It is well-known that T cell activation needs multiple receptors, including the cluster of differentiation 28 (CD28) which is a costimulatory receptor. The combinational use of agonist antibody against co-stimulatory receptors and antagonistic antibodies against immune checkpoints, such as anti-CD28 agonist antibody and anti-PD-1 antibody, could more effectively stimulate the anti-tumor immunity in cancer patients. Creative Biolabs has successfully established an optimized Magic™ “humanized” animal platform to offer specialty manipulated the hPD-1/hCD28 dual humanized mice for our clients all over the world.
Human PD-1 (programmed cell death protein 1, hPD-1), is a receptor protein on the surface of T cells. The ligation of hPD-1 and human programmed cell death ligand 1 (hPD-L1) can transmit inhibitory signals to T cells and reduce T cell proliferation.
CD28 is the only B7 family receptor constitutively expressed on naïve T cells. After combining of T cell receptor (TCR) with MHC molecules, activating T cell also needs CD28: B7 costimulatory signal. T cells have the ability to express multiple cytokines after co-activated by both CD28 and TCR. Mature T cells express hCTLA-4, which competes with hCD28 to bind B7, thus inhibiting its over-activation. hCD28 agonist antibodies can activate T cells and promote immune responses.
Tumor cells escape destruction by T cells by producing hPD-L1 on the membrane surface. Its mechanism of action is recognized as drug targets and has been adopted to design specific antibodies against hPD-1. hCD28 is a costimulatory receptor and a key mediator of T cell signaling after TCR activation. After binding to ligands B7-1 (CD80) and B7-2 (CD86), hCD28 activates and drives downstream signals of T cell function, proliferation, and survival. The phosphoinositide 3-kinase (PI3K) and T cell nuclear factor (NFAT) signal pathways could be activated by the ligation of hCD28 to its ligands. The unique feature of hCD28 is that it can also significantly induce JNK and NF-κB signaling. hCD28 can recruit the regulatory subunit of PI3K to the proximal membrane YXXM motif of its intracellular domain. PI3K then drives the phosphorylation activation of AKT and the activation of NFAT. Also, the distal end of the hCD28 membrane contains proline-rich motifs that can interact with proteins containing SH3 domains, such as growth factor receptor-binding protein 2 (GRB2) and lymphocyte-specific protein tyrosine kinases (LCK), which can mediate signal transduction through complexes of NF-κB, NK, and adapter 1 (AP1).
Fig.1 Structure of CD28/B7 superfamily members. (Sharpe, 2002)
The targets of immune agonist antibodies in the current study mainly belong to the B7/CD28 family and the tumor necrosis factor receptor superfamily (TNFRSF). The hCD28 agonist antibody could further augment the activation of T cells and stimulate the anti-tumor immunity in combination with other immune checkpoint inhibitors, such as anti-hPD-1 antibody. With advanced technology, Creative Biolabs has accumulated lots of experience in establishing multiple Magic™ “humanized” animal models, including the hPD-1/hCD28 dual humanized mice. We have provided professional preclinical CRO services for our clients from all over the world. If you have any problems in your drug development, please feel free to contact us for further discussions.
Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:
Reference
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