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My name is anti-cancer drugs. You all might be familiar with me. Most people don't want to have anything to do with me, all because of my opponent - the cancer cells, which are very horrible. However, as the old Chinese saying goes: "Good medicine tastes bitter", I actually help patients overcome the disease as quickly as possible. You can frequently see me in news reports, and now I would like to talk about myself.
According to WHO statistics, each year about 8,200,000 people die from cancer, which is expected to account for 13% of global deaths. Meanwhile, WHO predicted that cancer cases would increase by 70% in next 20 years. A statistical report in 2016 predicted the global top ten anti-cancer drugs in 2020, all of which are my family members.
Due to numerous family members and various mechanisms, I selectively introduce some to you. PD-1/PD-L1, a famous target recently, attracts a competitive market, which has a market peak as high as $35 billion. Merck (Merck), Bristol-Myers Squibb (BMS), AstraZeneca (AZN), Roche (Roche) were rushed to advance their clinical programs respectively. Since PD-1/PD-L1 is so valuable, you must be curious about what it is.
The full name of PD-1 is the molecule programmed death-1, which is identified by Ishida et al. via the subtractive hybridization technique in 1992[1, 2]. PD-1, a member of the CD28 family, contains two tyrosine residues in the cytoplasmic region. One is located near the N-terminus of immunoreceptor tyrosine-based inhibitory motif (ITIM), the other one is located near the C-terminus of the conversion immunoreceptor tyrosine-based inhibitory switch motif (the ITSM).
PD-L1 (CD274), a member of the B7 family, is the ligand of PD-1. It belongs to type I transmembrane protein and has a total length of 290 amino acids containing an Ig V-like domain, an Ig C-like domain, a hydrophobic transmembrane domain and an intracellular domain composed of 30 amino acids. Unlike other B7 family molecules, it has a negative role in the modulation of immune responses. PD-1 and PD-L1 are a pair of co-inhibitory molecules[3].
How does this pair of co-inhibitory molecules exert strong cytotoxicity toward the cancer cells?
Human health guardian T cells are activated by double signals. Firstly, T cell surface receptors (TCRs) recognize antigenic peptides presented by the antigen-presenting cells (APCs), which is the initial activation of T cells. Secondly, the costimulatory molecule on the surface of APCs binds to the costimulatory molecule on the surface of the corresponding T cell, which makes T cells fully activated to effector T cells. Under normal physiological conditions, the balance between costimulatory and coinhibitory molecules maintains T cells' immune effect to a proper depth and breadth, thereby maximally reducing damage to the surrounding normal tissues and avoiding autoimmune responses. However, tumor cells can abnormally upregulate the content of co-suppressed molecules PD-1 and PD-L1. After the binding of PD-L1 and PD-1, tyrosine phosphorylation in the ITSM domain recruits SHP-2 phosphatase, which can lead to dephosphorylation of Syk and phosphatidylinositol 3-kinase (PI3K) in the downstream, thereby delivering inhibitory signals to inhibit the function of lymphocytes and the release of cytokines, breaking the balance between costimulatory and coinhibitory molecules, inducing apoptosis of lymphocytes, further resisting the killing effect of lymphocytes, eventually leading to immune escape of tumor cells[4, 5].
Our family members are PD-1 inhibitors. The binding of PD-1 inhibitors to PD-1 impedes the binding of PD-1 to PD-L1, thereby preserving the activity of lymphocytes, keeping lymphocytes and cancer cells in a state of fighting continuously and killing cancer cells eventually.
Humans are constantly committed to expanding our family, which contributes to the discovery of TIM3, a new member of the anti-cancer family. When adaptive resistance to PD-1 inhibitors occurs in some patients, TIM3 inhibitors can effectively overcome the adaptation resistance and improve the survival rate. So, what is TIM3?
TIM, with the full name of T lymphocyte immune globulin mucin, also named CD366, was recognized in the process of studying asthma susceptible genes by Money, etc. in 2002[6]. Human TIM family includes only TIM1, TIM3 and TIM4, located on 5q33.3 of chromosome 5. The common structure of TIM molecules includes N-terminus of an immunoglobulin variable domain, mucin domain, a transmembrane region and the intracellular region.
As an important negative regulator of cellular immunity, TIM3 is highly expressed in T helper cell (Thl cells) and cytotoxic T cells (Tcl cells), and can produce inhibitory signals, leading to apoptosis of Thl cells and Tcl cells. Its ligand is galectin 9 (Gal-9), which is a soluble and widely expressed molecule, in conjunction with the oligosaccharide in the immunoglobulin variable region of TIM3 molecule[7]. Thus it has a negative regulation of the Thl immune response. When combined to its ligand galectin 9 (Gal-9), TIM3 promotes Thl cell apoptosis [8]. In other words, in the escape process of tumor immune surveillance, TIM3 has a similar effect with PD-1. Therefore, the combination of TIM3 inhibitors and PD-1 inhibitors might be a better treatment for cancer.
Cusabio, as a good partner of life science research, manufactures and provides PD-1 and TIM3 products including recombinant proteins in different expression systems and polyclonal antibody.
1. Recombinant Human Programmed cell death protein 1(PDCD1) (product code: CSB-YP619964HU)
2. Rabbit anti-Human PDCD1 Polyclonal antibody (product code: CSB-PA619964LA01HU)
3. PD-L1 Monoclonal Antibody (product code: CSB-MA878942A0m)
4. Human Programmed Death 1(PD-1)ELISA KIT (product code: CSB-E13643h)
5. Mouse Programmed Death 1(PD-1)ELISA Kit (product code: CSB-E13586m)
[1] Ishida Y, Agata Y, Shibahara K, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death [J]. EMBO J, 1992,11(11):3887-2895.
[2] Okazaki T, Wang J. PD-1/PD-L pathway and autoimmunity [J].Autoimmunity, 2005,38(5):353-357.
[3] Okudaira K, Hokari R, Tsuzuki Y, et al. Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model [J]. Int J Oncol, 2009,35(4):741-749.
[4] Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade [J]. Proc Natl Acad Sci USA, 2002,99(19):12293-12297.
[5] Dulos J, Carven GJ, van Boxtel SJ, et al. PD-1 blockade augments Th1 and Th17 and suppresses Th2 responses in peripheral blood from patients with prostate and advanced melanoma cancer [J]. J Immunother, 2012,35(2):169-178.
[6] Monney L, Sabatos CA, Gaglia JL, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune diease [J]. Nature, 2002,415(6871):536-541.
[7] Aaskura H, Kashio Y, Nakamura K, et al. Selective eosinophil adhesion to fibroblast via IFN-gamma-induced galectin-9 [J]. J Immunol, 2002,169(10):5912-5918.
[8] Kaori S, Pushpa J, Samuel M, et al. Emerging Tim-3 functions in anti-microbial and tumor immunity [J]. Trends Immunol, 2011,32(8):345-349.
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