after T cells are activated, they will induce hPD-1 expression. In addition to being expressed on activated T cells, hPD-1 is also expressed on activated B cells, natural killer cells (NK cells), monocytes, and some tumor cells. Human programmed cell death ligand-1 (hPD-L1) is a 40kD transmembrane protein encoded by the CD274 gene, which is induced to express on the surface of T cells, B cells, dendritic cells (DCs), macrophages, mesenchymal stem cells, bone marrow-derived mast cells and non-hematopoietic cells. The hPD-L1 on tumor tissues that respond to interferon and other inflammatory factors may be rapidly upregulated.
Human CD47 (hCD47) is also called integrin-associated protein (IAP) and is a member of the immunoglobulin superfamily. hCD47 is widely expressed on the surface of cells and can interact with human signal-regulatory protein α (hSIRPα) to mediate apoptosis, proliferation, and a series of reactions such as immunization. hSIRPα is widely expressed in many tissues. The combination of the hCD47 and hSIRPα makes the tumor cells resistant to host immune surveillance, which is one of the mechanisms of immune escape.
After binding the extracellular IgV-like structure of hPD-1 to hPD-L1, it promotes the phosphorylation of tyrosine in the ITSM domain of hPD-1, which in turn causes the dephosphorylation of downstream protein kinases Syk and PI3K, inhibiting downstream AKT and ERK. The activation of the pathway ultimately inhibits the transcription and translation of genes and cytokines required for T cell activation and plays a negative role in regulating T cell activity. hPD-1 promotes the apoptosis of antigen-specific T cells in lymph nodes through the interaction with its ligand hPD-L1. At the same time, hPD-1 binding to hPD-L1 inhibits Treg apoptosis and plays a vital role in maintaining the body's immune tolerance. Because hPD-1 is expressed only in activated T cells, the inhibitory signal mediated by hPD-1 only acts on T cells that have produced a tumor-specific response. The function of hPD-1+ CD8+ T cells is blocked by hPD-1 mediated inhibitory signal, thus, this mechanism is also called "tumor-specific selective suppression of T cells".
Similar to T cell activation, switching on macrophages seems to be a two-step process, which requires both up-regulating the "eat me" signal and down-regulating the "don't eat me" signal. The binding of hCD47 on the cell surface to the hSIRPα on phagocytes inhibits phagocytosis. Phagocytosis requires coordinated activation of the “eat me” signal and simultaneous interruption of the “don’t eat me” signal. No single event is sufficient to trigger a phagocytic chain reaction against cancer cells. Cancer cells themselves, as a kind of mutated cell, a special protein on the cell surface, will send a signal of "eat me" to our immune system. Based on this signal, the immune system in our body recognizes which objects need to be eliminated. But in most cases, cancer cells will evade the surveillance of the immune system through disguise. Most of the cancer cells have an overexpression of hCD47 protein, including various solid tumors and blood tumors. Thus, cancer cells depend on the hCD47 to avoid the phagocytosis of macrophages by transmitting a "don't eat me" signal. Therefore, both hSIRPα and hCD47 represent potential and broad anti-tumor immune targets.
Fig.1 The SIRPα/CD47 signaling pathway. (Vonderheide, 2015)
Clinically, in patients with a variety of tumors, applying hPD-1 or hPD-L1 immune checkpoint inhibitors can release the immunosuppression and expand the tumor-infiltrating CD8+ T cells, thus restoring the identification and killing effect on tumor cells. However, the occurrence of the failure of monotherapy and drug resistance, the combination of multiple drugs targeting different receptors or ligands has become the major research interest. The novel quadruple combination of anti-hSIRPα, anti-hCD47, anti-hPD-1, and anti-hPD-L1 antibodies is worthy of clinical investigation. Creative Biolabs has provided many kinds of stable and verified Magic™ “humanized” animal models, including the hPD-1/hPD-L1/hSIRPα/hCD47 quadruple humanized mice for our global clients. We have accumulated much experience in preclinical drug development. If you are willing to carry out your study projects which are performed using these humanized mice, please feel free to contact us for further discussions. Our scientists will work closely with you in your study implementation.
Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:
Reference
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