As we all know, the anti-hOX40 agonistic antibody could activate the adopted immune response, and the anti-hTLR9 agonistic antibody could stimulate the natural immune response. Thus, combining the above two different antibodies could be a more effective therapy for cancer treatment, especially for metastatic cancer. Creative Biolabs has successfully established an optimized Magic™ “humanized” animal platform to offer specialty manipulated hTLR9/hOX40 dual humanized mice for our clients all over the world.
Human TLR9 (hTLR9) is an important member of the human Toll-like receptors (hTLRs) family. hTLRs belong to pathogen-associated molecular patterns (PAMPs) recognition receptors. hTLR9 contains 1032 amino acids and is a type 1 transmembrane protein. The molecular structure of hTLR9 is composed of an extracellular region, a transmembrane region, and a cytoplasmic region. It has multiple leucine-rich repeat (LRR), a rich A cysteine-containing domain, a transmembrane domain, and a TIR (Toll/interleukin-1 receptor) domain. hTLR9 is mainly expressed in immune cells or tumor cells of epithelial origin. Recently, it has been found in cervical, liver, colorectal, gastric, prostate, breast, ovarian, and esophageal cancer. The expression intensity of hTLR9 is positively correlated with tumor invasion, metastasis, and poor prognosis.
Human OX40 (hOX40), is also called CD134 or TNFRSF4 (tumor necrosis factor receptor superfamily member 4). It was originally defined as a T cell activation marker and was later found to be a member of the NGFR/TNFR superfamily with co-activation function. The hOX40 gene is located on human chromosome 1 and encodes a 50kD type 1 transmembrane glycoprotein. It has dominant expression on activated effector T cells (Teffs) and regulatory T cells (Tregs), but also natural killer T cells (NKTs), natural killer cells (NKs), and neutrophils.
hTLR9 expressed by tumor cells can recognize exogenous TLR9 ligands and be specifically activated to initiate the downstream IKK/NF-κB, MAPK/AP-1, and PI3K/Akt signal cascade reactions. hTLR9-overexpressing tumor cells respond more significantly to hTLR9 ligand stimulation, showing more significant cell proliferation which mainly depends on cell cycle-dependent protein kinase 2 and PI3K/Akt signal activation. The up-regulated expression of TLR9 gene in tumor cells is accompanied by the enhancement of tumor cell invasion and metastasis ability, specifically, promoting the secretion of immunosuppressive cytokine IL-10, inhibiting the production of anti-tumor cytokine IL-12, and up-regulating the expression level of IL-1/8, intercellular adhesion molecules-1, matrix metalloproteinase-2, CXCR4 and other transfer-related molecules.
hOX40 combines with its ligand hOX40L (also called CD252 or TNFSF4) to transmit costimulatory signals. The interaction of hOX40 and hOX40L can recruit TNFR-related molecules in the intracellular region of hOX40 to form a signaling complex containing IKKα, IKKβ, PI3k, and PKB (Akt). Cooperating with TCR signaling, hOX40 also enhances the intracellular Ca2+, thereby enhancing NFAT entry into the nucleus. hOX40 can activate the classical NF-κB1 pathway, non-classical NF-κB2 pathway, PI3k/PKB, and NFAT pathways, thereby regulating genes that control T cell division and survival, as well as promoting the transcription of cytokine genes and the expression of cytokine receptors. hOX40 signaling can cause down-regulation including CTLA-4 and Foxp3. In short, when hOX40 binds to its ligand hOX40L, it helps to improve the immune system's response capacity.
Fig.1 OX40/OX40L pathway impacts the T cell lifespan. (Jensen, 2010)
To increase the single antibody effect and mobilize the host immune system against the tumor cells, targeting both hOX40 and hTLR9 pathways may be a key strategy for more effectively activating anti-tumor immune responses. There are many clinical trials underway of this combinational utilization. Creative Biolabs is a professional CRO company with many years of experience in drug development. We have assisted our global clients in their study project using our Magic™ “humanized” animal models. If you are planning to carry out research using these humanized mice, please feel free to contact us for more details.
Creative Biolabs also offers other various Humanized Mouse Models you may be interested in:
Reference
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